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The SARS-CoV-2 virus (COVID19) pandemic has placed extreme pressures on the Canadian Healthcare system. Many health care regions in Canada have cancelled or limited surgical and non-surgical interventions on patients to preserve healthcare resources for a predicted increase in COVID19 related hospital admissions. Also reduced health interventions may limit the risk of possible transmission of COVID19 to other patients and health care workers during this pandemic. The majority of institutions in Canada have developed their own operational mandates regarding access to surgical resources for patients suffering from Head and Neck Cancers during this pandemic. There is a large degree of individual practitioner judgement in deciding access to care as well as resource allocation during these challenging times. The Canadian Association of Head and Neck Surgical Oncology (CAHNSO) convened a task force to develop a set of guidelines based on the best current available evidence to help Head and Neck Surgical Oncologists and all practitioners involved in the care of these patients to help guide individual practice decisions. Main body: The majority of head and neck surgical oncology from initial diagnosis and work up to surgical treatment and then follow-up involves aerosol generating medical procedures (AGMPs) which inherently put head and neck surgeons and practitioners at high risk for transmission of COVID19. The aggressive nature of the majority of head and neck cancer negates the ability for deferring surgical treatment for a prolonged period of time. The included guidelines provide recommendations for resource allocation for patients, use of personal protective equipment for practitioners as well as recommendations for modification of practice during the current pandemic.# Introduction
The emergence of the SARS-CoV-2 virus (COVID19) as a novel virus causing severe respiratory illness was first described in December 2019 in Wuhan China. Since that time the World Health Organization (WHO) has declared COVID19 a pandemic (Mar 112,020) and health authorities have been mobilizing to accommodate a predicted surge in patients who require hospital and/or intensive care unit admission due to the direct effects of the virus . The reality of oncologic surgery is that any significant delay in time to treatment will often have a deleterious effect on survival and functional outcomes for the individual patient. This makes managing head and neck cancer patients in the pandemic era much more challenging due to resource limitations placed on the healthcare system by COVID19. In the 2003 Severe Acute Respiratory Syndrome (SARS) pandemic, significant limitations were placed on surgical resource access in Ontario which did have a long term effect both on patient care as well as economic impact on the healthcare system once the pandemic passed and the backlog of surgical patients placed an increased strain on the system resources .
Head and neck surgical oncology is particularly challenging in the COVID19 era as all aspects of patient care from initial consultation, to surgical treatment, then post-treatment follow-up involve some degree of AGMPs in standard practice. The upper aerodigestive tract includes the nasal cavities, nasopharynx, oral cavity, oropharynx, hypopharynx, larynx, and trachea. This tract is a zone of intense COVID-19 viral replication . There is growing evidence that personnel who perform procedures in the upper aerodigestive tract, and in particular otolaryngologists Head and Neck Surgeons are at high risk of not only becoming exposed to COVID-19, but also developing severe illness from the virus . In an anecdotal report from Wuhan, it was noted that 14 personnel became may have been infected from a single endoscopic trans-sphenoidal pituitary case, including every OR staff member that was involved in the case . Europe has seen the same high infection rate of otolaryngologists, as reported by intensive care units across the region . There was recently a report of four otolaryngologists in the UK having been infected, two of which are intubated and in critical condition in the ICU, after having contracted COVID-19 from asymptomatic patients . Reliable reports have documented active transmission in asymptomatic cases . The increased risk of contracting COVID-19 in these procedures is thought to be due to the high viral load in the upper respiratory tract . Not only this, but persons who are exposed to high viral loads, such as during surgery as opposed to contracting the virus in the community, are thought to suffer more severe illness due to the release of cytokine storms in these settings .
This new and emerging information has led to several specialty societies and health authorities making recommendations on the use of PPE in procedures that are considered aerosol-generating (aerosol generating medical procedures or AGMPs), where standard contact and droplet precautions are not sufficient to protect against aerosolized viral particles. Whereas many of these recommendations vary in the details, all published criteria in the literature now support the use of N95 masks and associated aerosolized droplet precautions with all aerosol-generating medical procedures, regardless of COVID-19 testing. Many guidelines go much farther, recommending PAPRs for all such cases . The question of whether this should be enacted relies on three central issues:
- The expected rate of community viral burden in the province of practice. 2. The rate of asymptomatic infection.
- The reliability of COVID-19 testing in asymptomatic patients.
With respect to the first issue, we know that community transmission of COVID-19 is rising across Canada, and is now responsible for more than half of infections in the country . Projections vary widely, but according to the federal health minister, "between 30 and 70 percent of Canadians could become infected with coronavirus" . Countries that did not prepare for this scenario are now facing such consequences, including Italy which is battling a high rate of health worker infections and COVID-related deaths.
With respect to the second issue, emerging data shows that asymptomatic infections may be much more common than previously thought. During the Centers for Disease Control, (CDC) investigation of the Diamond Princess cruise ship outbreak, 46.5% of infected individuals were asymptomatic at the time of testing, and 17.9% of those infected never developed symptoms . This is in alignment with findings in children, which show that more than 15% of patients have asymptomatic infection . There is also ample data to show that active transmission of the virus occurs in asymptomatic persons .
Finally, current methods of testing for the COVID-19 virus are not validated for use in asymptomatic persons. Departments of Public Health and the CDC have repeatedly warned about the false negative (and false positive) rate of nasal swabs in asymptomatic patients . Although a positive COVID-19 swab in an asymptomatic patient can be useful, a negative swab cannot be relied on to be accurate.
The current COVID19 pandemic makes treating head and neck cancers even more challenging in terms of triaging patients and allocating limited surgical resources. Surgical oncologists worldwide have published recommendations about application and utilization of surgical resources in these challenging times . Head and neck surgeons have the difficult task of following chronically ill patients while at the same time mitigating the risk of person to person contact . In doing so, head and neck cancer survivors may be impacted negatively in terms of quality of life as well as disease recurrence detection . Further, those with tracheostomies or laryngeal stomas are at increased risk of transmission and spread of COVID-19 .
In summary, we can conclude and/or infer the following from the available data: in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. D. Goldstein -a. substantial contributions to conception and design an analysis and interpretation of data; b. revising the article critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. J. Yoo -a. substantial contributions to conception and design an analysis and interpretation of data; b. revising the article critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Canadian Association of Head and Neck Surgical Oncology -a. substantial contributions to conception and design an analysis and interpretation of data; b. drafting the article and revising it critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
|
The SARS-CoV-2 virus (COVID19) pandemic has placed extreme pressures on the Canadian Healthcare system. Many health care regions in Canada have cancelled or limited surgical and non-surgical interventions on patients to preserve healthcare resources for a predicted increase in COVID19 related hospital admissions. Also reduced health interventions may limit the risk of possible transmission of COVID19 to other patients and health care workers during this pandemic. The majority of institutions in Canada have developed their own operational mandates regarding access to surgical resources for patients suffering from Head and Neck Cancers during this pandemic. There is a large degree of individual practitioner judgement in deciding access to care as well as resource allocation during these challenging times. The Canadian Association of Head and Neck Surgical Oncology (CAHNSO) convened a task force to develop a set of guidelines based on the best current available evidence to help Head and Neck Surgical Oncologists and all practitioners involved in the care of these patients to help guide individual practice decisions. Main body: The majority of head and neck surgical oncology from initial diagnosis and work up to surgical treatment and then follow-up involves aerosol generating medical procedures (AGMPs) which inherently put head and neck surgeons and practitioners at high risk for transmission of COVID19. The aggressive nature of the majority of head and neck cancer negates the ability for deferring surgical treatment for a prolonged period of time. The included guidelines provide recommendations for resource allocation for patients, use of personal protective equipment for practitioners as well as recommendations for modification of practice during the current pandemic.# Introduction
The emergence of the SARS-CoV-2 virus (COVID19) as a novel virus causing severe respiratory illness was first described in December 2019 in Wuhan China. Since that time the World Health Organization (WHO) has declared COVID19 a pandemic (Mar 112,020) and health authorities have been mobilizing to accommodate a predicted surge in patients who require hospital and/or intensive care unit admission due to the direct effects of the virus [1]. The reality of oncologic surgery is that any significant delay in time to treatment will often have a deleterious effect on survival and functional outcomes for the individual patient. This makes managing head and neck cancer patients in the pandemic era much more challenging due to resource limitations placed on the healthcare system by COVID19. In the 2003 Severe Acute Respiratory Syndrome (SARS) pandemic, significant limitations were placed on surgical resource access in Ontario which did have a long term effect both on patient care as well as economic impact on the healthcare system once the pandemic passed and the backlog of surgical patients placed an increased strain on the system resources [2].
Head and neck surgical oncology is particularly challenging in the COVID19 era as all aspects of patient care from initial consultation, to surgical treatment, then post-treatment follow-up involve some degree of AGMPs in standard practice. The upper aerodigestive tract includes the nasal cavities, nasopharynx, oral cavity, oropharynx, hypopharynx, larynx, and trachea. This tract is a zone of intense COVID-19 viral replication [1]. There is growing evidence that personnel who perform procedures in the upper aerodigestive tract, and in particular otolaryngologists Head and Neck Surgeons are at high risk of not only becoming exposed to COVID-19, but also developing severe illness from the virus [3,4]. In an anecdotal report from Wuhan, it was noted that 14 personnel became may have been infected from a single endoscopic trans-sphenoidal pituitary case, including every OR staff member that was involved in the case [5,6]. Europe has seen the same high infection rate of otolaryngologists, as reported by intensive care units across the region [7]. There was recently a report of four otolaryngologists in the UK having been infected, two of which are intubated and in critical condition in the ICU, after having contracted COVID-19 from asymptomatic patients [8]. Reliable reports have documented active transmission in asymptomatic cases [6]. The increased risk of contracting COVID-19 in these procedures is thought to be due to the high viral load in the upper respiratory tract [9]. Not only this, but persons who are exposed to high viral loads, such as during surgery as opposed to contracting the virus in the community, are thought to suffer more severe illness due to the release of cytokine storms in these settings [10].
This new and emerging information has led to several specialty societies and health authorities making recommendations on the use of PPE in procedures that are considered aerosol-generating (aerosol generating medical procedures or AGMPs), where standard contact and droplet precautions are not sufficient to protect against aerosolized viral particles. Whereas many of these recommendations vary in the details, all published criteria in the literature now support the use of N95 masks and associated aerosolized droplet precautions with all aerosol-generating medical procedures, regardless of COVID-19 testing. Many guidelines go much farther, recommending PAPRs for all such cases [4,11]. The question of whether this should be enacted relies on three central issues:
1. The expected rate of community viral burden in the province of practice. 2. The rate of asymptomatic infection.
3. The reliability of COVID-19 testing in asymptomatic patients.
With respect to the first issue, we know that community transmission of COVID-19 is rising across Canada, and is now responsible for more than half of infections in the country [12]. Projections vary widely, but according to the federal health minister, "between 30 and 70 percent of Canadians could become infected with coronavirus" [13]. Countries that did not prepare for this scenario are now facing such consequences, including Italy which is battling a high rate of health worker infections and COVID-related deaths.
With respect to the second issue, emerging data shows that asymptomatic infections may be much more common than previously thought. During the Centers for Disease Control, (CDC) investigation of the Diamond Princess cruise ship outbreak, 46.5% of infected individuals were asymptomatic at the time of testing, and 17.9% of those infected never developed symptoms [14]. This is in alignment with findings in children, which show that more than 15% of patients have asymptomatic infection [15]. There is also ample data to show that active transmission of the virus occurs in asymptomatic persons [16].
Finally, current methods of testing for the COVID-19 virus are not validated for use in asymptomatic persons. Departments of Public Health and the CDC have repeatedly warned about the false negative (and false positive) rate of nasal swabs in asymptomatic patients [16][17][18]. Although a positive COVID-19 swab in an asymptomatic patient can be useful, a negative swab cannot be relied on to be accurate.
The current COVID19 pandemic makes treating head and neck cancers even more challenging in terms of triaging patients and allocating limited surgical resources. Surgical oncologists worldwide have published recommendations about application and utilization of surgical resources in these challenging times [19][20][21][22][23][24][25][26][27][28]. Head and neck surgeons have the difficult task of following chronically ill patients while at the same time mitigating the risk of person to person contact [25,29]. In doing so, head and neck cancer survivors may be impacted negatively in terms of quality of life as well as disease recurrence detection [23]. Further, those with tracheostomies or laryngeal stomas are at increased risk of transmission and spread of COVID-19 [24].
In summary, we can conclude and/or infer the following from the available data: in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. D. Goldstein -a. substantial contributions to conception and design an analysis and interpretation of data; b. revising the article critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. J. Yoo -a. substantial contributions to conception and design an analysis and interpretation of data; b. revising the article critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Canadian Association of Head and Neck Surgical Oncology -a. substantial contributions to conception and design an analysis and interpretation of data; b. drafting the article and revising it critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
# Acknowledgements
The authors would like to acknowledge health professionals both and Canada and internationally who continue to show courage and leadership in providing health care services to those in need during the current pandemic.
# Declarations
The authors have no competing interests to declare.
Authors' contributions D.A. O'Connella. substantial contributions to conception and design an analysis and interpretation of data; b. drafting the article and revising it critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. H. Seikalya. substantial contributions to conception and design an analysis and interpretation of data; b. drafting the article and revising it critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. A. Isaac -a. substantial contributions to conception and design an analysis and interpretation of data; b. drafting the article and revising it critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. J. Pyne -a. substantial contributions to conception and design an analysis and interpretation of data; b. drafting the article and revising it critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. R.D. Hart -a. substantial contributions to conception and design an analysis and interpretation of data; b. revising the article critically for important intellectual content; c. final approval of the version to be submitted for publication, and d. agreement to be accountable for all aspects of the work Funding None.
# Availability of data and materials
Available upon request.
Ethics approval and consent to participate Not applicable.
# Consent for publication
All authors consent to the publication of the manuscript submitted.
# Competing interests
The authors have no relevant competing interests to declare.
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Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma. Although this is an aggressive disease, most patients respond well to initial treatment. The standard frontline treatment is R-CHOP chemoimmunotherapy for six cycles, however factors such as stage and prognostic features or risk factors may determine if abbreviated therapy may be appropriate. Radiation therapy may be part of a planned treatment course usually as consolidation post-chemoimmunotherapy. Additional or alternative chemotherapy may need to be considered based on high-risk molecular features (presence of MYC, BCL2 and/or BCL6 rearrangement), central nervous system (CNS) involvement at diagnosis or if a patient is at high-risk of secondary CNS relapse. In Canada, no unified national guideline exists for the treatment of DLBCL, and the provincial guidelines in existence vary. An evidence-based national treatment guideline supported by Canadian hematologists is warranted to ensure a consistent and optimal approach for the frontline treatment of DLBCL patients. A group of experts from across Canada developed a national evidence-based treatment guideline to provide healthcare professionals with clear guideline and best practices for the management of frontline DLBCL. Results of the current provincial guidelines in existence are presented with consensus recommendations based on available evidence.# Introduction
Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of B-cell malignancies that constitutes 30-40% of all Non-Hodgkin lymphomas and affects over 20,000 Canadians (census data from 1992-2010) 1 . The heterogenous nature of this type of lymphoma can result in diverse clinical presentations and prognosis with a wide spectrum of patient ages and comorbid conditions 2 .
Due to the aggressiveness of DLBCL, a rapid diagnosis and initiation of treatment is essential. Overall, frontline chemotherapy cures approximately 80-90% of patients with limited stage and 60-70% of advanced stage disease, depending on the presence of other risk factors 3 . When deciding on initial therapy, it is critical to consider the pathological components of the disease such as its molecular features, which can be determined through testing. Further, other clinical features of the patient may play a role in the length and intensity of the frontline standard of care (SOC) treatment. The current SOC for frontline treatment of DLBCL is R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab). A caveat to SOC would be for the extreme elderly unfit patients, where other treatment options such as reduced dose CHOP or R-mini-CHOP and R-CEOP (cyclophosphamide, etoposide, vincristine, prednisone, rituximab), are all potentially curative approaches. Optimization of frontline treatment for DLBCL requires consideration of disease stage, molecular features, as well as patient factors such as comorbidities.
Across Canada, treatment in the frontline setting is relatively standardized, but differences can occur with the length of treatment or in select cases, alternate rituximab combination therapy based on institutional guidelines. Further, in less common, and less data-driven scenarios such as the presence of cardiac dysfunction, there may be greater challenges in determining a standard treatment approach. Treatment guidelines for DLBCL are not available in all provinces and may differ based on provincial and institutional considerations. As there is currently no Canadian-wide guideline for the standardized management of DLBCL patients in the frontline setting, a group of Canadian DLBCL experts, in collaboration with Lymphoma Canada, have developed a nationwide consensus guideline. This guideline is based on the current best available evidence for the frontline management of patients with DLBCL.
# GUIDELINE RECOMMENDATIONS
- Recommendation for limited stage criteria and treatment; 5. Recommendation for CNS prophylaxis;
- Recommendation for pre-phase treatment.
# Methodology
An initial web-based search was performed on provincial cancer centers to identify DLBCL management guidelines. DLBCL provincial experts were contacted to verify guidelines and provide insight and input if a guideline could not be located. Once guidelines were collected, information was extracted and differentiated based on common treatment considerations. Following compilation of provincial standards, information was reviewed by a national panel of experts for consensus on the frontline treatment for DLBCL patients in Canada. The National Comprehensive Cancer Network categories of evidence and consensus (Table 1) were used to grade the level of evidence and support for the clinician recommendations for frontline treatment 4 .
A treatment algorithm was created based on these recommendations.
# CATEGORY 1
Based on the high-level evidence, there is uniform consensus that the intervention is appropriate.
# CATEGORY 2A
Based on the lower-level evidence, there is uniform consensus that the intervention is appropriate.
# CATEGORY 2B
Based on the lower-level evidence, there is consensus that the intervention is appropriate.
# CATEGORY 3
Based on any level of evidence, there is major disagreement that the intervention is appropriate.
# Results
An online search revealed existing DLBCL treatment and management guidelines in four provinces (British Columbia (BC), Alberta (AB), Ontario (ON), Nova Scotia (NS)). Three provinces (BC, AB, NS), had one guideline in existence for the province, while one province (ON) had three DLBCL guidelines. Specialists from the remaining provinces (Saskatchewan (SK), Manitoba (MB), Quebec (QC), Newfoundland and Labrador (NF), New Brunswick (NB), Prince Edward Island (PEI)) and territories (Northwest Territories (NWT), Yukon (YK), Nunavut (NU)) were then contacted. Specialists from all remaining provinces confirmed no official provincial guidelines were in existence. Physicians that do not have guidelines within their own province indicated they refer to BC Cancer (MB, PEI), Alberta Health Sciences (AHS) (SK), Nova Scotia Cancer Care Program (PEI), Princess Margaret Cancer Centre (PMCC) and the National Comprehensive Cancer Network (NCCN) guidelines and adopt these guidelines to what is available locally. Specific guidelines have not been uniformly adopted or endorsed, and feedback from specialists indicated interest in the creation of a national DLBCL treatment guideline for frontline management.
The information included in the existing guidelines was reviewed for common themes to determine the methodology for data extraction and compilation to highlight similarities and differences. For frontline treatment, the common themes for treatment determination included limited vs. advanced disease, additional comorbidities and in some cases integrated clinical risk factors. The information is summarized in Table 2.
Additional characteristics involved in the decision for treatment, including molecular characteristics and CNS involvement, have been summarized in Table 3.
# MYC-rearranged with no BCL2 mutation
# R-CHOP x 6 R-CHOP x 6
Considerations: CNS IPI risk factors prognostic for CNS relapse include age > 60 years, elevated LDH, ECOG performance status (PS) > 1, advanced stage disease (III, IV), > 1 extranodal (EN) site, adrenal/kidney involvement 5 . In addition, multiple EN sites (> 2), as well as uterine involvement have also been associated with high CNS risk 6 . Less information is known about risk with breast involvement.
Age
# Frontline Treatment for DLBCL
Frontline treatment for DLBCL is relatively standardized across Canada with most patients receiving R-CHOP given every 21 days. Considerations to guide therapy include stage of disease, as well as 'double-hit or triple-hit' disease (presence of MYC rearrangement typically with BCL2 or BCL6 rearrangements). In some provinces, IPI risk factors (age of the patient, ECOG performance status (PS), number of extranodal sites, and lactate dehydrogenase level) can be used to guide treatment. Further, the presence of CNS disease or those at high risk may receive alternate therapy to include CNS penetrant drugs such as high-dose methotrexate (HD-MTX).
In those with cardiac dysfunction, etoposide substitution (R-CEOP), or in some cases infusional anthracyclines (DA-EPOCH-R), may be used as an alternative. Data from existing guidelines were compiled and reviewed with recommendations established and consensus achieved amongst the expert panel.
# Limited Stage Disease
Modifications to the standard treatment of R-CHOP for patients with limited stage disease depends on disease factors such as bulk and distribution, and for some guidelines stage modified IPI. The absolute definition of bulky disease can differ. Some groups define it as the largest tumour diameter of ≥ 10 cm, whereas other groups have used more conservative measurements including 5, 7 or 7.5 cm 7 . In addition, a stage-modified IPI may be considered to determine suitability for a limited stage approach (age ≤ 60 years, stage I-II, ECOG status < 2, elevated LDH) .
All provinces recommend R-CHOP with variations in the number of cycles and use of PET imaging to guide the use of further therapy and radiotherapy (Table 2). The number of cycles of R-CHOP prior to the restaging interim PET scan varies per province (between 3-6 cycles), as well as the timing for when to schedule the PET scan. Further, the Deauville five-point scale assessment response may differ per province depending on when the PET scan is scheduled (i.e. interim or post-therapy). As performed in BC, if the interim PET is negative after 3 or 4 cycles of R-CHOP, i.e. CMR (complete metabolic response), the Deauville score associated with this response is 1-2, rather than the standard Deauville 1-3 score 11 . BC uses this more conservative scoring approach as it removes the necessity of further treatment with radiation 12 . A PET positive score in this scenario would be Deauville 3-5 rather than 4-5, as seen in other provinces, and radiation would be administered to include prior disease sites. On the other hand, for patients who receive six cycles of R-CHOP and undergo an end of treatment PET scan, a Deauville 4-5 score would require further treatment with radiation to PET positive areas (consolidation) for all other provinces. As the provinces have slightly different strategies, it is important to consult with a radiation oncologist. The BC guidelines recommend R-CHOP for 3 cycles, with one additional cycle of R-CHOP if PET negative. The NS guideline and ON (CCSEO, SHHC) guidelines also recommend three cycles while other provinces (AB, ON (PMCC), NS) recommend four cycles followed by an interim PET scan. With provinces that divide limited stage treatment based on high risk factors (AB, ON (SHHS, PMH), NS), 6 cycles of R-CHOP is recommended for more high risk patients.
Some guidelines rely on PET imaging results for further treatment decisions. For example, following 4 cycles of R-CHOP, if the interim PET is negative with a complete response, AB and ON (PMCC) recommend observation.
On the other hand, ON (CCSEO) and NS guidelines do not rely on PET to guide further treatment; their strategy involves combined-modality chemotherapy with involved-site radiation therapy (ISRT) or involved node radiation therapy (INRT). Guidelines for RT that predated modern imaging and planning techniques used involved fields (IFRT) defined by anatomic landmarks and often encompassed adjacent uninvolved lymph nodes 13 . Modern techniques for conformal RT deliver radiation more precisely based on target volume definitions (ISRT) often using reduced treatment volumes for the effective control of the at-risk involved sites of disease, thereby reducing normal tissue exposure 13 Considering these guidelines and current research, options for limited stage disease includes treatment with abbreviated therapy (R-CHOP x 4 plus 2 doses of Rituximab) as proven with the FLYER trial 9 , planned combined modality R-CHOP x 3 with ISRT, or PET-guided therapy. If bulky disease is present or the patient is not amenable to radiotherapy, the recommendation is to treat as advanced stage disease.
# RECOMMENDATIONS
Definition for limited stage disease: IPI 0-1, no bulky disease (provinces have different definitions of bulk disease), and ≤ 1 extranodal site.
Recommendation for the treatment of limited stage disease: R-CHOP x 3- -4 cycles, with exceptional 6 cycles, followed by PET scan. There is the option to give response-adapted treatment with PET (groups have different approaches).
# Advanced Stage Disease
For advanced stage disease which includes stage III/IV, and in some scenarios includes patients with B symptoms (BC) and bulk disease (> 10 cm in BC and NS; AB uses 7 cm cut-off), all guidelines recommend R-CHOP x 6 cycles. One guideline (ON) provides the option for an additional two cycles of R-CHOP if tolerated, however this is uncommon. Several of the guidelines highlight the use of end of treatment PET scan and/or the presence of bulk disease in assessing the need for radiation therapy following chemotherapy. A PET negative scan (Deauville 1-3) following R-CHOP will not require further treatment. If PET negative, but bulk was present at diagnosis, radiation is recommended (SEOCC). If PET positive (Deauville 4-5), the recommendation is radiation therapy (30-35 Gy) if feasible (BC, NS) 14 . Radiation is given to areas of residual positivity. One guideline (NS) recommends a more conservative approach with ISRT in this setting, prompting a discussion to determine critical issues (i.e. spinal cord involvement, age, comorbidities) that would preclude curative intent treatment at relapse.
Advanced stage disease that is high-risk was defined by existing guidelines as an IPI of 3 or higher. All guidelines recommend R-CHOP x 6 cycles. Additionally, with concomitant comorbidities, age and frailty, one guideline (NS) will consider dose adjustment of R-CHOP to R-mini-CHOP x 6 cycles as an option. However, data to support a standard approach in elderly and/or frail patients is lacking. Considering these guidelines and current research including the RICOVER trial 15 and the GOYA trial 16 , treatment for advanced stage patients is six cycles of R-CHOP; eight cycles is not justified.
Following R-CHOP, PET negative scans require no further treatment for the patient, while PET positivity recommends ISRT (30-35 Gy). Some guidelines advocate for radiation even with CR following R-CHOP for patients with bulky masses (> 10 cm), bone involvement, extradural tumor with spinal cord/nerve root compression, and impending or actual organ compromise. In BC, if the PET scan is negative after 6 cycles of R-CHOP, patients are observed even with bulky disease. Recent data from this centre demonstrated no difference in outcome in bulky versus non-bulky patients with an end of treatment PET-negative scan 7 .
One guideline (NS) does not recommend the use of ISRT following R-CHOP for this patient group. Other Considerations for Frontline Treatment
# RECOMMENDATIONS
# MOLECULAR FEATURES
Molecular characteristics of large B-cell lymphomas can alter prognosis, diagnostic classification, and treatment approach. The most frequent rearrangements include MYC, BCL2, and BCL6. Lymphomas found to have translocations for MYC in combination with BCL2 and/or BCL6 are no longer classified as DLBCL and are rather classified as High-Grade B-cell lymphoma with double-hit (DH) or triple-hit (TH) features. Though this is seen in only 5-10% of DLBCL cases, it is important for FISH (fluorescence in situ hybridization) testing to be done to identify this patient population in order to receive optimal treatment 17 .
# RECOMMENDATION
It is recommended that all patients with DLBCL be tested by FISH for MYC, with reflex testing for BCL2 and BCL6 if MYC positive.
# MYC REARRANGEMENT (Without Rearrangement of BCL2 or BCL6)
The MYC transcription factor is of vital importance to maintaining regular cell function and is the major molecular abnormality in aggressive B-cell lymphomas when rearranged 18 . In DLBCL, MYC rearrangement occurs in approximately 10% of cases 19 . Studies have suggested an inferior progression free survival (PFS) and overall survival (OS) for patients with MYC rearrangement compared to patients without . The prognostic relevance however of single-hit rearrangement remains controversial and has been reported variably.
One study suggested that MYC rearrangement poses a negative impact to OS only within the first two years following diagnosis, with no difference in survival probability in DLBCL without MYC rearrangement after two years 19 . However, rarely does DLBCL relapse after a progression-free timepoint of two years.
Only one guideline (AB) provided a treatment recommendation for single-hit MYC rearrangement DLBCL, which was R-CHOP for 6 cycles. However, for those aged <70 years with a high IPI score , the alternative treatment regimen is 4 cycles of R-CHOP followed by one cycle of either R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) or R-DICEP (dexamethasone, cyclophosphamide, etoposide, cisplatin). Alternative treatment approaches include R-CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine) or DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab).
# RECOMMENDATION
Recommendation for patients with MYC rearrangement: 6 cycles of R-CHOP.
# DOUBLE-HIT (MYC AND BCL2 OR BLC6) OR TRIPLE-HIT (MYC, BCL2, BCL6)
For DLBCL cases with MYC rearrangement, it is most often (58-83%) concurrent with dual translocation of BCL2 or BCL6 22 . Double-hit or triple-hit DLBCL is associated with shorter progression-free and overall survival following frontline therapy with R-CHOP . It is also associated with a higher risk for CNS relapse 25 . One study assessed whether partner genes associated with MYC rearrangement, including either immunoglobulin (IG) heavy chain or light chain or non-IG locus, can affect outcome 19 . When MYC is rearranged with an IG partner in double-hit DLBCL, it results in a significantly worse PFS and OS 19 . It is important to note that the outcome of double/triple hit lymphoma with R-CHOP has improved with more comprehensive testing, suggesting that older studies may have a selection bias 26 . However, since we cannot reliably distinguish lower risk patients with current methodology, dose intensified chemotherapy is recommended.
Following review, there are five guidelines that comment on the preferred treatment option for this patient population. DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) x 6 cycles was the preferred method, with consideration for radiation therapy in patients with bulky disease or if PET positive following treatment. One guideline (AB) provides further recommendation based on IPI risk factors. In Alberta, patients with double-hit or triple-hit lymphoma under the age of 70 years should receive more aggressive therapy, possibly including stem cell transplantation. Guidelines advise patients to receive R-CHOP and HD-MTX, then proceed to autologous transplant. This option is not recommended for patients that have previously received an intensified protocol such as DA-EPOCH-R.
# RECOMMENDATION
The recommended treatment for double-hit and triple-hit lymphoma is DA-EPOCH-R x 6 cycles.
*May consider HD-MTX at the end of regimen for high-risk CNS patients.
# CNS PROPHYLAXIS
The prognosis of DLBCL patients with CNS involvement is poor, with a median survival time of 2-6 months due to both rapid tumor growth and ineffective treatment strategies. CNS involvement, which can manifest in the brain parenchyma, leptomeningeal, spinal cord and eyes, mainly presents within one year of diagnosis and can occur in the following scenarios with respect to the status of systemic disease:
- Patient is in systemic remission, with isolated recurrence in the CNS;
- Remission following frontline treatment, but simultaneous systemic recurrence and CNS involvement;
- CNS involvement while the patient is receiving frontline treatment.
In addition to double-hit and triple-hit lymphoma, certain factors at diagnosis are correlated with a higher risk for CNS involvement including elevated LDH and multiple extranodal sites. Specific extranodal sites impart an elevated risk including kidney, adrenal glands, testes, and possible breast. The CNS-IPI was developed to identify patients at high risk of CNS disease, and incorporates all five IPI factors. Incidence is > 10% in those with a high-risk CNS-IPI and 25-35% in those with advanced stage and testicular or renal/kidney involvement; it remains unknown whether prophylaxis is protective. The optimal prophylactic strategy remains unclear.
The current Canadian guidelines that comment on CNS prophylaxis refer to the German High-Grade Lymphoma Study Group (DSHNHL) to determine patients that are high risk. This includes patients with a high CNS-IPI, kidney/adrenal or testicular involvement, as well as double/triple-hit lymphoma. Consideration is also given to prophylaxis in intravascular lymphoma. All guidelines recommend high-dose systemic methotrexate with leucovorin rescue in young patients with good renal function. The guidelines indicate a range of 2-4 cycles of high-dose methotrexate (3g/m 2 ). The day of administration is day 10-15 after R-CHOP typically after 2, 4 and 6 cycles, both for fit patients and those under the age of 70 years. Though initial data supports day 15 for better outcomes, recent evidence recommends scheduling before day 10 of R-CHOP cycles. In BC for limited stage testicular involvement, prophylaxis is given after chemotherapy. If issues with scheduling, tolerability or due to treatment delays, one guideline indicates that methotrexate can be administered once R-CHOP is completed, and then 3 cycles of HD-MTX can be performed every 2 weeks. If HD-MTX is not tolerable, another treatment strategy is four doses of intrathecal MTC/AraC/hydrocortisone. Further research on the use of HD-MTX and its benefits in this patient population is warranted.
# RECOMMENDATION
Patients at high-risk for CNS involvement could consider receiving prophylaxis with high-dose methotrexate (2-4 cycles, dose of 3g/m 2 ) in addition to R-CHOP. Patient characteristics and scheduling of HD-MTX administration may differ across institutions.
# CARDIAC DISEASE
Curative intent therapy for the frontline treatment of DLBCL is R-CHOP, a chemo-immunotherapy that includes doxorubicin, a known risk factor for cardiotoxicity . With an increasingly cumulative dose, R-CHOP can result in cardiac toxicity and in particular congestive heart failure, as a result of the toxic damage to the mitochondria of the cardiomyocytes. One study found that cardiomyopathy could be avoided by keeping a cumulative dose of doxorubicin below 450 mg/m 2 32 . Additionally, certain established cardiac risk factors such as advanced age, known cardiac disease, prior mediastinal radiation and diabetes mellitus, can increase the risk for anthracycline toxicity. Other methods have been employed to reduce the risk of cardiac toxicity, including the use of anthracycline analogues and alternative methods of drug delivery such as through a continuous slow infusion 33 .
Managing cardiac toxicity is an institutionally driven practice with little evidence for a nationally standardized recommendation. Options can include the use of ACE (angiotensin-converting enzyme) inhibitors or dexrazoxane with R-CHOP to prevent cardiomyopathy. Another treatment strategy includes DA-EPOCH-R, as continuous infusional doxorubicin has lower cardiotoxicity. For patients with reduced ejection fraction, substituting the doxorubicin in R-CHOP with etoposide (R-CEOP) or gemcitabine (R-GCVP) have shown promise in retrospective studies 34 . A study from BC demonstrated no reduction in survival when comparing R-CEOP versus R-CHOP, although the study is not powered to show a small difference .
# RECOMMENDATION
Recommendation for patients with cardiac toxicity: In this setting, curative therapy can be delivered. This will likely not involve R-CHOP alone, and may involve additional therapies as per institutional guidelines.
# PRE-PHASE THERAPY
Additional recommendations for optimal treatment strategies have been further listed by existing Canadian guidelines such as supportive/ancillary treatments, treatment for intermediary/grey zone DLBCL, and treatment based on specific anatomical tumor locations. Though certain institutional and provincial guidelines comment on intermediary and anatomical tumor locations, these are considered risk factors and do not require specific recommendations. Therefore, consensus was only required on pre-phase and prophylaxis treatment.
Pre-phase therapy can be considered a preventative strategy against toxicity such as febrile neutropenia, tumor lysis syndrome, and deterioration of performance status 37 . It can also be used to determine a patient's response to their upcoming chemotherapy regimen. Pre-phase therapy can include a regimen of corticosteroids with or without low dose chemotherapy 38 . Single-agent oral prednisone is the most commonly used regimen.
Other regimens include prednisone combined with vincristine and cyclophosphamide or cyclophosphamide alone 38 . Whether all DLBCL patients require pre-phase treatment, or whether there are certain risk factors such as advanced age that preclude its requirement, is still to be established.
For supportive medications during frontline treatment, two guidelines recommend prednisone prophylaxis (100 mg/day) for either 3-7 days (AB) or 5 days (ON) prior to R-CHOP or R-CEOP for patients > 60 years to prevent toxicity to chemotherapy regimen 39 . Another guideline (NS) provided numerous recommendations for supportive treatment. Allopurinol, a drug that prevents the build-up of uric acid, a side-effect of cytotoxic therapies for lymphoma, is recommended for patients at high risk for tumor lysis at a dose of 300mg daily x 5 days for the first cycle only of R-CHOP. As tumor lysis is rare in DLBCL, allopurinol is not commonly used. Granulocyte colony stimulating factor (G-CSF), can be used as a prophylaxis to regulate the production and function of neutrophils in order to accelerate neutrophil recovery time in patients receiving curative regimens . This is especially important for patients receiving curative regimens as if there is a delay in receiving cancer treatment due to adverse events such as neutropenia, it could compromise the outcome for that patient. Filgrastim/pegfilgrastim primary prophylaxis are two types of G-CSF recommended for use in patients aged > 65 years, HIV positive patients, or patients felt to be at high risk (> 20%) of febrile neutropenia (open wounds, active infection, bone marrow infiltration by cancer, poor performance status, combined chemo-radiation) . Pegfilgrastim is recommended in most cases where HD-MTX is used for CNS prophylaxis; filgrastim should be used to shorten the chemo-free interval and should be stopped 48 hours prior to chemotherapy.
# RECOMMENDATION
Should consider pre-phase administration of corticosteroids in symptomatic patients and/or older patients (> 60 years), and primary prophylaxis with G-CSF for > 60 years of age receiving R-CHOP or R-CEOP. However, any patient with an episode of febrile neutropenia, regardless of age, should receive subsequent G-CSF prophylaxis.
# Summary of Recommendations for DLBCL Treatment
- Definition for limited stage disease: IPI 0-1, no bulky disease (provinces have different definitions of bulk disease), and ≤ 1 extranodal site.
- Recommendation for limited stage disease: R-CHOP x 3- -4 cycles, with exceptional 6 cycles, followed by PET scan. There is the option to give response-adapted treatment with PET (groups have different approaches).
-*For R-CHOP x 3, proceed with either RT-planned combined modality, or proceed with PET imaging and if negative undergo one additional cycle of R-CHOP.
- Recommendation for advanced stage disease: standard therapy is 6 cycles of R-CHOP. Recommend ISRT if localized responding PET positive (Deauville 4-5) disease at the end of R-CHOP treatment.
-*If new site or progression (non-responding), treatment options can include ISRT or other salvage therapy.
- It is recommended that all patients with DLBCL be tested by FISH for MYC, with reflex testing for BCL2 and/ or BCL6 if MYC positive.
- Recommendation for patient with MYC rearrangement: 6 cycles of R-CHOP.
- The recommended treatment for double-hit and triple-hit lymphoma is DA-EPOCH-R x 6 cycles.
-*May consider HD-MTX at the end of regimen for high-risk CNS patients.
- Patients at high-risk for CNS involvement could consider receiving prophylaxis with high-dose methotrexate - Recommendation for patients with cardiac toxicity: In this setting, curative therapy can be delivered. This will likely not involve R-CHOP alone, and may involve additional therapies as per institutional guidelines.
- Should consider pre-phase administration of corticosteroids in symptomatic patients and/or older patients (> 60 years), and primary prophylaxis with G-CSF for > 60 years of age receiving R-CHOP or R-CEOP. However, any patient with an episode of febrile neutropenia, regardless of age, should receive subsequent G-CSF prophylaxis.
Based on these recommendations, a treatment algorithm for DLBCL patients undergoing frontline treatment provides the optimal treatment path(s) based on the patients' disease stage, molecular status and CNS and cardiac risk factors (Figure 1).
# Conclusion
Despite the widespread standardization of R-CHOP for the frontline treatment for DLBCL, there is still variability in the number of cycles of R-CHOP recommended, use of interim PET, and use of radiation consolidation. There are numerous patient factors to consider when determining the final treatment course. The guidelines in this report categorize treatment strategies based on limited and advanced DLBCL, while also considering other factors such as molecular features, CNS involvement, pre-phase treatment and cardiac toxicity. Molecular testing is recommended for all DLBCL patients. If patients are MYC positive, reflex testing for BCL2 and/or BLC6 will determine the frontline treatment approach. For MYC positive patients, accepted therapy includes R-CHOP x 6 cycles. If the patient tests positive for double-hit or triple-hit DLBCL, the optimal treatment strategy is DA-EPOCH-R.
For patients that test negative for molecular features, treatment strategy is based on limited versus advanced stage disease. For limited stage disease patients, risk factors may play a role in the number of R-CHOP cycles depending on the institution and province. Patients may undergo R-CHOP x 3, 4 or 6 cycles followed by a PET scan to assess response. There is the option to response-adapt with PET. Evidence supports patients receiving three cycles of R-CHOP to either undergo pre-planned RT combination modality or PET-guided treatment with one additional R-CHOP cycle if PET negative. For patients with advanced stage disease, the recommendation is for 6 cycles of R-CHOP followed by ISRT if there is localized residual disease.
Other important considerations include patients at risk for CNS involvement, patients with cardiac disease, and pre-phase treatment for patients at risk. For patients at risk for CNS involvement, there is the option to receive prophylaxis with high-dose systemic methotrexate in addition to leucovorin alongside R-CHOP. For patients with cardiac disease, curative therapy can be delivered through different treatment additions to R-CHOP as per institutional guidelines. For patients that are > 60 years of age that are symptomatic, corticosteroids could be considered, and primary prophylaxis with G-CSF should be considered in patients > 60 years of age.
|
Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma. Although this is an aggressive disease, most patients respond well to initial treatment. The standard frontline treatment is R-CHOP chemoimmunotherapy for six cycles, however factors such as stage and prognostic features or risk factors may determine if abbreviated therapy may be appropriate. Radiation therapy may be part of a planned treatment course usually as consolidation post-chemoimmunotherapy. Additional or alternative chemotherapy may need to be considered based on high-risk molecular features (presence of MYC, BCL2 and/or BCL6 rearrangement), central nervous system (CNS) involvement at diagnosis or if a patient is at high-risk of secondary CNS relapse. In Canada, no unified national guideline exists for the treatment of DLBCL, and the provincial guidelines in existence vary. An evidence-based national treatment guideline supported by Canadian hematologists is warranted to ensure a consistent and optimal approach for the frontline treatment of DLBCL patients. A group of experts from across Canada developed a national evidence-based treatment guideline to provide healthcare professionals with clear guideline and best practices for the management of frontline DLBCL. Results of the current provincial guidelines in existence are presented with consensus recommendations based on available evidence.# Introduction
Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of B-cell malignancies that constitutes 30-40% of all Non-Hodgkin lymphomas and affects over 20,000 Canadians (census data from 1992-2010) 1 . The heterogenous nature of this type of lymphoma can result in diverse clinical presentations and prognosis with a wide spectrum of patient ages and comorbid conditions 2 .
Due to the aggressiveness of DLBCL, a rapid diagnosis and initiation of treatment is essential. Overall, frontline chemotherapy cures approximately 80-90% of patients with limited stage and 60-70% of advanced stage disease, depending on the presence of other risk factors 3 . When deciding on initial therapy, it is critical to consider the pathological components of the disease such as its molecular features, which can be determined through testing. Further, other clinical features of the patient may play a role in the length and intensity of the frontline standard of care (SOC) treatment. The current SOC for frontline treatment of DLBCL is R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab). A caveat to SOC would be for the extreme elderly unfit patients, where other treatment options such as reduced dose CHOP or R-mini-CHOP and R-CEOP (cyclophosphamide, etoposide, vincristine, prednisone, rituximab), are all potentially curative approaches. Optimization of frontline treatment for DLBCL requires consideration of disease stage, molecular features, as well as patient factors such as comorbidities.
Across Canada, treatment in the frontline setting is relatively standardized, but differences can occur with the length of treatment or in select cases, alternate rituximab combination therapy based on institutional guidelines. Further, in less common, and less data-driven scenarios such as the presence of cardiac dysfunction, there may be greater challenges in determining a standard treatment approach. Treatment guidelines for DLBCL are not available in all provinces and may differ based on provincial and institutional considerations. As there is currently no Canadian-wide guideline for the standardized management of DLBCL patients in the frontline setting, a group of Canadian DLBCL experts, in collaboration with Lymphoma Canada, have developed a nationwide consensus guideline. This guideline is based on the current best available evidence for the frontline management of patients with DLBCL.
# GUIDELINE RECOMMENDATIONS
1. Recommendation for limited stage criteria and treatment; 5. Recommendation for CNS prophylaxis;
6. Recommendation for pre-phase treatment.
# Methodology
An initial web-based search was performed on provincial cancer centers to identify DLBCL management guidelines. DLBCL provincial experts were contacted to verify guidelines and provide insight and input if a guideline could not be located. Once guidelines were collected, information was extracted and differentiated based on common treatment considerations. Following compilation of provincial standards, information was reviewed by a national panel of experts for consensus on the frontline treatment for DLBCL patients in Canada. The National Comprehensive Cancer Network categories of evidence and consensus (Table 1) were used to grade the level of evidence and support for the clinician recommendations for frontline treatment 4 .
A treatment algorithm was created based on these recommendations.
# CATEGORY 1
Based on the high-level evidence, there is uniform consensus that the intervention is appropriate.
# CATEGORY 2A
Based on the lower-level evidence, there is uniform consensus that the intervention is appropriate.
# CATEGORY 2B
Based on the lower-level evidence, there is consensus that the intervention is appropriate.
# CATEGORY 3
Based on any level of evidence, there is major disagreement that the intervention is appropriate.
# Results
An online search revealed existing DLBCL treatment and management guidelines in four provinces (British Columbia (BC), Alberta (AB), Ontario (ON), Nova Scotia (NS)). Three provinces (BC, AB, NS), had one guideline in existence for the province, while one province (ON) had three DLBCL guidelines. Specialists from the remaining provinces (Saskatchewan (SK), Manitoba (MB), Quebec (QC), Newfoundland and Labrador (NF), New Brunswick (NB), Prince Edward Island (PEI)) and territories (Northwest Territories (NWT), Yukon (YK), Nunavut (NU)) were then contacted. Specialists from all remaining provinces confirmed no official provincial guidelines were in existence. Physicians that do not have guidelines within their own province indicated they refer to BC Cancer (MB, PEI), Alberta Health Sciences (AHS) (SK), Nova Scotia Cancer Care Program (PEI), Princess Margaret Cancer Centre (PMCC) and the National Comprehensive Cancer Network (NCCN) guidelines and adopt these guidelines to what is available locally. Specific guidelines have not been uniformly adopted or endorsed, and feedback from specialists indicated interest in the creation of a national DLBCL treatment guideline for frontline management.
The information included in the existing guidelines was reviewed for common themes to determine the methodology for data extraction and compilation to highlight similarities and differences. For frontline treatment, the common themes for treatment determination included limited vs. advanced disease, additional comorbidities and in some cases integrated clinical risk factors. The information is summarized in Table 2.
Additional characteristics involved in the decision for treatment, including molecular characteristics and CNS involvement, have been summarized in Table 3.
# MYC-rearranged with no BCL2 mutation
# R-CHOP x 6 R-CHOP x 6
Considerations: ** CNS IPI risk factors prognostic for CNS relapse include age > 60 years, elevated LDH, ECOG performance status (PS) > 1, advanced stage disease (III, IV), > 1 extranodal (EN) site, adrenal/kidney involvement 5 . In addition, multiple EN sites (> 2), as well as uterine involvement have also been associated with high CNS risk 6 . Less information is known about risk with breast involvement.
Age
# Frontline Treatment for DLBCL
Frontline treatment for DLBCL is relatively standardized across Canada with most patients receiving R-CHOP given every 21 days. Considerations to guide therapy include stage of disease, as well as 'double-hit or triple-hit' disease (presence of MYC rearrangement typically with BCL2 or BCL6 rearrangements). In some provinces, IPI risk factors (age of the patient, ECOG performance status (PS), number of extranodal sites, and lactate dehydrogenase level) can be used to guide treatment. Further, the presence of CNS disease or those at high risk may receive alternate therapy to include CNS penetrant drugs such as high-dose methotrexate (HD-MTX).
In those with cardiac dysfunction, etoposide substitution (R-CEOP), or in some cases infusional anthracyclines (DA-EPOCH-R), may be used as an alternative. Data from existing guidelines were compiled and reviewed with recommendations established and consensus achieved amongst the expert panel.
# Limited Stage Disease
Modifications to the standard treatment of R-CHOP for patients with limited stage disease depends on disease factors such as bulk and distribution, and for some guidelines stage modified IPI. The absolute definition of bulky disease can differ. Some groups define it as the largest tumour diameter of ≥ 10 cm, whereas other groups have used more conservative measurements including 5, 7 or 7.5 cm 7 . In addition, a stage-modified IPI may be considered to determine suitability for a limited stage approach (age ≤ 60 years, stage I-II, ECOG status < 2, elevated LDH) [8][9][10] .
All provinces recommend R-CHOP with variations in the number of cycles and use of PET imaging to guide the use of further therapy and radiotherapy (Table 2). The number of cycles of R-CHOP prior to the restaging interim PET scan varies per province (between 3-6 cycles), as well as the timing for when to schedule the PET scan. Further, the Deauville five-point scale assessment response may differ per province depending on when the PET scan is scheduled (i.e. interim or post-therapy). As performed in BC, if the interim PET is negative after 3 or 4 cycles of R-CHOP, i.e. CMR (complete metabolic response), the Deauville score associated with this response is 1-2, rather than the standard Deauville 1-3 score 11 . BC uses this more conservative scoring approach as it removes the necessity of further treatment with radiation 12 . A PET positive score in this scenario would be Deauville 3-5 rather than 4-5, as seen in other provinces, and radiation would be administered to include prior disease sites. On the other hand, for patients who receive six cycles of R-CHOP and undergo an end of treatment PET scan, a Deauville 4-5 score would require further treatment with radiation to PET positive areas (consolidation) for all other provinces. As the provinces have slightly different strategies, it is important to consult with a radiation oncologist. The BC guidelines recommend R-CHOP for 3 cycles, with one additional cycle of R-CHOP if PET negative. The NS guideline and ON (CCSEO, SHHC) guidelines also recommend three cycles while other provinces (AB, ON (PMCC), NS) recommend four cycles followed by an interim PET scan. With provinces that divide limited stage treatment based on high risk factors (AB, ON (SHHS, PMH), NS), 6 cycles of R-CHOP is recommended for more high risk patients.
Some guidelines rely on PET imaging results for further treatment decisions. For example, following 4 cycles of R-CHOP, if the interim PET is negative with a complete response, AB and ON (PMCC) recommend observation.
On the other hand, ON (CCSEO) and NS guidelines do not rely on PET to guide further treatment; their strategy involves combined-modality chemotherapy with involved-site radiation therapy (ISRT) or involved node radiation therapy (INRT). Guidelines for RT that predated modern imaging and planning techniques used involved fields (IFRT) defined by anatomic landmarks and often encompassed adjacent uninvolved lymph nodes 13 . Modern techniques for conformal RT deliver radiation more precisely based on target volume definitions (ISRT) often using reduced treatment volumes for the effective control of the at-risk involved sites of disease, thereby reducing normal tissue exposure 13 Considering these guidelines and current research, options for limited stage disease includes treatment with abbreviated therapy (R-CHOP x 4 plus 2 doses of Rituximab) as proven with the FLYER trial 9 , planned combined modality R-CHOP x 3 with ISRT, or PET-guided therapy. If bulky disease is present or the patient is not amenable to radiotherapy, the recommendation is to treat as advanced stage disease.
# RECOMMENDATIONS
Definition for limited stage disease: IPI 0-1, no bulky disease (provinces have different definitions of bulk disease), and ≤ 1 extranodal site.
Recommendation for the treatment of limited stage disease: R-CHOP x 3* -4 cycles, with exceptional 6 cycles, followed by PET scan. There is the option to give response-adapted treatment with PET (groups have different approaches).
# Advanced Stage Disease
For advanced stage disease which includes stage III/IV, and in some scenarios includes patients with B symptoms (BC) and bulk disease (> 10 cm in BC and NS; AB uses 7 cm cut-off), all guidelines recommend R-CHOP x 6 cycles. One guideline (ON) provides the option for an additional two cycles of R-CHOP if tolerated, however this is uncommon. Several of the guidelines highlight the use of end of treatment PET scan and/or the presence of bulk disease in assessing the need for radiation therapy following chemotherapy. A PET negative scan (Deauville 1-3) following R-CHOP will not require further treatment. If PET negative, but bulk was present at diagnosis, radiation is recommended (SEOCC). If PET positive (Deauville 4-5), the recommendation is radiation therapy (30-35 Gy) if feasible (BC, NS) 14 . Radiation is given to areas of residual positivity. One guideline (NS) recommends a more conservative approach with ISRT in this setting, prompting a discussion to determine critical issues (i.e. spinal cord involvement, age, comorbidities) that would preclude curative intent treatment at relapse.
Advanced stage disease that is high-risk was defined by existing guidelines as an IPI of 3 or higher. All guidelines recommend R-CHOP x 6 cycles. Additionally, with concomitant comorbidities, age and frailty, one guideline (NS) will consider dose adjustment of R-CHOP to R-mini-CHOP x 6 cycles as an option. However, data to support a standard approach in elderly and/or frail patients is lacking. Considering these guidelines and current research including the RICOVER trial 15 and the GOYA trial 16 , treatment for advanced stage patients is six cycles of R-CHOP; eight cycles is not justified.
Following R-CHOP, PET negative scans require no further treatment for the patient, while PET positivity recommends ISRT (30-35 Gy). Some guidelines advocate for radiation even with CR following R-CHOP for patients with bulky masses (> 10 cm), bone involvement, extradural tumor with spinal cord/nerve root compression, and impending or actual organ compromise. In BC, if the PET scan is negative after 6 cycles of R-CHOP, patients are observed even with bulky disease. Recent data from this centre demonstrated no difference in outcome in bulky versus non-bulky patients with an end of treatment PET-negative scan 7 .
One guideline (NS) does not recommend the use of ISRT following R-CHOP for this patient group. Other Considerations for Frontline Treatment
# RECOMMENDATIONS
# MOLECULAR FEATURES
Molecular characteristics of large B-cell lymphomas can alter prognosis, diagnostic classification, and treatment approach. The most frequent rearrangements include MYC, BCL2, and BCL6. Lymphomas found to have translocations for MYC in combination with BCL2 and/or BCL6 are no longer classified as DLBCL and are rather classified as High-Grade B-cell lymphoma with double-hit (DH) or triple-hit (TH) features. Though this is seen in only 5-10% of DLBCL cases, it is important for FISH (fluorescence in situ hybridization) testing to be done to identify this patient population in order to receive optimal treatment 17 .
# RECOMMENDATION
It is recommended that all patients with DLBCL be tested by FISH for MYC, with reflex testing for BCL2 and BCL6 if MYC positive.
# MYC REARRANGEMENT (Without Rearrangement of BCL2 or BCL6)
The MYC transcription factor is of vital importance to maintaining regular cell function and is the major molecular abnormality in aggressive B-cell lymphomas when rearranged 18 . In DLBCL, MYC rearrangement occurs in approximately 10% of cases 19 . Studies have suggested an inferior progression free survival (PFS) and overall survival (OS) for patients with MYC rearrangement compared to patients without [20][21] . The prognostic relevance however of single-hit rearrangement remains controversial and has been reported variably.
One study suggested that MYC rearrangement poses a negative impact to OS only within the first two years following diagnosis, with no difference in survival probability in DLBCL without MYC rearrangement after two years 19 . However, rarely does DLBCL relapse after a progression-free timepoint of two years.
Only one guideline (AB) provided a treatment recommendation for single-hit MYC rearrangement DLBCL, which was R-CHOP for 6 cycles. However, for those aged <70 years with a high IPI score [4][5] , the alternative treatment regimen is 4 cycles of R-CHOP followed by one cycle of either R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) or R-DICEP (dexamethasone, cyclophosphamide, etoposide, cisplatin). Alternative treatment approaches include R-CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine) or DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab).
# RECOMMENDATION
Recommendation for patients with MYC rearrangement: 6 cycles of R-CHOP.
# DOUBLE-HIT (MYC AND BCL2 OR BLC6) OR TRIPLE-HIT (MYC, BCL2, BCL6)
For DLBCL cases with MYC rearrangement, it is most often (58-83%) concurrent with dual translocation of BCL2 or BCL6 22 . Double-hit or triple-hit DLBCL is associated with shorter progression-free and overall survival following frontline therapy with R-CHOP [23][24] . It is also associated with a higher risk for CNS relapse 25 . One study assessed whether partner genes associated with MYC rearrangement, including either immunoglobulin (IG) heavy chain or light chain or non-IG locus, can affect outcome 19 . When MYC is rearranged with an IG partner in double-hit DLBCL, it results in a significantly worse PFS and OS 19 . It is important to note that the outcome of double/triple hit lymphoma with R-CHOP has improved with more comprehensive testing, suggesting that older studies may have a selection bias 26 . However, since we cannot reliably distinguish lower risk patients with current methodology, dose intensified chemotherapy is recommended.
Following review, there are five guidelines that comment on the preferred treatment option for this patient population. DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) x 6 cycles was the preferred method, with consideration for radiation therapy in patients with bulky disease or if PET positive following treatment. One guideline (AB) provides further recommendation based on IPI risk factors. In Alberta, patients with double-hit or triple-hit lymphoma under the age of 70 years should receive more aggressive therapy, possibly including stem cell transplantation. Guidelines advise patients to receive R-CHOP and HD-MTX, then proceed to autologous transplant. This option is not recommended for patients that have previously received an intensified protocol such as DA-EPOCH-R.
# RECOMMENDATION
The recommended treatment for double-hit and triple-hit lymphoma is DA-EPOCH-R x 6 cycles.
*May consider HD-MTX at the end of regimen for high-risk CNS patients.
# CNS PROPHYLAXIS
The prognosis of DLBCL patients with CNS involvement is poor, with a median survival time of 2-6 months due to both rapid tumor growth and ineffective treatment strategies. CNS involvement, which can manifest in the brain parenchyma, leptomeningeal, spinal cord and eyes, mainly presents within one year of diagnosis and can occur in the following scenarios with respect to the status of systemic disease:
1. Patient is in systemic remission, with isolated recurrence in the CNS;
2. Remission following frontline treatment, but simultaneous systemic recurrence and CNS involvement;
3. CNS involvement while the patient is receiving frontline treatment.
In addition to double-hit and triple-hit lymphoma, certain factors at diagnosis are correlated with a higher risk for CNS involvement including elevated LDH and multiple extranodal sites. Specific extranodal sites impart an elevated risk including kidney, adrenal glands, testes, and possible breast. The CNS-IPI was developed to identify patients at high risk of CNS disease, and incorporates all five IPI factors. Incidence is > 10% in those with a high-risk CNS-IPI and 25-35% in those with advanced stage and testicular or renal/kidney involvement; it remains unknown whether prophylaxis is protective. The optimal prophylactic strategy remains unclear.
The current Canadian guidelines that comment on CNS prophylaxis refer to the German High-Grade Lymphoma Study Group (DSHNHL) to determine patients that are high risk. This includes patients with a high CNS-IPI, kidney/adrenal or testicular involvement, as well as double/triple-hit lymphoma. Consideration is also given to prophylaxis in intravascular lymphoma. All guidelines recommend high-dose systemic methotrexate with leucovorin rescue in young patients with good renal function. The guidelines indicate a range of 2-4 cycles of high-dose methotrexate (3g/m 2 ). The day of administration is day 10-15 after R-CHOP typically after 2, 4 and 6 cycles, both for fit patients and those under the age of 70 years. Though initial data supports day 15 for better outcomes, recent evidence recommends scheduling before day 10 of R-CHOP cycles. In BC for limited stage testicular involvement, prophylaxis is given after chemotherapy. If issues with scheduling, tolerability or due to treatment delays, one guideline indicates that methotrexate can be administered once R-CHOP is completed, and then 3 cycles of HD-MTX can be performed every 2 weeks. If HD-MTX is not tolerable, another treatment strategy is four doses of intrathecal MTC/AraC/hydrocortisone. Further research on the use of HD-MTX and its benefits in this patient population is warranted.
# RECOMMENDATION
Patients at high-risk for CNS involvement could consider receiving prophylaxis with high-dose methotrexate (2-4 cycles, dose of 3g/m 2 ) in addition to R-CHOP. Patient characteristics and scheduling of HD-MTX administration may differ across institutions.
# CARDIAC DISEASE
Curative intent therapy for the frontline treatment of DLBCL is R-CHOP, a chemo-immunotherapy that includes doxorubicin, a known risk factor for cardiotoxicity [30][31] . With an increasingly cumulative dose, R-CHOP can result in cardiac toxicity and in particular congestive heart failure, as a result of the toxic damage to the mitochondria of the cardiomyocytes. One study found that cardiomyopathy could be avoided by keeping a cumulative dose of doxorubicin below 450 mg/m 2 32 . Additionally, certain established cardiac risk factors such as advanced age, known cardiac disease, prior mediastinal radiation and diabetes mellitus, can increase the risk for anthracycline toxicity. Other methods have been employed to reduce the risk of cardiac toxicity, including the use of anthracycline analogues and alternative methods of drug delivery such as through a continuous slow infusion 33 .
Managing cardiac toxicity is an institutionally driven practice with little evidence for a nationally standardized recommendation. Options can include the use of ACE (angiotensin-converting enzyme) inhibitors or dexrazoxane with R-CHOP to prevent cardiomyopathy. Another treatment strategy includes DA-EPOCH-R, as continuous infusional doxorubicin has lower cardiotoxicity. For patients with reduced ejection fraction, substituting the doxorubicin in R-CHOP with etoposide (R-CEOP) or gemcitabine (R-GCVP) have shown promise in retrospective studies 34 . A study from BC demonstrated no reduction in survival when comparing R-CEOP versus R-CHOP, although the study is not powered to show a small difference [35][36] .
# RECOMMENDATION
Recommendation for patients with cardiac toxicity: In this setting, curative therapy can be delivered. This will likely not involve R-CHOP alone, and may involve additional therapies as per institutional guidelines.
# PRE-PHASE THERAPY
Additional recommendations for optimal treatment strategies have been further listed by existing Canadian guidelines such as supportive/ancillary treatments, treatment for intermediary/grey zone DLBCL, and treatment based on specific anatomical tumor locations. Though certain institutional and provincial guidelines comment on intermediary and anatomical tumor locations, these are considered risk factors and do not require specific recommendations. Therefore, consensus was only required on pre-phase and prophylaxis treatment.
Pre-phase therapy can be considered a preventative strategy against toxicity such as febrile neutropenia, tumor lysis syndrome, and deterioration of performance status 37 . It can also be used to determine a patient's response to their upcoming chemotherapy regimen. Pre-phase therapy can include a regimen of corticosteroids with or without low dose chemotherapy 38 . Single-agent oral prednisone is the most commonly used regimen.
Other regimens include prednisone combined with vincristine and cyclophosphamide or cyclophosphamide alone 38 . Whether all DLBCL patients require pre-phase treatment, or whether there are certain risk factors such as advanced age that preclude its requirement, is still to be established.
For supportive medications during frontline treatment, two guidelines recommend prednisone prophylaxis (100 mg/day) for either 3-7 days (AB) or 5 days (ON) prior to R-CHOP or R-CEOP for patients > 60 years to prevent toxicity to chemotherapy regimen 39 . Another guideline (NS) provided numerous recommendations for supportive treatment. Allopurinol, a drug that prevents the build-up of uric acid, a side-effect of cytotoxic therapies for lymphoma, is recommended for patients at high risk for tumor lysis at a dose of 300mg daily x 5 days for the first cycle only of R-CHOP. As tumor lysis is rare in DLBCL, allopurinol is not commonly used. Granulocyte colony stimulating factor (G-CSF), can be used as a prophylaxis to regulate the production and function of neutrophils in order to accelerate neutrophil recovery time in patients receiving curative regimens [40][41] . This is especially important for patients receiving curative regimens as if there is a delay in receiving cancer treatment due to adverse events such as neutropenia, it could compromise the outcome for that patient. Filgrastim/pegfilgrastim primary prophylaxis are two types of G-CSF recommended for use in patients aged > 65 years, HIV positive patients, or patients felt to be at high risk (> 20%) of febrile neutropenia (open wounds, active infection, bone marrow infiltration by cancer, poor performance status, combined chemo-radiation) [42][43][44][45][46] . Pegfilgrastim is recommended in most cases where HD-MTX is used for CNS prophylaxis; filgrastim should be used to shorten the chemo-free interval and should be stopped 48 hours prior to chemotherapy.
# RECOMMENDATION
Should consider pre-phase administration of corticosteroids in symptomatic patients and/or older patients (> 60 years), and primary prophylaxis with G-CSF for > 60 years of age receiving R-CHOP or R-CEOP. However, any patient with an episode of febrile neutropenia, regardless of age, should receive subsequent G-CSF prophylaxis.
# Summary of Recommendations for DLBCL Treatment
• Definition for limited stage disease: IPI 0-1, no bulky disease (provinces have different definitions of bulk disease), and ≤ 1 extranodal site.
• Recommendation for limited stage disease: R-CHOP x 3* -4 cycles, with exceptional 6 cycles, followed by PET scan. There is the option to give response-adapted treatment with PET (groups have different approaches).
-*For R-CHOP x 3, proceed with either RT-planned combined modality, or proceed with PET imaging and if negative undergo one additional cycle of R-CHOP.
• Recommendation for advanced stage disease: standard therapy is 6 cycles of R-CHOP. Recommend ISRT if localized responding PET positive (Deauville 4-5) disease at the end of R-CHOP treatment.
-*If new site or progression (non-responding), treatment options can include ISRT or other salvage therapy.
• It is recommended that all patients with DLBCL be tested by FISH for MYC, with reflex testing for BCL2 and/ or BCL6 if MYC positive.
• Recommendation for patient with MYC rearrangement: 6 cycles of R-CHOP.
• The recommended treatment for double-hit and triple-hit lymphoma is DA-EPOCH-R x 6 cycles.
-*May consider HD-MTX at the end of regimen for high-risk CNS patients.
• Patients at high-risk for CNS involvement could consider receiving prophylaxis with high-dose methotrexate • Recommendation for patients with cardiac toxicity: In this setting, curative therapy can be delivered. This will likely not involve R-CHOP alone, and may involve additional therapies as per institutional guidelines.
• Should consider pre-phase administration of corticosteroids in symptomatic patients and/or older patients (> 60 years), and primary prophylaxis with G-CSF for > 60 years of age receiving R-CHOP or R-CEOP. However, any patient with an episode of febrile neutropenia, regardless of age, should receive subsequent G-CSF prophylaxis.
Based on these recommendations, a treatment algorithm for DLBCL patients undergoing frontline treatment provides the optimal treatment path(s) based on the patients' disease stage, molecular status and CNS and cardiac risk factors (Figure 1).
# Conclusion
Despite the widespread standardization of R-CHOP for the frontline treatment for DLBCL, there is still variability in the number of cycles of R-CHOP recommended, use of interim PET, and use of radiation consolidation. There are numerous patient factors to consider when determining the final treatment course. The guidelines in this report categorize treatment strategies based on limited and advanced DLBCL, while also considering other factors such as molecular features, CNS involvement, pre-phase treatment and cardiac toxicity. Molecular testing is recommended for all DLBCL patients. If patients are MYC positive, reflex testing for BCL2 and/or BLC6 will determine the frontline treatment approach. For MYC positive patients, accepted therapy includes R-CHOP x 6 cycles. If the patient tests positive for double-hit or triple-hit DLBCL, the optimal treatment strategy is DA-EPOCH-R.
For patients that test negative for molecular features, treatment strategy is based on limited versus advanced stage disease. For limited stage disease patients, risk factors may play a role in the number of R-CHOP cycles depending on the institution and province. Patients may undergo R-CHOP x 3, 4 or 6 cycles followed by a PET scan to assess response. There is the option to response-adapt with PET. Evidence supports patients receiving three cycles of R-CHOP to either undergo pre-planned RT combination modality or PET-guided treatment with one additional R-CHOP cycle if PET negative. For patients with advanced stage disease, the recommendation is for 6 cycles of R-CHOP followed by ISRT if there is localized residual disease.
Other important considerations include patients at risk for CNS involvement, patients with cardiac disease, and pre-phase treatment for patients at risk. For patients at risk for CNS involvement, there is the option to receive prophylaxis with high-dose systemic methotrexate in addition to leucovorin alongside R-CHOP. For patients with cardiac disease, curative therapy can be delivered through different treatment additions to R-CHOP as per institutional guidelines. For patients that are > 60 years of age that are symptomatic, corticosteroids could be considered, and primary prophylaxis with G-CSF should be considered in patients > 60 years of age.
# Conflict of Interest Disclosures
The following represents disclosure information from the authors within the last two years related to the subject matter of this guideline.
MS: Novartis, Kite/Gilead, BMS; MB: Novartis, Kite/Gilead; JK: Kite/Gilead, BMS, Novartis; KS: Kite/Gilead, BMS, Merck, Roche; PS: Novartis, BMS; MMK: Roche; RT: n/a
# YOU DON'T HAVE TO FACE LYMPHOMA ALONE.
Lymphoma Canada connects patients, their family and friends, medical professionals, researchers, volunteers and donors, to build a strong lymphoma community.
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To provide guidance about the management of direct oral anticoagulants (DOACs) in obese patients.Four DOACs are approved for clinical use in Canada: apixaban, dabigatran, edoxaban and rivaroxaban. The clinical guides for each of the DOACs contains information about mechanism of action, licensed indications, side-effect profiles, and approved dosing regimens . According to the Health Canada, obesity is defined by a body mass index (BMI) >30 kg/m 2 .No randomized controlled trials have examined the safety and efficacy of DOACs only in obese or very obese patients. In most instances, 90-100 kg or BMI >30 kg/m 2 . A high weight alone does not necessarily indicate obesity, thereby limiting the interpretation of data from trials that reported weight only. Although information remains somewhat limited for some indications, based on the data below, there is increasing comfort using DOACs in patients with class I (BMI 30.0-34.9) and class II (BMI 35.0-39.9) obesity.#
- Studies in venous thromboembolism: In a systematic review and meta-analysis of patients with VTE treated with apixaban, dabigatran, and rivaroxaban, anticoagulant efficacy was similar in patients 100kg or <100kg groups.
- Studies in atrial fibrillation: A systematic review and subsequently published post-hoc subgroup analyses of large randomized trials suggest that, among atrial fibrillation patients, apixaban, dabigatran, rivaroxaban and edoxaban are equivalent to vitamin K antagonists in terms of efficacy and safety in obese patients. A retrospective study was done at an integrated multisite health-care system of DOAC use across all BMI categories. No differences were found in stroke rates or risk of intracranial hemorrhage between normal BMI and those with category 1 or higher obesity (43.9% apixaban, 36.4% rivaroxaban, 9.5% dabigatran and 0.1% edoxaban).
- Studies in orthopedic surgery: In a study that compared clinical outcomes in patients undergoing total hip and knee arthroplasty, no significant differences between the efficacy and safety of dabigatran and enoxaparin in patients with a BMI>30 were noted. A study evaluating patients undergoing total hip or knee arthroplasty found no differences in the reduction in venous thromboembolism (VTE) risk with rivaroxaban versus enoxaparin in patients >90kg compared with those with lower weights. Finally, in a subgroup analysis of pooled data from studies comparing apixaban and enoxaparin, there were no differences in VTE or bleeding events when patients with BMI30. ) or warfarin (1208 patients) and who had a body weight more than 100 kg and less than 300 kg, no significant difference was seen in the rate of recurrent venous thromboembolism or bleeding in the two treatment groups. In this study, the median BMI was 38.8 kg/m² in the DOAC group and 39.2 kg/m² in the warfarin group; in the DOAC group, 43.6% had a BMI >40, while in the warfarin group this was 45.3%. - A retrospective 1:1 propensity score matched cohort study of 2890 VTE patients from US claims data (using ICD-9 and ICD-10 codes for morbid obesity) showed similar bleeding and recurrent VTE risk between warfarin and rivaroxaban. A similar study from the same group looking at 3563 atrial fibrillation patients showed similar bleeding and stroke/systemic embolism risk between warfarin and rivaroxaban.
- If DOACs are to be used in patients with a BMI >40 or >120 kg, patients should be informed of the limitations of the available information and potential risk of under-dosing.
# SPECIAL CONSIDERATIONS:
Data regarding safety and efficacy of DOACs in the pediatric population are very limited. DOACs are contraindicated in pregnancy and while breast feeding.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Apixaban (Eliquis®)
- Dabigatran (Pradaxa®)
# Date of version: 29August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To provide guidance about the management of direct oral anticoagulants (DOACs) in obese patients.Four DOACs are approved for clinical use in Canada: apixaban, dabigatran, edoxaban and rivaroxaban. The clinical guides for each of the DOACs contains information about mechanism of action, licensed indications, side-effect profiles, and approved dosing regimens [see Clinical Guides Apixaban (Eliquis®), Dabigatran (Pradaxa®), Edoxaban (Lixiana®), and Rivaroxaban (Xarelto®)]. According to the Health Canada, obesity is defined by a body mass index (BMI) >30 kg/m 2 .No randomized controlled trials have examined the safety and efficacy of DOACs only in obese or very obese patients. In most instances, <20% of patients enrolled in DOAC trials weighed >90-100 kg or BMI >30 kg/m 2 . A high weight alone does not necessarily indicate obesity, thereby limiting the interpretation of data from trials that reported weight only. Although information remains somewhat limited for some indications, based on the data below, there is increasing comfort using DOACs in patients with class I (BMI 30.0-34.9) and class II (BMI 35.0-39.9) obesity.#
• Studies in venous thromboembolism: In a systematic review and meta-analysis of patients with VTE treated with apixaban, dabigatran, and rivaroxaban, anticoagulant efficacy was similar in patients <100 kg and ≥100 kg. Another study found no association between BMI and risk of VTE recurrence or bleeding events in rivaroxaban-treated patients. A third retrospective study of apixaban vs warfarin used pooled data from various U.S. databases to analyze outcomes in over 43,000 patients with VTE who were classified as either obese or morbidly obese. No significant difference in recurrent VTE or major bleeding were identified (slightly lower risk for both outcomes in the apixaban arm). Subgroup analysis of patients in the Hokusai VTE study with edoxaban showed no significant difference in efficacy or safety in the >100kg or <100kg groups.
• Studies in atrial fibrillation: A systematic review and subsequently published post-hoc subgroup analyses of large randomized trials suggest that, among atrial fibrillation patients, apixaban, dabigatran, rivaroxaban and edoxaban are equivalent to vitamin K antagonists in terms of efficacy and safety in obese patients. A retrospective study was done at an integrated multisite health-care system of DOAC use across all BMI categories. No differences were found in stroke rates or risk of intracranial hemorrhage between normal BMI and those with category 1 or higher obesity (43.9% apixaban, 36.4% rivaroxaban, 9.5% dabigatran and 0.1% edoxaban).
• Studies in orthopedic surgery: In a study that compared clinical outcomes in patients undergoing total hip and knee arthroplasty, no significant differences between the efficacy and safety of dabigatran and enoxaparin in patients with a BMI>30 were noted. A study evaluating patients undergoing total hip or knee arthroplasty found no differences in the reduction in venous thromboembolism (VTE) risk with rivaroxaban versus enoxaparin in patients >90kg compared with those with lower weights. Finally, in a subgroup analysis of pooled data from studies comparing apixaban and enoxaparin, there were no differences in VTE or bleeding events when patients with BMI<30 were compared with those with a BMI >30. ) or warfarin (1208 patients) and who had a body weight more than 100 kg and less than 300 kg, no significant difference was seen in the rate of recurrent venous thromboembolism or bleeding in the two treatment groups. In this study, the median BMI was 38.8 kg/m² in the DOAC group and 39.2 kg/m² in the warfarin group; in the DOAC group, 43.6% had a BMI >40, while in the warfarin group this was 45.3%. • A retrospective 1:1 propensity score matched cohort study of 2890 VTE patients from US claims data (using ICD-9 and ICD-10 codes for morbid obesity) showed similar bleeding and recurrent VTE risk between warfarin and rivaroxaban. A similar study from the same group looking at 3563 atrial fibrillation patients showed similar bleeding and stroke/systemic embolism risk between warfarin and rivaroxaban.
• If DOACs are to be used in patients with a BMI >40 or >120 kg, patients should be informed of the limitations of the available information and potential risk of under-dosing.
# SPECIAL CONSIDERATIONS:
Data regarding safety and efficacy of DOACs in the pediatric population are very limited. DOACs are contraindicated in pregnancy and while breast feeding.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Apixaban (Eliquis®)
• Dabigatran (Pradaxa®)
•
# Date of version: 29August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To assist health care professionals in the management of portal vein thrombosis (PVT).The portal vein is one of the splanchnic veins, formed at the confluence of the superior mesenteric and splenic veins and carries blood from the gastrointestinal tract to the liver. PVT can occur in the main portal vein, in the left or right portal branches, and/or in the smaller, intrahepatic branches. PVT is an uncommon site of thrombosis, estimated to occur in 4 per 100,000 individuals. Risk factors include liver cirrhosis, abdominal surgery, abdominal malignancy, thrombophilia, myeloproliferative neoplasms (MPN), hormone use, local inflammation (such as pancreatitis), inflammatory bowel disease, or intra-abdominal infections. Most patients with PVT are asymptomatic and the diagnosis is made on abdominal imaging for other reasons. The most common clinical manifestation of PVT is abdominal pain.# MANAGEMENT OF PORTAL VEIN THROMBOSIS:
The management of PVT is based on limited observational studies and expert opinion. Given the moderate/weak level of evidence, the risks and benefits of anticoagulation need to be carefully weighed considering individual patient circumstances.
- Anticoagulation is recommended for patients with symptomatic or extensive PVT and in those with extension of the PVT into the superior mesenteric vein in order to prevent portal hypertension and bowel ischemia/infarction. This is based on observational studies suggesting that patients with PVT treated with anticoagulation have a low (~2%) rate of bowel ischemia and decreased thrombus progression and extension. Recurrent thrombosis is common (~5%) in the absence of anticoagulation or if anticoagulants are discontinued. - Patients with PVT who are potential candidates for liver transplantation should also be considered for anticoagulation since their prognosis may be improved as a result. - The role of anticoagulation in patients with asymptomatic PVT is controversial. In patients with underlying malignancy, incidentally detected thrombosis appears to carry a similar prognosis to symptomatic thrombosis and is managed with anticoagulation. In a registry of patients with splanchnic vein thrombosis (majority having PVT and receiving anticoagulation) including patients with liver cirrhosis and cancer, outcomes were similar between the symptomatic and asymptomatic patients. - The role of anticoagulation in patients with portal vein thrombosis and cavernous transformation is very unclear. Cavernous transformation suggests a chronic thrombosis which is unlikely to extend or induce bowel ischemia; hence, the risks of anticoagulation may outweigh any benefits. - Anticoagulant options in the acute phase include unfractionated heparin and low molecular weight heparin (LMWH). Heparin may be used if there is concern for imminent bleeding, with the option of discontinuing heparin in the presence of bleeding. LMWH is recommended in patients with PVT and cancer and may be preferred in patients with liver disease or thrombocytopenia. LMWH, given at less than full therapeutic doses, may be an option for patients with localized PVT and patients at high bleeding risk.
- Data regarding the direct oral anticoagulants (DOACs) is limited to mostly case reports and case series describing their use. One small randomized clinical trial assessed rivaroxaban 10 mg twice daily versus warfarin predominately in patients with cirrhosis who had a surgically-provoked portal vein thrombus. Rivaroxaban use resulted in higher recanalization rates and lower rates of mortality and cirrhotic decompensations. Extrapolation of these results to other populations should be done with caution. o Long-term anticoagulation may be achieved with LMWH or warfarin (target INR 2.0-3.0). If warfarin is used, the pre-warfarin INR should be normal and patients should be carefully monitored. - Active bleeding is an absolute contraindication to anticoagulation. This may occur in patients with bleeding from esophageal varices or tumour site bleeding. Anticoagulation of PVT is associated with increased rates of gastrointestinal bleeding. Attempts to decrease bleeding risk, including endoscopy and variceal banding in patients with liver disease or surgical resection of a known gastrointestinal cancer, should be completed prior to anticoagulation if feasible. - Previous bleeding or the presence of esophageal varices alone should not be considered a contraindication to anticoagulation. - Bleeding risk should be assessed against the potential benefits of anticoagulation. Bleeding is more common in patients with cirrhosis and in those with platelet counts of <50 x 10 9 /L. An assessment of the presence of ongoing risk factors for thrombosis can assist in determining optimal duration of anticoagulation.
# DURATION OF THERAPY:
- The duration of anticoagulation in patients with PVT is uncertain and is largely extrapolated from data on lower extremity deep vein thrombosis. Treatment duration is based on the estimated thrombosis and bleeding risks, as well as individual informed patient preference.
PVT occurring in the context of a reversible risk factor should generally be treated for 3 months. Patients who have an unprovoked PVT or an ongoing risk factor should be treated for at least 3-6 months, with consideration for long-term therapy with periodic reassessment of bleeding risk.
# TRANSJUGULAR INTRAHEPATIC SHUNT (TIPS):
In patients with liver cirrhosis, portal hypertension and PVT, portosystemic shunt has been used as a treatment option. In a small, retrospective study involving 52 patients, thrombosis burden improved the most in patients treated with TIPS when compared to anticoagulation or no treatment. Further studies are needed to compare effectiveness of anticoagulation and TIPS. However, this treatment option maybe considered in patients with significant portal hypertension.
# Date of version: 14November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
|
To assist health care professionals in the management of portal vein thrombosis (PVT).The portal vein is one of the splanchnic veins, formed at the confluence of the superior mesenteric and splenic veins and carries blood from the gastrointestinal tract to the liver. PVT can occur in the main portal vein, in the left or right portal branches, and/or in the smaller, intrahepatic branches. PVT is an uncommon site of thrombosis, estimated to occur in 4 per 100,000 individuals. Risk factors include liver cirrhosis, abdominal surgery, abdominal malignancy, thrombophilia, myeloproliferative neoplasms (MPN), hormone use, local inflammation (such as pancreatitis), inflammatory bowel disease, or intra-abdominal infections. Most patients with PVT are asymptomatic and the diagnosis is made on abdominal imaging for other reasons. The most common clinical manifestation of PVT is abdominal pain.# MANAGEMENT OF PORTAL VEIN THROMBOSIS:
The management of PVT is based on limited observational studies and expert opinion. Given the moderate/weak level of evidence, the risks and benefits of anticoagulation need to be carefully weighed considering individual patient circumstances.
• Anticoagulation is recommended for patients with symptomatic or extensive PVT and in those with extension of the PVT into the superior mesenteric vein in order to prevent portal hypertension and bowel ischemia/infarction. This is based on observational studies suggesting that patients with PVT treated with anticoagulation have a low (~2%) rate of bowel ischemia and decreased thrombus progression and extension. Recurrent thrombosis is common (~5%) in the absence of anticoagulation or if anticoagulants are discontinued. • Patients with PVT who are potential candidates for liver transplantation should also be considered for anticoagulation since their prognosis may be improved as a result. • The role of anticoagulation in patients with asymptomatic PVT is controversial. In patients with underlying malignancy, incidentally detected thrombosis appears to carry a similar prognosis to symptomatic thrombosis and is managed with anticoagulation. In a registry of patients with splanchnic vein thrombosis (majority having PVT and receiving anticoagulation) including patients with liver cirrhosis and cancer, outcomes were similar between the symptomatic and asymptomatic patients. • The role of anticoagulation in patients with portal vein thrombosis and cavernous transformation is very unclear. Cavernous transformation suggests a chronic thrombosis which is unlikely to extend or induce bowel ischemia; hence, the risks of anticoagulation may outweigh any benefits. • Anticoagulant options in the acute phase include unfractionated heparin and low molecular weight heparin (LMWH). Heparin may be used if there is concern for imminent bleeding, with the option of discontinuing heparin in the presence of bleeding. LMWH is recommended in patients with PVT and cancer and may be preferred in patients with liver disease or thrombocytopenia. LMWH, given at less than full therapeutic doses, may be an option for patients with localized PVT and patients at high bleeding risk.
o Data regarding the direct oral anticoagulants (DOACs) is limited to mostly case reports and case series describing their use. One small randomized clinical trial assessed rivaroxaban 10 mg twice daily versus warfarin predominately in patients with cirrhosis who had a surgically-provoked portal vein thrombus. Rivaroxaban use resulted in higher recanalization rates and lower rates of mortality and cirrhotic decompensations. Extrapolation of these results to other populations should be done with caution. o Long-term anticoagulation may be achieved with LMWH or warfarin (target INR 2.0-3.0). If warfarin is used, the pre-warfarin INR should be normal and patients should be carefully monitored. • Active bleeding is an absolute contraindication to anticoagulation. This may occur in patients with bleeding from esophageal varices or tumour site bleeding. Anticoagulation of PVT is associated with increased rates of gastrointestinal bleeding. Attempts to decrease bleeding risk, including endoscopy and variceal banding in patients with liver disease or surgical resection of a known gastrointestinal cancer, should be completed prior to anticoagulation if feasible. • Previous bleeding or the presence of esophageal varices alone should not be considered a contraindication to anticoagulation. • Bleeding risk should be assessed against the potential benefits of anticoagulation. Bleeding is more common in patients with cirrhosis and in those with platelet counts of <50 x 10 9 /L. An assessment of the presence of ongoing risk factors for thrombosis can assist in determining optimal duration of anticoagulation.
# DURATION OF THERAPY:
• The duration of anticoagulation in patients with PVT is uncertain and is largely extrapolated from data on lower extremity deep vein thrombosis. Treatment duration is based on the estimated thrombosis and bleeding risks, as well as individual informed patient preference.
PVT occurring in the context of a reversible risk factor should generally be treated for 3 months. Patients who have an unprovoked PVT or an ongoing risk factor should be treated for at least 3-6 months, with consideration for long-term therapy with periodic reassessment of bleeding risk.
# TRANSJUGULAR INTRAHEPATIC SHUNT (TIPS):
In patients with liver cirrhosis, portal hypertension and PVT, portosystemic shunt has been used as a treatment option. In a small, retrospective study involving 52 patients, thrombosis burden improved the most in patients treated with TIPS when compared to anticoagulation or no treatment. Further studies are needed to compare effectiveness of anticoagulation and TIPS. However, this treatment option maybe considered in patients with significant portal hypertension.
# Date of version: 14November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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We would like to thank Canadian Centre on Substance Use and Addiction and the Behavioural Supports Ontario Substance Use Collaborative for their support and contributions throughout the development of the Guidelines and Tonya Mahar (Manager, Library Services, Baycrest) for her assistance with literature searches. Finally the CCSMH would like to acknowledge the continued dedication of its Steering Committee members and the outstanding contributions of our Director,#
This publication is intended for information purposes only, and is not intended to be interpreted or used as a standard of medical practice. Best efforts were used to ensure that the information in this publication is accurate; however the publisher and every person involved in the creation of this publication disclaim any warranty as to the accuracy, completeness or currency of the contents of this publication. This publication is distributed with the understanding that neither the publisher nor any person involved in the creation of this publication is rendering professional advice. Physicians and other readers must determine the appropriate clinical care for each individual patient on the basis of all the clinical data available for the individual case. The publisher and every person involved in the creation of this publication disclaim any liability arising from contract, negligence, or any other cause of action, to any party, for the publication contents or any consequences arising from its use. The views expressed herein do not necessarily represent the views of Health Canada.
We encourage the copy and distribution of these guidelines; provided that the appropriate attribution is given. Please see the suggested citation below.
# Suggested citation: Canadian Guidelines on
Benzodiazepine Receptor Agonist Use Disorder Among Older Adults. Canadian Coalition for Seniors ' Mental Health, Toronto, Canada (2019) Funding for the CCSMH Substance Use Disorder Guidelines was provided by Health Canada, Substance Use and Addictions Program. The CCSMH gratefully acknowledges Health Canada for its ongoing support and continued commitment to the area of seniors' mental health.
In addition, special thanks to the Co-Leads and individual working group members who dedicated countless number of hours and engaged in the creation of guidelines and recommendations.
Benzodiazepine Receptor Agonists: Drugs referred to as BZRAs act as allosteric modulators of gammaaminobutyric acid (GABA) activity by binding to inotropic benzodiazepine receptors at the GABA A receptor complex . BZRAs increase GABA binding and chloride ion channel opening, facilitating inhibitory activity . Some of these drugs have a benzodiazepine chemical structure (i .e ., alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam) while others, referred to as non-benzodiazepine receptor agonists, novel benzodiazepine receptor agonists, or z-drugs (i .e ., zolpidem, zopiclone), do not . We use the term BZRAs for both . Our recommendations deal with all BRZAs as they have similar benefits, side effects, and risks . These drugs have regulatory approval for the management of anxiety and panic disorders, short-term treatment of insomnia, seizures, alcohol withdrawal, sedation, and spasticity . They are also often used in an off-label manner (i .e ., any use of a drug beyond what Health Canada has reviewed and authorized to be marketed in Canada and as indicated on the product label), for example to treat anxious depression or the behavioural and psychological symptoms of dementia (BPSD), which are also described as responsive behaviours .
# Definition of Key Terms
BZRA Use Disorder: This refers to a problematic pattern of BZRA use leading to clinically significant impairment or distress . According to DSM-5 criteria BZRA use disorder is manifested by at least two of the criteria below occurring within a 12-month period (American Psychiatric Association, 2013) . It is important to note that among older adults, some of these criteria may be modified by the aging process or their social roles (e .g ., retirement from work), resulting in more subtle presentations (Kuerbis et al ., 2014) .
✚ The BZRA is taken in larger amounts or over a longer period of time than intended .
✚ Persistent desire or unsuccessful efforts to cut down or control BZRA use .
✚ A great deal of time is spent in activities to obtain BZRAs, use them, or recover from their effects .
✚ Craving, or a strong desire or urge to use a BZRA .
✚ Recurrent BZRA use resulting in a failure to fulfill major role obligations at work, school, or home .
✚ Continued use of the BZRA despite persistent or recurrent social or interpersonal problems caused or exacerbated by their effects .
✚ Important social, occupational, or recreational activities are given up or reduced because of BZRA use .
✚ Recurrent BZRA use in situations in which it is physically hazardous .
✚ Continued use of the BZRA despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by drug use .
✚ Tolerance as defined by either a need for markedly increased amounts of the BZRA to achieve intoxication or desired effect OR a markedly diminished effect with continued use of the same amount of the BZRA (note: criterion not considered to be met for an individual taking the drug under medical supervision) .
✚ Withdrawal as manifested by either characteristic withdrawal symptoms (i . e . , autonomic hyperactivity, hand tremor, insomnia, nausea or vomiting, transient sensory hallucinations or illusions, psychomotor agitation, anxiety, and/or seizures) OR the BZRA (or a closely related substance such as alcohol) is taken to relieve or avoid withdrawal symptoms .
# Diagnosis
✚ 1 symptom or less, no diagnosis ✚ 2-3 symptoms, mild BZRA Use Disorder ✚ 4-5 symptoms, moderate BZRA Use Disorder ✚ 6 or more symptoms, severe BZRA Use Disorder Remission ✚ 3-12 months with no criteria other than craving is considered early remission .
✚ More than 12 months is considered sustained remission .
# Summary of Recommendations and Grades
W e used the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation) as a method of grading the quality of evidence and the strength of recommendations . In following the GRADE process, the initial step was to grade the quality of available evidence supporting each recommendation . Subsequently, we identified the overall strength of the recommendation taking into account the quality of the evidence but also other factors such as the potential to do harm, the cost and feasibility .
We have also developed a separate category for recommendations which are not primarily based on empirical evidence; but have agreement that they represent best clinical practice . Examples would include: optimal assessment processes and those related to education and/or policy . These recommendations have been categorized as "C" for consensus . We did not use the GRADE process for these recommendations . Other guideline groups have used a similar approach e .g . British Association for Psychopharmacology Guidelines (Lingford-Hughes et al ., 2012) . While such recommendations lack empirical evidence, we believe they are also useful and important . The quality of evidence for each recommendation is determined through an examination of the following factors: (1) Study design and the quality of the studies that were included, (2) the directness of the evidence (generalizability or applicability) and
(3) the confidence that patients will benefit from the treatment .
The strength of each recommendation is determined through an examination of the following factors:
(1) The balance between benefits and undesirable effects/ risks, (2) uncertainty or variability of patient values and preferences and (3) the resources associated with management options .
# GRADE
# QUALITY OF EVIDENCE
# STRENGTH OF RECOMMENDATION
# HIGH
Further research is unlikely to change confidence in the estimate of effect
# MODERATE
Further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate
# LOW
Further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate
# STRONG
Strong recommendations indicate high confidence that desirable consequences of the proposed course of action outweigh the undesirable consequences or vice versa .
# WEAK
Weak recommendations indicate that there is either a close balance between benefits and down sides (including adverse effects and burden of treatment), uncertainty regarding the magnitude of benefits and down sides, uncertainty or great variability in patients' values and preferences, or that the cost or burden of the proposed intervention may not be justified .
(adapted from Guyatt et al, 2008) RECOMMENDATION #1:
# RECOMMENDATION #4:
An assessment of risk for BZRA use disorder and other potential adverse effects from these agents should be done prior to prescribing a BZRA.
# RECOMMENDATION #5:
If a BZRA is being considered, the older adult should be informed of both the limited benefits and risks associated with use, as well as alternatives, prior to deciding on a management plan.
# RECOMMENDATION #6:
Initiating treatment with a BZRA should be a shared decision between the prescriber and the older adult (or their substitute decision-maker). There should be agreement and understanding on how the BZRA is to be used (including planned duration of no more than 2 to 4 weeks) and monitored.
# RECOMMENDATION #7:
Older adults who are receiving a BZRA should be:
a. Educated and provided the opportunity to discuss the ongoing risks of taking BZRAs.
# RECOMMENDATION #23:
Older adults with a BZRA use disorder whose drug use is escalating in spite of medical supervision, have failed prior efforts to withdraw their BZRA, are at high risk for relapse or harm, and/or suffer from significant psychopathology should be considered for referral to a specialty addiction or mental health service.
D espite consensus that benzodiazepine receptor agonists (BZRAs) should be avoided whenever possible in older adults (Kuhn-Thiel et al ., 2014;American Geriatrics Society, 2019), clinicians continue to frequently prescribe these medications in this patient population . Recent Canadian data suggest high rates of use persist among older adults, especially females, with 18 .7% of females reporting past-year use (Statistics Canada, 2016) . There is evidence, however, that the overall rate of use of BZRAs is gradually dropping in Canada . Davies et al . (2018) reported that the prescription rate for benzodiazepines among Ontario residents aged 65 and over declined from 23 .2% in 1998 to 14 .9% in 2013 . A Quebec study of older adults reported that 9 .5% of those taking benzodiazepines met Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for substance dependence (Voyer et al ., 2010) .
S trategies to prevent BZRA use disorder include avoiding the initial prescription of BZRAs, particularly if consumption of these agents would place the older adult at high risk for harm, and following good prescribing practices when they are used . Informed older patients and well-trained prescribers, supported by a health care system that offers ready access to nonpharmacological alternatives, are required to achieve these aims .
# Minimizing BZRA Use and Preventing BZRA Use Disorder
# RECOMMENDATION #1:
Long-term use of BZRAs (> 4 weeks) in older adults should be avoided for most indications because of their minimal efficacy and risk of harm. Older adults have increased sensitivity to BZRAs and decreased ability to metabolize some longer-acting agents, such as diazepam. All BZRAs increase the risk of cognitive impairment, delirium, falls, fractures, hospitalizations, and motor vehicle crashes. Alternative management strategies for insomnia, anxiety disorders, and the behavioural and psychological symptoms of dementia (BPSD) are recommended.
BZRAs are not first-line agents for the treatment of anxiety, insomnia, or BPSD in older adults because of their minimal efficacy and concerns about adverse effects (el-Guebaly et al ., 2010;Vaapio et al ., 2015;Gage, 2016;Jansen et al ., 2016) . These drugs are included in commonly used lists of medications to avoid in older adults (Hamilton et al ., 2011;Kuhn-Thiel et al ., 2014;American Geriatrics Society, 2019) .
Age-related changes in pharmacokinetics and pharmacodynamics result in a greater risk of adverse effects with BZRAs in older adults at doses lower than cited as effective (Tamblyn et al ., 2005;Vaapio et al ., 2015) . Adverse effects include falls, fractures, cognitive impairment, delirium, incontinence, respiratory depression, and unplanned hospitalization (American Geriatrics Society, 2009;Assem-Hilger et al ., 2009;Lin et al ., 2017) . BZRAs can also negatively affect driving skills and are associated with higher motor vehicle crash rates at all ages (Leufkens & Vermeeren, 2009;Kang et al ., 2012) .
Prescribers need to be aware of how frequently and quickly dependency on BZRAs can develop . As many as 15% of regular users have been found to be dependent after 4 months and 50% after 2 years of use, with some sources citing even higher rates (el-Guebaly et al ., 2010) . Efforts to reduce physiological dependency would include minimizing dosages, prescribing only for short periods of time, and/or only using intermittently (Ibid) . It should be noted that there are a few conditions, such as REM sleep disorder, for which longer-term use of a BZRA might be appropriate (Aurora et al ., 2010) .
# RECOMMENDATION #2:
Appropriate first-line non-pharmacological options for the treatment of insomnia and anxiety disorders include cognitive behaviour therapies (CBTs) provided in various formats. Both the American College of Physicians ( 2016) and the European Sleep Research Society (2017) recommend CBT for insomnia (CBTi) as the first-line treatment for insomnia, with BZRAs and other sedative-hypnotics reserved for use in patients who fail to benefit from CBTi (Qaseem et al ., 2016;Riemann et al ., 2017) . This recommendation is based on the results of numerous randomized controlled trials involving a wide range of patients (including older adults with multiple comorbidities) and the poor risk/benefit ratio of pharmacotherapies for insomnia . Both CBTi provided by a therapist (individually or as a group) or using a selfhelp approach (e .g ., CBTi-based books, online services, and apps) has been shown to be effective . Sleepwell (Sleepwell . ca, 2018) provides information about and links to selfhelp CBTi resources . Simple sleep hygiene approaches can be attempted, although the evidence in support of this approach is limited and equivocal (Irish et al ., 2015) .
A meta-analysis by Hendricks et al . (2008) showed that CBT provided in a group or individually is an effective treatment for anxiety (Hendriks et al ., 2008;Ursuliak et al ., 2008;Soyka, 2017) . Enhanced CBT modifies the standard approach to CBT to better meet the needs of an older population (Mohlman et al ., 2003;Cassidy & Rector, 2008;Ursuliak et al ., 2008) and significantly improves measures of depression, anxiety, and quality of life in depressed and anxious seniors (Ursuliak et al ., 2008) . Exposure and response prevention can be used in CBT to reduce anxiety symptoms and redress the underlying avoidance that perpetuates anxiety disorders (Davis et al ., 2012) .
# RECOMMENDATION #3:
A BZRA should only be considered in the management of insomnia or anxiety after failing adequate trials of nonpharmacological interventions or safer pharmacological alternatives OR for short-term bridging until more appropriate treatment becomes effective.
The most effective approach to minimizing BZRA use disorders is avoiding their use . Strategies for this include: primary prevention of conditions in which BZRAs are often prescribed (e .g ., insomnia, anxiety disorders, and depressive disorders); greater use of non-pharmacological alternatives; preferential use of recommended first-line pharmacological treatments for anxiety and depression; and, ongoing education about the risks of BZRA use (Glass et al ., 2005;Sithamparanathan et al ., 2012;Gage, 2016) .
Antidepressants (Selective serotonin reuptake inhibitors and Serotonin and norepinephrine reuptake inhibitors ) are recommended first-line pharmacotherapy for anxiety and depressive disorders in older adults (Katzman et al ., 2014;Kok, 2014;Thorlund et al ., 2015) . BZRAs are not recommended for these indications other than for short-term use to relieve severe anxiety (Qaseem et al ., 2016) . As noted, insomnia should not be treated with BZRAs or other sedative-hypnotics options unless more effective and safer non-pharmacological options have been tried and shown to be ineffective . The 2017 practice guideline by the American Academy of Sleep Medicine for the pharmacological treatment of insomnia provides no strong recommendation for any medication currently approved or commonly used to treat insomnia in the United States (Qaseem et al ., 2016;Riemann et al ., 2017) .
# RECOMMENDATION #4:
An assessment of risk for BZRA use disorder and other potential adverse effects from these agents should be done prior to prescribing a BZRA. Awareness of risk factors for developing dependence on a BZRA and BZRA use disorder can help avoid inappropriate use . Identified risk factors include: older age, female gender, dependent personality, and concurrent or previous substance use disorder (Gage, 2016) . As the dose of BZRA can affect the likelihood of success with tapering (more likely if < 10 mg diazepam equivalent/day equivalent), use of lower doses might help decrease rates of BZRA use disorders overall (J . Brett & Murnion, 2015) .
# RECOMMENDATION #5:
If a BZRA is being considered, the older adult should be informed of both the limited benefits and risks associated with use, as well as alternatives, prior to deciding on a management plan. Awareness of the risks of BZRAs is important both for patients and prescribers (Cook et al ., 2007;Canham et al ., 2014) . Patient knowledge has been shown to correlate with successful tapering of medications, while the attitudes and skills of primary care physicians have an impact on efforts to reduce doses among chronic users of BZRAs . Lack of awareness of the risks of use can limit efforts to optimize use and lead to delayed recognition of use disorder and other adverse effects, such as fatigue, falls, and depression . Older patients are less likely to recognize dependency or bring concerns to their physicians, whose own lack of awareness might make it even more difficult to identify the presence of a disorder (Kuerbis et al ., 2014) . It is recommended that clinicians offer patients education about the risks of BZRAs and make greater use of non-pharmacological and alternative pharmacological therapies . Physicians often describe having limited skills in reducing BZRA dosages or knowledge of alternative treatments (Cook et al ., 2007) .
# RECOMMENDATION #6:
Initiating treatment with a BZRA should be a shared decision between the prescriber and the older adult (or their substitute decision-maker). There should be agreement and understanding on how the BZRA is to be used (including planned duration of no more than 2 to 4 weeks) and monitored. BZRAs are high-risk medications in older adults . As a result, their prescription should follow the same principles used with other high-risk medication (please see narrative for recommendations #5 and #7) . Prescriptions should be limited to 14 to 28 days .
# RECOMMENDATION #7:
Older adults who are receiving a BZRA should be: a. Educated and provided the opportunity to discuss the ongoing risks of taking BZRAs.
Awareness among older adults of BZRA risks allows them to make informed decisions and may improve outcomes (Funk, 2004;Say et al ., 2006;Moreau et al ., 2012;Turner & Tannenbaum, 2017) . Pharmacist-led educational interventions consisting of a patient brochure about the risks of BZRAs and alternatives (Tannenbaum et al ., 2014;Martin & Tannenbaum, 2017) coupled with an evidence-based pharmaceutical opinion recommending deprescription that is communicated to the prescribing physician (Martin et al ., 2018) and one-time counselling of patients (Salonoja et al ., 2010) have been shown to decrease the use of BZRAs in community dwelling older adults . BZRA product monographs for the treatment of insomnia recommend short treatment durations (i . e . , 2 to 4 weeks or less) . When BZRAs are used as a bridging medication for anxiety disorders, it may take 4 to 6 weeks for patients to begin to respond to the first-line treatment . Longer-term use should only be considered in exceptional circumstances (e . g . , end-of-life care) . As with any medication, the prescribing health care practitioners must provide appropriate follow-up care . Patients should be monitored for evidence of effectiveness and signs of any complications . Drug therapy should be stopped if it is not effective or the risks of continued use outweigh the benefits . (Salonoja et al ., 2010;Mugunthan et al ., 2011;Soyka, 2017) . Organizational strategies in care facilities that are useful in BZRA reduction include pharmacist-led chart audits, medication reviews, interdisciplinary care conferences, and educational sessions for staff (Westbury et al ., 2010) . Some strategies to improve BZRA prescribing practices have also successfully focused on optimizing the use of other psychotropic medications, such as reducing the use of antipsychotics . (Westbury et al ., 2018) .
# RECOMMENDATION #9:
Health care institutions, including acute care hospitals and long-term care facilities, should implement protocols that minimize new prescriptions for BZRAs because of the potential for harm and the risk of this leading to long-term use following discharge to the community or other transitions in care.
Transitions of care are high-risk periods for older adults . BZRAs are frequently used during hospital admissions, often with the intent of short-term use . However, database studies have found that a small but significant percentage of the long-term use of BZRAs in the community start during hospitalizations .
A Canadian study found that 3 .5% of older hospitalized patients had a BZRA prescription that lasted beyond the hospital stay, with 1 .5% still receiving BZRAs 6 months after discharge (Bell et al ., 2007) . Risks for long-term use included concurrent alcohol use, intensive care unit (ICU) stay, comorbid medical conditions, and use of multiple other medications .
Choosing Wisely Canada (CWC) is a national voice for reducing unnecessary tests and treatments in health care . A Psychiatry CWC recommendation is to avoid routine continued use of BZRAs that were initiated during an acute care hospital admission without a careful review and plan for tapering and discontinuing, ideally prior to hospital discharge . Medication reconciliation (the systematic and comprehensive review of all the medications a patient is taking to ensure that medications being added, changed, or discontinued are carefully evaluated) is a Required Organizational Practice of Accreditation Canada and should be done when older adults are admitted, transferred, and discharged from a health care facility (Accreditation Canada et al . , 2012) . There are a variety of approaches to medication reconciliation . We recommend that it include a comprehensive review of the appropriateness of current medications and development of a management plan related to ongoing use . Such an approach offers opportunities to critically review the indications for BZRAs, consider the risk/benefits of continued use for individual patients, and optimize BZRA use .
# RECOMMENDATION #10:
Health care practitioners, older adults, and their families should advocate for adequate access and funding of effective non-pharmacological alternatives for the management of insomnia, anxiety disorders, and BPSD.
There is good evidence that the first-line treatments for most patients with these conditions are non-pharmacological .
Even when pharmacological treatment is indicated, it should be used along with non-pharmacological interventions . However, there is limited access to and provincial coverage for non-pharmacological treatments, especially if not provided by a physician . Even when provided by a physician, there are often limits placed on the frequency and duration of therapy . Advocacy by individuals, seniors' groups, and national organizations and associations can potentially help to change rules for the provincial funding of non-pharmacological treatments (CMPA, Arya, 2013; . Individual clinicians may suggest to those they care for that they write letters to their Member of Parliament (MP) or provincial representative .
The limitations to access and to funding are unlikely to change without effort from providers, those in need of care, and the organizations that advocate for them .
# RECOMMENDATION #11:
Clinicians should be aware that BZRAs are prescribed more frequently to women and the potential implicit bias that may lead to inappropriate use. Historically, marketing of psychiatric medications has tended to emphasize their use by women . Women are more frequently portrayed in print advertisements for antidepressants or anti-anxiety medications targeted at prescribers (Munce et al ., 2004) . The concept of implicit bias (the attitudes or stereotypes that affect our understanding, actions, and decisions in an unconscious manner) has affected perspectives in a variety of fields, including health care . The association between gender and use of BZRAs has been shown in multiple drug database studies and reports (CIHI, 2018) . Implicit bias may be contributing to this greater likelihood of BZRA use among women in the management of anxiety and insomnia . Clinicians should minimize use of BZRAs regardless of the gender of the person being treated but should be aware of the higher use among women and the potential role of implicit bias in their prescribing practices .
# Recognition and Assessment of BZRA Use Disorder
C linicians may underestimate the likelihood of substance misuse or a substance use disorder among older adults . It is therefore important to conduct a comprehensive history of current and past use of substances, including BZRAs . Although our Guidelines are described in four separate documents, multiple substance use is common . A comprehensive assessment is recommended when substance use disorder is suspected .
# RECOMMENDATION #12:
All older adults should be asked about current and past consumption of substances that might lead to substance use disorders, including BZRAs, during periodic health examinations, admissions to facilities or services, perioperative assessments, when considering the prescription of a BZRA, and at transitions in care.
Substance use (e .g ., alcohol, BZRAs , cannabis, hallucinogens, inhalants, opioids, stimulants, tobacco) is common among older Canadians (Patten, 2018) but often remains unrecognized by their health care providers (Saitz et al ., 1997) . Inquiring about current and prior use of these substances in a nonjudgmental, non-ageist manner will normalize conversations about them and help determine if use is or was present . This information is a necessary first step in the detection of substance use disorders and can aid in the assessment of presentations where their use may be a contributing factor to other medical concerns (e .g ., confusion, falls) . Detection of use can also lead to the avoidance of adverse drug interactions and provide opportunities for education, counselling, and/ or referral of the older adult to treatment programs .
# RECOMMENDATION #13:
Health care practitioners should be aware of and vigilant to the symptoms and signs of substance use disorders, including BZRA use disorder. Particular attention should be paid to this possibility when assessing common conditions encountered in older adults, such as falls and cognitive impairment. Lack of awareness or recognition of BZRA use disorders among both older adults and their clinicians is of concern . Use of DSM-5 criteria are recommended for the detection of a BZRA use disorder (the 11 DSM-5 criteria for BZRA use disorder are listed on page 5 above) . The number of diagnostic criteria present can be used to gauge the severity of the substance use disorder: 2 to 3 indicates mild severity, while 4 to 5 would be indicative of moderate severity, and 6+ would indicate the presence of a severe substance use disorder . There are unique challenges (e .g ., higher likelihood of impaired cognition interfering with ability to self-monitor, sensitivity to BZRAs, changes in activity and role obligations, attributing manifestations to other known health issues) in the diagnosis of a substance use disorder in an older adult using these criteria (Rao & Crome, 2016;Han & Moore, 2018) .
Another diagnostic system used in some countries is the International Classification of Diseases (ICD-10), which separates Harmful Use from Dependence . The latter includes cravings, tolerance, evidence of withdrawal, difficulties controlling use, neglect of alternative pleasures or interests, and persisting use despite evidence of harm . The fiveitem Severity of Dependence Scale is a recommended instrument for the detection of BZRA psychological dependency in the community (de las Cuevas et al ., 2000) .
A single screening question ("How many times in the past year have you used an illegal drug or used a prescription medication for non-medical reasons?") was validated for the detection of substance use disorders in an American primary care setting (Smith et al ., 2010), but is not recommended for use in Canada prior to testing in our country . A two-question pre-screen (a positive response to either having tried to cut down or having used more than intended over the last year) has been suggested as a way to detect individuals who require a more in-depth assessment for a possible substance use disorder (Schonfeld et al ., 2015) .
# RECOMMENDATION #14:
Assessment of older adults suspected of having a BZRA use disorder should include indication, dose, duration, features indicative of BZRA use disorder, readiness to change, and presence of both medical and psychiatric comorbidities, including any other past or current substance use or misuse.
The assessment should be done in a nonjudgmental, nonageist manner, taking into account the values and experiences of the older adult (Royal College of Psychiatrists, 2015) . A systematic evaluation of BZRA use as well as the characteristics of the older adult, including their environment are required . Inquiry about the BZRA would include onset of consumption, indication(s) for use, name of agent(s), manner taken (dose, route, duration), how BZRA was obtained (including whether aberrant drug-taking behaviours are present), pattern of intake (e .g ., escalating vs . stable), and use of other substances .
The presence of substance use disorder criteria, severity of the disorder (if present), prior interventions, and readiness to change should also be determined . The characteristics of the older adult that must be noted include age, gender, personal and family psychiatric history (including past history of substance use disorders), medical history (including potential BZRA adverse effects, such as anterograde amnesia, inattention, delirium, disinhibition, sedation, motor impairment, imbalance, and falls), other medication use (including potential adverse interactions), intake of caffeine, and functional status (Griffin et al ., 2013) .
Patient assessment should include vital signs, indications of possible withdrawal, focused physical examination including balance and gait, and a mental status exam including an objective brief assessment of cognition . Living arrangements (including stability) and social support, both currently and potentially available, should be determined . When possible, collateral information should be obtained (J . Brett & Murnion, 2015) . The information gathered should then be used to construct a treatment plan with the older adult . Among U .S . veterans, more than 25% of those with one substance use disorder had an additional substance use disorder (Bhalla et al ., 2017) . Rounsaville et al . (2003) wrote in their review of the topic that, "Substance abusing patients who exclusively abuse a single substance have become progressively scarce and unrepresentative of the general population of substance abusers in community and clinical settings" . Narcotic overdoses are significantly more likely to occur if an opioid is combined with a BZRA (Karaca-Mandic et al ., 2017;Sun et al ., 2017) . In the United States, benzodiazepines are present in more than 30% of overdoses involving prescription opioids (Karaca-Mandic et al ., 2017) . There is also a higher mortality rate with an opioid overdose if the two are combined (Dasgupta et al ., 2016) . The Center for Disease Control and Prevention (CDC) 2016 Guideline for prescribing opioids for chronic pain recommends avoidance of concurrent prescription of opioid pain medication and benzodiazepines whenever possible (Dowell et al ., 2016) . Canadian guidelines on the management of chronic noncancer pain state that opioids and benzodiazepines should be prescribed together only rarely (Busse et al ., 2017) . Alcohol can potentiate and worsen sedation when combined with a variety of medications, including BZRAs . As with opioids, there are observational studies that suggest that the combination of alcohol and benzodiazepines is common among patients who are admitted with overdoses and is associated with a higher risk of death (Koski et al ., 2003;Jones et al ., 2014;Zanjani et al ., 2016) .
# Management of BZRA Use Disorder
T his section focuses on the management of individuals who have developed a BZRA use disorder . Even without evidence of a BZRA use disorder, clinicians will often wish to deprescribe BZRAs in older patients because of the risk of side effects . Many of the recommendations in this section of the document, such as those focusing on gradual dose reduction, are also relevant to this group .
# RECOMMENDATION #16:
A person-centred, stepped-care approach to enable the gradual withdrawal and discontinuation of BZRAs should be used. Clinicians and patients should share in: a) planning and applying a gradual dose reduction scheme supported by appropriate education of the patient; b) identifying and optimizing alternatives to manage the underlying health issue(s) that initiated or perpetuated the use of BZRAs; c) developing strategies to minimize acute withdrawal and managing rebound symptoms as needed; and d) establishing a schedule of visits for reviewing progress. A stepped care approach to deprescribing BZRAs, starting with brief interventions and then progressing to multicomponent approaches, was pioneered by Lader and Russel (1993) and remains the standard of care (Lingford-Hughes et al ., 2012) . The stepped care approach emphasizes patient involvement in developing and modifying the treatment plan . Jansen and colleagues summarize the importance of shared decision-making in reducing inappropriate drug therapy in older adults, highlighting the need to respect patient goals and values (Jansen et al ., 2016) . A large study of older adult BZRAs users given instructions to reduce use coupled with a lecture about risks by a geriatrician revealed a sustained decrease in regular use by 35% (Salonoja et al ., 2010) .
Self-efficacy (an individual's belief in their ability to achieve goals) is a predictor of adherence with a tapering protocol (Belanger et al . , 2005) . Canadian print and online educational resources include the Sleepwell website, deprescribing . org, and the Canadian Deprescribing Network . A Canadian guideline on deprescribing BZRAs used primarily for insomnia was published recently (Pottie et al . , 2018) .
Gradual dose reduction (GDR) is the central tenet in discontinuing long-term BZRA use . A pharmacist working together with the older adult and prescriber can assist in the development of a practicable dose reduction plan, making modifications as necessary . Establishing a plan is required for regular meetings to both monitor progress of deprescription and assess and manage underlying health issue(s) that may have instigated or perpetuated BZRA use . An approach to overcoming resistance is important and can include: involving the family, explaining that tapering is a therapeutic trial that can be halted, and emphasizing that tapering often results in the person having better mood, energy, and function, with reduced risk of falls and other adverse events .
# RECOMMENDATION #17:
Abrupt discontinuation of a BZRA after intermediate to long-term use (> 4 weeks) in individuals with BZRA use disorder should be avoided due to the risk of withdrawal symptoms, substance dependence reinforcement, rebound phenomena, and/or higher likelihood of relapse with resumption of BZRA use. BZRA withdrawal is characterized by a constellation of physical, emotional, and cognitive symptoms that range in severity . They include hypertension, tachycardia, agitation, depressive or anxiety symptoms, tremor, headache, and paresthesias . Less commonly, they include psychosis, depersonalization, delirium, seizures, and rarely death (Hoffman et al ., 2014) . Onset varies with the elimination half-life of the BZRA (1 to 2 days for short-acting agents and up to several weeks for longacting ones) (Naranjo et al ., 1981;Greenblatt et al ., 1983;Leslie & Inouye, 2011;White et al ., 2012;Hoffman et al ., 2014) . A small number of patients may experience a protracted withdrawal syndrome lasting months .
As a result of age-related decreases in drug clearance, withdrawal symptoms may be less acute in older adults (Schweizer et al ., 1989;Cantopher et al ., 1990), but these individuals may be more prone to cognitive effects such as confusion (Foy et al ., 1986) . Risk factors for BZRA withdrawal include greater daily doses of the BZRA, use of short-acting agents, and chronic sustained use . Symptoms of depression and anxiety, less education, and certain personality traits increase the risk of severe withdrawal symptoms (Rickels et al ., 1990;Nelson & Chouinard, 1999) . The greater prevalence of cardiovascular disease and cognitive impairment among older adults predisposes them to experiencing delirium or demand-related cardiovascular ischemia during withdrawal, especially in the postoperative setting (Biswas et al ., 2005;Brown & Deiner, 2016) . Older adults with BZRA use disorders may require increased doses of anaesthetic agents for induction (White et al ., 2012;Moran et al ., 2015) .
Supervised GDR is the preferred tapering strategy . The ideal rate of tapering has not been established, although initially decreasing the dosage by 10% to 25% every 1 to 2 weeks is a reasonable strategy for most older adults, though the type of BZRA, dosage used, and duration of therapy will influence this . With GDR, withdrawal symptoms are usually mild or absent (Paquin et al ., 2014;Ng et al ., 2018;Pottie et al ., 2018) .
Various rates of tapering have been studied but not compared head-to-head . During the earlier stages of withdrawal, dose reductions are generally better tolerated than in the latter stages, when the pace of tapering may have to be slowed . It may take up to 6 months to successfully wean an older adult off a BZRA (Lader & Russell, 1993;Voshaar et al ., 2006;Lingford-Hughes et al ., 2012;RACGP, 2017) .
Please see Table 1 for suggestions on tapering . Knowing the indication for the BZRA may aid in the identification of likely relapse symptoms . Inpatient admission should be a consideration for patients withdrawing from very high doses .
Patients who have had a short duration of use or have been taking very low dosage of a BZRA may not require tapering . (Busto et al ., 1986;Tyrer et al ., 1990;Rickels et al ., 2008) . While these scales have been used to monitor older patients in deprescribing programs and clinical trials, they have not been specifically validated among adults at an advanced age or those with cognitive impairment . In order to manage distressing symptoms during withdrawal, judicious use of a BZRA guided by symptoms may be required .
# RECOMMENDATION #19:
Regimens involving multiple BZRAs should be simplified and converted to a single BZRA. The risks (e .g ., adverse drug events, non-adherence, drug interactions) of the simultaneous use of multiple medications in older people are well documented (Cooper et al ., 2015) . Therapeutic duplication (i .e ., concurrent use of more than one drug from a class) represents potentially inappropriate medication use . The concurrent consumption of multiple BZRAs can result in exaggerated pharmacological effects, unintended overdosing, and other potential adverse reactions . While concurrent use of two or more BZRAs may be intentional, it often arises when patients have multiple prescribers and/or pharmacies . In an effort to minimize the risk of adverse effects and also to set the stage for an attempt to wean the older adult off BZRAs, it is recommended that multiple BZRA regimens be simplified to the use of a single BZRA . This will require a dosage of the BZRA used that is equipotent to the sum of the multiple BZRAs that the older adult had been taking (Ashton, 2007) . Various BZRA equivalency tables are available in print and online, for example: .benzo . org .uk/bzequiv .htm .
# RECOMMENDATION #20:
The routine switching of a short half-life BZRA with one having a long half-life to aid in withdrawing BZRAs is not generally recommended in older adults. Switching may have a role in certain situations, such as when withdrawal is being hindered by a limited number of available BZRA pill strengths or when alprazolam is the agent of dependence or misuse. There is limited evidence to support switching from a shortto a long half-life BZRA before beginning GDR (Denis et al ., 2006) . It may be useful if reduction of the short half-life BZRA causes problematic withdrawal symptoms . Avoidance of routine replacement with long half-life BZRA is prudent in older adults because they are prone to drug accumulation with long half-life agents due to age-related changes in pharmacokinetic processes . Alprazolam is considered to have some unique properties that increase its misuse liability (Ait-Daoud et al ., 2018) . As a result, it should be tapered very slowly, and substitution with a longer halflife BZRA, such as clonazepam could be considered with this drug . Advice from a specialty service may be required in dealing with alprazolam, especially if it has been used at a high dose and/or a prolonged period of time . Gould et al . (2014) found odds ratios for not using benzodiazepines at the completion of the intervention and then 3 and 12 months afterwards of 5 .06, 3 .90, and 3 .00, respectively, when GDR was combined with psychological interventions (Gould et al ., 2014 .) Systematic reviews by Reeve (2017) and Paquin (2014) provided similar support . A Cochrane Review (Darker et al ., 2015) of mixed-age benzodiazepine users reported that GDR plus CBT was more likely to result in discontinuation of benzodiazepines at the completion of treatment (relative risk 1 .40) and at 3-month follow-up (RR 1 .51) but with unclear longer-term benefits .
Research to date has focused on benzodiazepines . It is likely similar benefits would apply to withdrawal from z-drugs, but this requires extrapolation from the available data . There are few (if any) potential risks, durable effects beyond the end of the intervention, and secondary benefits (i .e ., dealing with emotional distress, sleep, quality of life) . Access, feasibility in individuals with moderate-to-severe cognitive impairment, and the need for a motivated patient may be limiting . Further work is needed to better define the specific cognitive and/or behavioural elements that are most beneficial .
# RECOMMENDATION #22:
Substituting a pharmacologically different drug as a specific intervention to mitigate BZRA withdrawal symptoms during gradual dose reduction is not routinely recommended.
Adding a pharmacologically different medication when withdrawing a BZRA has been studied in a small number of trials involving older adults . Melatonin, trazodone, carbamazepine, paroxetine, divalproex, buspirone, and progesterone have been examined as agents either prescribed on a temporary or permanent basis (Gould et al ., 2014;Paquin et al ., 2014;Wright et al ., 2015;Reeve et al ., 2017) . Their routine use cannot be recommended because of the lack of consistent benefit and the heterogeneity of these studies .
Other considerations include potential toxicity of replacement agents, risks of polypharmacy, and misalignment with the desire of most patients to avoid unnecessary medications . Gabapentinoids (gabapentin and pregabalin) have been considered potentially helpful because they are GABA analogs . However, they cannot be recommended, as they have not been well-studied in BZRA withdrawal (Fluyau et al ., 2018) . These drugs are not approved for the indication of BZRA withdrawal and carry their own risk for misuse (Mayor, 2018;Peckham et al ., 2018) .
A recent review (Markota et al ., 2016) advises against the routine use of another pharmacological agent to support efforts to discontinue BZRAs . The British Association for Psychopharmacology (Lingford-Hughes et al ., 2012) likewise cautions against routinely using another drug but notes that this can be considered for individual patients . The use of pharmacologically distinct medications may be appropriate when being used for the treatment of an ongoing condition that instigated or is perpetuating the use of the BZRA .
# RECOMMENDATION #23:
Older adults with a BZRA use disorder whose drug use is escalating in spite of medical supervision, have failed prior efforts to withdraw their BZRA, are at high risk for relapse or harm, and/or suffer from significant psychopathology should be considered for referral to a specialty addiction or mental health service.
Many older adults with BZRA use disorders can be successfully treated as outpatients in a primary care setting . Those who have failed previous attempts of withdrawal or are at high risk of relapse, including individuals with severe concurrent psychopathology, should be referred for specialty care (Lader & Russell, 1993;Welsh Government, 2011;Paquin et al ., 2014;Yokoi et al ., 2014;J . Brett & Murnion, 2015) . The ideal specialty program would take a holistic interdisciplinary approach consisting of medical, addiction, and psychiatric expertise, with access to support from pharmacists, case managers, and peer support workers working collectively to translate the treatment plan into action . Unfortunately, few centres can offer such a comprehensive "one-stop" service, able to address the unique needs of older adults . In the treatment of concurrent disorders, addiction and mental health conditions should be treated in parallel as opposed to sequentially . Strategies such as very short dispensing periods or daily witnessed ingestion may be helpful for patients who have significant difficulty controlling their intake of BZRAs . Individuals withdrawing from high doses of BZRAs or multiple substances, those who are physically frail, and those who lack community supports should be considered for inpatient treatment in a suitable facility .
# Ethical Challenges in Deprescribing
C linical Practice Guidelines (CPGs) can inform appropriate care but do not, in isolation, define it (College of Physicians & Surgeons of Ontario (CPSO, 2017) . Good care can deviate from CPGs given the nuances and complexities of individual cases . An older adult's perception of the balance between benefits versus risks of BZRA use is dependent upon being fully informed of such considerations and alternatives by their physician . The older adult's personal values and other factors further delineate the clinician's assessment of whether withdrawal of the BZRA is indicated .
Proposing that a BZRA be discontinued may be met with resistance, particularly when the older adult perceives the BZRA to be beneficial . The perception of benefit is likely related to the degree to which the older adult was impacted by the original target symptoms, as well as the degree to which these symptoms improved with the BZRA . The clinician must consider the possibility of harm from continued use, which would include the development of a substance use disorder arising from the BZRA . Although avoiding or discontinuing the long-term use of a BZRA is in general the recommended course of action for the majority of older adults, it does not follow that this is indicated for each individual . Discontinuing a medication is an active intervention, the ethics of which can be informed by several bioethical models . Shared decision-making should incorporate clinical judgment, patient values, and lived experience but must also be made within the confines of professional standards of practice .
After considering all perspectives, if the clinician believes that the harms of continuing BZRA therapy significantly outweigh the benefits, deprescribing should be actively encouraged and adopted . Prescribers who are uncomfortable continuing to prescribe a BZRA to an older adult do not have a duty to do so, as it is ethically indefensible to provide treatment against sound medical judgement, though it is emphasized that discontinuing a BZRA being used long-term should never be done abruptly (Weijer et al ., 1998;Lantos et al ., 2011;A . Brett & McCullough, 2012;Kapoor et al ., 2018) .
# Future Directions
C oncern about the risks of BZRAs for older adults has grown in recent years . The developers of these guidelines hope to inspire prescribers and health care team members, as well as older adults and their families, to consider, implement, and support alternatives to these medications . This document bridges the gap between knowledge and practice and is designed to facilitate change at personal, institutional, and system levels .
These guideline developers advocate for integration of policies and specialized clinical education that supports progressive models of care, to empower older adults to participate in shared decision-making when the prescribing and deprescribing of BZRAs is being considered . It is also important to ensure access to clinicians who are able to offer non-pharmacological therapies such as CBT and CBTi to older adults, in order to both prevent the inappropriate use of BZRAs and to aid those who are experiencing symptoms of a substance use disorder . We encourage hospitals, other health care facilities, community-based agencies, and their quality improvement teams to routinely explore the impact of care transitions on prescribing patterns . The health care system is striving to provide holistic, personcentred care to older adults with substance use disorders . However, more education is required to support primary care physicians and other clinicians caring for these individuals . Unfortunately, in some regions of Canada, access to specialized addiction and/or mental health services for older adults is limited or non-existent . To this end, we encourage the development of comprehensive, evidence-based, interprofessional models of care that support the full scope of practice of all team members . It is important to emphasize that more research is needed to determine the optimal treatment and models of care for older adults with substance use disorders (Lehmann & Fingerhood, 2018) . Over time, it will be increasingly important to develop systems of care able to meet the complex health needs of diverse groups of older adults, including the growing number of baby boomers .
The CCSMH welcomes your feedback and requests both your support and active participation in the wide dissemination of these important guidelines .
We would also like to thank Dr. Simon Davies, Dr. Barbara Farrell, Dr. Meldon Kahan and Dr. Karen Reimers for their support in reviewing the guideline documents and providing clinical perspective to the CCSMH.
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We would like to thank Canadian Centre on Substance Use and Addiction and the Behavioural Supports Ontario Substance Use Collaborative for their support and contributions throughout the development of the Guidelines and Tonya Mahar (Manager, Library Services, Baycrest) for her assistance with literature searches. Finally the CCSMH would like to acknowledge the continued dedication of its Steering Committee members and the outstanding contributions of our Director,#
This publication is intended for information purposes only, and is not intended to be interpreted or used as a standard of medical practice. Best efforts were used to ensure that the information in this publication is accurate; however the publisher and every person involved in the creation of this publication disclaim any warranty as to the accuracy, completeness or currency of the contents of this publication. This publication is distributed with the understanding that neither the publisher nor any person involved in the creation of this publication is rendering professional advice. Physicians and other readers must determine the appropriate clinical care for each individual patient on the basis of all the clinical data available for the individual case. The publisher and every person involved in the creation of this publication disclaim any liability arising from contract, negligence, or any other cause of action, to any party, for the publication contents or any consequences arising from its use. The views expressed herein do not necessarily represent the views of Health Canada.
We encourage the copy and distribution of these guidelines; provided that the appropriate attribution is given. Please see the suggested citation below.
# Suggested citation: Canadian Guidelines on
Benzodiazepine Receptor Agonist Use Disorder Among Older Adults. Canadian Coalition for Seniors ' Mental Health, Toronto, Canada (2019) Funding for the CCSMH Substance Use Disorder Guidelines was provided by Health Canada, Substance Use and Addictions Program. The CCSMH gratefully acknowledges Health Canada for its ongoing support and continued commitment to the area of seniors' mental health.
In addition, special thanks to the Co-Leads and individual working group members who dedicated countless number of hours and engaged in the creation of guidelines and recommendations.
Benzodiazepine Receptor Agonists: Drugs referred to as BZRAs act as allosteric modulators of gammaaminobutyric acid (GABA) activity by binding to inotropic benzodiazepine receptors at the GABA A receptor complex . BZRAs increase GABA binding and chloride ion channel opening, facilitating inhibitory activity . Some of these drugs have a benzodiazepine chemical structure (i .e ., alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam) while others, referred to as non-benzodiazepine receptor agonists, novel benzodiazepine receptor agonists, or z-drugs (i .e ., zolpidem, zopiclone), do not . We use the term BZRAs for both . Our recommendations deal with all BRZAs as they have similar benefits, side effects, and risks . These drugs have regulatory approval for the management of anxiety and panic disorders, short-term treatment of insomnia, seizures, alcohol withdrawal, sedation, and spasticity . They are also often used in an off-label manner (i .e ., any use of a drug beyond what Health Canada has reviewed and authorized to be marketed in Canada and as indicated on the product label), for example to treat anxious depression or the behavioural and psychological symptoms of dementia (BPSD), which are also described as responsive behaviours .
# Definition of Key Terms
BZRA Use Disorder: This refers to a problematic pattern of BZRA use leading to clinically significant impairment or distress . According to DSM-5 criteria BZRA use disorder is manifested by at least two of the criteria below occurring within a 12-month period (American Psychiatric Association, 2013) . It is important to note that among older adults, some of these criteria may be modified by the aging process or their social roles (e .g ., retirement from work), resulting in more subtle presentations (Kuerbis et al ., 2014) .
✚ The BZRA is taken in larger amounts or over a longer period of time than intended .
✚ Persistent desire or unsuccessful efforts to cut down or control BZRA use .
✚ A great deal of time is spent in activities to obtain BZRAs, use them, or recover from their effects .
✚ Craving, or a strong desire or urge to use a BZRA .
✚ Recurrent BZRA use resulting in a failure to fulfill major role obligations at work, school, or home .
✚ Continued use of the BZRA despite persistent or recurrent social or interpersonal problems caused or exacerbated by their effects .
✚ Important social, occupational, or recreational activities are given up or reduced because of BZRA use .
✚ Recurrent BZRA use in situations in which it is physically hazardous .
✚ Continued use of the BZRA despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by drug use .
✚ Tolerance as defined by either a need for markedly increased amounts of the BZRA to achieve intoxication or desired effect OR a markedly diminished effect with continued use of the same amount of the BZRA (note: criterion not considered to be met for an individual taking the drug under medical supervision) .
✚ Withdrawal as manifested by either characteristic withdrawal symptoms (i . e . , autonomic hyperactivity, hand tremor, insomnia, nausea or vomiting, transient sensory hallucinations or illusions, psychomotor agitation, anxiety, and/or seizures) OR the BZRA (or a closely related substance such as alcohol) is taken to relieve or avoid withdrawal symptoms .
# Diagnosis
✚ 1 symptom or less, no diagnosis ✚ 2-3 symptoms, mild BZRA Use Disorder ✚ 4-5 symptoms, moderate BZRA Use Disorder ✚ 6 or more symptoms, severe BZRA Use Disorder Remission ✚ 3-12 months with no criteria other than craving is considered early remission .
✚ More than 12 months is considered sustained remission .
# Summary of Recommendations and Grades
W e used the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation) as a method of grading the quality of evidence and the strength of recommendations . In following the GRADE process, the initial step was to grade the quality of available evidence supporting each recommendation . Subsequently, we identified the overall strength of the recommendation taking into account the quality of the evidence but also other factors such as the potential to do harm, the cost and feasibility .
We have also developed a separate category for recommendations which are not primarily based on empirical evidence; but have agreement that they represent best clinical practice . Examples would include: optimal assessment processes and those related to education and/or policy . These recommendations have been categorized as "C" for consensus . We did not use the GRADE process for these recommendations . Other guideline groups have used a similar approach e .g . British Association for Psychopharmacology Guidelines (Lingford-Hughes et al ., 2012) . While such recommendations lack empirical evidence, we believe they are also useful and important . The quality of evidence for each recommendation is determined through an examination of the following factors: (1) Study design and the quality of the studies that were included, (2) the directness of the evidence (generalizability or applicability) and
(3) the confidence that patients will benefit from the treatment .
The strength of each recommendation is determined through an examination of the following factors:
(1) The balance between benefits and undesirable effects/ risks, (2) uncertainty or variability of patient values and preferences and (3) the resources associated with management options .
# GRADE
# QUALITY OF EVIDENCE
# STRENGTH OF RECOMMENDATION
# HIGH
Further research is unlikely to change confidence in the estimate of effect
# MODERATE
Further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate
# LOW
Further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate
# STRONG
Strong recommendations indicate high confidence that desirable consequences of the proposed course of action outweigh the undesirable consequences or vice versa .
# WEAK
Weak recommendations indicate that there is either a close balance between benefits and down sides (including adverse effects and burden of treatment), uncertainty regarding the magnitude of benefits and down sides, uncertainty or great variability in patients' values and preferences, or that the cost or burden of the proposed intervention may not be justified .
(adapted from Guyatt et al, 2008) RECOMMENDATION #1:
# RECOMMENDATION #4:
An assessment of risk for BZRA use disorder and other potential adverse effects from these agents should be done prior to prescribing a BZRA.
[Consensus]
# RECOMMENDATION #5:
If a BZRA is being considered, the older adult should be informed of both the limited benefits and risks associated with use, as well as alternatives, prior to deciding on a management plan.
[Consensus]
# RECOMMENDATION #6:
Initiating treatment with a BZRA should be a shared decision between the prescriber and the older adult (or their substitute decision-maker). There should be agreement and understanding on how the BZRA is to be used (including planned duration of no more than 2 to 4 weeks) and monitored.
[Consensus]
# RECOMMENDATION #7:
Older adults who are receiving a BZRA should be:
a. Educated and provided the opportunity to discuss the ongoing risks of taking BZRAs.
# RECOMMENDATION #23:
Older adults with a BZRA use disorder whose drug use is escalating in spite of medical supervision, have failed prior efforts to withdraw their BZRA, are at high risk for relapse or harm, and/or suffer from significant psychopathology should be considered for referral to a specialty addiction or mental health service.
[Consensus] D espite consensus that benzodiazepine receptor agonists (BZRAs) should be avoided whenever possible in older adults (Kuhn-Thiel et al ., 2014;American Geriatrics Society, 2019), clinicians continue to frequently prescribe these medications in this patient population . Recent Canadian data suggest high rates of use persist among older adults, especially females, with 18 .7% of females reporting past-year use (Statistics Canada, 2016) . There is evidence, however, that the overall rate of use of BZRAs is gradually dropping in Canada . Davies et al . (2018) reported that the prescription rate for benzodiazepines among Ontario residents aged 65 and over declined from 23 .2% in 1998 to 14 .9% in 2013 . A Quebec study of older adults reported that 9 .5% of those taking benzodiazepines met Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for substance dependence (Voyer et al ., 2010) .
S trategies to prevent BZRA use disorder include avoiding the initial prescription of BZRAs, particularly if consumption of these agents would place the older adult at high risk for harm, and following good prescribing practices when they are used . Informed older patients and well-trained prescribers, supported by a health care system that offers ready access to nonpharmacological alternatives, are required to achieve these aims .
# Minimizing BZRA Use and Preventing BZRA Use Disorder
# RECOMMENDATION #1:
Long-term use of BZRAs (> 4 weeks) in older adults should be avoided for most indications because of their minimal efficacy and risk of harm. Older adults have increased sensitivity to BZRAs and decreased ability to metabolize some longer-acting agents, such as diazepam. All BZRAs increase the risk of cognitive impairment, delirium, falls, fractures, hospitalizations, and motor vehicle crashes. Alternative management strategies for insomnia, anxiety disorders, and the behavioural and psychological symptoms of dementia (BPSD) are recommended.
[GRADE: Evidence: Moderate; Strength: Strong] BZRAs are not first-line agents for the treatment of anxiety, insomnia, or BPSD in older adults because of their minimal efficacy and concerns about adverse effects (el-Guebaly et al ., 2010;Vaapio et al ., 2015;Gage, 2016;Jansen et al ., 2016) . These drugs are included in commonly used lists of medications to avoid in older adults (Hamilton et al ., 2011;Kuhn-Thiel et al ., 2014;American Geriatrics Society, 2019) .
Age-related changes in pharmacokinetics and pharmacodynamics result in a greater risk of adverse effects with BZRAs in older adults at doses lower than cited as effective (Tamblyn et al ., 2005;Vaapio et al ., 2015) . Adverse effects include falls, fractures, cognitive impairment, delirium, incontinence, respiratory depression, and unplanned hospitalization (American Geriatrics Society, 2009;Assem-Hilger et al ., 2009;Lin et al ., 2017) . BZRAs can also negatively affect driving skills and are associated with higher motor vehicle crash rates at all ages (Leufkens & Vermeeren, 2009;Kang et al ., 2012) .
Prescribers need to be aware of how frequently and quickly dependency on BZRAs can develop . As many as 15% of regular users have been found to be dependent after 4 months and 50% after 2 years of use, with some sources citing even higher rates (el-Guebaly et al ., 2010) . Efforts to reduce physiological dependency would include minimizing dosages, prescribing only for short periods of time, and/or only using intermittently (Ibid) . It should be noted that there are a few conditions, such as REM sleep disorder, for which longer-term use of a BZRA might be appropriate (Aurora et al ., 2010) .
# RECOMMENDATION #2:
Appropriate first-line non-pharmacological options for the treatment of insomnia and anxiety disorders include cognitive behaviour therapies (CBTs) provided in various formats. [GRADE: Evidence: Moderate; Strength: Strong] Both the American College of Physicians ( 2016) and the European Sleep Research Society (2017) recommend CBT for insomnia (CBTi) as the first-line treatment for insomnia, with BZRAs and other sedative-hypnotics reserved for use in patients who fail to benefit from CBTi (Qaseem et al ., 2016;Riemann et al ., 2017) . This recommendation is based on the results of numerous randomized controlled trials involving a wide range of patients (including older adults with multiple comorbidities) and the poor risk/benefit ratio of pharmacotherapies for insomnia . Both CBTi provided by a therapist (individually or as a group) or using a selfhelp approach (e .g ., CBTi-based books, online services, and apps) has been shown to be effective . Sleepwell (Sleepwell . ca, 2018) provides information about and links to selfhelp CBTi resources . Simple sleep hygiene approaches can be attempted, although the evidence in support of this approach is limited and equivocal (Irish et al ., 2015) .
A meta-analysis by Hendricks et al . (2008) showed that CBT provided in a group or individually is an effective treatment for anxiety (Hendriks et al ., 2008;Ursuliak et al ., 2008;Soyka, 2017) . Enhanced CBT modifies the standard approach to CBT to better meet the needs of an older population (Mohlman et al ., 2003;Cassidy & Rector, 2008;Ursuliak et al ., 2008) and significantly improves measures of depression, anxiety, and quality of life in depressed and anxious seniors (Ursuliak et al ., 2008) . Exposure and response prevention can be used in CBT to reduce anxiety symptoms and redress the underlying avoidance that perpetuates anxiety disorders (Davis et al ., 2012) .
# RECOMMENDATION #3:
A BZRA should only be considered in the management of insomnia or anxiety after failing adequate trials of nonpharmacological interventions or safer pharmacological alternatives OR for short-term bridging until more appropriate treatment becomes effective.
[GRADE: Evidence: Moderate; Strength: Strong] The most effective approach to minimizing BZRA use disorders is avoiding their use . Strategies for this include: primary prevention of conditions in which BZRAs are often prescribed (e .g ., insomnia, anxiety disorders, and depressive disorders); greater use of non-pharmacological alternatives; preferential use of recommended first-line pharmacological treatments for anxiety and depression; and, ongoing education about the risks of BZRA use (Glass et al ., 2005;Sithamparanathan et al ., 2012;Gage, 2016) .
Antidepressants (Selective serotonin reuptake inhibitors [SSRIs] and Serotonin and norepinephrine reuptake inhibitors [SNRIs]) are recommended first-line pharmacotherapy for anxiety and depressive disorders in older adults (Katzman et al ., 2014;Kok, 2014;Thorlund et al ., 2015) . BZRAs are not recommended for these indications other than for short-term use to relieve severe anxiety (Qaseem et al ., 2016) . As noted, insomnia should not be treated with BZRAs or other sedative-hypnotics options unless more effective and safer non-pharmacological options have been tried and shown to be ineffective . The 2017 practice guideline by the American Academy of Sleep Medicine for the pharmacological treatment of insomnia provides no strong recommendation for any medication currently approved or commonly used to treat insomnia in the United States (Qaseem et al ., 2016;Riemann et al ., 2017) .
# RECOMMENDATION #4:
An assessment of risk for BZRA use disorder and other potential adverse effects from these agents should be done prior to prescribing a BZRA. [Consensus] Awareness of risk factors for developing dependence on a BZRA and BZRA use disorder can help avoid inappropriate use . Identified risk factors include: older age, female gender, dependent personality, and concurrent or previous substance use disorder (Gage, 2016) . As the dose of BZRA can affect the likelihood of success with tapering (more likely if < 10 mg diazepam equivalent/day equivalent), use of lower doses might help decrease rates of BZRA use disorders overall (J . Brett & Murnion, 2015) .
# RECOMMENDATION #5:
If a BZRA is being considered, the older adult should be informed of both the limited benefits and risks associated with use, as well as alternatives, prior to deciding on a management plan. [Consensus] Awareness of the risks of BZRAs is important both for patients and prescribers (Cook et al ., 2007;Canham et al ., 2014) . Patient knowledge has been shown to correlate with successful tapering of medications, while the attitudes and skills of primary care physicians have an impact on efforts to reduce doses among chronic users of BZRAs . Lack of awareness of the risks of use can limit efforts to optimize use and lead to delayed recognition of use disorder and other adverse effects, such as fatigue, falls, and depression . Older patients are less likely to recognize dependency or bring concerns to their physicians, whose own lack of awareness might make it even more difficult to identify the presence of a disorder (Kuerbis et al ., 2014) . It is recommended that clinicians offer patients education about the risks of BZRAs and make greater use of non-pharmacological and alternative pharmacological therapies . Physicians often describe having limited skills in reducing BZRA dosages or knowledge of alternative treatments (Cook et al ., 2007) .
# RECOMMENDATION #6:
Initiating treatment with a BZRA should be a shared decision between the prescriber and the older adult (or their substitute decision-maker). There should be agreement and understanding on how the BZRA is to be used (including planned duration of no more than 2 to 4 weeks) and monitored. [Consensus] BZRAs are high-risk medications in older adults . As a result, their prescription should follow the same principles used with other high-risk medication (please see narrative for recommendations #5 and #7) . Prescriptions should be limited to 14 to 28 days .
# RECOMMENDATION #7:
Older adults who are receiving a BZRA should be: a. Educated and provided the opportunity to discuss the ongoing risks of taking BZRAs.
[GRADE: Evidence: Moderate; Strength: Strong]
Awareness among older adults of BZRA risks allows them to make informed decisions and may improve outcomes (Funk, 2004;Say et al ., 2006;Moreau et al ., 2012;Turner & Tannenbaum, 2017) . Pharmacist-led educational interventions consisting of a patient brochure about the risks of BZRAs and alternatives (Tannenbaum et al ., 2014;Martin & Tannenbaum, 2017) coupled with an evidence-based pharmaceutical opinion recommending deprescription that is communicated to the prescribing physician (Martin et al ., 2018) and one-time counselling of patients (Salonoja et al ., 2010) have been shown to decrease the use of BZRAs in community dwelling older adults . BZRA product monographs for the treatment of insomnia recommend short treatment durations (i . e . , 2 to 4 weeks or less) . When BZRAs are used as a bridging medication for anxiety disorders, it may take 4 to 6 weeks for patients to begin to respond to the first-line treatment . Longer-term use should only be considered in exceptional circumstances (e . g . , end-of-life care) . As with any medication, the prescribing health care practitioners must provide appropriate follow-up care . Patients should be monitored for evidence of effectiveness and signs of any complications . Drug therapy should be stopped if it is not effective or the risks of continued use outweigh the benefits . (Salonoja et al ., 2010;Mugunthan et al ., 2011;Soyka, 2017) . Organizational strategies in care facilities that are useful in BZRA reduction include pharmacist-led chart audits, medication reviews, interdisciplinary care conferences, and educational sessions for staff (Westbury et al ., 2010) . Some strategies to improve BZRA prescribing practices have also successfully focused on optimizing the use of other psychotropic medications, such as reducing the use of antipsychotics . (Westbury et al ., 2018) .
# RECOMMENDATION #9:
Health care institutions, including acute care hospitals and long-term care facilities, should implement protocols that minimize new prescriptions for BZRAs because of the potential for harm and the risk of this leading to long-term use following discharge to the community or other transitions in care. [GRADE: Evidence: Low; Strength: Strong]
Transitions of care are high-risk periods for older adults . BZRAs are frequently used during hospital admissions, often with the intent of short-term use . However, database studies have found that a small but significant percentage of the long-term use of BZRAs in the community start during hospitalizations .
A Canadian study found that 3 .5% of older hospitalized patients had a BZRA prescription that lasted beyond the hospital stay, with 1 .5% still receiving BZRAs 6 months after discharge (Bell et al ., 2007) . Risks for long-term use included concurrent alcohol use, intensive care unit (ICU) stay, comorbid medical conditions, and use of multiple other medications .
Choosing Wisely Canada (CWC) is a national voice for reducing unnecessary tests and treatments in health care . A Psychiatry CWC recommendation is to avoid routine continued use of BZRAs that were initiated during an acute care hospital admission without a careful review and plan for tapering and discontinuing, ideally prior to hospital discharge . Medication reconciliation (the systematic and comprehensive review of all the medications a patient is taking to ensure that medications being added, changed, or discontinued are carefully evaluated) is a Required Organizational Practice of Accreditation Canada and should be done when older adults are admitted, transferred, and discharged from a health care facility (Accreditation Canada et al . , 2012) . There are a variety of approaches to medication reconciliation . We recommend that it include a comprehensive review of the appropriateness of current medications and development of a management plan related to ongoing use . Such an approach offers opportunities to critically review the indications for BZRAs, consider the risk/benefits of continued use for individual patients, and optimize BZRA use .
# RECOMMENDATION #10:
Health care practitioners, older adults, and their families should advocate for adequate access and funding of effective non-pharmacological alternatives for the management of insomnia, anxiety disorders, and BPSD.
[GRADE: Evidence: Low; Strength: Strong]
There is good evidence that the first-line treatments for most patients with these conditions are non-pharmacological .
Even when pharmacological treatment is indicated, it should be used along with non-pharmacological interventions . However, there is limited access to and provincial coverage for non-pharmacological treatments, especially if not provided by a physician . Even when provided by a physician, there are often limits placed on the frequency and duration of therapy . Advocacy by individuals, seniors' groups, and national organizations and associations can potentially help to change rules for the provincial funding of non-pharmacological treatments (CMPA, Arya, 2013; . Individual clinicians may suggest to those they care for that they write letters to their Member of Parliament (MP) or provincial representative .
The limitations to access and to funding are unlikely to change without effort from providers, those in need of care, and the organizations that advocate for them .
# RECOMMENDATION #11:
Clinicians should be aware that BZRAs are prescribed more frequently to women and the potential implicit bias that may lead to inappropriate use. [GRADE: Evidence: Low; Strength: Weak] Historically, marketing of psychiatric medications has tended to emphasize their use by women . Women are more frequently portrayed in print advertisements for antidepressants or anti-anxiety medications targeted at prescribers (Munce et al ., 2004) . The concept of implicit bias (the attitudes or stereotypes that affect our understanding, actions, and decisions in an unconscious manner) has affected perspectives in a variety of fields, including health care . The association between gender and use of BZRAs has been shown in multiple drug database studies and reports (CIHI, 2018) . Implicit bias may be contributing to this greater likelihood of BZRA use among women in the management of anxiety and insomnia . Clinicians should minimize use of BZRAs regardless of the gender of the person being treated but should be aware of the higher use among women and the potential role of implicit bias in their prescribing practices .
# Recognition and Assessment of BZRA Use Disorder
C linicians may underestimate the likelihood of substance misuse or a substance use disorder among older adults . It is therefore important to conduct a comprehensive history of current and past use of substances, including BZRAs . Although our Guidelines are described in four separate documents, multiple substance use is common . A comprehensive assessment is recommended when substance use disorder is suspected .
# RECOMMENDATION #12:
All older adults should be asked about current and past consumption of substances that might lead to substance use disorders, including BZRAs, during periodic health examinations, admissions to facilities or services, perioperative assessments, when considering the prescription of a BZRA, and at transitions in care.
[Consensus]
Substance use (e .g ., alcohol, BZRAs [and other sedatives, hypnotics, or anxiolytics], cannabis, hallucinogens, inhalants, opioids, stimulants, tobacco) is common among older Canadians (Patten, 2018) but often remains unrecognized by their health care providers (Saitz et al ., 1997) . Inquiring about current and prior use of these substances in a nonjudgmental, non-ageist manner will normalize conversations about them and help determine if use is or was present . This information is a necessary first step in the detection of substance use disorders and can aid in the assessment of presentations where their use may be a contributing factor to other medical concerns (e .g ., confusion, falls) . Detection of use can also lead to the avoidance of adverse drug interactions and provide opportunities for education, counselling, and/ or referral of the older adult to treatment programs .
# RECOMMENDATION #13:
Health care practitioners should be aware of and vigilant to the symptoms and signs of substance use disorders, including BZRA use disorder. Particular attention should be paid to this possibility when assessing common conditions encountered in older adults, such as falls and cognitive impairment. [Consensus] Lack of awareness or recognition of BZRA use disorders among both older adults and their clinicians is of concern . Use of DSM-5 criteria are recommended for the detection of a BZRA use disorder (the 11 DSM-5 criteria for BZRA use disorder are listed on page 5 above) . The number of diagnostic criteria present can be used to gauge the severity of the substance use disorder: 2 to 3 indicates mild severity, while 4 to 5 would be indicative of moderate severity, and 6+ would indicate the presence of a severe substance use disorder . There are unique challenges (e .g ., higher likelihood of impaired cognition interfering with ability to self-monitor, sensitivity to BZRAs, changes in activity and role obligations, attributing manifestations to other known health issues) in the diagnosis of a substance use disorder in an older adult using these criteria (Rao & Crome, 2016;Han & Moore, 2018) .
Another diagnostic system used in some countries is the International Classification of Diseases (ICD-10), which separates Harmful Use from Dependence . The latter includes cravings, tolerance, evidence of withdrawal, difficulties controlling use, neglect of alternative pleasures or interests, and persisting use despite evidence of harm . The fiveitem Severity of Dependence Scale is a recommended instrument for the detection of BZRA psychological dependency in the community (de las Cuevas et al ., 2000) .
A single screening question ("How many times in the past year have you used an illegal drug or used a prescription medication for non-medical reasons?") was validated for the detection of substance use disorders in an American primary care setting (Smith et al ., 2010), but is not recommended for use in Canada prior to testing in our country . A two-question pre-screen (a positive response to either having tried to cut down or having used more than intended over the last year) has been suggested as a way to detect individuals who require a more in-depth assessment for a possible substance use disorder (Schonfeld et al ., 2015) .
# RECOMMENDATION #14:
Assessment of older adults suspected of having a BZRA use disorder should include indication, dose, duration, features indicative of BZRA use disorder, readiness to change, and presence of both medical and psychiatric comorbidities, including any other past or current substance use or misuse.
[Consensus]
The assessment should be done in a nonjudgmental, nonageist manner, taking into account the values and experiences of the older adult (Royal College of Psychiatrists, 2015) . A systematic evaluation of BZRA use as well as the characteristics of the older adult, including their environment are required . Inquiry about the BZRA would include onset of consumption, indication(s) for use, name of agent(s), manner taken (dose, route, duration), how BZRA was obtained (including whether aberrant drug-taking behaviours are present), pattern of intake (e .g ., escalating vs . stable), and use of other substances .
The presence of substance use disorder criteria, severity of the disorder (if present), prior interventions, and readiness to change should also be determined . The characteristics of the older adult that must be noted include age, gender, personal and family psychiatric history (including past history of substance use disorders), medical history (including potential BZRA adverse effects, such as anterograde amnesia, inattention, delirium, disinhibition, sedation, motor impairment, imbalance, and falls), other medication use (including potential adverse interactions), intake of caffeine, and functional status (Griffin et al ., 2013) .
Patient assessment should include vital signs, indications of possible withdrawal, focused physical examination including balance and gait, and a mental status exam including an objective brief assessment of cognition . Living arrangements (including stability) and social support, both currently and potentially available, should be determined . When possible, collateral information should be obtained (J . Brett & Murnion, 2015) . The information gathered should then be used to construct a treatment plan with the older adult . Among U .S . veterans, more than 25% of those with one substance use disorder had an additional substance use disorder (Bhalla et al ., 2017) . Rounsaville et al . (2003) wrote in their review of the topic that, "Substance abusing patients who exclusively abuse a single substance have become progressively scarce and unrepresentative of the general population of substance abusers in community and clinical settings" . Narcotic overdoses are significantly more likely to occur if an opioid is combined with a BZRA (Karaca-Mandic et al ., 2017;Sun et al ., 2017) . In the United States, benzodiazepines are present in more than 30% of overdoses involving prescription opioids (Karaca-Mandic et al ., 2017) . There is also a higher mortality rate with an opioid overdose if the two are combined (Dasgupta et al ., 2016) . The Center for Disease Control and Prevention (CDC) 2016 Guideline for prescribing opioids for chronic pain recommends avoidance of concurrent prescription of opioid pain medication and benzodiazepines whenever possible (Dowell et al ., 2016) . Canadian guidelines on the management of chronic noncancer pain state that opioids and benzodiazepines should be prescribed together only rarely (Busse et al ., 2017) . Alcohol can potentiate and worsen sedation when combined with a variety of medications, including BZRAs . As with opioids, there are observational studies that suggest that the combination of alcohol and benzodiazepines is common among patients who are admitted with overdoses and is associated with a higher risk of death (Koski et al ., 2003;Jones et al ., 2014;Zanjani et al ., 2016) .
# Management of BZRA Use Disorder
T his section focuses on the management of individuals who have developed a BZRA use disorder . Even without evidence of a BZRA use disorder, clinicians will often wish to deprescribe BZRAs in older patients because of the risk of side effects . Many of the recommendations in this section of the document, such as those focusing on gradual dose reduction, are also relevant to this group .
# RECOMMENDATION #16:
A person-centred, stepped-care approach to enable the gradual withdrawal and discontinuation of BZRAs should be used. Clinicians and patients should share in: a) planning and applying a gradual dose reduction scheme supported by appropriate education of the patient; b) identifying and optimizing alternatives to manage the underlying health issue(s) that initiated or perpetuated the use of BZRAs; c) developing strategies to minimize acute withdrawal and managing rebound symptoms as needed; and d) establishing a schedule of visits for reviewing progress. [GRADE: Evidence: Moderate; Strength: Strong] A stepped care approach to deprescribing BZRAs, starting with brief interventions and then progressing to multicomponent approaches, was pioneered by Lader and Russel (1993) and remains the standard of care (Lingford-Hughes et al ., 2012) . The stepped care approach emphasizes patient involvement in developing and modifying the treatment plan . Jansen and colleagues summarize the importance of shared decision-making in reducing inappropriate drug therapy in older adults, highlighting the need to respect patient goals and values (Jansen et al ., 2016) . A large study of older adult BZRAs users given instructions to reduce use coupled with a lecture about risks by a geriatrician revealed a sustained decrease in regular use by 35% (Salonoja et al ., 2010) .
Self-efficacy (an individual's belief in their ability to achieve goals) is a predictor of adherence with a tapering protocol (Belanger et al . , 2005) . Canadian print and online educational resources include the Sleepwell website, deprescribing . org, and the Canadian Deprescribing Network . A Canadian guideline on deprescribing BZRAs used primarily for insomnia was published recently (Pottie et al . , 2018) .
Gradual dose reduction (GDR) is the central tenet in discontinuing long-term BZRA use . A pharmacist working together with the older adult and prescriber can assist in the development of a practicable dose reduction plan, making modifications as necessary . Establishing a plan is required for regular meetings to both monitor progress of deprescription and assess and manage underlying health issue(s) that may have instigated or perpetuated BZRA use . An approach to overcoming resistance is important and can include: involving the family, explaining that tapering is a therapeutic trial that can be halted, and emphasizing that tapering often results in the person having better mood, energy, and function, with reduced risk of falls and other adverse events .
# RECOMMENDATION #17:
Abrupt discontinuation of a BZRA after intermediate to long-term use (> 4 weeks) in individuals with BZRA use disorder should be avoided due to the risk of withdrawal symptoms, substance dependence reinforcement, rebound phenomena, and/or higher likelihood of relapse with resumption of BZRA use. [GRADE: Evidence: Moderate; Strength: Strong] BZRA withdrawal is characterized by a constellation of physical, emotional, and cognitive symptoms that range in severity . They include hypertension, tachycardia, agitation, depressive or anxiety symptoms, tremor, headache, and paresthesias . Less commonly, they include psychosis, depersonalization, delirium, seizures, and rarely death (Hoffman et al ., 2014) . Onset varies with the elimination half-life of the BZRA (1 to 2 days for short-acting agents and up to several weeks for longacting ones) (Naranjo et al ., 1981;Greenblatt et al ., 1983;Leslie & Inouye, 2011;White et al ., 2012;Hoffman et al ., 2014) . A small number of patients may experience a protracted withdrawal syndrome lasting months .
As a result of age-related decreases in drug clearance, withdrawal symptoms may be less acute in older adults (Schweizer et al ., 1989;Cantopher et al ., 1990), but these individuals may be more prone to cognitive effects such as confusion (Foy et al ., 1986) . Risk factors for BZRA withdrawal include greater daily doses of the BZRA, use of short-acting agents, and chronic sustained use . Symptoms of depression and anxiety, less education, and certain personality traits increase the risk of severe withdrawal symptoms (Rickels et al ., 1990;Nelson & Chouinard, 1999) . The greater prevalence of cardiovascular disease and cognitive impairment among older adults predisposes them to experiencing delirium or demand-related cardiovascular ischemia during withdrawal, especially in the postoperative setting (Biswas et al ., 2005;Brown & Deiner, 2016) . Older adults with BZRA use disorders may require increased doses of anaesthetic agents for induction (White et al ., 2012;Moran et al ., 2015) .
Supervised GDR is the preferred tapering strategy . The ideal rate of tapering has not been established, although initially decreasing the dosage by 10% to 25% every 1 to 2 weeks is a reasonable strategy for most older adults, though the type of BZRA, dosage used, and duration of therapy will influence this . With GDR, withdrawal symptoms are usually mild or absent (Paquin et al ., 2014;Ng et al ., 2018;Pottie et al ., 2018) .
Various rates of tapering have been studied but not compared head-to-head . During the earlier stages of withdrawal, dose reductions are generally better tolerated than in the latter stages, when the pace of tapering may have to be slowed . It may take up to 6 months to successfully wean an older adult off a BZRA (Lader & Russell, 1993;Voshaar et al ., 2006;Lingford-Hughes et al ., 2012;RACGP, 2017) .
Please see Table 1 for suggestions on tapering . Knowing the indication for the BZRA may aid in the identification of likely relapse symptoms . Inpatient admission should be a consideration for patients withdrawing from very high doses .
Patients who have had a short duration of use or have been taking very low dosage of a BZRA may not require tapering . (Busto et al ., 1986;Tyrer et al ., 1990;Rickels et al ., 2008) . While these scales have been used to monitor older patients in deprescribing programs and clinical trials, they have not been specifically validated among adults at an advanced age or those with cognitive impairment . In order to manage distressing symptoms during withdrawal, judicious use of a BZRA guided by symptoms may be required .
# RECOMMENDATION #19:
Regimens involving multiple BZRAs should be simplified and converted to a single BZRA. [Consensus] The risks (e .g ., adverse drug events, non-adherence, drug interactions) of the simultaneous use of multiple medications in older people are well documented (Cooper et al ., 2015) . Therapeutic duplication (i .e ., concurrent use of more than one drug from a class) represents potentially inappropriate medication use . The concurrent consumption of multiple BZRAs can result in exaggerated pharmacological effects, unintended overdosing, and other potential adverse reactions . While concurrent use of two or more BZRAs may be intentional, it often arises when patients have multiple prescribers and/or pharmacies . In an effort to minimize the risk of adverse effects and also to set the stage for an attempt to wean the older adult off BZRAs, it is recommended that multiple BZRA regimens be simplified to the use of a single BZRA . This will require a dosage of the BZRA used that is equipotent to the sum of the multiple BZRAs that the older adult had been taking (Ashton, 2007) . Various BZRA equivalency tables are available in print and online, for example: https://www .benzo . org .uk/bzequiv .htm .
# RECOMMENDATION #20:
The routine switching of a short half-life BZRA with one having a long half-life to aid in withdrawing BZRAs is not generally recommended in older adults. Switching may have a role in certain situations, such as when withdrawal is being hindered by a limited number of available BZRA pill strengths or when alprazolam is the agent of dependence or misuse. There is limited evidence to support switching from a shortto a long half-life BZRA before beginning GDR (Denis et al ., 2006) . It may be useful if reduction of the short half-life BZRA causes problematic withdrawal symptoms . Avoidance of routine replacement with long half-life BZRA is prudent in older adults because they are prone to drug accumulation with long half-life agents due to age-related changes in pharmacokinetic processes . Alprazolam is considered to have some unique properties that increase its misuse liability (Ait-Daoud et al ., 2018) . As a result, it should be tapered very slowly, and substitution with a longer halflife BZRA, such as clonazepam could be considered with this drug . Advice from a specialty service may be required in dealing with alprazolam, especially if it has been used at a high dose and/or a prolonged period of time . Gould et al . (2014) found odds ratios for not using benzodiazepines at the completion of the intervention and then 3 and 12 months afterwards of 5 .06, 3 .90, and 3 .00, respectively, when GDR was combined with psychological interventions (Gould et al ., 2014 .) Systematic reviews by Reeve (2017) and Paquin (2014) provided similar support . A Cochrane Review (Darker et al ., 2015) of mixed-age benzodiazepine users reported that GDR plus CBT was more likely to result in discontinuation of benzodiazepines at the completion of treatment (relative risk [RR] 1 .40) and at 3-month follow-up (RR 1 .51) but with unclear longer-term benefits .
Research to date has focused on benzodiazepines . It is likely similar benefits would apply to withdrawal from z-drugs, but this requires extrapolation from the available data . There are few (if any) potential risks, durable effects beyond the end of the intervention, and secondary benefits (i .e ., dealing with emotional distress, sleep, quality of life) . Access, feasibility in individuals with moderate-to-severe cognitive impairment, and the need for a motivated patient may be limiting . Further work is needed to better define the specific cognitive and/or behavioural elements that are most beneficial .
# RECOMMENDATION #22:
Substituting a pharmacologically different drug as a specific intervention to mitigate BZRA withdrawal symptoms during gradual dose reduction is not routinely recommended. [GRADE: Evidence: Moderate; Strength: Strong]
Adding a pharmacologically different medication when withdrawing a BZRA has been studied in a small number of trials involving older adults . Melatonin, trazodone, carbamazepine, paroxetine, divalproex, buspirone, and progesterone have been examined as agents either prescribed on a temporary or permanent basis (Gould et al ., 2014;Paquin et al ., 2014;Wright et al ., 2015;Reeve et al ., 2017) . Their routine use cannot be recommended because of the lack of consistent benefit and the heterogeneity of these studies .
Other considerations include potential toxicity of replacement agents, risks of polypharmacy, and misalignment with the desire of most patients to avoid unnecessary medications . Gabapentinoids (gabapentin and pregabalin) have been considered potentially helpful because they are GABA analogs . However, they cannot be recommended, as they have not been well-studied in BZRA withdrawal (Fluyau et al ., 2018) . These drugs are not approved for the indication of BZRA withdrawal and carry their own risk for misuse (Mayor, 2018;Peckham et al ., 2018) .
A recent review (Markota et al ., 2016) advises against the routine use of another pharmacological agent to support efforts to discontinue BZRAs . The British Association for Psychopharmacology (Lingford-Hughes et al ., 2012) likewise cautions against routinely using another drug but notes that this can be considered for individual patients . The use of pharmacologically distinct medications may be appropriate when being used for the treatment of an ongoing condition that instigated or is perpetuating the use of the BZRA .
# RECOMMENDATION #23:
Older adults with a BZRA use disorder whose drug use is escalating in spite of medical supervision, have failed prior efforts to withdraw their BZRA, are at high risk for relapse or harm, and/or suffer from significant psychopathology should be considered for referral to a specialty addiction or mental health service.
[Consensus]
Many older adults with BZRA use disorders can be successfully treated as outpatients in a primary care setting . Those who have failed previous attempts of withdrawal or are at high risk of relapse, including individuals with severe concurrent psychopathology, should be referred for specialty care (Lader & Russell, 1993;Welsh Government, 2011;Paquin et al ., 2014;Yokoi et al ., 2014;J . Brett & Murnion, 2015) . The ideal specialty program would take a holistic interdisciplinary approach consisting of medical, addiction, and psychiatric expertise, with access to support from pharmacists, case managers, and peer support workers working collectively to translate the treatment plan into action . Unfortunately, few centres can offer such a comprehensive "one-stop" service, able to address the unique needs of older adults . In the treatment of concurrent disorders, addiction and mental health conditions should be treated in parallel as opposed to sequentially . Strategies such as very short dispensing periods or daily witnessed ingestion may be helpful for patients who have significant difficulty controlling their intake of BZRAs . Individuals withdrawing from high doses of BZRAs or multiple substances, those who are physically frail, and those who lack community supports should be considered for inpatient treatment in a suitable facility .
# Ethical Challenges in Deprescribing
C linical Practice Guidelines (CPGs) can inform appropriate care but do not, in isolation, define it (College of Physicians & Surgeons of Ontario (CPSO, 2017) . Good care can deviate from CPGs given the nuances and complexities of individual cases . An older adult's perception of the balance between benefits versus risks of BZRA use is dependent upon being fully informed of such considerations and alternatives by their physician . The older adult's personal values and other factors further delineate the clinician's assessment of whether withdrawal of the BZRA is indicated .
Proposing that a BZRA be discontinued may be met with resistance, particularly when the older adult perceives the BZRA to be beneficial . The perception of benefit is likely related to the degree to which the older adult was impacted by the original target symptoms, as well as the degree to which these symptoms improved with the BZRA . The clinician must consider the possibility of harm from continued use, which would include the development of a substance use disorder arising from the BZRA . Although avoiding or discontinuing the long-term use of a BZRA is in general the recommended course of action for the majority of older adults, it does not follow that this is indicated for each individual . Discontinuing a medication is an active intervention, the ethics of which can be informed by several bioethical models . Shared decision-making should incorporate clinical judgment, patient values, and lived experience but must also be made within the confines of professional standards of practice .
After considering all perspectives, if the clinician believes that the harms of continuing BZRA therapy significantly outweigh the benefits, deprescribing should be actively encouraged and adopted . Prescribers who are uncomfortable continuing to prescribe a BZRA to an older adult do not have a duty to do so, as it is ethically indefensible to provide treatment against sound medical judgement, though it is emphasized that discontinuing a BZRA being used long-term should never be done abruptly (Weijer et al ., 1998;Lantos et al ., 2011;A . Brett & McCullough, 2012;Kapoor et al ., 2018) .
# Future Directions
C oncern about the risks of BZRAs for older adults has grown in recent years . The developers of these guidelines hope to inspire prescribers and health care team members, as well as older adults and their families, to consider, implement, and support alternatives to these medications . This document bridges the gap between knowledge and practice and is designed to facilitate change at personal, institutional, and system levels .
These guideline developers advocate for integration of policies and specialized clinical education that supports progressive models of care, to empower older adults to participate in shared decision-making when the prescribing and deprescribing of BZRAs is being considered . It is also important to ensure access to clinicians who are able to offer non-pharmacological therapies such as CBT and CBTi to older adults, in order to both prevent the inappropriate use of BZRAs and to aid those who are experiencing symptoms of a substance use disorder . We encourage hospitals, other health care facilities, community-based agencies, and their quality improvement teams to routinely explore the impact of care transitions on prescribing patterns . The health care system is striving to provide holistic, personcentred care to older adults with substance use disorders . However, more education is required to support primary care physicians and other clinicians caring for these individuals . Unfortunately, in some regions of Canada, access to specialized addiction and/or mental health services for older adults is limited or non-existent . To this end, we encourage the development of comprehensive, evidence-based, interprofessional models of care that support the full scope of practice of all team members . It is important to emphasize that more research is needed to determine the optimal treatment and models of care for older adults with substance use disorders (Lehmann & Fingerhood, 2018) . Over time, it will be increasingly important to develop systems of care able to meet the complex health needs of diverse groups of older adults, including the growing number of baby boomers .
The CCSMH welcomes your feedback and requests both your support and active participation in the wide dissemination of these important guidelines .
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We would also like to thank Dr. Simon Davies, Dr. Barbara Farrell, Dr. Meldon Kahan and Dr. Karen Reimers for their support in reviewing the guideline documents and providing clinical perspective to the CCSMH.
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# Background
The anal canal is delimited superiorly by the proximal extent of the levator-external anal sphincter complex and inferiorly by the anal verge (the junction between the anal mucosa and the hair-bearing skin). Lesions that involve the hair-bearing skin (peri-anal skin within 5 cm of the anal verge) are considered cancers of the anal margin and should also be treated as anal cancers.
This guideline was developed to outline the management recommendations for patients with squamous cell carcinomas that arise within the anal canal. Adenocarcinomas of the anal canal should be treated like rectal cancers (see the Early-Stage Rectal Cancer Clinical Practice Guideline).
# Search Strategy
Randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data.
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with squamous cell carcinomas that arise within the anal canal. Different principles may apply to pediatric patients.
# Recommendations
# Suggested Diagnostic Work-Up
The incidence of squamous cell carcinomas that arise within the anal canal has increased with the prevalence of Human Papilloma Virus (HPV) infection, Human Immunodeficiency Virus (HIV) infection, and immunosuppression required for organ transplantation. If the use of chemotherapy or radiotherapy is considered and HIV infection is suspected, HIV serology and an evaluation of the CD4 count are suggested in addition to the complete blood count and both liver and renal function tests.
CT chest abdomen pelvis, MRI of the pelvis are recommended. The addition of a PET/CT scan to the staging workup has a significant impact on therapy planning, particularly identifying those patients who need higher-dose RT to the groin and those with otherwise occult metastatic disease. A metaanalysis of 12 studies concluded that a PET CT changed nodal status in 28% of patients and should be considered 1 . Suspicious lymph nodes should be evaluated with a biopsy by fine-needle aspirate.
Female patients should have a gynecological assessment (including a Pap smear) to exclude a synchronous cervical cancer. A colonoscopy should be performed to detect synchronous lesions.
# Stage Information
# Goals of Therapy and Recommendations for Potentially Curable Cancer of the Anal Canal
- To render the patient free of disease and to delay or prevent recurrence. 2. To improve the patient's quality of life (to eliminate tumour-related symptoms) and to preserve continence.
Consider treatment on a clinical trial, if available. - Consider a wide local excision provided that surgical resection can be completed to achieve negative margins and to preserve continence (no involvement of the anal sphincter).
# Stage I
- Consider a wide local excision provided that surgical resection can be completed to achieve negative margins and to preserve continence (no involvement of the anal sphincter). - Consider primary chemoradiotherapy (as described for stage II and IIIA disease) if sphincter
# Stage
Recommendations preservation (maintenance of continence) is not possible with a wide local excision. - Consider an abdominoperineal resection for residual or recurrent disease.
# Stage II Stage IIIA
- Primary chemoradiotherapy involves the sequential administration of Mitomycin C (10 to 12 mg/m 2 IV) followed by a continuous intravenous infusion of 5-Fluorouracil (4,000 mg/m 2 over ninetysix hours) during week one (and, possibly, week five) of a course of radiation (4,500 to 5,400 cGy to the perineum and regional lymph nodes). Randomized trials have used a single dose of Mitomycin C at 12 mg/m 2 . This is an evidence based option that is also supported by real world data. 8 This regimen requires placement of a central venous catheter ("CVC") or a peripherally inserted central catheter ("PICC line"). - Consider an abdominoperineal resection for residual or recurrent disease. Stage IIIB - Primary chemoradiotherapy (as described for stage II and IIIA disease). Consider a boost, if indicated. - Consultation with the multidisciplinary and surgical team should be sought to determine the role of further surgery.
# Post-Curative Therapy Guidelines
- Perform a digital rectal examination and consider anoscopy at six to eight weeks after completion of the therapy. Consider biopsy of any suspicious lesions at three months after completion of therapy, but recognize that tumors may continue to respond up to six months after the radiation 9 . - Perform salvage surgery for biopsy-proven persistent, progressive, or recurrent disease.
- After achieving a complete response, repeat digital rectal examination, anoscopy, and examination of the inguinal lymph nodes every four months for two years then every six months for the balance of five years. - Female patients should have a gynecological assessment (including a Pap smear) due to the increased risk of cervical cancer. A colonoscopy should be obtained as outlined in the colorectal cancer screening guidelines.
# Recommendations for Locally Recurrent Cancer of the Anal Canal
- For patients whose disease recurs despite prior radical chemoradiotherapy, consider surgical resection, if possible after repeating full staging investigations. Consider palliative therapy (see below) if surgical resection is not possible. 2. For patients whose disease recurs after not having received prior chemoradiotherapy, consider radical chemoradiotherapy (see above) with or without surgery.
# Goals of Therapy and Recommendations for Metastatic Cancer of the Anal Canal
- To maintain or to improve the patient's quality of life (to control or to delay the onset of tumorrelated symptoms). 2. To prolong life, if possible.
Metastatic anal canal cancer describes the situation where a cancer that originated within the anal canal has spread beyond the regional lymph nodes to other organs. This represents an incurable situation for which palliative options (e.g.: best supportive care, palliative chemotherapy) may be considered.
Palliative chemotherapy regimens are generally continued as long as tumor shrinkage or stability is confirmed, as long as the side effects remain manageable, as long as the patient wishes to continue, and as long as the treatment remains medically reasonable.
Carboplatin/paclitaxel (Carboplatin AUC 5 on day 1 every 28 days and paclitaxel at 80 mg/m2 on days 1, 8, 15 every 28 days). The InterAACT randomized phase II trial demonstrated the superiority of carboplatin/paclitaxel compared to cisplatin and infusional 5FU in inoperable, locally recurrent or metastatic SCC of the anal canal for overall survival (OS). OS was a secondary endpoint of this trial. Preliminary findings presented at ESMO 2018 demonstrated OS was 12.3 months with cisplatin/5FU versus 20 months with carboplatin and paclitaxel, hazard ratio 2.0 (p = 0.014). There was no difference in response rate, the primary endpoint of this trial (57.1% with cisplatin/5-FU compared to 59.0% with carboplatin/paclitaxel). Median PFS was 5.7 months for cisplatin/5-FU versus 8.1 months for carboplatin/paclitaxel (p = 0.375). The incidence of serious adverse events (SAEs) was lower with carboplatin/paclitaxel; SAEs were reported in 62% of cisplatin/5-FU patients compared with 36% of patients receiving carboplatin/paclitaxel (p = 0.016). There are no randomized phase III trials in this setting, and patients should be encouraged to participate in clinical trials 10 .
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta GI Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2008, and updated in 2010, 2011, 2013, and 2020.
# Levels of Evidence
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# Background
The anal canal is delimited superiorly by the proximal extent of the levator-external anal sphincter complex and inferiorly by the anal verge (the junction between the anal mucosa and the hair-bearing skin). Lesions that involve the hair-bearing skin (peri-anal skin within 5 cm of the anal verge) are considered cancers of the anal margin and should also be treated as anal cancers.
This guideline was developed to outline the management recommendations for patients with squamous cell carcinomas that arise within the anal canal. Adenocarcinomas of the anal canal should be treated like rectal cancers (see the Early-Stage Rectal Cancer Clinical Practice Guideline).
# Search Strategy
Randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data.
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with squamous cell carcinomas that arise within the anal canal. Different principles may apply to pediatric patients.
# Recommendations
# Suggested Diagnostic Work-Up
The incidence of squamous cell carcinomas that arise within the anal canal has increased with the prevalence of Human Papilloma Virus (HPV) infection, Human Immunodeficiency Virus (HIV) infection, and immunosuppression required for organ transplantation. If the use of chemotherapy or radiotherapy is considered and HIV infection is suspected, HIV serology and an evaluation of the CD4 count are suggested in addition to the complete blood count and both liver and renal function tests.
CT chest abdomen pelvis, MRI of the pelvis are recommended. The addition of a PET/CT scan to the staging workup has a significant impact on therapy planning, particularly identifying those patients who need higher-dose RT to the groin and those with otherwise occult metastatic disease. A metaanalysis of 12 studies concluded that a PET CT changed nodal status in 28% of patients and should be considered 1 . Suspicious lymph nodes should be evaluated with a biopsy by fine-needle aspirate.
Female patients should have a gynecological assessment (including a Pap smear) to exclude a synchronous cervical cancer. A colonoscopy should be performed to detect synchronous lesions.
# Stage Information
# Goals of Therapy and Recommendations for Potentially Curable Cancer of the Anal Canal
1. To render the patient free of disease and to delay or prevent recurrence. 2. To improve the patient's quality of life (to eliminate tumour-related symptoms) and to preserve continence.
Consider treatment on a clinical trial, if available. • Consider a wide local excision provided that surgical resection can be completed to achieve negative margins and to preserve continence (no involvement of the anal sphincter).
# Stage I
• Consider a wide local excision provided that surgical resection can be completed to achieve negative margins and to preserve continence (no involvement of the anal sphincter). • Consider primary chemoradiotherapy (as described for stage II and IIIA disease) if sphincter
# Stage
Recommendations preservation (maintenance of continence) is not possible with a wide local excision. • Consider an abdominoperineal resection for residual or recurrent disease.
# Stage II Stage IIIA
• Primary chemoradiotherapy [2][3][4][5][6][7] involves the sequential administration of Mitomycin C (10 to 12 mg/m 2 IV) followed by a continuous intravenous infusion of 5-Fluorouracil (4,000 mg/m 2 over ninetysix hours) during week one (and, possibly, week five) of a course of radiation (4,500 to 5,400 cGy to the perineum and regional lymph nodes). Randomized trials have used a single dose of Mitomycin C at 12 mg/m 2 . This is an evidence based option that is also supported by real world data. 8 This regimen requires placement of a central venous catheter ("CVC") or a peripherally inserted central catheter ("PICC line"). • Consider an abdominoperineal resection for residual or recurrent disease. Stage IIIB • Primary chemoradiotherapy (as described for stage II and IIIA disease). Consider a boost, if indicated. • Consultation with the multidisciplinary and surgical team should be sought to determine the role of further surgery.
# Post-Curative Therapy Guidelines
• Perform a digital rectal examination and consider anoscopy at six to eight weeks after completion of the therapy. Consider biopsy of any suspicious lesions at three months after completion of therapy, but recognize that tumors may continue to respond up to six months after the radiation 9 . • Perform salvage surgery for biopsy-proven persistent, progressive, or recurrent disease.
• After achieving a complete response, repeat digital rectal examination, anoscopy, and examination of the inguinal lymph nodes every four months for two years then every six months for the balance of five years. • Female patients should have a gynecological assessment (including a Pap smear) due to the increased risk of cervical cancer. A colonoscopy should be obtained as outlined in the colorectal cancer screening guidelines.
# Recommendations for Locally Recurrent Cancer of the Anal Canal
1. For patients whose disease recurs despite prior radical chemoradiotherapy, consider surgical resection, if possible after repeating full staging investigations. Consider palliative therapy (see below) if surgical resection is not possible. 2. For patients whose disease recurs after not having received prior chemoradiotherapy, consider radical chemoradiotherapy (see above) with or without surgery.
# Goals of Therapy and Recommendations for Metastatic Cancer of the Anal Canal
1. To maintain or to improve the patient's quality of life (to control or to delay the onset of tumorrelated symptoms). 2. To prolong life, if possible.
Metastatic anal canal cancer describes the situation where a cancer that originated within the anal canal has spread beyond the regional lymph nodes to other organs. This represents an incurable situation for which palliative options (e.g.: best supportive care, palliative chemotherapy) may be considered.
Palliative chemotherapy regimens are generally continued as long as tumor shrinkage or stability is confirmed, as long as the side effects remain manageable, as long as the patient wishes to continue, and as long as the treatment remains medically reasonable.
Carboplatin/paclitaxel (Carboplatin AUC 5 on day 1 every 28 days and paclitaxel at 80 mg/m2 on days 1, 8, 15 every 28 days). The InterAACT randomized phase II trial demonstrated the superiority of carboplatin/paclitaxel compared to cisplatin and infusional 5FU in inoperable, locally recurrent or metastatic SCC of the anal canal for overall survival (OS). OS was a secondary endpoint of this trial. Preliminary findings presented at ESMO 2018 demonstrated OS was 12.3 months with cisplatin/5FU versus 20 months with carboplatin and paclitaxel, hazard ratio [HR] 2.0 (p = 0.014). There was no difference in response rate, the primary endpoint of this trial (57.1% with cisplatin/5-FU compared to 59.0% with carboplatin/paclitaxel). Median PFS was 5.7 months for cisplatin/5-FU versus 8.1 months for carboplatin/paclitaxel (p = 0.375). The incidence of serious adverse events (SAEs) was lower with carboplatin/paclitaxel; SAEs were reported in 62% of cisplatin/5-FU patients compared with 36% of patients receiving carboplatin/paclitaxel (p = 0.016). There are no randomized phase III trials in this setting, and patients should be encouraged to participate in clinical trials 10 .
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta GI Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2008, and updated in 2010, 2011, 2013, and 2020.
# Levels of Evidence
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial GI Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2020) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/.
The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of CancerControl Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerControl Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Andrew Scarfe has nothing to disclose.
Dr. Dan Schiller has nothing to disclose.
Dr. Patricia Tang reports receiving grants from Pfizer and Roche, and other support from Amgen, Taiho, AstraZeneca and Genomic Health.
Derek Tilley has nothing to disclose.
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Également disponible en français sous le titre : Utilisation recommandée du palivizumab pour réduire les complications de l'infection par le virus respiratoire syncytial chez les nourrissons This publication can be made available in alternative formats upon request.# PREAMBLE
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# SUMMARY OF INFORMATION CONTAINED IN THIS NACI STATEMENT
The following highlights key information for immunization providers. Please refer to the remainder of the Statement for details.
# What a) Respiratory syncytial virus disease
Respiratory syncytial virus (RSV) causes yearly outbreaks of respiratory tract disease, in Canada from late fall to early spring. It is the most common cause of lower respiratory tract illness in young children worldwide. While many infections are simple colds, children less than 2 years of age are at risk of severe disease such as bronchiolitis or pneumonia and may be hospitalized. Underlying health conditions, especially premature birth, chronic lung disease and congenital heart disease (CHD) redispose to severe RSV illness. Reinfections occur throughout life as infection produces only partial and temporary immunity, although reinfections are usually milder than the initial one.
# b) Palivizumab
At present there is no vaccine available to prevent RSV. The only means of prophylaxis against RSV disease is temporary passive protection with the monoclonal antibody preparation Palivizumab (Synagis TM ). Palivizumab (PVZ) has only been studied in children less than 2 years of age with underlying health conditions. Efficacy in early studies was 38-78% in different patient groups, and further studies, mainly observational, showed wide variation in effect with some studies showing no benefit. PVZ has been used for over 2 decades in many countries and has a good safety record, with very rare cases of anaphylaxis being the major serious adverse event (SAE) It is an expensive product, with wide ranging estimates of cost-effectiveness (or value for money). Estimated incremental effectiveness ratios (ICERs) ranged from less than $1,000 per quality-adjusted life year (QALY) to over 2 million dollars per QALY in various scenarios. In various high risk groups, 64% to 100% of estimates were < $50,000 per QALY. In rare scenarios it may be dominant (i.e, less costly and more effective). RSV vaccines are currently under study.
# Who
# NACI makes the following recommendations for public health program level decision-making:
- PVZ should be offered to premature infants of < 30 weeks gestational age (wGA) and < 6 months of age at onset of or during the RSV season; children aged < 24 months with chronic lung disease of prematurity who require ongoing oxygen therapy within the 6 months preceding or during the RSV season; infants aged < 12 months with haemodynamically significant CHD and infants born at < 36 wGA and age < 6 months old living in remote northern Inuit communities who would require air transport for hospitalization. For children with both CHD and chronic lung disease, recommendations for chronic lung disease should be followed. PVZ may be considered for premature infants of 30-32 wGA and age <3 months who are at high risk for exposure to RSV; selected children <24 months of age with severe chronic lung disease due to cystic fibrosis or other etiology who require ongoing oxygen therapy or assisted ventilation in the months preceding or during the RSV season; infants <12 months of age with haemodynamically significant chronic cardiopathy other than congenital; children aged 12-24 months awaiting heart transplant or having received a heart transplant within 6 months of onset of the RSV season; and children aged <24 months with severe immunodeficiency. It may also be considered for term infants aged <6 months living in remote Inuit communities with very high rates of hospitalization for RSV among term infants and for infants of < 36 weeks gestational age and age <6 months living in other remote communities with high rates of hospitalization for RSV and where air transport would be required for hospitalization. PVZ may be considered when all other measures to control a RSV outbreak in a NICU have failed. PVZ should not be offered to otherwise healthy infants born at or after 33 wGA; or to siblings in multiple births who do not otherwise qualify for prophylaxis. It should not be offered routinely for children <24 months of age with cystic fibrosis; for children <24 months of age with Down syndrome without other criteria for PVZ; or for healthy term infants living in remote northern Inuit communities,unless hospitalization rates for RSV are very high. It should not be used for the prevention of recurrent wheezing or asthma in the absence of other indications. PVZ should not be given to prevent hospital-associated RSV infection in eligible children who remain in hospital. It may be considered when all other measures have failed to control an RSV outbreak in a neonatal intensive care unit.
Since in Canada PVZ is not readily available for purchase, no specific recommendations are made for individual-level decision making.
# How
- The dose of PVZ is 15 mg/kg by intramuscular injection, starting with the onset of the local RSV season. Eligible children who are in hospital should receive their first dose on discharge (or within 48-72 hr before discharge to facilitate vial sharing). The interval between the first and second doses should be 21-28 days and between subsequent doses 28-35 days, for a maximum of 4 doses. An extra dose should be given after cardiac bypass or extracorporeal membrane oxygenation.
An extra dose may be considered in remote Northern areas where RSV outbreaks may continue longer than is usual elsewhere. PVZ should be discontinued for the season if a child is hospitalized for RSV infection. If feasible, clinics or appointments should be organized to facilitate vial sharing, to reduce costs. PVZ is contraindicated in individuals with known significant hypersensitivity reaction to PVZ or any component of the product (humanized monoclonal antibody, glycine, histidine). Moderate to severe illness, with or without fever, is a reason to consider deferring PVZ, to avoid superimposing adverse effects from PVZ on the underlying illness, or mistakenly identifying a manifestation of the underlying illness as a complication of PVZ. The decision to delay PVZ depends on the severity and etiology of the underlying disease. Minor illnesses such as the common cold, with or without fever, are not contraindications to use of PVZ. PVZ contains antibody only against RSV and may be co-administered with any other live or inactivated vaccines.
# I. INTRODUCTION
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract illness in young children worldwide 1,2 .
At present the only immunizing agent available for the prevention of serious RSV disease is PVZ, a monoclonal anti-RSV antibody. Several active vaccine candidates are currently undergoing clinical trials in infants, pregnant women and adults 3 . RSV vaccines will not be addressed in this Statement.
In June 2002, Health Canada approved PVZ (Synagis TM ) for the prevention of serious lower respiratory tract disease caused by RSV in infants at high risk of serious RSV disease. In 2003, the National Advisory Committee on Immunization (NACI) published recommendations on the use of PVZ or the prevention of RSV disease 4 . At that time, NACI recommended PVZ be used during the RSV season for premature infants (less than or equal to 32 weeks' gestational age (wGA) who would be less than six months of chronological age at the start of RSV season, children less than 24 months of age with chronic lung disease of prematurity (CLD) requiring oxygen and/or medical therapy in the previous six months or other pulmonary disorders requiring oxygen therapy, and children less than 24 months of age with hemodynamically significant congenital heart disease (hsCHD). PVZ prophylaxis could also be considered for children born at less than 35 wGA who are less than 6 months of age at the start of RSV season and who live in remote northern communities 4 . Since the 2003 statement, NACI recommendations have been modified in the Canadian Immunization Guide (CIG) but no new Statement has been issued. From 2013, in addition to the above recommendations, the CIG stated that PVZ prophylaxis may benefit selected infants between 33 and 35 wGA who are less than 6 months of age at the start of the RSV season and may be considered for infants in this gestational age group who live in rural or remote communities according to an assessment of access to medical care (e.g., requirement for air transportation to hospital facilities) and other factors known to increase risk. In addition, PVZ prophylaxis should be considered for all Inuit children in northern remote communities who are younger than 6 months of age at the start of RSV season, regardless of wGA.
Since the publication of the NACI statement in 2003, there have been a series of updated PVZ guidance documents published by expert committees including the American Academy of Pediatrics (AAP) in 2009 and 2014 and the Canadian Paediatric Society (CPS) in 2015 8 which have made PVZ prophylaxis recommendations that differ significantly from the 2003 NACI guidance and highlight the need to reassess NACI's recommendations. A summary of current criteria for PVZ eligibility in Canadian provinces and territories and in ten other northern hemisphere countries, "Recommendations for use of Palivizumab in Canada and internationally", is presented in Appendix A.
The purpose of this document is to update previous NACI recommendations for the use of PVZ, taking into consideration recent data on burden of illness due to RSV disease, the efficacy and effectiveness of PVZ in infants at risk of more severe RSV disease and economic implications of PVZ use.
# Guidance Objective:
The objective of this advisory committee statement is to review evidence and develop guidance on strategies to prevent severe consequences of RSV infection in children at high risk of severe RSV disease by administration of monoclonal antibody. SYNCYTIAL VIRUS INFECTION IN INFANTS (2) The effectiveness of PVZ prophylaxis on reducing the complications associated with RSV in infants For details of methodology and results in the document "NACI Literature Review on the Effects of PVZ Prophylaxis on Reducing the Complications Associated with Respiratory Syncytial Virus in Infants" which will be forthcoming. Data are summarized in Section IV.2 of this Statement 12 .
(3) The cost-effectiveness of PVZ prophylaxis for RSV For details of methodology and results see "Cost-Effectiveness of PVZ Prophylaxis for Respiratory Syncytial Virus (RSV): A Systematic Review." Data are summarized in Section V.1 of this Statement.
In addition to these systematic reviews, other literature searches included:
(4) An environmental scan of recommendations for use of PVZ in Canadian provinces and territories and in other Northern hemisphere countries (5) A rapid literature review on the safety of PVZ ( 6) Informal literature reviews when information was needed to address specific questions.
Results of ( 4) and ( 5) are added to this document as Appendices A and B. Information and data from the informal reviews (6) are presented in the text of this document.
In order to develop comprehensive, appropriate immunization program recommendations, NACI considers a number of factors. In addition to critically appraising evidence on burden of disease and vaccine characteristics such as safety, efficacy, immunogenicity and effectiveness, NACI uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to ethics, equity, feasibility, and acceptability (EEFA) are systematically assessed and integrated into its guidance 13 . The NACI Secretariat applied this framework with accompanying evidence-informed tools (Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, Acceptability Matrix) to systematically consider these programmatic factors for the development of clear, comprehensive, appropriate recommendations for timely, transparent decision-making. For details on the development and application of NACI's EEFA Framework and evidence-informed tools (including the Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, and Acceptability Matrix), please see .
For this Statement, NACI reviewed the key questions for the systematic literature reviews as proposed by the RSV Working Group. Following literature searches and critical appraisal of individual studies, proposed recommendations for PVZ use were developed. The RSV Working Group chair and PHAC medical specialist presented the evidence and proposed recommendations to NACI on February 5, 2020. Following thorough review of the evidence and consultation at the NACI meetings of February 5, 2020, September 24, 2020 and October 22, 2021, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text.
# III. EPIDEMIOLOGY
RSV is an enveloped RNA virus belong to the family Paramyxoviridae. There are 2 subgroups based on differences in the G surface protein, and numerous genotypes within these subgroups. Humans are the only source of infection and transmission occurs from direct or indirect exposure to respiratory secretions containing the virus 14 .
RSV infects almost all infants by 2 years of age 1,2 . The most common clinical presentations of RSV in young children requiring hospitalization are bronchiolitis (an acute lower respiratory tract infection associated with tachypnea, cough, and wheezing), and pneumonia 14,15 . Primary infection does not confer complete protective immunity. Reinfections occur throughout life but are usually less severe, mainly presenting as upper respiratory tract illness in older children and adults 14 .
Hospitalization rates are highest in children < 1 year of age and especially in the first 2 months of life 16 . Hospitalization rates per 1000 children per year in high income countries are reported as 26.3 (95% CI 22.8, 30.2), 11.3 (95% CI 6.1, 20.9) and 1.4 (95% CI 0.9, 2.0) for age groups 0-5 months, 6-11 months and 12-59 months respectively 2 . In Canada, similar rates of 20, 10.2, and 4.8 per 1000 per year are reported for children aged < 6 months 15 , <1year, and 1-3 years, respectively 17 . In Ontario, 9% of annual hospital admissions of children <1 year of age were attributed to RSV 17 . The casefatality rate in high income countries is usually <0.5%, with higher rates in infants with co-morbidities 1,18 . Eighty-two percent of deaths in one Canadian study were in children with underlying risk factors for severe RSV disease 19 .
Most children less than 2 years of age hospitalized with RSV infection have no co-morbidities 1,17 , but higher rates and durations of hospitalization and more intensive care unit admissions have been reported in premature infants and in those with CLD or CHD 1,8,17 . Children with other lung diseases not associated with prematurity such as cystic fibrosis 20 or with other chronic conditions including immunodeficiency 21,22 and children living in indigenous communities in the far north 23 may also be at increased risk of severe RSV disease. RSV is being increasingly recognized as an important cause of morbidity and mortality in the elderly 24 .
In temperate climates, RSV causes epidemics every winter. In Canada the RSV season typically begins in October or November and lasts until April or May, with most cases occurring in December through March 25 . Studies of temporal trends in RSV hospitalization rates have shown conflicting results, likely due to differences in testing policies, sensitivity of diagnostic tests used, and criteria for hospitalization 1 . One recent US study reported decreased RSV hospitalization rates from 1997 to 2012 for all infants and for infants with CLD and high risk CHD but not for other high risk infants 26 .
# III.1 Burden of Disease in Specific High Risk Groups
Data from the burden of RSV illness systematic review performed for the development of this statement are summarized and integrated into the relevant sections below. In view of the small numbers of articles identified and heterogeneity in the methodology used and outcomes studied, the interpretation of the findings must be viewed with caution. Information from earlier studies and from the 2018-2020 literature review is also presented here.
The systematic literature review on the burden of RSV disease in young children (BODsr), limited to publications from 2014 to September 2018, and the 2020 updated review yielded no studies of burden of RSV illness in premature infants of <29 wGA. Data from studies of less premature infants are summarized here.
In study-level comparisons, one study of moderate to low certainty of evidence (COE) found similar RSVH rates for infants of 29-32 wGA and 33-36 wGA during their first RSV season (RR 1.20, 95% CI 0.92, 1.56) 27 . Another, also rated as moderate to low COE, found a relative risk of RSVH of 2.05 (95% CI 1. 89, 2.22) between infants of 33-36 wGA and term infants age <24 months 28 . Very low COE was found for RSVH in one study of infants <33 wGA compared to term infants in their first RSV season (RR 3.88, 95% CI 1.13, 13.30) 29 .
Single arm pooled proportions for RSVH (Table 1) were 5.1%, 2.8%, 3.3% and 4.1 for infants of 29 to <33 wGA 27,29 , 32-34 wGA 30 , 32/33 to 35 wGA 27,28, and 35 wGA 30 respectively. RSVH rate for healthy term infants was 1.2%. Three of four studies in this group reported RSVH during the first year of life (0.8% to 1.5%) 29,36,37 , and one study reported RSVH to age 24 months (1.3%) 28 . 37 , Zomer-Kooijker 2014 36 .
Between-study comparisons using pooled data (all assessed by GRADE at very low COE due to the indirect nature of the evidence) showed RR for RSVH for premature infants versus term infants of 4.3 (95% CI 3.7, 4.8, p=0.000) for infants of 29-32 to 32 wGA respectively (ROB low) 38 . RSVH rate during RSV season was 3.4% in infants of 33-35 wGA in a 2015-2017 retrospective cohort study in Quebec by Papenburg et al. (ROB moderate) 39 . In addition, a systematic review, rated by AMSTAR as average, reported on seven observational prospective studies carried out between 2000 and 2008.
The pooled RSVH rate for otherwise healthy infants of 33-<35 wGA was 3.4% or 5.5 per 100 patientseasons 40 .
Earlier literature was reviewed for data about more severely premature infants. RSVH rates for infants during their 1 st RSV season in the placebo arm of a 1996-1997 PVZ RCT were (% and 95% CI) 10.0 43 . Other observational studies, ROB low 44 or moderate , have reported RSVH rates of 10.4%, 7.7%, 13% and 13.5% in the first year of life for infants born at <29, <28, <29 or ≤30 wGA without other comorbidities. These early preterm infants receive little or no maternal antibody and their narrower airway passages increase their vulnerability to the effects of RSV infection.
Infants of 29-32 wGA are also at increased risk of RSVH in comparison to healthy term infants but RSVH rates are lower than those for more premature infants, at 5.7 to 9.9% in their 1 st RSV season (ROB moderate) 45,46 . Infants of 32 or 33 to 35 wGA have reported RSVH rates of 2.8 to 6.5% in their 1st year of life or 1 st RSV season (ROB moderate) 45,48 . In the study of Boyce et al., RSVH rates for premature infants in the 2 nd 6 months of life were similar to those for low risk term infants in the 1 st 6 months (ROB moderate) 43 . In another study, RSVH rates for preterm infants of 32-34 of wGA (20% of whom received PVZ), were similar to those of 1 month old term infants by 4.2 -4.5 months of age (ROB moderate) 49 .
Chronological age is an important risk factor for RSVH (ROB moderate) 16,43,49 Between-study comparisons (all at very low COE) using pooled data showed mean differences in LOS between premature versus term infants of 6.5 days (95% CI 3.9, 9.1, p < 0. 59 .
In earlier literature, premature infants have also been reported to have longer median hospital stays than term infants 60 . In a prospective cohort study in 2008-9, infants of 28 to < 33 wGA with confirmed RSVH had a mean LOS of 7.2 ± 3.3 days (ROB low) 61 .
# III.1.1.3. ICU Admission and Mechanical Ventilation
In the BODsr, one study looked at ICU admission, ICU LOS, mechanical ventilation (MV) and duration of MV in infants of 29-32 versus 33-35 wGA. There was no significant difference in any of these parameters (low to very low COE) 50 .
Single arm pooled proportions of patients hospitalized for RSV that were admitted to ICU were 51.7, 19.1, 31.5 and 13.9 for infants of 29-32 wGA 50 , 32-34 wGA 30 , 32-35 wGA 30,35,50 and 35 wGA 30 , respectively. Rate of ICU admission for hospitalized healthy term infants was 15.8% 37,52,53 . (Table 3) 30,35,50 , respectively. MV rate for healthy term infants was 14.0% 52,53 . (Table 5) 55 .
In earlier literature, premature infants have also been reported to have an increased risk for ICU admission compared to term infants 60 . In a prospective cohort study in 2008-9, 5.9% of infants of 28 to 6 months of age required intensive care, but 14% of those aged 3 to <6 months and 27% of those aged < 3 months were admitted to ICU (actual ages) 64 .
# III.1.1.4. Mortality
In a meta-analysis of studies from 1990-2007, all-cause mortality during their first RSV season was 0.99% and 0.13% for infants of ≤32 wGA and 32-35 wGA respectively. RSV attributable mortality was 0.03% for the two groups combined (AMSTAR rating average) 74 . In another systematic review of literature from 1975 to 2011, the weighted mean case fatality rate for children aged ≤ 24 months hospitalized with RSV was 1.2% (range, 0-8.3%; median, 0%; n = 10) for preterm infants 29-30 wGA or > 32 wGA who are at significantly increased risk of severe RSV disease, which are currently used in several Canadian provinces and territories and internationally (see Appendix A below). The risk factors identified as significant and used in these risk scores vary widely. The validity of such scores, especially those validated with data from several years ago or from different geographical settings, has been questioned 7,34, .
Young chronological age during the RSV season is the most consistent risk factor identified. Other factors include environmental and host factors that increase risk of exposure to RSV or of more severe RSV disease. The risk of RSV hospitalization associated with these individual factors has been difficult to determine because of inconsistent results in different studies. Most environmental and host factors increase the risk for RSVH only slightly and their individual contribution to the burden of RSV disease is limited 7,70 . In a multiple logistic-regression analyses of risk factors which included male gender, child care attendance, smoke exposure, lack of breastfeeding, and other children in the house, only preterm birth and young chronologic age independently correlated with more severe RSV disease after adjusting for other covariates 69 .
# III.1.2 Chronic Lung Disease of Prematurity and Other Chronic Lung Diseases
CLD has been defined by the AAP as "born at gestational age of <32 weeks with need for supplemental O2 for at least the first 28 days after birth" 6 . Some studies defined CLD as the need for O2 at 36 weeks post conceptual age. The BODsr and the 2020 updated literature search did not identify any studies of this risk group.
In a systematic review of data to December 2015, rated average by AMSTAR, RSVH rates for children with CLD in the first 2 years of life without prophylaxis were 12-21% with a weighted mean of 16.8%. CLD was associated with a higher rate of RSVH than other high-risk groups and was a significant independent risk factor for RSVH with odds ratios of 2.2 to 7.2 72 . The Canadian Paediatric Society statement reported RSVH of 6.0 to 22.6 % in studies carried out between 1995 and 2009 8 . RSVH rate of 16.8% in the first year of life was reported in a 1992-6 retrospective cohort study (ROB moderate) 42 . RSVH rate was 12.8% for children ≤ 24 months of age with CLD in the control arm of a PVZ RCT (ROB moderate) 48 and 15.7 % for children within 12 months of initial discharge in the control arm of a PVZ observational study (ROB moderate) 44 . A 1989-93 study reported higher rates in the first year of life than in the second (38.8% vs. 7.3%) (ROB moderate) 43 . Winterstein et al. compared RSVH rates in infants with CLD and in healthy term infants with siblings. The peak RSVH rate for those with CLD was 15.3 /1000 patient-seasons at age 9 months. The RSVH rate for infants with CLD at 18.5 months was similar to that of healthy term infants aged 1 month (9/1000 patient-seasons) 73 .
In that study, 42.7% of the infants with CLD had received PVZ.
There are limited data on outcomes other than hospitalization. In the systematic review of Paes, rated by AMSTAR as average, the mean length of hospital stay for RSV was 4-11 days, with one study reporting 29% of those hospitalized admitted to ICU and 24% undergoing mechanical ventilation 72 . In the retrospective cohort study of Stevens et al. (ROB low) the mean LOS was 9.4 days and 9.1% were admitted to ICU 42 . A meta-analysis, rated by AMSTAR as average, reported an all-cause mortality rate of 0.34% during the first RSV season 74 . In a systematic review of literature from 1975 to 2011, the weighted mean case fatality rate for infants age ≤ 24 months hospitalized with RSV was 4.1% (range, 0-10.5%; median, 7.0%; n = 6) for children with CLD (rated by AMSTAR as poor) 66 .
Data on RSV risk in children with chronic lung disease of etiology other than prematurity are limited. The BODsr identified two studies. Increased rates of RSVH were reported in infants < 24 months old with congenital cystic lung disease (CCLD) (8.3%, 95% CI 0.
# III.1.3 Cystic Fibrosis
The BODsr identified two studies of infants with cystic fibrosis (CF). Pooled proportion for RSVH was 12.3% (95% CI 1.3, 30.8) (ROB high) 77,78 . In between-study comparisons, RR for RSVH in comparison to term infants was 10.3 (95% CI 3.3, 31.6, p<0.000) and actual risk difference was 11.1% (95% CI -3.7, 25.9, p=0.140). One study, with a small number of admissions, reported a mean LOS of 47.00 (12.53, 81.47) (ROB moderate) much higher than in previously published studies but not commented on by the authors 77 . The other study (moderate ROB) reported a mean LOS of 10 days
. Due to a lack of data (standard deviation not reported by Groves et al.), pooling was not conducted from these studies for this outcome.
In the study of Bjornson, the proportion of the population at risk that was admitted to ICU because of RSV was 2.4% (95% CI -0.9, 5.6) (ROB moderate) 77 . Of the 5 admitted to hospital, 2 were admitted to ICU (40%) and one required mechanical ventilation. Mean duration of ICU admission was 5.00 days (95% CI -2.84, 12.84) (ROB moderate) 77 . The other study did not report on ICU admissions 78 .
Earlier reports also indicate that RSVH occurs more frequently in children with cystic fibrosis than in healthy children. In a systematic review rated as average by AMSTAR, rates of RSVH were 6.4-18.1%, 2.5-4.3 times higher than in healthy children. Average LOS was 2-11 days and ICU admission was reported in 12.5 % (1 of 8 hospitalized patients 22 . Another systematic review of PVZ prophylaxis in cystic fibrosis, rated as good by AMSTAR, reported RSVH rates in patients not receiving PVZ of 7.5-11.7% 20
# . SYNCYTIAL VIRUS INFECTION IN INFANTS
# III.1.4 Congenital Heart Disease
Children with hsCHD were at high risk of RSV morbidity and mortality in the era when corrective surgery was usually delayed. As repair early in infancy became the norm, the risk of severe RSV disease is expected to have decreased although data to support this are sparse. A US study showed decreasing RSVH rates before PVZ prophylaxis was recommended for this group of patients 79 .
The BODsr identified one study of children with hsCHD. Using combined data from 1997 and 2000, RSVH incidence per 1000 births of infants with hsCHD was 23 (95% CI 20, 26) (ROB moderate) 79 . Between-study comparison with RSVH rates for healthy term infants could not be made. For other reported hospitalization-related outcomes, only combined data including years after PVZ became available was presented, and therefore these outcomes were excluded from analysis.
In earlier studies, a systematic review of data from 1995 to 2015, rated as average by AMSTAR, reported RSVH rates of 3.8 to 10.2 % in children < 2 years of age with hsCHD 65 . The Canadian Paediatric Society statement reported RSVH rates of 1.3 to 15% in studies carried out between 1992 and 2008 8 . RSVH rates decreases with age. Rates in the placebo arm of a 1998-2002 RCT were 9.7% for all infants (< 24 months old), 12.2% for infants < 6 months old, 7.3% for those 6 to 12 months old and 4.3% for those 1-2 years old (ROB low) 80 . In observational studies, the RSV hospitalization rate in infants with hsCHD is also significantly higher in those aged <12 months than in those aged 12-24 months. In the study identified in the BODsr, reporting on RSVH in the USA from 1997 to 2012 and spanning the pre and post PVZ eras, 85% of hospitalizations occurred in the 1st year of life 79 . Chiu et al. in Taiwan in 2005-10 reported RSVH rates of 4.8% and 2.1% with cyanotic and acyanotic hsCHD respectively in the first year of life and 0.9% and 0.56% in the second year (ROB moderate) 81 . Resch reported a 9.6% hospitalization rate in 2004-08 study including children with hsCHD and nonhemodynamically significant CHD, some of whom received PVZ, with 56 of 58 infections occurring in the 1st year of life 82 . In a study of children with CHD (not necessarily hemodynamically significant) using Medicaid data from 1989-93, estimated RSVH rate was 9.2% in the 1st year and 1.8% in the 2nd year (ROB moderate) 43 .
In the systematic review of Checchia, median LOS for RSVH for children with hsCHD was 7 to 9.7 days. The proportion of hospitalised patients admitted to ICU was 30.4 -46%, median ICU LOS was 10 days and the proportion receiving mechanical ventilation was 30% 65 . In the placebo arm of the1998-2002 RCT, mean LOS was 13.3 days, 38.1% of those hospitalized were admitted to ICU for a mean of 19.2 days and 22.2% required MV for a mean of 25.3 days (ROB low) 80 . In the study of Chu, children with hsCHD (with or without PVZ prophylaxis) hospitalized for RSV had longer mean hospital LOS (12.1 versus 3.4 days, p<0.001), higher rates of MV (21.9% vs 2.3%, p<0.001) and higher rates of respiratory syncytial virus-associated mortality (2.8 versus 0.1%, p<0.001) when compared with children without hsCHD 79 .
Feltes et al. reported RSV-related deaths among hospitalized infants with hsCHD of 0.6% (ROB low) 80 . In a meta-analysis of studies from 1990 to 2007 all-cause mortality rate in the first RSV season was 4.17% and RSV-attributable mortality was 0.62% (AMSTAR rating average) 74 . In a systematic review of literature from 1975 to 2011, the weighted mean case fatality rate for infants age ≤ 24 months hospitalized with RSV was 5.2% (range, 2.0-37.0%; median, 5.9%; n = 7) for children with CHD (AMSTAR rating poor) 66 .
# III.1.5 Down Syndrome
There is evidence that children with Down syndrome have a higher risk of RSVH than healthy children. This increase is partially explained by co-morbidities such as CHD, CLD or prematurity. Excluding children with these comorbidities, risk remains increased. Possible explanations for this include anatomic abnormalities of the upper respiratory tract, airway malacia, swallowing dysfunction, hypotonia and immune dysfunction 83 .
The BODsr did not identify any studies of children with Down syndrome that were limited to those < 2 yr of age. A single observational study of moderate COE comparing RSV outcomes in children with Down syndrome and healthy children < 3 years of age was identified. For children with Down sndrome and no other risk factors for severe RSV, RSVH rate was reported to be 2%, vs 1.1% in healthy controls, but the RSVH data had some inconsistencies and could not be further assessed. The median LOS was 5 days versus 2 days for healthy controls (mean difference 3.00 days, 95% CI 1.95, 4.05) (low COE) 84 .
A meta-analysis published in 2018 of studies to May 2017, rated by AMSTAR as average, reported a pooled odds ratio (OR) 83 . The authors report that in the single study that included only infants with no other risk factors, there was no mortality and LOS, oxygen need, ICU admission and mechanical ventilation did not differ from those reported for the whole group. An earlier systematic review , rated by AMSTAR as average, reported RSVH rates of 3.6 -13.5% in infants with Down syndrome and no other known risk factors for severe RSV. Risk ratio vs healthy infants was 3.5-10.5 and average LOS was 4-5 days 22 .
III.1.6.Immunocompromised Children RSV can cause significant morbidity and mortality in immunocompromised children. Serum and secretory antibodies are important in preventing RSV infection and T cells are required to efficiently clear the virus. There is very little population based data on the burden of RSV disease in this group. Although most infections occur in young children, immunocompromised older children and adults are also at risk of severe RSV disease and death. Morbidity varies by severity of immunocompromised 22 .
The BODsr identified two studies of immunocompromised children. A USA multicenter study in 2004-2012 reported on RSV hospitalization in liver transplant recipients <18 years of age 85 . Multivariate analyses identified age <2 years at transplant as a predictor of RSVH (P < .001). RSVH rate in the first 2 years post-transplant (for all aged <18 yr) was 5.3% (95% CI 4.4, 6.2) (ROB moderate). Between-study comparisons (all at very low COE) showed a RR for RSVH of 4.4 (95% CI 4.0, 4.9, p<0.000) versus healthy term infants. Actual risk difference was 4.1% (95% CI 3.2, 5.04, p=0.000). The proportion of hospitalized patients that were admitted to ICU was 22.2% (95% CI 15.2, 29.2) (ROB low). RR for ICU admission among those hospitalized for RSV was 1.4 (95% CI 0.8, 2.5, p=0.242, very low COE) versus healthy term infants. Actual risk difference was 6.4% (95% CI -7.8, 20.6, p=0.375; very low COE). Of those admitted to hospital, 10.4 % (95% CI 5.2, 15.5), received MV (ROB low). RR for MV amongst those admitted to hospital was 0.7 (95% CI 0.5, 1.1, p=0.156) versus healthy term infants, with actual risk difference of -3.6% (95% CI -11.5, 4.3, p=0.372, all at very low COE) 85 .
The second study was of RSV infections in children less than 18 years of age with sickle cell disease. This single center retrospective study reported a RSVH rate of 63 per 1000 person-years (95% CI 44, 87) for children < 2 years of age (ROB moderate). Other outcomes (LOS, ICU admission, mechanical ventilation), were reported only for all children aged less than 18 years and did not differ significantly from those of healthy term infants age < 2 years 86 .
An earlier systematic review, rated as average by AMSTAR, reported that most RSV infections in haematopoietic stem cell and solid organ transplant recipients occur in the first 2 years after transplant. Immunocompromised children < 2 years of age with RSVH had a median LOS of 7 and 10 days, with ICU admission occurring in 13% and 19.1% and intubation and/or mechanical ventilation in 3% and 14.3%. Overall case fatality rates were 0% and 4.8% 22 . In a Danish study of children less than 2 years old, carried out in 1997-2003, rates of first hospitalization for RSV were 21.3% in children with congenital immunodeficiencies and 8.4% in children with cancer, while the overall rate in the population of this age was 2.8%. Duration of hospitalization was not increased (ROB moderate) 21 .
El Saleeby et al. reported on RSV infections in 58 individuals aged < 21 years with cancer in Tennessee between 1997 and 2005. In multivariate analysis, age ≤ 2 yr and absolute lymphocyte counts of < 100/mm 3 at the time of RSV infection were found to be independent predictors of the development of LRTI, with OR of 9.84 (95% CI 1.95, 49.8) and 7.17 (95% CI 1.17, 44.03) respectively. These factors were also significantly associated with death 87 . In a Seattle study of HSCT recipients, the majority of whom were adults, absolute lymphocyte count of ≤100 / mm3 at the time of symptom onset was a risk factor for RSV disease progression 88 .
# III.1.7 Children Residing in Remote Communities
The BODsr identified two studies of infants in remote communities. Data from the two studies were not pooled due to differences in study design and patient populations.
One study of infants living in Canadian northern Inuit communities, carried out in 2009, (about 20% of the birth cohort, with or without prematurity or co-morbidities) reported an overall RSVH rate of 66.9 admissions per 1000 live births per year among children <1 year of age (ROB high), with regional RSVH rates of 2.0% in the Northwest Territories, 7.5% in Nunavut, and 17.6% in Nunavik. In different areas of Nunavut rates were 19.5%, 9.1% and 3.7% 23 .
The second was a study of healthy term Native American infants living on reservations in southwestern USA 89 . The RSVH rate was 12.8% (95% CI 10.1, 15.5) (ROB high). In between-study comparisons (very low COE), RR for RSVH was 10.7 (95% CI 9.4, 12.1, p<0.000). Actual risk difference was 11.6% (95% CI 8.9, 14.3, p=0.000). Mean LOS was 4.7 days (95% CI 4.2, 5.2) (ROB moderate). Mean difference in LOS versus healthy term infants was 1.2 days (95% CI -0.10, 2.5), p <0.802, very low COE). The proportion of hospitalized patients that were admitted to the ICU (ROB moderate) was 6.3% (95% CI 1.0, 11.6). RR for ICU admission was 0.4 (95% CI 0.04, 1.2, p=0.091). The actual risk difference was -9.5% (95% CI -22.9, 3.9, p=0. 164 ). Mechanical ventilation was required for 2.5% of hospitalized patients (95% CI 0.9, 5.9) (ROB moderate) for a mean duration of 6.5 days (95% CI 3.6, 9.4) (ROB moderate).
The 2020 literature search update did not identify any studies of populations living in remote communities. Subsequent to that search, results of a recent observational study from Nunavik, Quebec became available (ROB high) 90 . RSVH rates for 2013-2019 was 5.0 % for all infants < 1 yr of age (7.3% after adjustment for possible under detection by rapid antigen test compared to PCR), a much lower rate than that reported in 2009 91 . Previous studies indicate that children living in remote northern Inuit communities have high rates of RSV infection. In 2002, 16.6% of Baffin Island infants less than 1 year of age were admitted to Baffin Regional Hospital for RSV (ROB moderate). Rates ranged from 6.3% for infants from Iqaluit to 34.9% for infants from high risk rural communities. For infants of less than 6 months of age, overall RSVH rate was 25% and was 51% in high risk communities 91 . Singleton et al. reported the YK district of Alaska as having the highest rate of RSVH in the world, with 43.9% of premature infants and 14.8% of term infants < 1 year of age hospitalized annually in the pre-PVZ era (ROB high) 92 . These rates are many fold higher than the overall rates of 1-2% for term infants reported in developed countries and the infected infants frequently require air transfer to community hospitals or to tertiary care institutions.
Data on the burden of RSV illness in children living in other aboriginal communities in North America is very limited 93 and there is no information for other remote communities.
# III.1.8 Other High Risk Infants
The BODsr and the 2020 literature search update did not identify any additional groups at risk for severe RSV disease.
# III.2. RSV Infection and Long Term Sequelae: Recurrent Wheezing, Asthma and Pulmonary Function
Several studies have shown RSV LRTI in early life to be associated with recurrent wheezing in childhood. Some studies suggest that post RSV recurrent wheezing is transient, with wheezing decreasing to background levels over the first decade 94 . Whether RSV in infancy predisposes to the development of asthma, or if infants genetically predisposed to develop asthma are at increased risk of severe RSV disease in infancy, is not known 95 but there is some indirect evidence for the latter. In a prospective cohort of healthy term newborns, infants who later developed severe RSV infection and post-RSV wheezing had lower results on pulmonary function tests in the neonatal period than those that did not 36 , and another study showed bronchial hyper-responsiveness in otherwise healthy term neonates who later developed severe bronchiolitis 96 . Genetic factors predisposing to severe RSV have been described 94,95 . An association between early rhinovirus infection and asthma has been reported 95 , as well as an association between asthma and the frequency of respiratory viral infections in early life rather than any specific etiology 97 . A recent World Health Organization review determined that the evidence is inconclusive in establishing a causal association between RSV lower respiratory tract infection and recurrent wheezing in childhood or asthma and that the evidence does not establish that RSV monoclonal antibody will have a substantial effect on these outcomes 98
# . SYNCYTIAL VIRUS INFECTION IN INFANTS
The BODsr identified 6 studies that assessed long term respiratory sequelae of RSV infection in infancy.
A study of children born at 32-35 wGA with or without RSVH at < 12 months of age found small increases in the proportions with parent or physician reported simple wheeze (< 3 episodes within 12 months) (RR 1.4, 95% CI 1.15, 1.60, absolute increase 18%), parent or physician reported recurrent wheezing (≥3 episodes in 12 months) (RR 1.70, 95% CI 1.27, 2.29, absolute increase 19%), or physician reported severe wheeze (≥ 1 hospitalizations or ≥3 medically-attended episodes or on medication for wheeze for 3 consecutive months or 5 cumulative months) (RR 1.59, 95% CI 1.13, 2.24, absolute increase 14%) from 2 to 6 years of age. There was little to no difference in wheezing during the 6 th year, with RR 1. 16 32 .
A study compared infants born at < 33 wGA versus at term for wheezing in the year following RSVH. There was no significant difference in simple, recurrent or severe wheeze between the two groups (RR 0.54, 95% CI 0.18-1.55; RR 0.80, 95% CI 0.04, 16.14; RR 0.00, 95% CI -0.34, 0.34 respectively but numbers with RSV were small) (very low COE) 29 .
A study of wheezing in the first year of life in healthy term infants with RSV infection who did or did not require hospitalization found little or no difference in parent-reported days with wheeze per month between the two groups (mean difference 0.70; 95% CI -0.94, 2.34) (very low COE) 36 .
Relative risk for physician diagnosed asthma at age 7 years among healthy term infants born to mothers with asthma who had RSV versus another respiratory infection in the first year of life was RR 2. 33 99 . Some studies also addressed pulmonary function. There was little to no difference in the proportion of children born at 32-35 wGA with Force Expiratory Volume in one minute (FEV1) Z score ranking of -2 or -1 in the 6 th year of life among those who did or did not have RSVH at age < 12 months (RR 0.83, 95% CI 0.45, 1.53) (COE low). 32 Infants with or without RSVH at age < 24 months were evaluated at age 17-20 or 28-31 years. Prebronchodilator, there was a small decrease in mean percent of predicted FEV1 (mean difference -7.63, 95% CI -11.35, -3.91) and in the mean percent of predicted Forced Vital Capacity (FVC) (mean difference -4.74, 95% CI -7.80, -1.67) (COE low). There was little or no difference in the mean percent of predicted FEV1/FVC (mean difference -3.20, 95% CI -9.07, 2.67) or the mean percent of predicted Maximum Expiratory Flow after 50% of expired FVC (MEF50) (mean difference -4.00 95% CI -14.95, 6.95) (COE very low) 99,100 . There was little to no difference in the change in mean percent predicted FEV1 (mean difference 0.81, 95% CI -0.67, 2.30) (COE low) after administration of bronchodilator. There was very uncertain evidence on the change in mean percent predicted FVC (mean difference 0.60, 95% CI -0.67, 1.87) (COE very low), FEV1/FVC (mean difference -0.20 95% CI -2.71, 2.31) and the change in mean percent of predicted MEF50 (mean difference 3.70, 95% CI -5.42, 12.82) after administration of bronchodilator (COE very low).There was little or no difference for fractional exhaled nitrous oxide between those with or without RSVH at age < 24 month (mean difference -1.00 95% CI -14.49, 12.49) (COE low) 99,100 .
Single arm data showed rates of recurrent wheezing after RSVH in infancy of 12.4% (95% CI 6.3, 18.5; ROB moderate) for parent-reported or physician-diagnosed recurrent wheezing and 8.0% (95% CI 3.0, 13.0) for physician diagnosed severe wheezing at age 6 yr 32 . In other studies rates of physician-diagnosed asthma after RSVH in the first year of life were 26.9% (95% CI 14.9, 39.0; ROB low) at age 7 yr 97 , and 23.3% (95% CI 10.6, 35.9; ROB moderate) at age 28-31 yr 99 .
The 2020 literature review update identified two studies that looked at long term recurrent wheezing or asthma. In a prospective birth cohort study, premature infants of 32-25 wGA were followed up at 6 years of age for parent-reported wheeze within the previous 12 months. Wheeze was reported for 27.7% of children with RSVH in infancy versus 17.6% for those without RSVH (OR 1.80, 95% CI 1.11, 2.85). After adjustment for confounding factors, OR was 1.89 (95% CI 1.06, 3.32). When stratified by atopic predisposition (defined as atopic disease in at least one parent), the difference was significant only for the group without atopic predisposition (ROB high) 101 . A retrospective matched cohort study of term infants without hsCHD, congenital lung disease or respiratory tract anomalies who did or did not have RSV infection in the first year of life assessed asthma or reactive airway disorder, identified from administrative claims databases, in the first 5 years of life. Cumulative incidence of asthma or reactive airway disorder for children with or without a history of RSV infection was 25.2% vs 11.4%, aOR (95% CI) 2.6 (2.5, 2.9), p <.0001; 35.4% vs 16.7%, aOR 2.8 (2.6, 2.9), p <.0001; and 24.4% vs 12.7%, aOR 2.2 (2.0, 2.4), p <.0001 in three administrative databases (ROB high) 102 .
# III.3 RSV Reinfection
Reinfections with RSV occur throughout life. Naturally acquired immunity does not protect against subsequent infection, although it may modify disease severity with the initial infection usually being the most severe infection during childhood . In addition, two antigenically distinct RSV subgroups, A and B, may circulate during the same season 105,106 . In a study of 30 infants under 2 years of age with bronchopulmonary dysplasia (BPD), one child had two RSVH in the same season (3.3%) 107 . Two prospective studies from Spain of children born at ≤ 32 weeks gestation reported recurrent RSVH in the same season in 6/584 (1.0%) and 9/999 (0.9%) of patients 108,109 . For these reasons, previous statements from NACI 4 and AAP 5 recommended continuation of PVZ if an infant had a breakthrough RSV infection while receiving prophylaxis. However, more recent data suggest that repeat RSV infections in the same season are rare. A study of 240 premature infants of <28 wGA or birth weight <1000 g in Denmark identified only 1 child with two RSVH in the same season (0.4%) 110 . In a placebo-controlled trial of PVZ in children with CHD, only 0.39% of children (3 of 648 in the placebo group and 2 of 639 who received PVZ) had more than 1 RSVH in the same season 80 . In another study of 429 premature infants followed for 1 year, there were no RSV reinfections 111 112 . In another outpatient study of children less than 5 years of age, of 1802 children with RSV respiratory tract infections over 2 seasons only 1 had two infections in the same season, one of RSV-A and one of RSV-B 113 . Because of the rarity of repeat infections in the same season, the AAP (2014) 6 and CPS (2015) 8 now recommend that if a child experiences a breakthrough RSVH while receiving PVZ, monthly prophylaxis should be discontinued.
# III.4 RSV Infection Risk and Siblings of Multiple Births
In a case-control study of preterm infants with BPD, fourteen sets of twins and two sets of triplets were matched with 34 singleton infants for date of birth and gestational age. The risk of developing RSV illness was significantly higher in multiple-birth infants than in singletons (53% vs 24%; p=.01), as were the rate of RSVH (32% vs 18%; p=.05) and the rate of RSV pneumonia (24% vs. 6%, p = 0.05).
After controlling for confounders in a matched logistic multiple regression analysis, multiple birth was still significantly associated only with the development of pneumonia (p=.048) 114 . In another study, Resch and colleagues retrospectively evaluated rates of hospitalization due to respiratory illness in 435 premature infants of 29-36 weeks gestation without chronic lung disease. They found that multiple birth was associated with RSVH (55% vs. 15%, p = 0.013). Multivariate analysis to consider confounding factors was not done 115 .
In contrast, two larger prospective studies of risk factors linked to RSVH, involving a total of 2326 premature infants, found similar proportions of infants of multiple births in the groups with RSVH and in the control groups 71,116 .
In a retrospective study of infants hospitalized with RSV bronchiolitis, twins represented 7.6 % (66/875) of hospitalizations. Of the 53 pairs of twins with at least one twin with RSVH, if one twin was hospitalized the other had a 34% chance of also being hospitalized with bronchiolitis (24% chance of being hospitalized with RSV positive bronchiolitis) during the same period. However, infants in the twin group were younger and had lower gestational age than singletons. In multivariate analysis, being born a twin was not a significant risk factor for RSV disease severity 117 .
# III.5 Healthcare Associated RSV Infections
RSV is frequently transmitted in hospitals, including in neonatal intensive care units 118 . The available data indicates that RSV infection rates during the birth hospitalization do not differ among infants who receive PVZ prophylaxis while in the neonatal unit compared with those who receive PVZ starting at hospital discharge . These studies were rated as fair (Harris criteria) 122 . The 2003 NACI statement on PVZ did not address the issue of administration of PVZ to in-patients 4 . The 2014 AAP Statement states that infants in a neonatal unit who qualify for prophylaxis may receive a dose 48-72 hours before discharge home or promptly after discharge 6 . The CPS states that for eligible infants being discharged home for the first time during RSV season, PVZ should be started just before discharge 8 . The United Kingdom's Green Book states that infants in neonatal units who are in the appropriate risk groups should begin PVZ 24 to 48 hours before being discharged. 123 To avoid wastage when vials are being opened daily for single infants about to be discharged, coordinating administrations to three times weekly has been suggested 121 .
PVZ has frequently been used to control RSV outbreaks in neonatal units. In some instances PVZ was administered to all exposed infants 118, , in others only to those would have qualified for PVZ as outpatients 118,127,128 . PVZ was started after other infection control measures had failed in some outbreaks 118,124 , and at the time of recognition of the outbreak in others 118, . The incremental role played by PVZ in control of these outbreaks could not be determined 118 . PVZ may be useful when other measures have failed to control an outbreak or when it is anticipated that adherence to infection control recommendations will be poor 118,126 .
Although not addressed in the AAP 2014 or the CPS statements, the 2009 AAP PVZ statement indicates that infants who have begun PVZ prophylaxis earlier in the season and are hospitalized on the date when a dose is due should receive that dose as scheduled 5 . Likewise the UK Green Book states that those infants that have begun a course of PVZ but are subsequently hospitalized should continue to receive it whilst they remain in hospital 123 .
IV. PRODUCT
# IV.1 Preparation Authorized for Use in Canada
The only product currently authorized for use in Canada for prevention of serious RSV disease is PVZ (Synagis®, AbbVie AstraZeneca, Mississauga, Ontario). PVZ is a humanized monoclonal antibody (IgG1κ) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of RSV, a surface protein that is highly conserved among RSV isolates. It is a composite of 95% human and 5% murine amino acid sequences 129 . It was authorized for use in Canada in 2002.
PVZ solution for injection is available in 50 mg/0.5 ml and 100 mg/1 ml single use vials. Non-medicinal ingredients included are chloride, glycine, histidine and water for injection 129 .
# IV.2 Efficacy and Effectiveness
Studies of the efficacy and effectiveness of PVZ in preventing severe consequences of RSV infection in children at high risk of severe RSV disease are reported in the document "NACI Literature Review on the Effects of PVZ Prophylaxis on Reducing the Complications Associated with Respiratory Syncytial Virus in Infants" which will be forthcoming. Results are summarized below. In mixed populations of infants at risk of severe RSV infection, PVZ prophylaxis is associated with reductions of 38 -86% in the risk of RSV-associated hospital admissions, with number needed to treat (NNT) to prevent one hospitalization of 2 to 24. Differences in the health conditions of the mixed populations preclude definitive conclusions about relative benefits for different patient groups. Studies of mixed populations will not be discussed further here, but are included in the Literature Review which will be forthcoming. Twelve studies examined the effect of PVZ prophylaxis on RSVH in premature infants without CLD: a systematic review and meta-analysis of average quality 74 , four RCT reports of good 41,48 or average quality 111,130 , six observational cohort studies of either good 131 , average or fair 27,44,49 , or poor 47,132 quality and one case-control study of fair quality 133 .
The systematic review and meta-analysis of studies from 1990 to 2007 found that compared to no prophylaxis, PVZ use was associated with 72% fewer RSVH in infants born at ≤32 wGA and 74% fewer in infants born at 32-35 wGA 74 . The IMPACT RCT, carried out in 1996, reported a 78% decrease in rate of hospitalization for RSV in premature infants aged ≤ 6 months without CLD who received PVZ, with a NNT of 16 48 . The decrease was 47% for infants ≤ 32 wGA and 72% for those 32-35 wGA 48 . Notario et al. further analyzed the data from the IMpact study by gestational age groups. PVZ resulted in significant reductions in hospitalization rates for infants of 28-31 wGA (73%), 29-32 wGA (80%), 32-34 wGA (82%), and 32-35 wGA (82%), but not for those <29 wGA or 33-35 wGA. The numbers in these two latter groups were small 41 . NNT ranged from 13 to 21 and decreased with increased gestational age. A similar significant protective effect of PVZ prophylaxis was found in a later RCT of infants 33-35 wGA enrolled in 2008-10 (82%. NNT 24) 111 and a small RCT of infants born at ≤32 wGA enrolled in 2009-11 (OR 0.26, NNT 5) 130 .
In the prospective case-control study rated as fair quality, conducted from 2002 to 2006, PVZ effectiveness for prevention of RSVH was 74% of 29-35 wGA infants. Effectiveness was not observed in those < 29 wGA but the numbers were small 133 .
Observational cohort studies had conflicting results about the impact of PVZ prophylaxis on RSVH in premature infants. A retrospective cohort study of fair quality of children born in 2012-2015 found a 38% lower RSVH rate in the first RSV season in infants 29-32 wGA who received PVZ compared to infants receiving no prophylaxis (NNT 53), but no statistically significant difference in RSVH in infants 33-36 wGA who did and did not receive PVZ prophylaxis. However, numbers of children prescribed PVZ and adherence to PVZ prophylaxis in the latter group were low 27 .
In an observational study rated fair quality, PVZ prophylaxis did not significantly reduce RSVH rate for infants of ≤ 28 wGA without CLD enrolled between 2011-2013 compared with a historic control group born in 2000-2008 44 . However, the sample sizes were small.
PVZ was not significantly effective in cohorts of children born at 32-35 wGA in 2002-3 in a study rated as good quality 131 . Another cohort study of infants born at 32-34 wGA from 1995-2004, rated as fair quality, found a significant reduction in RSVH in Texas (OR=0.45, 95% CI 0.26, 0.78, p =.005) but not in Florida (OR=0.81, 95% CI 0.42, 1.58, p =.54) 49 .
In a study rated as poor quality, PVZ prophylaxis was found to significantly reduce RSVH in a cohort of children born at ≤30 wGA in 1999-2004 (1.1 % vs 13.6%, NNT 9) 47 .
# SYNCYTIAL VIRUS INFECTION IN INFANTS
In summary, there is good evidence, based on early RTC, of the efficacy of PVZ in premature infants of 28-35 wGA. The conflicting results of observational studies on infants of 32-36 wGA are difficult to explain, but may in part be due to differences in study design, adherence, location and era. Three studies, one of good and two of fair quality, suggested lack of effect in infants of < 29 wGA but this may be the result of small numbers of infants without CLD in this very premature group 41,44,133 . One observational study of poor quality supported a protective effect in infants of ≤ 30 wGA. In general, it appears there is evidence in support of the effectiveness of PVZ in reducing RSVH in children born prematurely, although the level of prematurity at which PVZ is most effective is not clear from the data.
# IV.2.1.2. Mortality
The only study that examined all-cause mortality was a systematic review and meta-analysis of average quality by Checchia et al. In infants born at ≤32 wGA. PVZ recipients had a significantly reduced risk of all-cause mortality (OR=0.25, 95% CI 0.13, 0.49, p<0.001) compared to recipients of placebo or no intervention, while in infants born at 32-35 weeks' GA, the difference was not significant (OR=0.22, 95% CI 0.03, 1.89, p=0.085) 74 .
It is possible that there may be a differential impact of PVZ prophylaxis on all-cause mortality in this population, showing a protective effect in infants born at ≤32 weeks' GA, but not at lesser levels of prematurity (32-35 weeks' GA). However, these findings are based upon few studies which may have been underpowered to detect difference in mortality in the less premature infants.
# IV.2.1.3 Long Term Sequelae
# IV.2.1.3.1 Recurrent Wheezing and Atopic Asthma
Six reports examined the effect of PVZ prophylaxis on the risk of wheezing in the first few years of life: Two reports of average or fair quality from a RCT 111,134 and four reports from two cohort studies of good 135 , average or fair 136,137 and poor 138 quality. One study 111 investigated parent-reported wheezing only, while the other five investigated physician-diagnosed or both parent-reported and physician-diagnosed wheezing. Three studies found that PVZ prophylaxis in otherwise healthy premature infants born at 33-35 wGA 111,138 or ≤35 wGA 136 , resulted in a significant reduction (46-66%) in the risk of wheezing in children in the first year of life 111 , up to age 3 138 , or up to 2 years after enrollment at age ≤36 months 136 . In another report from the cohort study of Simoes et al., children who had received PVZ prophylaxis had a significantly decreased incidence of physician-diagnosed wheezing 24-months after study enrollment and a significantly longer time to a third physiciandiagnosed wheezing episode compared to children receiving no intervention, but only in children without a family history of asthma or atopy. There was no significant difference in these outcomes in children with a family history of asthma or atopy 135 . A follow-up of the cohort of children born at 33-35 wGA initially assessed for wheezing at age 3 years 138 found that children who had received PVZ prophylaxis had reduced rates of physician-diagnosed recurrent wheezing during the first 6 years of life compared to children who had not received prophylaxis. However, this association was found only in the subgroups of children with a family history of allergy. The authors distinguished atopic asthma (recurrent wheezing and elevated IgE) from recurrent wheezing and found rates of atopic asthma were similar in children who received PVZ and those who did not, regardless of family history of allergy 137 .
On follow-up at age 6 years of the infants enrolled in the Blanken et al. RCT, the difference between PVZ and placebo recipients was significant only for those with parent reported infrequent wheeze (1-3 episodes per year). There was no significant difference in physician diagnosed asthma or the use of asthma medication in the previous 12 months and pulmonary function at 6 years of age did not differ between the groups 134 .
It appears PVZ may have a consistent impact in reducing the incidence of recurrent wheezing in young children in the first few years of life, but the findings are contradictory as to the relative impact of PVZ versus a family history of atopy on subsequent recurrent wheezing in older children. It also is not clear from these studies at what level of prematurity PVZ may be most effective in having a long term impact. The NNT to prevent one case of recurrent wheezing was 7-8 in infants of 48 .
In an observational study rated as fair, PVZ prophylaxis reduced RSVH rate by 86% (NNT 13) in the first 6 months after initial hospital discharge for infants with CLD enrolled between 2011 and 2013 compared with a historic control group born in 2000-2008. By gestational age, reduction was significant for those of ≤28 wGA (89%, NNT 12) and not those 29-35 wGA, but numbers in the latter group were small 44 . An earlier prospective observational cohort study of poor quality of infants born at ≤32 wGA, carried out in 1999-2002 , found PVZ prophylaxis to be associated with a reduced risk of RSVH (RR=0.15, 95% CI 0.05, 0.49, p<0.01; NNT 3) in the 1st RSV 139 . Another prospective observational study of poor quality that included children up to 24 months of age with CLD also reported reduced risk of RSVH (RR=0.28, 95% CI 0.14, 0.58, p<0.007; NNT 8) 46 . In a prospective case-control study, rated as fair quality, of infants ≤35 wGA and <12 months or 12-24 months of age, conducted from 2002 to 2006, there was no significant reduction in hospitalization rate 133 .
The results suggest that PVZ prophylaxis provides a reduction in the risk of RSV-associated hospital admissions in this population, but the influence of gestational age on this benefit is not clear.
# IV.2.2.2 Mortality
A meta-analysis of average quality showed no observed effect of PVZ vs no intervention/placebo on all-cause mortality for preterm CLD (0.22% vs. 0.34%; Peto OR, 0.83; 95% CI 0.13, 5.25), but there were only 3 events in the prophylaxis group and 2 events in the placebo/no intervention group 74 . 144 .
No conclusions on the effectiveness of PVZ prophylaxis in reducing the risk of RSVH in children with cystic fibrosis can be drawn from the findings of these studies. Only the observational study of Groves et al. found a significant preventive effect of PVZ prophylaxis on RSVH 78 . The rate of RSVH in the control group in that study was very high and the number of participants was small. Most studies had small numbers and may have been underpowered to detect an effect. The exception was the large study of Winterstein et al, which used a health care provider administrative database 142 . It may be that some children with cystic fibrosis, e.g, those with significant chronic lung disease in the first 1 or 2 years of life, may benefit. Robinson et al examined the effect of PVZ prophylaxis on the use of oxygen therapy due to RSV in children with cystic fibrosis. No significant difference between the groups was found in the need for oxygen therapy; however, the number of outcomes was small (PVZ prophylaxis group, n=1; placebo intervention group, n=0) 140 . In the study of Bjornson, increased respiratory support, either MV or oxygen therapy, was required by 2.2 % of PVZ recipients and 1.2% of the control group (p 0.58) 77 . In the study of Buchs, no patients required supplemental oxygen or MV 144 .
# IV.2.3.3 All-Cause Mortality
The RCT study examined the effectiveness of PVZ prophylaxis in reducing all-cause mortality in children with cystic fibrosis. However, as there were no deaths identified in either group during the 6 months of follow-up during the study, no conclusion can be drawn about the effect of PVZ prophylaxis on this outcome 140 . A larger cohort study by Fink et al. also reported no difference in all-cause mortality before age 2 years between those who did or did not receive PVZ 145 .
# IV.2.3.4. Long-Term Sequelae
# IV.2.3.4.1 Lung Function
A small historical cohort study of fair quality found no significant difference in lung function (as assessed by measurement of FEV1) between children with cystic fibrosis who had and had not received PVZ was found on follow-up assessments at 6 years of age 78 . The cohort study by Fink et al., rated as of poor quality, also found no difference in FEV1 at age 7 years between those who did or did not receive PVZ 145 .
# IV.2.3.4.2 Growth Parameters
The RCT found no significant differences between the PVZ and placebo groups at 12 month followup with respect to weight gain or weight to height ratio 140 . A small historical cohort study found no significant differences in growth parameters (weight, height, body mass index) at 6 years of age between children who did and did not receive PVZ prophylaxis 78 . The case control study of Buchs et al, also found no significant difference between PVZ recipients and controls in growth in the first 3 years of life 144 .
# IV.2.3.4.3 P. aeruginosa and S aureus Colonization
The RCT found no statistically significant differences in the numbers of children with P. aeruginosa airway colonization in children receiving PVZ compared to those receiving placebo at 12 months follow-up. 140 In the study by Groves et al, the median time to a first isolate of P. aeruginosa was SYNCYTIAL VIRUS INFECTION IN INFANTS significantly shorter in PVZ recipients than in non-recipients and the relative risk of a first isolate during the study period was also significantly increased in PVZ recipients. However, at follow-up at 6 years of age there was no significant difference in chronic P. aeruginosa colonization rates between the two groups 78 . Buchs et al, reported that PVZ prophylaxis had no significant effect on age at first colonization with P. aeruginosa or S. aureus or in the proportion of children colonized with P. aeruginosa by age 3 years. The proportion of infants colonized with S. aureus by age 3 years was significantly increased in the PVZ recipients (97%) in comparison to controls (85%) 144 . Fink et al. also reported no difference in time to first P. aeruginosa colonization between those with or without PVZ prophylaxis 145 .
The results from the these studies appear consistent with no significant differences in the longer term sequelae examined between children with cystic fibrosis who have and have not received PVZ prophylaxis. However, the number of children studied was small. Five studies examined the efficacy or effectiveness of PVZ prophylaxis in children with hsCHD. A good quality RCT carried out in 1998-2002 80 found that children with hsCHD and ≤24 months of age at the start of the RSV season who received PVZ prophylaxis had a significant relative decrease in RSVH compared to children receiving placebo (RD=45%, p=0.003; NNT 23). This was statistically significant in children with acyanotic CHD (RD=58%, p=0.003; NNT 15), but not in children with cyanotic CHD (RD=29%, p=0.285). An observational cohort study of fair quality of infants < 1year of age, with PVZ recipients in 2013-2015 followed prospectively and controls from 2010-15 identified retrospectively found a significant reduction of 49% (NNT 45) for all cases and 65% (NNT 31) for the subgroup with cyanotic hsCHD but a non-significant reduction of 35% for those with acyanotic disease
. A significant relative risk of 0.28 (72% reduction, NNT 7) in hospitalization for all cases of hsCHD < 1 year of age was reported in a small observational study of fair quality with PVZ recipients enrolled between 2014-16 and historical controls born in 2007-09 147 . An earlier poor quality observational cohort study with PVZ recipients from 2003-07 and historical controls born 1998-03 did not find PVZ prophylaxis to result in a significant reduction in RSVH compared to no intervention in children with CHD who were born at ≤36 w GA and ≤24 months of age at the start of the RSV season (RR=0.58, 95% CI 0.21, 1.65), but the RSVH rate in the control population was very low (2.9%) 148 . In a prospective case-control study of fair quality, carried out from 2002-6, significant PVZ effectiveness was not observed, either in the first or the second year of life 133 .
These studies show conflicting results on the protective effect of PVZ on RSVH in infants with hsCHD. The two studies that did not show a significant effect 133,148 had smaller numbers of participants than two larger studies that showed 45-49% risk reduction 80,146 . One of these studies showed significant protection in children with cyanotic heart disease but not in those with acyanotic heart disease 146 , but the other showed the opposite 80 . The reasons for these discrepancies are not evident but may be due to inadequate sample size to detect a difference in the subgroups. SYNCYTIAL The RCT involving children with hsCHD and ≤24 months of age found PVZ recipients to have a significant relative decrease in the total number of RSVH days/100 children compared to placebo recipients (RD=56%, p=0.003) 80 . For those admitted to hospital because of RSV, mean LOS was 10.8 days for PVZ recipients and 13.3 days for placebo, not significantly different. In the study of Chiu et al, the LOS was not significantly different in patients who did or did not receive PVZ, either for the total group or for those with cyanotic or acyanotic hsCHD 146 .
# IV.2.4.2.2 Admission to and Length of Stay in Intensive Care Unit due to RSV
The RCT of children with hsCHD aged ≤24 months reported that compared to placebo recipients, PVZ recipients had a relative decrease in the number of admissions to ICU but the reduction was not significant (RD=46%, p=0.094) 80 . In the observational cohort studies, Chiu et al, reported no significance differences in rates of admission to ICU in those who received PVZ and those who did not, either for the total group or for those with cyanotic or acyanotic hsCHD, and Harris et al also found no significant difference in rate of admission to ICU. In the three studies, the proportions of infants hospitalized for RSV who required ICU admission were also not significantly different in the groups that received PVZ and those that did not 80,146,148 .
In the RCT the total number of days/100 children in an ICU due to RSV did not differ significantly between PVZ and placebo recipients 80 . In the cohort study of Harris, mean ICU LOS decreased from 14.9 to 10 days but the difference was not significant 148 .
# IV.2.4.2.3 Use of Mechanical Ventilation (MV) due to RSV
The RCT by Feltes et al. found no significant difference in the use of MV, reported as total days/100 children, between children with hsCHD and ≤24 months of age at the start of the RSV season who received PVZ compared to placebo recipients (RD=41%, p=0.282) 80 .
# IV.2.4.2.4. Duration of Oxygen Therapy due to RSV
The RCT found that compared to placebo, children who received PVZ prophylaxis had significantly less total days/100 children on oxygen therapy (RD=73%, p=0.014) 80 .
These results suggest that for children with hsCHD who are hospitalized with RSV infection, having received PVZ does not affect the severity of illness, as manifested by hospital LOS, ICU admission, ICU LOS, or need for MV, although the number of studies is small.
# IV.2.4.3 All-Cause Mortality
Both the RCT by Feltes et al. and the cohort study by Harris et al. examined all-cause mortality in this population 80,148 . In the RCT, there was no significant difference in all-cause mortality between children with hsCHD and ≤24 months of age at the start of the RSV season who received PVZ compared to 150 . After adjusting for hsCHD, insignificant CHD, gestational age, and birth weight, the analysis found that compared to no intervention receipt of PVZ was associated with a statistically significantly 72% reduction in RSVH (IRR=3.63 95% CI 1.52, 8.67, p=0.002; NNT 12). Significant reduction in hospitalization was also found when the analysis was restricted to children with at least one standard risk criteria for RSV prophylaxis (hsCHD, born at ≤35 wGA, CLD) (IRR 3.39 (1.02-11.25)). However, when the analysis was restricted to children with no standard RSV risk criteria, the difference in RSVH between children receiving PVZ prophylaxis and children receiving no intervention was not significant (IRR=6.57 95% CI 0.70, 62.16). The third study, rated as good, reported a decrease in overall RSVH after PVZ prophylaxis was approved in Japan for all children with Down syndrome. For all children, the adjusted odds ratio (aOR) for those receiving PVZ was 0.41 (95% CI 0.18, 0.92, p=0.03) but there were no differences in RSVH in the groups without hsCHD (aOR 0. 43 150 .
The significance of the results from these studies, one of poor quality 150 and the other involving very few children 149 , is unclear, but suggests that PVZ may not benefit children with Down syndrome who do not have other conditions that may warrant PVZ administration. Further studies would be required before conclusions can be drawn on the benefit of PVZ in this population IV.2.6 Infants Residing in Remote Communities IV.2.6.1 RSV-Associated Hospitalizations There were two cohort studies of poor quality that examined this outcome 92,152 . The Banerji et al. study included Inuit children from Nunavut, Canada who were born at either <36 wGA and/or had significant cardiac or respiratory disease and were <6 months of age at the start of the 2009-10 RSV season. Children who received PVZ had significantly fewer RSVH (2/91, 2.2%) compared to PVZ eligible children receiving no intervention (5/10, 50%) (OR=0.04, 95% CI 0.008, 0.26, p=0.0005). The number needed to treat to prevent one RSVH was 2 152 . As not all PVZ eligible infants were identified, the actual reduction rate is likely to be less than that reported. In the study by Singleton et al., RSVH were assessed in Alaskan Aboriginal children before and after introduction of a PVZ program for high risk infants in 1998.There was a significant reduction in RSVH in infants born at ≤36 wGA (relative rate 0.34, 95% CI 0.17, 0.68, p<0.001). After the PVZ program introduction, among high risk infants the rate of first RSVH was 0.55 per 1000 PVZ protected days and 1.07 per 1000 unprotected days (relative rate 0.52; 95% CI 0.28, 0.93). The number needed to treat to prevent one RSVH was 4 92 .
Although Inuit infants residing in remote northern communities are known to be at high risk of RSVH 23 , data on PVZ effectiveness to prevent hospitalization in this group is very limited. After completion of the PVZ effectiveness literature review, the results of a program providing PVZ prophylaxis to healthy term infants less than 3 months of age during RSV season in Nunavik, Quebec became available 90 . The quality of the study was rated as fair. Between November 2016 and June 2019, 73% of 646 eligible healthy term infants received some PVZ but only 37% received all recommended doses on time. PVZ effectiveness was assessed by 1) comparing RSVH in infants who received all doses of PVZ on time and those who received no PVZ and 2) comparing RSVH during PVZ-protected and unprotected days. RSVH occurred in 10/237 infants (4.2%) who received PVZ and in 7/177 (4.0%) of those who did not. PVZ direct effectiveness was calculated to be -6.7% with wide 95% CI of -174.8, 85.5. RSVH rates were 37.6/100,000 PVZ-protected days and 39.1/100,000 unprotected days, for a direct protective effect of 3.8% with 95% CI -1167. Several studies were identified in the literature search on burden of RSV illness that described the impact of the 2014 AAP revised recommendations for PVZ use on RSVH by analyses of sequential time periods before and after implementation of the revised recommendations 6 . These studies did not meet the criteria for the literature review because children who did or did not receive PVZ were not identified, but are summarized here.
In a single tertiary center study from North Dakota, the rate of RSVH per 1,000 children <24 months old was 5.37 in the pre-2014 guideline period (2012-13 and 2013-14 seasons) and 5.78 in the post-2014 guideline period (2014-2015 season) (rate difference of +0.4, 95% CI −1.2, +2, p 0.622). The number of RSV admissions was 194. The number of doses of PVZ administered per 1000 children <24 months of age was 21.7 in the pre-2014 guideline period and 10.3 doses in the post-2014 guideline period, a reduction of 11.4 doses (95% CI 14.3, 8.4, p <0.001) 153 .
Another single center study from Milwaukee looked at numbers of RSVH in infants less than 1 year old born at ≥29-35 wGA and the proportions of all RSV admissions that were in this gestational age group 2 seasons before and two after implementation of the 2014 AAP guidelines (2012-2017). The number of RSVH was 91.There were no significant differences in the number of admissions or the proportion of admissions in this gestational age group before and after implementation of the new guidelines. Duration of hospitalization increased from a median of 5.86 days before to a median of 7.86 days (p 0.02) after implementation but there was no difference in need for ICU, supplemental oxygen, or MV 154 .
A single center study from Ohio looked at RSVH in infants <12 months old before and after implementation of the 2014 guidelines. Of 1063 RSVH, infants born at 29 0/7 -34 6/7 wGA accounted for 7.1% (34/482) in the 2013-4 season and 9.8% (57/581) in 2014-5 season (not significantly different). Infants of 29-34 wGA who were <6 months old constituted 3.5% (17/482) of RSVH in 2013-14 versus 7.1% (41/581) in 2014-15 (P = .01). Among 290/7-346/7 wGA otherwise healthy infants who were <3 months old, oxygen administration (40.0% vs 78.9%; p 0.05), pediatric ICU admission (30.0% vs 68.4%; p 0.04), MV (10.0% vs 52.6%; 0.04), duration of hospitalization (1.8 vs 8.8 days; p 0.04) were all higher in 2014-15. No differences in morbidity were observed between 2013-14 and 2014-15 in premature infants aged 3 to <6 or 6 to <12 months. PVZ eligibility decreased from 32.3% in 2013-14 to 1.8% in 2014-15 (P < .001) 51 .
A large study used commercial and Medicaid databases to assess infants born between July 1, 2011 and June 30, 2016. Infants were categorized as preterm or term and hospitalizations for RSV for infants aged < 6 months identified. Rate ratios comparing hospitalization rates for preterm and term infants were calculated. Seasonal rate ratios prior to the guidance change for preterm versus term infants ranged from 1.6 to 3.4. After the guidance change, seasonal rate ratios ranged from 2.6 to 5.6. In 2014 to 2016, the risk associated with prematurity of 29-34 wGA versus term birth was significantly higher than in 2012 to 2014 (2.00, p<0.0001 for commercially insured infants and 1.46, p<0.0001 for Medicaid insured infants, p<0.0001). PVZ use decreased by 74-97% in different wGA and age groups Another study investigated the effect of the change in recommendations for children with hsCHD. The 2014 AAP guidelines recommended PVZ prophylaxis for those in the first year of life whereas previous guidelines recommended prophylaxis for those < 2 years of age. A US national administrative healthcare database was reviewed to identify children age < 24 months with CHD admitted with RSV in the 2012-2014 and 2014-2016 RSV seasons. There were 644 RSV admissions in the 2012-13 and 2013-2014 seasons and 625 in the 2014-15 and 2015-2016 seasons. There was no change in LOS, ICU admission rate, or in-hospital mortality for children 13-24 months old with CHD after the change in recommendations. There were no deaths in 13-24 month olds, regardless of era. The population studied was not limited to those with hsCHD 157 .
Following publication of the revised recommendations from the AAP in 2014, Italy implemented similar limitations for PVZ use for otherwise healthy premature infants in the fall of 2016. In a population of 284,902 children aged <2 years in one region of Italy, the number of RSVH was 1729. Following the change in policy a reduction in the number of RSVH from 6.3/1000 (95% CI 6.0, 6.7) to 5.5/1000 (95% CI 5.0, 5.9) was observed. There was no significant difference in wGA or age on admission of children admitted with RSV in the 2 seasons before and the season after the change in policy. The number of prescriptions for PVZ decreased by 48% after the change in policy 158 .
A retrospective review of RSVH of children ≤ 1 years of age over three consecutive RSV seasons (2014-15, 2015-16, 2016-2017) was carried out in single tertiary center in Italy. Total RSV admissions for the 3 seasons was 366. The proportion that were preterm increased in the 3 seasons from 6.6%, to 7.3%, to 9.2%, respectively for the 29 -< 36 wGA group, and from 5.1% to 6.4% to 8.3%, respectively, for the 33 -< 36 wGA subgroup. These increases were not statistically significant but sample size was small 159 .
Another retrospective cohort study of RSVH among infants born at 29-35 wGA in the season before (2015-2016) or after (2016-2017) the introduction of more restricted recommendations for PVZ was conducted in three neonatal ICUs in Italy. There were 262 infants enrolled in 2015-16 and 274 in 2016-17. RSVH occurred in 1.9 and 5.1% in infants in 2015-16 and 2016-17 respectively (odds ratio 2.77; 95% CI 0.98, 7.8, p 0.045. The proportion of infants not receiving PVZ increased significantly from 63.7% in 2015-16 to 80.6% in 2016-17(p-value < 0.0001) 160 .
In summary, there is little population-based data on the effect of the 2014 change in AAP recommendations on RSVH of premature infants of 29 to 35/36 wGA. One small single center study reported no difference in overall RSVH rates. A large administrative database study showed a 1.4 to 2.7 fold increase in RSVH rates in premature infants aged < 3 months. Other studies looked at the proportions of children admitted with RSV who were of 29-35 wGA. Two single center studies showed no difference in this proportion. One showed no difference in morbidity of those admitted, while the other reported a shift towards younger age, and higher morbidity in those admitted who were < 3 months old but not in older infants. Another large database study compared ratios of premature to term infants among those admitted with RSV and reported an increase of 1.5 to 2 fold. One study of children with CHD aged 13-24 months showed no increase in morbidity in those hospitalized with RSV. A similar policy change was made in Italy. Two studies there showed no significant impact while a third reported a 2.7 fold increase in RSVH rates in infants of 29 to <36 wGA. However there are important variations in RSVH rates from 1 season to another, and these studies covered only 1 or 2 seasons before and after policy change.
# IV.3 Immunogenicity
# IV.3.1 PVZ Levels
PVZ is a passive immunizing agent. A PVZ serum concentration of ≥ 30 ug/mL was shown to reduce replication of RSV in the lungs of the cotton rat by 99% 161 . Based on this data, ≥40 ug/mL was chosen arbitrarily as the preferred target trough level in clinical trials in infants 48,80,162 . In these studies, 5 doses of 15 mg/kg were given at intervals of 30 days. A pharmacokinetic computer model based on data from 22 clinical trials suggested that this schedule would provide levels above the target trough for 6 months 163 .
The half-life of PVZ is 19-27 days 164 . Trough PVZ levels increase with sequential doses. Mean ± SD trough serum concentrations 30 days after 15 mg/kg doses one, two, three, and four were 37±21 ug/mL, 57± 41 ug/mL, 68±51 ug/mL, and 72±50 ug/mL, respectively 165 . In a study of PVZ in children with CHD, serum concentrations (mean ±SD) before the second and fifth doses were 55.5 ±19 ug/mL and 90.8 ±35 ug/mL. In 139 patients who underwent cardiac bypass, PVZ levels measured just before and the day after bypass were 98.0 ±52 ug/mL and 41.4 ±33 ug/mL, respectively, a decrease of 58% (p=0.0001) 80 . Previous NACI guidance and the AAP state that for children with CHD who will continue to require prophylaxis, a 15 mg/kg dose of PVZ should be given after cardiac bypass 4,6 . The AAP also suggests that if prophylaxis is still indicated, an extra 15 mg/kg dose be considered at the conclusion of extracorporeal membrane oxygenation 6 .
The possibility of giving fewer than 5 doses of PVZ has been explored. A recent modeling study predicted that levels of 30 to 40 ug/mL would be maintained for 181 days if doses 1 and 2 were given 29 days apart and the subsequent 3 doses 38 days apart. With only 4 doses these levels would be maintained for 143 days 166 . The CPS recommends that programs should administer a maximum of 3 to 5 doses, with 4 doses probably being sufficient in all risk groups if PVZ is started only when there is RSV activity in the community, especially if doses 2, 3, and 4 are given 38 days apart 8 . However, administration at 38 day intervals is more complex to implement and may result in more wastage; an interval of 35 days may be more practical. A program in British Columbia gave 4 doses of PVZ with interval of 21-28 days between the first 2 doses and 28-35 days between subsequent doses. RSVH occurred in 10 of 666 infants (1.5 %). All were PVZ breakthrough cases with the exception of one set of twins who were hospitalized 65 days after the 4th dose. Eighteen others (2.7%) were hospitalized for bronchiolitis while receiving PVZ but not tested for RSV. A 3-dose schedule was provided for 514 lower risk children born at 29 to <35 wGA and without chronic lung or CHD. One child was admitted for RSV while receiving PVZ and another was admitted 58 days after the 3rd dose 167 . A further cohort study of 391 children with CHD in British Columbia who received 4 doses of PVZ 2012 through 2016 showed an admission rate for proven or potential (not tested) RSV lower respiratory tract infection of 6.2 per 100 PVZ approvals 168 , a rate similar to the 5.3% observed in PVZ recipients in a clinical trial of 5 monthly doses in children with CHD (respiratory illnesses that were not tested for RSV were excluded) 80 . Only one child had RSVH more than 30 days following the last dose of PVZ. In another SYNCYTIAL VIRUS INFECTION IN INFANTS study, protective neutralizing antibody levels (defined as neutralization titre (NT95) of ≥ 1 in 12 dilution) were present at an average of 55 days (range 28-105 days) after the final dose of PVZ. Protective neutralizing antibody levels were also found in 54% of control infants aged 4-11 months who did not receive PVZ, suggesting that humoral response to subclinical RSV infections may contribute to neutralizing titers that persist after PVZ administration 169 .
Concern has been expressed about the substantial inter-and intra-individual variability in PVZ levels 163,165 and implications for protection if fewer PVZ doses or longer dose intervals are used. Low trough levels after the first dose has led to suggestions for a shorter interval between the first and second doses 170 . Troughs of <40 ug/ml after the first dose were reported in 33% of recipients 164 . In one report, 46% of breakthrough RSV infections occurred in the interval after the first dose 171 but this high rate has not been replicated in other studies. A retrospective review of 42 patients hospitalized with RSV despite PVZ showing a correlation between lower PVZ levels and admission to an ICU. Mean levels were 47.2 ug/mL in those who required ICU care and 98.7 ug/mL in those who did not (P < 0.0001). In multivariate analysis in the above study, including potential confounding factors, the only parameter associated with ICU admission was PVZ level 172 .
# IV.3.2. Dose Schedules and RSV Seasonality
The annual "RSV season" is the period during which the risk of acquiring RSV is sufficiently high to warrant prophylaxis of high risk infants. The season usually starts in October or November in Canada and ends in April or May, with most cases occurring in December through March. The duration of the annual RSV season varies with year and location, and was reported as varying from 13 to 23 weeks in various locations in the USA 7 and from 90 to 181 days in Hamilton, Ontario 173 . Because 5 monthly doses should provide protective levels for > 6 months, a maximum of 5 doses is recommended by the AAP 6 . Use of PVZ can be optimized if local virology laboratory data are used to determine when to begin prophylaxis 173 . Where such data are unavailable, the start date may be determined by paediatric RSVH data, or based on previous seasons. In some areas, 4 monthly doses may be sufficient 174 . In Canada, some programs start routinely in November or December and others use local laboratory and hospitalization data to define the RSV season (see Appendix A). The latter may be more complicated to implement than using fixed dates but may make more efficient use of the product.
Occasional RSVH may be expected before or after the main season in some areas, but maximum benefit from prophylaxis will be achieved during the peak of the season.
# IV.4 Safety
PVZ is generally considered to be a safe product. Since the description of adverse events (AEs) in the NACI 2003 PVZ statement 4
# IV.4.1 Rapid Literature Review
Nine RCTs, two population based cohort studies, 26 descriptive reports from registries or cohorts, and 2 case reports were identified. The most commonly reported AE considered related to PVZ were injection site reactions, fever, nervousness or irritability, cough, rhinitis, and diarrhea. PVZ related serious adverse events (SAEs) were very rare, reported in 1% or less of recipients, with most studies reporting none. Most were hypersensitivity reactions. Three reports of anaphylaxis were identified. PVZ discontinuation because of AEs occurred in 0-2.3% of recipients. There were no deaths attributable to PVZ. Repeated injections of a humanized monoclonal antibody raised concern for the development of immune mediated disease. Studies showed no increased risk of autoimmune disease or atopy in children exposed to PVZ.
# IV.4.2 Data from the Canada Vigilance Program
A review of AEs reported to the Canada Vigilance Program, Health Canada, identified 259 case reports of AE following PVZ, with 237 classified as serious. The most frequent events were respiratory at 137 (53%), of which 113 were infections, mainly reported because of PVZ product failure, followed by hypersensitivity reactions at 23 (9%). Other events reported are expected complications of the underlying conditions for which PVZ is recommended and are consistent with those reported in the product monograph. The role of PVZ in these AEs is unknown as causality was not assessed.
# IV.5 Vaccine Administration
PVZ is given at a dose of 15 mg/kg of body weight by intramuscular injection.
For dose intervals and numbers of doses see Immunogenicity, section IV.3, above.
# IV.6 Storage Requirements
PVZ should be stored between +2 and +8°C in its original container. It should not be frozen. Vials are for single use and do not contain a preservative.
If an entire vial (50 mg or 100 mg) is not required for a patient's monthly injection, physicians should arrange for more than one patient to receive PVZ within 6 hours 4 or on that same clinic day 175 in order to minimize product wastage. Opened vials containing product not used within 6 hours should be discarded and not stored. Weekly clinics for eligible infants in a specific locality facilitate efficient use with minimal wastage.
# IV.7 Simultaneous Administration with Other Vaccines
PVZ is an antibody directed specifically against RSV and does not contain other antibodies or human serum. It is not expected to interfere with the immune response to live or inactivated vaccines 7,129 . Children receiving PVZ should receive all routine childhood vaccines and any other vaccines that may be indicated because of underlying health conditions, following recommended schedules. SYNCYTIAL
# IV.8 Contraindications and Precautions
# Contraindications
Significant hypersensitivity to any component of PVZ is a contraindication to use of this product.
# Precautions
Minor illnesses such as the common cold, with or without fever, are not contraindications to use of PVZ. Moderate to severe illness, with or without fever, is a reason to consider deferring PVZ, to avoid superimposing adverse effects from PVZ on the underlying illness, or mistakenly identifying a manifestation of the underlying illness as a complication of PVZ. The decision to delay PVZ depends on the severity and etiology of the underlying disease.
# V. ECONOMICS V.1 Systematic Review
A systematic review of the cost-effectiveness of PVZ prophylaxis for RSV was conducted. Studies carried out in OECD countries and published from 2000 to 2018 were reviewed. The original review has been published 176 . For the purposes of NACI's decision-making, changes to the reporting and discussion were made to the original review, and can be found as a NACI Supplement entitled "Cost-Effectiveness of PVZ for Respiratory Syncytial Virus (RSV): A Systematic Review" which will be forthcoming. Changes include currency reported in Canadian dollars, a section on Canadian studies, alternate subgroups reported, and additional commentary. Results from the supplement are summarized here. Of 28 studies included in the final analysis, 20 were cost-utility analyses and 8 were cost-effectiveness analyses. Two economic evaluations were trial-based 177,178 , and the rest were considered model-based. Studies were conducted in the US (n=6), Canada (n=5), Netherlands (n=3), the United Kingdom (n=3), Spain (n=3), Austria (n=2), Germany (n=2), and Italy, Mexico, New Zealand, and Sweden (1 each). Base-case analyses were conducted from a health system payer perspective (n=15) or a societal perspective (n=13). Eight of the payer perspective studies performed additional analyses from a societal perspective. The majority of studies were industry sponsored (n=17, 61%). Cost-effectiveness outcomes were reported as ICERs, mostly represented as the incremental cost per additional QALY (n=20) and cost per hospitalization avoided (n=6). ICERs were adjusted to 2017 Canadian dollars (CAD).
PVZ prophylaxis ranged from being a dominant strategy (i.e,less costly and more effective) to having an ICER of $2,975,489/QALY. The wide variation in ICERs depended on the perspective, study setting, population, local RSV epidemiology, healthcare system, and key model input parameters such as rate of reduction in RSVH (39%-96%), estimated RSV-related mortality (1%-8.1%), PVZ costs ($1,099-$2,198 per 100-mg vial), dosage schedules, and vial usage.
# V.1.1 Economic Evaluations with Outcomes Expressed in Cost per Qaly
Data are summarized in Tables 1 and 2. For studies reporting cost-effectiveness in terms of cost per QALY from a health system payer perspective, there were 22 cost-effectiveness estimates for preterm infants, ranging between $6,216 per QALY and $938,623 per QALY 82, . The subgroups with the next highest numbers of estimates were (i) preterm infants stratified by risk factor scores 185,186,189 , (ii) infants with CHD 82,179,181,182, , and (iii) infants with CLD 82,181,182,187,191 . The proportion of reported cost-effectiveness estimates that fall below different thresholds is shown in Table 1. The largest agreement among reported estimates falling below the commonly used threshold of $50,000/QALY were infants with CLD (n =6 out of 6 studies), preterm infants (n=18/22), and infants with CHD (n=8/10). For premature infants no specific trend was detected between wGA and the ICER. From a societal perspective, PVZ prophylaxis was considered a dominant strategy (i.e,less costly and more effective) in some instances for preterm infants 183, , term infants in the Canadian Arctic 196 , and infants with CHD 182 . However, there was high heterogeneity in the study design and model parameters among reviewed studies including those that reported PVZ prophylaxis to be a dominant strategy. There does not appear to be a common driver for dominance of PVZ prophylaxis. In other scenarios, ICERs <$200,000/QALY were observed. Generally, one would expect ICERs from a societal perspective to be lower than those from a payer perspective, but this trend was not observed. Payer and societal perspective estimates frequently came from different studies and there was heterogeneity in model designs and differences between setting-specific costs and RSV epidemiology that may account for larger ICERs under a societal perspective.
Twelve of these studies were industry sponsored. It was noted that 50% of all estimates of $200,000/QALY were from studies funded by industry (S. Mac Six studies reported cost-effectiveness in terms of cost per hospitalizations avoided (HA) 179, . A study of healthy term infants in different regions of the Canadian Arctic compared two scenarios of PVZ prophylaxis for infants who were less than 6 months of age, from a payer perspective. The ICER ranged from being dominant (i.e,less costly and more effective) in specific Arctic regions to $593,250/HA in the Northwest Territories 197 . Also from the payer perspective, a Florida study of preterm infants (<32 wGA), term infants with CHD, CLD, combinations of all three groups and infants with no indications for PVZ) reported ICERs between $413,127/HA (preterm infants) and $2,924,911/HA (infants with no indication) 201 .
From a societal perspective, a study from the Netherlands of preterm infants (< 28 wGA) with additional risk factors (BPD, male sex, birth weight < 2,500 grams) found ICERs ranging between $24,875/HA and $1,572,268/HA depending on the month of the prophylaxis 198 . In a study from Germany of preterm infants (<35 wGA) with additional risk factors, from a societal perspective ICERs ranged between $11,821/HA and $364,462/HA for preterm infants with CLD and risk factors and preterm male infants without CLD and with no siblings in school, respectively 199 . A New Zealand study analyzed cost-effectiveness of prophylaxis in preterm infants (<28, 29-31 wGA) with or without CLD from a societal perspective. The ICERs ranged from $33,376/HA for preterm infants discharged home on oxygen, to $37,213/HA for infants ≤ 28 wGA with no CLD, to $193,859/HA for preterm (29-31 wGA) infants with CLD 200 .
# V.1.3 Economic Evaluations with Outcomes Expressed in Other Ratios
An economic evaluation on term infants with CHD in western Canada found that from a societal perspective, the base-case ICER was $18,155 per one day of hospitalization avoided 148 . A study of preterm infants (< 32 wGA) or with CLD or significant CHD in France found that from a societal perspective, the base-case ICER was $43,856/ ife year (LY) gained and $33,450/LY gained for preterm infants with CLD and preterm infants with CHD, respectively. From a payer perspective, the ICER was $16,368/LY gained for infants with CLD 202 . In a study of preterm infants with CLD in the US, the model used a reduction in incidence of RSV infection, ranging from 50% ($66,494 per RSV infection episode avoided) to 83% reduction (PVZ prophylaxis a dominant strategy, i.e,less costly and more effective) from a payer perspective 178 .
# V.1.4 Economic Evaluations in Canadian Settings
There were five economic evaluations conducted in Canadian settings 148,186,189,196,197 . Populations studied were term infants from the Canadian Arctic 196,197 , preterm infants 186 , infants with CF 189 , and infants with CHD 148 . These studies assumed 4.5 to 6 doses of PVZ per RSV season at a cost of $1,599 -$1,718 (2017 CAD) per 100 mg of PVZ. In the above studies, the effectiveness of PVZ was measured in reduction in RSVH, which ranged between 42% and 96%. Mortality rates were incorporated into two models, at 1% and 8.1% 186,196 . Sequelae were incorporated into two models (in one sequelae of RSV infection, the other sequelae associated with CF) 186,189 . The most influential parameters on the cost-effectiveness outcomes in the five Canadian studies were: RSVH rates 196,197 , cost of PVZ 148,189 , and cost for hospitalization 196,197 186 . For infants less than 24 months of age with CF, PVZ was determined unlikely to be cost-effective from a payer perspective ($693,105/QALY for all and $167,107/QALY for high risk infants) 189 . In the study of PVZ cost-effectiveness in children < 24 months of age with CHD, from a societal perspective the ICER was $18,155/day of hospitalization avoided and considered unlikely to be cost-effective 148 .
These latter three studies may be generalizable to most Canadian provinces given they used PVZ costs ($1,468 -$1,505 per 100 mg vial, original costs) similar to those in other Canadian provinces, dosing schedules close to 5 injections per season (4.5 to 5.39 vials per season), healthcare costs from British Columbia and Ontario, and included model parameters of relevance to the Canadian healthcare system. Studies of cost-effectiveness of PVZ prophylaxis for infants from smaller Canadian provinces (e.g. Maritimes provinces) were lacking. The most frequently reported influential parameters affecting the ICER were the RSVH rates and cost of PVZ used. Reduction in RSVH varied drastically between 39% and 96% depending on the population of interest, and the source of the data. The cost of a 100mg vial of PVZ also ranged between $1,099 and $2,198 (2017 CAD). However, vial usage and dosage scheme only affected the ICERs in four 181,183,195,200 , and three studies 185,187,200 , respectively. In studies addressing drug wastage, ICERs fluctuated up to 50% depending on the assumed vial usage. In a New Zealand study, assuming no vial sharing (entire 100 mg vial is used per injection) increased cost per case averted by up to 50% (i.e,worse value for money) 200 , while another study in Spain concluded a lower ICER (i.e,better value for money) when 50-mg vials were used instead of 100mg 183 . It has been suggested in the literature that vial usage efficiency can be achieved for PVZ 203 . Discounting was also frequently reported as being influential on the ICER. Discount rates varied across studies (3-5%). Currently Canadian guidelines recommend a discount rate of 1.5% for costs and outcomes 204 . The only exceptions were the six studies from the US. Choice of payer or societal perspective may influence the costs and the benefits included in the analysis. Among the studies that used a societal perspective, the following costs outside of the healthcare system were considered: time loss from work due to asthma; indirect costs of nosocomial infections; travel costs (i.e,hotel, transportation); productivity loss (i.e,caregiving, leisure, future productivity of children); and school absenteeism. 183,185,195 .
Despite the similarities in PVZ prophylaxis cost and dosage schedule, estimated reduction rates of RSVH varied from 39% to 96% depending on the infant population, and literature referenced. Sixtyeight percent of the studies (S. Mac personal communication June 2019) used the IMPACT-RSV trial for some of their model parameters, a trial that included Canadian children and concluded that reduction in RSVH was 78% for preterm infants, 39% for children with CLD and 55% overall. While the subgroup of Canadian subjects in that study showed a 40% overall reduction in RSVH, the trend was similar to that seen in US (56%), and UK subjects (64%) 48 . It is noted that the IMPACT-RSV trial was carried out in 1996 and that with changes in the management of prematurity, CLD and CHD, as well as RSV infection, model parameters based on that study may not be appropriate today.
# V.2 Cost-Effectiveness Study in Nunavik, Quebec
In addition to the studies in the systematic review, preliminary results of a cost-effectiveness study in the region of Nunavik, Northern Quebec were reported to NACI on March 13, 2019 (R. Gilca, Institut national de santé publique de Québec, personal communication, Nov. 18 2020) 206 . Starting in the 2016-17 season, healthy full-term infants <3 months of age at the start of the RSV season or born during the RSV season became eligible for up to 3 doses of PVZ. For the 2017-18 season, infants meeting these criteria were eligible for up to 5 doses. The objectives were to estimate the healthcare cost of RSVH in the targeted population and the cost of the PVZ program, and to estimate cost per hospitalization averted.
The analysis below is based on the first 2 years of the program. It is being updated to include 4 years of data and will be published. The conclusions remain unchanged.
# VI. ETHICS, EQUITY, FEASIBILITY AND ACCEPTABILITY (EEFA) CONSIDERATIONS
The peer-reviewed EEFA Framework 13 was applied to this guidance to ensure the systematic consideration of factors critical for comprehensive immunization program decision-making and successful implementation of recommendations. The use of this EEFA Framework empowers the committee to review and balance all of the available evidence and transparently summarize their rationale for appropriate, timely recommendations. The evidence-informed tools associated with the framework (Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, Acceptability Matrix) ensure that issues related to EEFA of expert committee guidance are systematically and adequately integrated.
# Ethics considerations
To support ethics deliberation and decision-making, NACI's Ethics Integrated Filters for core ethical dimensions (respect for persons and communities, beneficence and non-maleficence, justice, trust) and procedural ethical dimensions (accountability, inclusiveness, responsibility, responsiveness, transparency) were applied. NACI followed its established methodology, standard operating procedures (SOP), and conflict of interest guidelines to ensure a robust analysis of evidence, with transparency about knowns and unknowns, as well as certainty of evidence, and to maintain stakeholder trust. In order to respect the right to exercise informed choice, NACI reviewed the best, current evidence available for groups of infants and children at risk of RSV and summarized it for stakeholders throughout this guidance document, including recent data on burden of illness due to RSV disease, the efficacy and effectiveness of PVZ in infants at risk of more severe RSV disease and economic implications of PVZ use. NACI also considered evidence for minimizing the risk of harm and maximizing benefits for all potential key populations in their deliberations. These findings should be interpreted with caution given that some potential concerns were identified regarding availability of evidence; small numbers of articles were identified for some risk groups and situations and there was significant heterogeneity in methodology used and the outcomes studied. Furthermore, with no evidence of lowered mortality rates from RSV or of long term benefit from PVZ, the high cost of PVZ prophylaxis programs must also be balanced against costs of other health care interventions if these other interventions may be compromised by provision of PVZ programs. Therefore, NACI will continue to monitor the evidence related to use of PVZ in different groups, including the cost-effectiveness of PVZ programs and alternative dosage schedules and newer products which may be more costeffective and will update the statement and its recommendations as needed.
# Equity considerations
NACI reviewed the epidemiology of RSV and the results of the systematic review on the burden of RSV disease in young children in high-income countries comparable to Canada (summarized in Section III) to identify distinct inequities associated with COVID-19, potential reasons for these inequities, and suggested interventions to reduce inequities and improve access to vaccine when it becomes available.
The risk of severe RSV illness is influenced by gestational age at birth, underlying health conditions, and age. As it is not feasible to provide PVZ prophylaxis to all infants at some increased risk of RSV disease, in principle it should be provided to high risk groups at equivalent risk of severe disease. Specific recommendations are needed for selective PVZ prophylaxis for identifiable high-risk subgroups of infants and children who are more vulnerable than others to the adverse effects of RSV infection, and whose risk of severe outcome are within a similar range and for whom PVZ prophylaxis has been shown to be effective. However, the limited nature and heterogeneity of the data available makes assessment of degree of risk somewhat arbitrary. For certain very rare conditions, risk of severe RSV illness may be high but epidemiologic data are not available, and the number of children with certain rare diseases may not be sufficient for PVZ effectiveness to be studied. In these circumstances, extrapolation may be made from data on conditions of pathophysiological similarity with documented increased risk of RSV and where PVZ has been shown to be effective. In most provinces and territories, physicians may request PVZ by exception for children that do not meet specific criteria for PVZ. While this permits flexibility for use in children with rare conditions, it may also introduce inequity. Those making requests for exceptions and those assessing these requests must do so fairly, to avoid inequity.
Infants living in remote northern Inuit communities and other remote rural communities may also be at increased risk of severe outcomes resulting from RSV infection. Limited local access to medical care may necessitate medical evacuations requiring air transportation to hospital facilities. Therefore, additional resources may be needed for provision of PVZ prophylaxis and for monitoring and followup of infants living in remote locations. PVZ prophylaxis should also be provided as close to home as possible given that the number and frequency of visits over a short period of time and the strict injection intervals may be a barrier for families due to out-of-pocket expenses if the family has to travel some distance to receive PVZ and/or take time off work for these visits. In these cases, assistance may need to be given to some families so that they can benefit from the PVZ prophylaxis program. NACI will continue to monitor the evidence related to severity of RSV disease in infants with pre-existing conditions and in infants living in remote northern Inuit communities and other remote rural communities.
# Feasibility considerations
Provision of PVZ prophylaxis is complex and integration into existing active vaccination programs is not feasible due to the dosing schedule and the seasonal nature of the disease. In particular, the need for multiple injections over a short time period may create scheduling challenges; up to 4 doses must be given at 28-35 day intervals during the period that the local annual RSV outbreak is underway. Unlike vaccines, PVZ dose depends on weight and precise timing of visits for PVZ administration is crucial for appropriate protection and it is not possible to combine all visits with visits for other vaccines or routine child care. Additionally, PVZ is provided in multi-dose vials which, once opened, must be used within 6 hours or discarded and wasted. where very few children are candidates for PVZ, further increasing the cost. Therefore, important considerations for the implementation of a new PVZ prophylaxis program include limiting prophylaxis to those groups at highest risk of severe outcomes, scheduling specific PVZ clinics during the RSV season, recognizing the potential impact on existing local programs, and involving of local care givers in planning for program implementation.
# Acceptability considerations
Very limited acceptability data are currently available specific to PVZ prophylaxis and the perception of RSV disease in parents or guardians of high risk infants. Likely barriers to acceptability and adherence include:
- The number and frequency of visits, especially if families have to travel some distance to receive prophylaxis and it is not possible to combine visits for PVZ with visits for other vaccines or routine health care needs; Out-of-pocket expenses if appointments require long-distance travel to the treatment center and time away from work. Lack of knowledge about the risk of RSV infection in high risk children.
There is some evidence indicating that Indigenous populations in Canada are at higher risk of nonadherence than non-Indigenous populations and that acceptance is lower in remote northern populations 207,208 . Nurses and midwives working with a population in the Canadian North have also expressed concerns regarding lack of data about the efficacy and safety of PVZ in healthy term infants 207 . Low acceptability of PVZ prophylaxis by families may result in decreased adherence to PVZ schedules and diminish effectiveness 209 . Therefore, implementation of a new program should include ongoing education of local health care providers, families and guardians of infants for whom PVZ is indicated, and their active involvement in planning of the intervention. Provision of PVZ in local clinics as close to home as is feasible and sufficient resources to provide assistance for families who may need some additional support to be able to travel to the clinic are also important considerations. SYNCYTIAL
# VII. RECOMMENDATIONS
Following the thorough review of available evidence summarized above, as well as the systematic assessment of ethics, equity, feasibility and acceptability considerations with the peer-reviewed EEFA Framework, NACI makes the following evidence-informed recommendations.
# RECOMMENDATIONS FOR PUBLIC HEALTH PROGRAM LEVEL DECISION-MAKING (i.e,provinces/territories making decisions for publicly funded immunization programs)
In considering these recommendations and for the purposes of publicly funded program implementation, provinces and territories may take into account local programmatic factors (e.g. current programs, resources). Recognizing that there are differences in operational contexts across Canada, jurisdictions may wish to refer to the Management Options Table below for a summary of the relative merits of vaccinating different high risk groups, if prioritization of targeted immunization programs is required for implementation.
# Preterm infants without CHD or CLD: Recommendation 1.1: NACI recommends that PVZ should be offered to infants born at < 30 weeks, 0 days gestation and aged < 6 months at the onset of or during the RSV season. (Strong NACI Recommendation)
NACI concludes that there is fair evidence to recommend PVZ use in this population (Grade B evidence).
# Recommendation 1.2: NACI recommends that PVZ may be considered for infants of 30 to 32 weeks, 6 days gestation aged < 3 months at the onset of or during the RSV season if they are at high risk of exposure to RSV from day care attendance or presence of another preschool child or children in the home. (Discretionary NACI Recommendation)
NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Recommendation 1.3: NACI recommends that PVZ should not be offered to otherwise healthy infants born at or after 33 weeks, 0 days gestation (Strong NACI Recommendation)
NACI concludes that there is fair evidence to recommend against PVZ use in this population (Grade C evidence).
# Summary of evidence and rationale:
- There is good evidence that risk of RSVH is higher in premature infants born at lower gestational age, with reported rates of 7.7 to 13.6% in the first year of life for those of < 28 or < 29 wGA . These infants receive little or no maternal antibody and their narrower airway passages increase their vulnerability to the effects of RSV infection.
- There is good evidence that infants of 30-32 wGA are also at increased risk of RSVH in comparison to term infants but hospitalization rates are lower, at 5.1 in the systematic review of publications from 2014-2018 (BODsr) (see Section III.1.1.), 5.7 -9.9% in earlier literature 41-43, 45, 46 and 4.3 % in a more recent study 38 . There is fair evidence that RSVH rates for infants of 29-32 and 33-35 wGA are 4.6 and 2.8 times higher than in term infants, respectively (Section III.1.1.). Earlier studies show inconsistent evidence on the risk of RSVH in infants of 32-35 wGA. Rates of 2.85 to 6.5% in the first year of life or first RSV season have been reported 40,45,48 , while two more recent studies reported rates of 4.0 and 3.4% 38,39 . RSVH rate for healthy term infants in the BODsr was 1.2%. There is fair evidence that premature infants hospitalized for RSV have a longer LOS than term infants, with mean difference in LOS between premature and term infants of 7.97 days for infants of 29-32 wGA and 1.06 days for infants of 32/33-35 wGA. There is fair evidence that premature infants with RSVH have a higher rate of ICU admission than term infants, with RR of 4.0 for infants of 29-32 wGA and 3.0 for 32-35 wGA. There is fair evidence that premature infants of 29-35 wGA with RSVH have a higher rate of MV than term infants, with RR of 1.9 for infants of 29-32 wGA and 1.2 for 33-35 wGA.(Section III.1.1) There is fair evidence that chronological age is an important risk factor for RSVH, with most infections occurring in the first 2-3 months of life 16,49 . There is insufficient evidence of the effectiveness of PVZ in reducing risk of RSVH in premature infants born at < 30 wGA. three studies, two rated as good and one as fair, did not show a significant effect on RSVH in this group, but the numbers of participants were small (total 228 for the three studies). One larger study of premature infants born at ≤30 wGA, rated as poor quality, showed a reduction of 92% with NNT of 9. There is good evidence that PVZ is effective in reducing RSVH rates by 38-80% in premature infants of ≤32 wGA without CLD or hsCHD (NNT 53, 5, 17). There is conflicting evidence about the effect of PVZ on RSVH rates in premature infants born at 32-35 wGA without CLD or hsCHD. Two RCT and one observational study showed reductions of 55-82% (NNT 22, 24) and 55%, while 3 observational studies did not show a significant effect. There is fair evidence (one systematic review) of an association between PVZ receipt and lower all-cause mortality in infants born at ≤ 32 wGA but no evidence for an effect of PVZ on RSV specific mortality 74 . ICERs for preterm infants were < $50,000 per QALY in 82% of estimates (payer perspective) and were dominant (i.e,less costly and more effective) in infants of < 32 wGA (societal perspective). No specific trend was detected between wGA thresholds and ICERs, but numbers of estimates in the wGA groups were small. ICERs were <$50,000/QALY in 100% of estimates for infants of < 29wGA, 67% for 29-32 wGA, 100% for <32 wGA and for < 33 wGA and 67% for 32-35 wGA (payer perspective). In one Canadian study, ICERs were < $50,000 per QALY for infants of 32-35 wGA with high or moderate RSV risk scores (payer perspective). Although burden of illness is higher in infants of 30-35 wGA than in term infants and there is good evidence of PVZ effectiveness for those of 30-32 wGA, cost is of concern for PVZ use in these older gestational age groups. In Canada it is estimated that 8% of infants are born prematurely 67 , and that 5% of the birth cohort may be born at 32-35 wGA 34 .
Recommendations are based on providing prophylaxis for the premature infants at highest risk. NACI concludes that there is fair evidence to recommend against PVZ use in this population (Grade C evidence).
# Summary of evidence and rationale:
- Most studies of twins and other multiple births have reported similar risks of RSVH in infants of multiple and singleton births, either without 71,116 or after 114,117 adjustment for confounding factors. One study reported a higher rate of RSVH in infants of multiple births but potential confounding factors were not considered 115 .
- There are no data on PVZ use in this group.
- Evidence is based on review of key studies, without formal quality appraisal. NACI concludes that there is good evidence to recommend PVZ use in this population (Grade A evidence).
# Chronic Lung Disease of Prematurity and other chronic lung diseases
# Summary of evidence and rationale:
- RSVH rate for infants with CLD of prematurity in the first 2 years of life is high (12-21%) 42,44,48,72 . For hospitalized patients, high rates of ICU admission (29%) and MV (24%) have been reported 72 . There is good evidence that PVZ reduces RSVH in infants of ≤ 35 wGA with CLD age < 24 m (RD 39%, NNT 21) 48 . There is fair evidence that PVZ reduces the rate of RSVH in infants with CLD during their first 6 months post initial discharge (RD 86% NNT13) 44 and poor evidence in infants with CLD aged < 6 m at onset of RSV season (RD 85%, 72%; NNT 3, 8) 46,139 . There is insufficient evidence of the effect of PVZ in infants with CLD aged < 12 months or 6-12 months. There is no evidence concerning the effect of PVZ on other hospitalization-related outcomes or RSV long term sequelae in infants with CLD. There is insufficient evidence that PVZ has an effect on all-cause mortality or RSV related mortality in children with CLD as numbers studied are insufficient to detect an effect 74 . Studies on cost-effectiveness of PVZ prophylaxis reported ICERs of < $50,000 per QALY in all estimates (payer or society perspective); ICERs for infants discharged home on oxygen were < $50,000 per hospitalization avoided, and < $50,000 per life year gained. NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of evidence and rationale:
- There is fair evidence for increased rates of RSVH in infants with chronic lung disease of etiology other than prematurity (congenital cystic lung disease 8.3%, chronic interstitial lung disease 30%, congenital lung and airway malformations 8.3-13.7%, and some neuromuscular conditions that affect ability to clear airway secretions 9.9-15.9%v 21,75,76 . There is no evidence concerning the effect of PVZ on RSV disease in these conditions. It is postulated that infants with CLD of severity comparable to CLD of prematurity may benefit from PVZ. NACI concludes that there is fair evidence to recommend against routine PVZ use in this population (Grade D evidence).
# Cystic fibrosis:
# Summary of evidence and rationale:
- RSVH occurs more frequently in children with CF than in healthy children. RSVH in the systematic review was 12.3% (Section III.1.3). There are limited data about other hospitalization related outcomes.
- There is inconsistent evidence on the effect of routine administration of PVZ to infants with CF on RSVH, with all but one study showing no effect 77,78,140, . There is fair evidence that routine administration of PVZ to infants with CF does not significantly affect long term pulmonary function, growth or airway bacterial colonization 78,140,144,145 . One Canadian study estimated an ICER of over $600,000 per QALY (payer perspective) for routine PVZ prophylaxis in infants with cystic fibrosis 189 NACI concludes that there is insufficient evidence to recommend use in this population. (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of evidence and rationale:
- There is no evidence on the burden of RSV illness in the subgroup of infants with CF with severe chronic lung disease in infancy. There is no evidence concerning the effect of PVZ prophylaxis on RSV disease in this subgroup.
- It is postulated that infants with CF lung disease of severity comparable to CLD of prematurity may benefit from PVZ. NACI concludes that there is good evidence to recommend PVZ use in this population (Grade A evidence)
# Congenital heart disease and other chronic cardiopathy:
# Summary of evidence and rationale:
- There is good evidence that children <24 months of age with hsCHD are at increased risk for RSVH with rates of 2.3-10.2% reported 65,79,80 . There is good evidence that the RSVH rates for infants with CHD is significantly higher in the first year of life than the second year 43,79,81 . There is good evidence that PVZ reduces the risk of RSVH in children with hsCHD aged < 24 months (RD 45%, NNT 23) 80 . There is good evidence that PVZ reduces the risk of RSVH in children with hsCHD aged < 6 months (RD 51%, NNT 16) and fair evidence in children aged <12 months (RD 49%-72%, NNT 45, 7) 44,80,147 . There is good evidence that PVZ reduces the overall number of days of hospitalization for RSV in children with hsCHD 80 but not the LOS for those admitted with RSV 80,146 , and good evidence that PVZ does not affect the proportion of hospitalized children admitted to ICU, the duration of ICU stay, or the proportion requiring MV 80,146,148 . There is insufficient evidence on the effect of PVZ on all-cause mortality or RSV mortality in children with hsCHD 80,148 . Studies on cost-effectiveness of PVZ prophylaxis reported ICERs of < $50,000 per QALY in 80% of estimates (payer perspective) and 63% of estimates (societal perspective). An ICER of $18,155 per day of hospitalization avoided was estimated in a Canadian study 148 NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of evidence and rationale:
- There is no evidence about the burden of RSV illness or the use of PVZ in this group. It is postulated that infants with cardiac dysfunction of severity similar to that of children with haemodynamically significant CHD may benefit from PVZ. NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of evidence and rationale:
- There is no evidence about the burden of RSV illness or the use of PVZ in this group. It is postulated that these infants will have severe cardiac dysfunction and will likely receive immunosuppressive therapy during the RSV season and that they may benefit from PVZ.
Recommendation 4.4: NACI recommends that for children with both haemodynamically significant CHD and chronic lung disease, recommendations for chronic lung disease (above) should be followed. (Strong NACI Recommendation) NACI concludes that there is insufficient evidence to support a recommendation for this population (Grade I evidence)
# Summary of evidence and rationale:
- There are no data on burden of RSV illness or effectiveness of PVZ for this group. Chronic lung disease may warrant prophylaxis for a second RSV season whereas hsCHD alone usually will not. NACI concludes that there is fair evidence to recommend against routine PVZ use in this population (Grade D evidence).
# Summary of evidence and rationale
- RSVH occurs more frequently in children with Down syndrome without hsCHD, CLD or prematurity than in healthy children. There are limited data about other hospitalization related outcomes 22,83 . Three studies of PVZ prophylaxis in infants with Down syndrome and without hsCHD, CLD or prematurity showed no effect on RSVH .
# Recommendation 5.2: NACI recommends that PVZ should be offered to children with Down syndrome who qualify for prophylaxis because of hsCHD, chronic lung disease, prematurity or immunodeficiency. (Strong NACI Recommendation)
NACI concludes that there is fair evidence to recommend PVZ use in this population (Grade B evidence).
# Summary of evidence and rationale
- See evidence for hsCHD, chronic lung disease, prematurity or immunodeficiency, above. One study found reduction in RSVH rates in infants with Down syndrome who met standard criteria for receipt of PVZ 150 . NACI concludes that there insufficient evidence to recommend routine PVZ prophylaxis in this population. (Grade I evidence). Therefore this recommendation is based on expert opinion. NACI will continue to monitor the evidence as it evolves.
# Immunocompromised Children:
# Summary of evidence and rationale:
- Rates of RSVH in such communities vary widely by community and by year 23, .
- There is one study of fair quality showing no effect of PVZ prophylaxis on RSVH in healthy full term infants living in a northern Inuit population in Canada with rate of RSVH in all infants < 1 year of age of 5% 90 .
- A qualitative study of PVZ prophylaxis in healthy full term infants living in one northern Inuit population in Canada identified significant acceptability and feasibility issues 207 .
# Recommendation 7.3: NACI recommends that PVZ prophylaxis may be considered for healthy full term infants aged <6 months at the onset of, or during, the RSV season living in remote northern Inuit communities with documented very high RSV hospitalization rates for term infants. (Discretionary NACI Recommendation)
NACI concludes that there is insufficient evidence to make a recommendation for or against PVZ use in healthy term infants living in remote northern Inuit communities with very high RSV hospitalization rates (Grade I evidence). Therefore, this recommendation is based on expert opinion, with consideration of the high burden of illness in these communities and need for air transport if hospitalization or specialized ambulatory care is required. NACI will continue to monitor the evidence as it evolves. SYNCYTIAL VIRUS INFECTION IN INFANTS Summary of evidence and rationale:
- Term infants living in some remote northern Inuit communities have very high rates of RSVH and frequently require air transfer to tertiary care institutions 23,91,92 . Rates of RSVH as high as 20% to 50% of all live births have been reported in some remote communities. There are no studies of PVZ prophylaxis in healthy term infants living in remote northern Inuit communities with very high RSVH rates.
- Studies of cost-effectiveness of PVZ prophylaxis estimated ICERs of < $50,000 per QALY for term infants residing in select communities in the Eastern Canadian Arctic with high RSV hospitalization rates, whereas PVZ was dominant (i.e,less costly and more effective) in other select communities. However, these estimates used data for PVZ effectiveness from premature infants and effectiveness in term infants is yet to be established 196 . A qualitative study of PVZ prophylaxis in healthy full term infants living in one northern Inuit population in Canada identified significant acceptability and feasibility challenges 207 . NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore this recommendation is based on expert opinion.
# Summary of Evidence and Rationale
- There is limited evidence on the burden of RSV disease in infants living in other remote aboriginal communities in North America and no evidence for those in other remote communities.
- There is no evidence on the effect of PVZ on RSV disease in these communities. One study of motavizumab, another RSV monoclonal antibody, reported a 87% relative reduction in risk of RSVH in healthy term Native American infants living on reservations in southwestern USA 89 .
# Prevention of Subsequent Recurrent Wheezing
# Summary of Evidence and Rationale
- It is not known whether RSV in infancy predisposes to the development of asthma, or if infants genetically predisposed to develop asthma are at increased risk of severe RSV disease requiring RSVH in infancy, is not known. Recurrent wheezing in childhood occurs in healthy term infants hospitalized for RSV in infancy in proportions similar to those reported for infants at high risk of RSVH in infancy 29 . Although PVZ administration to infants born at < 36 wGA has an impact on physician diagnosed recurrent wheezing in the first 1-6 years of life (NNT 3 to 15), findings are contradictory as to PVZ effectiveness in the absence or presence of a family history of atopy . There are no data on the effect of early receipt of PVZ on subsequent wheezing or asthma in children over 7 years of age or in adults. NACI concludes that there is fair evidence to recommend against PVZ use in this population (Grade D evidence).
# Use of PVZ in hospitalized infants
# Summary of Evidence and Rationale
- Studies showed that RSV infection rates in NICU did not differ when infants received PVZ prophylaxis in the NICU or starting at hospital discharge .
# Recommendation 9.2: NACI recommends that PVZ prophylaxis may be considered when all other measures to control an RSV outbreak in a NICU have failed. (Discretionary NACI Recommendation)
NACI concludes that there is insufficient evidence to recommend PVZ use in this situation (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of Evidence and Rationale
- PVZ, in addition to other infection control measures, has been used to control NICU outbreaks, but the specific role played by PVZ is unclear 118, .
# Summary of Evidence and Rationale
- Administering the first dose before discharge avoids the need of a visit to a health care facility soon after discharge and may improve adherence. In hospital, to avoid wastage when vials are opened for individual infants, administration may be coordinated to 3 times weekly.
Recommendation 9.4: NACI recommends that an infant who has begun PVZ prophylaxis earlier in the season and is re-hospitalized on the date when a dose is due should receive that dose as scheduled, providing that the admitting institution is able to supply PVZ when due. (Strong NACI Recommendation)
NACI concludes that there is insufficient evidence to recommend PVZ use in this situation (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of Evidence and Rationale
- Keeping to the child's existing PVZ schedule avoids the need to reschedule appointments and may improve adherence. NACI concludes that there is fair evidence for this PVZ schedule (Grade B evidence).
# Summary of evidence and rationale:
- A dose of 15 mg/kg every 30 days resulted in target serum PVZ levels assumed to be protective based on animal studies 162 . Longer dose intervals have been used based on a PVZ half-life of 19-27 days and observed accumulation of PVZ after the second dose 48,164,166,167 . Evidence is based on review of key studies, without formal quality appraisal. c. An extra dose may also be considered in remote Northern areas where RSV outbreaks may continue longer than is usual elsewhere NACI concludes that there is insufficient evidence to determine the optimum number of PVZ doses (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of Evidence and Rationale
- Studies suggest that 4 doses are sufficient to provide protection throughout the usual RSV season . A study of children undergoing cardiac bypass reported a 58% decrease in PVZ level after bypass 80 . It is assumed that extracorporeal membrane oxygenation may have a similar effect 6 . Dose sparing can be achieved by:
-Starting PVZ only when the local RSV season has begun 173,174 ; -Favoring the longer interval between doses after dose 2; -Organizing clinics or appointments for PVZ administration that facilitate vial sharing.
- Evidence is based on review of key studies, without formal quality appraisal.
# Recommendation 10.3: NACI recommends that PVZ should be discontinued for the season if a child is hospitalized because of RSV infection. (Strong NACI Recommendation
). NACI concludes that there is fair evidence that recurrent severe RSV infections in a single season are rare (Grade B evidence).
# Summary of Evidence and Rationale
- Reported rates of second episodes of RSVH in the same season vary from in 0% to 1.0% of the cohort studied 80, , except for a rate of 3.3% in a very small study in 1988 107 .
- Evidence is based on review of key studies, without formal quality appraisal.
# RECOMMENDATIONS FOR FOR INDIVIDUAL LEVEL DECISION-MAKING
(For example, individuals wishing to prevent RSV disease or a clinician wishing to advise individual patients with conditions not currently included in public health programs about preventing RSV.) PVZ is not readily available for private purchase in Canada, is costly, and cost may or may not be reimbursed by private insurance plans. No specific recommendations are made for individual level decision-making.
# MANAGEMENT OPTIONS TABLE (Recommendations for public health program level decision-making)
Various options for the use of PVZ, and the decision on which options are preferable will depend on the considerations listed below:
# Options
# Considerations Decision Points
Cohorts at risk:
PVZ, a monoclonal antibody that provides temporary passive protection against severe RSV infection, is the only prophylaxis presently available.
PVZ has only been investigated in children < 24 months old with underlying conditions putting them at increased risk for severe RSV illness and is not recommended for healthy term infants or for individuals over 24 months old.
# Epidemiology
Risk of severe RSV illness is influenced by gestational age at birth, underlying health conditions, and age.
Infants are at highest risk of severe RSV disease in their 1st RSV season and especially at age < 3 months.
-Targeting PVZ prophylaxis to infants at highest risk of severe RSV infection permits most efficient use of PVZ -For healthy preterm infants, PVZ is recommended for those <30 wGA as they are at highest risk. -If resources permit, PVZ may be considered for those of 30-32 wGA if they are at high risk of RSV exposure and < 3 months of age.
RSV causes yearly epidemics from winter to early spring -Use of current local data to determine when PVZ prophylaxis should be started permits most efficient use of PVZ.
# Otherwise healthy premature infants:
Otherwise healthy premature infants have increased risk of severe RSV infection in comparison with term infants. Risk of hospitalization is highest in those < 30 wGA (7.7 to 13%) although also increased in those of 29-32 and 33-35 wGA (4.6 and 2-3 times that of term infants).
PVZ was effective in preventing hospitalization in studies of infants of ≤32 wGA (rate decrease 38-74%, NNT 9 to 54 in different studies). For infants of 32-35 wGA rate decreases of 72-83% with NNT of 12-14 were reported but some studies showed no effect. Studies specific to infants of < 29 wGA did not show an effect but numbers studied were very small.
In Canada 7.7-8% of births are at < 37 wGA and an estimated 5% are 32-35 wGA.
Cost-effectiveness studies of PVZ
# Economics:
PVZ is costly, and the main cost of prophylaxis programs is the product itself. Studies reported a wide range of ICERs depending on the population, setting, baseline hospitalization rates, as well as model structure and study design. Estimated ICERs of <$50,000 per QALY have been reported in selected scenarios but dominant (i.e,less costly and more effective) in very few.
Unlike vaccines, PVZ dose varies with weight. Once opened, a vial must be used that day or discarded.
-Arranging for vial-sharing by scheduling a number
# Children with chronic lung disease of prematurity or of other etiology:
Use of PVZ may be individualized depending on the severity of the chronic lung disease (e.g. oxygen dependence)
Children with CLD of prematurity have a 12-21% risk of hospitalization for RSV. PVZ is effective to prevent hospitalization (rate reduction 39% and NNT 21 in the 1 st 2 years of life, 86%, NNT 13 in the 1 st year).
There are data on increased rates of RSV hospitalization in chronic lung disease of other etiologies but PVZ has not been investigated.
There are data that children with cystic fibrosis have an increased risk of RSV hospitalization but studies to date suggest that PVZ is not protective.
# Down syndrome, Immunocompromised and other chronic conditions
Recommendations are based on PVZ effectiveness and risk of severe RSV disease in different risk groups. For certain very rare conditions, risk of severe RSV illness may be high but epidemiologic data are not available.
Likewise, the number of children with certain rare diseases is not sufficient for PVZ effectiveness to be studied.
In these circumstances, extrapolation may be made from data on conditions of pathophysiological similarity with documented increased risk of RSV and PVZ effectiveness.
No studies of cost-effectiveness of PVZ prophylaxis were identified for these populations.
# Use of PVZ for preterm infants of <37 wGA or for term infants living in remote Inuit communities
# Use of PVZ in term infants may be based on local rates of hospitalization of term infants with RSV and costs of transport to distant hospitals
Studies indicate that children living in some remote Inuit communities, including term infants, are at high risk of RSV hospitalization.
Limited data suggests that PVZ reduces RSV hospitalization of infants of <37 wGA living in remote Inuit communities (rate reduction 96%, 66%, NNT 2,4).
One study offering PVZ to term Inuit infants in an area where baseline rate of
# Options
# Considerations Decision Points
RSVH was not very high showed no effect.
Canadian modelling has suggested that PVZ prophylaxis for term infants may be dominant (i.e,less costly and more effective) in remote Inuit communities with very high baseline RSV hospitalization rates. ICERs were <$50,000/QALY in 75% of estimates, but efficacy was based on studies of preterm infants 6. Use of PVZ for term infants living in other remote aboriginal or other remote communities
# Use of PVZ in term infants may be based on local rates of hospitalization of term infants with RSV and costs of transport to distant hospitals
Limited data suggest that RSV hospitalization rates may be increased in other isolated aboriginal communities. There are no data from Canada.
There are no data on PVZ use in these communities. SYNCYTIAL
# Serological correlate of protection:
Determination of the minimum antibody level required to protect against severe RSV infection in humans and development of a commercially available test for RSV antibody would permit more judicious use of costly monoclonal antibody products, as many infants will develop natural antibody during their first or second year of life.
# RSV monoclonal antibody efficacy/effectiveness in infants living in remote communities, especially in Inuit infants in the far North:
There is (good) evidence of a high burden of RSV disease in Inuit infants in the far North but limited data on the effectiveness of PVZ to prevent hospitalization and the need for air transfer.
# Burden of RSV disease in infants with Down syndrome and efficacy/effectiveness of RSV monoclonal antibody to prevent hospitalization in this population:
The literature suggests that infants with Down syndrome without recognized clinical criteria for PVZ prophylaxis may have high rates of RSV hospitalization. The reasons for this susceptibility are not clear but may relate to immunodeficiency in this population. There is very limited data on the use of PVZ infants with Down syndrome.
# Efficacy/effectiveness of RSV monoclonal antibody in otherwise healthy premature infants born at < 29 wGA:
Studies of the efficacy/effectiveness of PVZ prophylaxis in severely premature infants of < 29 wGA failed to show protection, but the numbers of infants studied were very small. Such studies could not be done in countries where PVZ is now recommended for these infants. 1. Development of a RSV surveillance system with data for each province and territory, analogous to FluWatch, could provide timely data on which to determine when RSV monoclonal antibody prophylaxis programs should most efficiently begin and end.
Studies of the burden of severe RSV disease in immunocompromised populations, stratified by age group (especially focusing on those ≤ 2 years of age) and by severity of immunosuppression (especially focusing on those with antibody deficiencies, as these individuals may not benefit from RSV vaccines in the future and thus may continue to warrant RSV monoclonal passive prophylaxis).
Ranking Individual Studies, Strength of Recommendations, Grade of Evidence Evidence from controlled trial(s) without randomization.
# II-2
Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.
# II-3
Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
# III
Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.
# Good
A study (including meta-analyses or systematic reviews) that meets all designspecific criteria- well.
# Fair
A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion- but has no known "fatal flaw".
# Poor
A study (including meta-analyses or systematic reviews) that has at least one design-specific- "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations. recommended interval for the second dose was 28 days and for subsequent doses 35 days. In YK the interval for the second dose was 18-24 days and the subsequent doses 28-30 days. The recommended interval in MB was 28 days up to the fourth dose, 35 days between doses 4 and 5 and 42 days between doses 5 and 6.
The maximum number of doses was 5 in 7 PT (AB, NB, NS, PE, ON, QC, SK), 6 in one (MB), 6 with extension based on local epidemiology in one (NU), and 4 in one (NL). In BC the maximum number of doses was 4 for infants of < 29 wGA and those with CLD or hsCHD, and 3 for premature infants of ≥29 wGA and no CLD or hsCHD. Two did not state a maximum (YK, NT).
# International:
Premature infants without chronic lung disease or hemodynamically significant congenial heart disease (hsCHD).
Three countries used gestational age alone with varying wGA limits: < 26 (Sweden), < 29 (US) and <32 (Netherlands). Four countries (Austria, Germany, Italy, Spain) recommended prophylaxis for all infants below a specific wGA (< 28 to <31), and for less premature infants (up to 34 to 36 wGA) using risk scores. Three countries (France, Switzerland, UK) did not provide prophylaxis for prematurity alone.
Chronic lung disease of prematurity (CLD) and other chronic lung conditions All 10 countries recommended prophylaxis for infants with chronic lung disease of prematurity. Eight countries, all but Switzerland and the UK, included those age < 24 months requiring treatment in the previous 6 months, with 5 of these including all infants < 12 months and one including all infants < 6 months old regardless of treatment. Switzerland recommended prophylaxis only for those < 1 year old. The UK recommended prophylaxis using a gestational age and chronological age grid which encompassed infants of ≤ 34 wGA and age 9 to 1.5 months.
Eight countries, all but France and Spain, also recommended prophylaxis for children aged < 1 or < 2 years with other pulmonary conditions, either routinely or on individual assessment. These tracheostomy.
# Congenital heart disease
All ten countries recommended prophylaxis for infants with significant CHD, to age 2 years in France, Spain, and Netherlands, for the first year of life only in Italy, Sweden, Switzerland, and for the first year with consideration of extension to the second year in the US. Germany recommended prophylaxis to age 6 months, with individual consideration for age 6-12 months. The UK included infants of ≤26 to ≤32 wGA and age 1.5 to 6 months based on a grid using these two parameters. Austria recommended prophylaxis until surgical correction or heart transplantation, regardless of age.
# Other clinical conditions:
Other clinical conditions were considered after individual assessment in eight countries (all but France and Spain). These included immunodeficiency of varying degrees in all eight, neurological or neuromuscular conditions without mention of clearance of respiratory secretions in Austria, Germany, Sweden, and Switzerland, trisomy 21
# Results
# Literature Review
# Randomized Controlled Trials
Nine double blind RCTs were identified. Four were placebo controlled 48,80,111,140,141 , two compared lyophilized and liquid forms of PVZ 212,213 and three compared PVZ to otavizumab (MVZ) (another monoclonal antibody directed against respiratory syncytial virus that was not licensed . Quality for seven was rated as good while one 111 was rated as fair. The ninth was a conference abstract assessed in a systematic review that included additional information and was rated as good.
In the initial PVZ IMPACT RCT of children born at ≤ 35 weeks gestational age (wGA) and aged ≤ 6 months or age ≤ 24 months with bronchopulmonary dysplasia (BPD), rates of AE reported by the blinded investigator as potentially related to the study drug were similar in the PVZ and placebo groups (11% and 10% respectively). There were no significant differences in types of AE, including injection site reactions. There were no SAE. Discontinuation of PVZ because of AE was rare (0.3%). There were 4 (0.4%) deaths in the PVZ group and 5 (1%) with placebo for reasons judged unrelated to the study drug. The number of infants receiving PVZ was 1002 48 .
An RCT of children ≤ 24 months old with hemodynamically significant CHD (hsCHD) reported similar overall rates of AE (96% vs 97%) and AE judged related to study drug by the blinded investigator (7.2% vs 6.9%) in PVZ and placebo groups respectively. There were more SAE in the placebo group (63% vs Results of an RCT of PVZ in children <2 years old with cystic fibrosis were presented as a conference abstract 141 and was the only study in a later systematic review 140 . There were no significant differences in overall rates of AE, SAE, rates of AE related to study drug (5.4% vs 4.4%) or SAE related to study drug (0 vs 2.1%) with PVZ vs placebo respectively. PVZ was discontinued because of SAE in one case. There were no deaths. The number of children receiving PVZ was 92.
An RCT of otherwise healthy premature infants born at 33-35 wGA and aged ≤ 6 months reported only hospitalizations and deaths as AE. Hospitalization rates were higher with placebo than with PVZ (21.9% vs 12.6%, p 0.04) but when hospitalizations for RSV were removed the difference was not significant (19.1% vs 14.0% for placebo vs PVZ). There were no deaths. The number of infants receiving PVZ was 214 111 .
Two RCTs comparing lyophilized and liquid preparations of PVZ in children with chronic lung disease age ≤ 24 months or born at ≤ 35 wGA and age ≤ 6 months 212 or infants born at ≤ 35 wGA 213 found no significant differences in overall rates of AE 213 or SAE 212,213 . SAE occurred in 5.9% and 2.6% of lyophilized PVZ recipients and 8.5% and 3.3% of liquid PVZ recipients in the two studies but none were judged related to the study drugs. There was one death in a child who received lyophilized PVZ that was deemed not related to the study drug 212 . The total numbers of infants exposed to PVZ were 413 212 and 305 213 .
In doses of PVZ. SAE possibly or probably related to PVZ occurred in 10 subjects (0.09%), a rate of 2 per 10,000 doses). SAE were dyspnea or cyanosis with or without fever (4), As well as rash, thrombocytopenia, osteomyelitis, seizure, hypo-responsiveness, and fever with restlessness. There were 3 deaths, one unrelated to PVZ and two not assessable 222 . A later publication reported data from the same registry for 2009-2016, when 12,729 subjects received 63,572 doses. SAE probably related to PVZ were reported in 8 cases (0.06%), or 1.3 per 10,000 doses. These events were described as breathing cessation (2), rash, rash with fever, urticaria, agitation, erythema at injection site, and acute restriction of leg mobility (1 each). There were 9 deaths, none related to PVZ 223 .
An international prospective observational study from 15 A case report described non-fatal anaphylaxis of onset 20 minutes after a dose of PVZ. 239 The child had received 5 doses of PVZ the previous season and one previous dose in the current season). Anaphylaxis has rarely been reported. The manufacturers in 2002 reported 2 cases of anaphylaxis after administration of 2,000,000 doses of PVZ 240 .
In another case report a child developed apnea, bradycardia and oxygen desaturation 8 hours after the 1 st dose of PVZ. The child was found to have parainfluenza virus 1 and rhinovirus/enterovirus in a nasopharyngeal swab. Review of data reported to the Drug Commission of the German Medical Association from 1998 to 2017 revealed 93 reports of apnea/bradycardia, desaturations or cardiorespiratory event after PVZ administration, of which all but 29 were associated with a concurrent infection. There were 3 fatal cases of cardiorespiratory events within 48 hours of PVZ, all without concomitant infection but all with severe CHD. The authors concluded that there was insufficient information to assess the association of cardiorespiratory events after PVZ administration 241 .
3.1.5. Detection and Clinical Significance of Anti-PVZ Antibodies:
In an early study, antibody to PVZ was detected in 1.2 % of PVZ and 2.8% of placebo recipients, suggesting that the binding of PVZ to antibody was non-specific 48 . In subsequent studies, anti-PVZ antibody has been detected in 1.5-5.9% of PVZ recipients 212,213,216, . Antibody was generally present transiently and at low levels and there was no boosting with subsequent doses or differences in responses between the 1 st and 2 nd year of PVZ exposure 231,232 . Anti-PVZ antibody was not associated with presence or type of AE events including potentially immune-mediated reactions, and did not affect PVZ levels.
# Data From the Canada Vigilance Program
There were 259 unique case reports of AE following PVZ administration to Dec. 31, 2018, of which 237 were considered serious. The most frequent events were respiratory at 137 (53%), of which 113 were infections (mainly reported because of PVZ product failure), followed by hypersensitivity reactions at 23 (9%). Other events reported are expected complications of the underlying conditions for which PVZ is recommended and are consistent with those reported in the product monograph. The role of PVZ in these AE is unknown as causality was not assessed.
# Summary
The most commonly reported AE considered related to PVZ were injection site reactions, fever, nervousness or irritability, cough, rhinitis, and diarrhea. PVZ related SAE were rare, reported in 1% or less of recipients with most studies reporting none. Most were hypersensitivity reactions. Three reports of anaphylaxis were identified. PVZ discontinuation because of AE occurred in 0-2.3% of recipients. There were no deaths attributable to PVZ.
Repeated injections of a humanized monoclonal antibody raises concern for the development of immune mediated disease 217,242 . Studies showed no increased risk of autoimmune disease or atopy in children exposed to PVZ.
# APPENDIX A: CURRENT CRITERIA FOR RECEIPT OF PVZ IN CANADIAN PROVINCES AND TERRITORIES AND INTERNATIONALLY
Eligibility criteria for PVZ (PVZ) prophylaxis were obtained from all Canadian provinces and territories and from 10 northern hemisphere countries. Data are summarized in the table below.
# Canada:
Premature infants without chronic lung disease or hemodynamically significant congenital heart disease (hsCHD). NACI in 2003 recommended PVZ prophylaxis for infants of ≤ 32 weeks gestational age (wGA) and age < 6 months at the start of the RSV season. The current Canadian Immunization Guide (CIG) states that selected infants of 33-35 wGA may also benefit, based on local considerations. The Canadian Paediatric Society (CPS) in 2015 stated that it is reasonable but not essential to offer prophylaxis to premature infants born at < 30 wGA and aged <6 months.
Six provinces and territories (PT) followed the current CIG recommendations for infants ≤ 32 wGA and selected infants of 33-35 wGA (AB, MB, NB, NT, ON, SK). All 6 PT used defined risk scores to determine eligibility for this group, but the risk criteria and scoring systems used varied across all PT. Two PT offered prophylaxis for those ≤ 29 wGA and for those 29-35 wGA with risk factors (BC, YT). One territory offered PVZ for all < 36 wGA (NU).Only one province followed the NACI recommendation (QC). Three provinces followed the CPS recommendation of prophylaxis for those < 30 wGA (NL, NS, PE).
# Chronic lung disease of prematurity (CLD) and other chronic lung conditions
In 2003, NACI recommended PVZ for children age < 24 months at the start of the RSV season with CLD requiring therapy in the previous 6 months or with other pulmonary disorders requiring oxygen therapy, while the current CIG only mentions children with CLD. CPS recommends prophylaxis for those with CLD of age < 12 months at the start of the RSV season who require ongoing treatment, but for their second RSV season only if still requiring supplemental oxygen or weaned off oxygen in the previous 3 months. Children with cystic fibrosis, upper airway obstruction, or chronic pulmonary disorders other than CLD should not be offered prophylaxis routinely, but it may be considered for those < 24 months old who are on home oxygen or have had a prolonged hospitalization for severe pulmonary disease.
Eight PT followed the NACI recommendation of prophylaxis for children with CLD (AB, MB, NB, NS, ON, PE, QC, SK) while in three PT infants were eligible only to age 12 months (BC, NL, YT). In one territory all infants with CLD and age < 12 months old and those 12-24 months requiring treatment the previous 3 months were eligible (NU) while in another selected infants with CHD who were < 36 wGA and age < 24 months were eligible only a case-by-case basis (NT).
Nine PT provided prophylaxis for other chronic pulmonary conditions for infants of age <24 months (8) or <12 months (1), with some PT requiring individual assessment. Conditions included cystic fibrosis (7), congenital lung or airway abnormalities (4), and neuromuscular conditions affecting ability 99 to clear airway secretions (5). Other conditions included were requirement for home respiratory support (O2, mechanical ventilation, tracheostomy, CPAP) and other severe pulmonary disability.
Congenital heart disease included cystic fibrosis in 5 countries, neuromuscular conditions interfering with clearing of respiratory secretions in 2, congenital anomalies of the respiratory tract or lung in 4, and other conditions such as chronic pulmonary conditions requiring long term need for oxygen therapy, mechanical ventilation or NACI in 2003 and the current CIG recommend prophylaxis for children with hsCHD and age < 24 months. CPS recommends prophylaxis for those of age <12 months only.
Six PT offered prophylaxis for children with hsCHD aged < 24 months (AB, NB, NT, NS, PE, SK), 4 for those < 12 months and for 12-24 months after individual assessment (BC, MB, ON, YK). Three limited prophylaxis to the first 12 months (NL, NU, QC).
# Other clinical conditions:
CPS states that prophylaxis may be considered for children < 24 months old with Down syndrome or immunodeficiency if they are on home oxygen, have had a prolonged hospitalization for severe pulmonary disease, or are severely immunocompromised.
Ten PT listed other clinical criteria for prophylaxis, some requiring individual assessment. Seven offered prophylaxis for Down syndrome (1 requiring additional comorbidity); eight for immunodeficiency (degree of severity varied), and one for neuromuscular conditions without mention of clearance of respiratory secretions.
In four PT, prophylaxis was offered to siblings of a multiple birth if one sibling qualified for prophylaxis (AB, BC, ON, YK), in all but one (ON) only if infants were premature. In one province, all infants of a multiple birth (other than twins), who were of ≤ 35 6/7 wGA and < 3 months old were eligible for prophylaxis (AB). In another, a twin of an approved child may be eligible after assessment (NT).
In all but two PT (NB, YK), protocols stated that other medical conditions may be considered on request after individual assessment. "May be administered" in text; summary says "Recommended" 21% oxygen for at least the first 28 days after birth, 1 st yr of life. 2. Methods
# Rapid literature Review
A rapid literature review of the safety of PVZ was conducted using the following sources:
-A systematic review of PVZ safety published in 2013 (rated average by AMSTAR) was used to identify studies published before 2013 211 . These studies were reviewed. -A literature search, based on the research question below, was conducted. The search strategy was developed with a Health Canada librarian (LG), included publications from 2013 onwards and was performed on April 24, 2019. The detailed search strategy is presented below. Because of time constraints, the literature search was limited to two bibliographic databases (MEDLINE and EMBASE) -Studies cited in the references obtained in the search that were not included in (1) or (2) were also reviewed.
Screening, eligibility assessment, data extraction and quality assessment were completed by a single reviewer. A data summary table with ratings of the quality of the evidence using NACI's standard methodology (Table B) was produced (Table C). Results from the accepted studies were synthesized narratively. Articles retrieved in the Health Canada literature search were loaded into RefWorks (ProQuest LLC, Ann Arbor, MI) and uploaded to DistillerSR (Evidence Partners, Ottawa, Canada). Duplicate records were removed. Records were screened by title and abstract. The full texts for articles that were relevant based on the inclusion and exclusion criteria, or that had insufficient information to exclude, were retrieved and assessed for eligibility through full-text screening.
Studies were included if they met the following criteria: -The study involved administration of PVZ intramuscularly to children.
The study presented data on safety or AE. (If PVZ was administered but these were not mentioned in the abstract, the study was nevertheless included for full text review as studies could include safety data without reference in the abstract).
# Good
A study (including meta-analyses or systematic reviews) that meets all design-specific criteria- well.
# Fair
A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion- but has no known "fatal flaw".
# Poor
A study (including meta-analyses or systematic reviews) that has at least one designspecific- "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
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Également disponible en français sous le titre : Utilisation recommandée du palivizumab pour réduire les complications de l'infection par le virus respiratoire syncytial chez les nourrissons This publication can be made available in alternative formats upon request.# PREAMBLE
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# SUMMARY OF INFORMATION CONTAINED IN THIS NACI STATEMENT
The following highlights key information for immunization providers. Please refer to the remainder of the Statement for details.
# What a) Respiratory syncytial virus disease
Respiratory syncytial virus (RSV) causes yearly outbreaks of respiratory tract disease, in Canada from late fall to early spring. It is the most common cause of lower respiratory tract illness in young children worldwide. While many infections are simple colds, children less than 2 years of age are at risk of severe disease such as bronchiolitis or pneumonia and may be hospitalized. Underlying health conditions, especially premature birth, chronic lung disease and congenital heart disease (CHD) redispose to severe RSV illness. Reinfections occur throughout life as infection produces only partial and temporary immunity, although reinfections are usually milder than the initial one.
# b) Palivizumab
At present there is no vaccine available to prevent RSV. The only means of prophylaxis against RSV disease is temporary passive protection with the monoclonal antibody preparation Palivizumab (Synagis TM ). Palivizumab (PVZ) has only been studied in children less than 2 years of age with underlying health conditions. Efficacy in early studies was 38-78% in different patient groups, and further studies, mainly observational, showed wide variation in effect with some studies showing no benefit. PVZ has been used for over 2 decades in many countries and has a good safety record, with very rare cases of anaphylaxis being the major serious adverse event (SAE) It is an expensive product, with wide ranging estimates of cost-effectiveness (or value for money). Estimated incremental effectiveness ratios (ICERs) ranged from less than $1,000 per quality-adjusted life year (QALY) to over 2 million dollars per QALY in various scenarios. In various high risk groups, 64% to 100% of estimates were < $50,000 per QALY. In rare scenarios it may be dominant (i.e, less costly and more effective). RSV vaccines are currently under study.
# Who
# NACI makes the following recommendations for public health program level decision-making:
PVZ should be offered to premature infants of < 30 weeks gestational age (wGA) and < 6 months of age at onset of or during the RSV season; children aged < 24 months with chronic lung disease of prematurity who require ongoing oxygen therapy within the 6 months preceding or during the RSV season; infants aged < 12 months with haemodynamically significant CHD and infants born at < 36 wGA and age < 6 months old living in remote northern Inuit communities who would require air transport for hospitalization. For children with both CHD and chronic lung disease, recommendations for chronic lung disease should be followed. PVZ may be considered for premature infants of 30-32 wGA and age <3 months who are at high risk for exposure to RSV; selected children <24 months of age with severe chronic lung disease due to cystic fibrosis or other etiology who require ongoing oxygen therapy or assisted ventilation in the months preceding or during the RSV season; infants <12 months of age with haemodynamically significant chronic cardiopathy other than congenital; children aged 12-24 months awaiting heart transplant or having received a heart transplant within 6 months of onset of the RSV season; and children aged <24 months with severe immunodeficiency. It may also be considered for term infants aged <6 months living in remote Inuit communities with very high rates of hospitalization for RSV among term infants and for infants of < 36 weeks gestational age and age <6 months living in other remote communities with high rates of hospitalization for RSV and where air transport would be required for hospitalization. PVZ may be considered when all other measures to control a RSV outbreak in a NICU have failed. PVZ should not be offered to otherwise healthy infants born at or after 33 wGA; or to siblings in multiple births who do not otherwise qualify for prophylaxis. It should not be offered routinely for children <24 months of age with cystic fibrosis; for children <24 months of age with Down syndrome without other criteria for PVZ; or for healthy term infants living in remote northern Inuit communities,unless hospitalization rates for RSV are very high. It should not be used for the prevention of recurrent wheezing or asthma in the absence of other indications. PVZ should not be given to prevent hospital-associated RSV infection in eligible children who remain in hospital. It may be considered when all other measures have failed to control an RSV outbreak in a neonatal intensive care unit.
Since in Canada PVZ is not readily available for purchase, no specific recommendations are made for individual-level decision making.
# How
The dose of PVZ is 15 mg/kg by intramuscular injection, starting with the onset of the local RSV season. Eligible children who are in hospital should receive their first dose on discharge (or within 48-72 hr before discharge to facilitate vial sharing). The interval between the first and second doses should be 21-28 days and between subsequent doses 28-35 days, for a maximum of 4 doses. An extra dose should be given after cardiac bypass or extracorporeal membrane oxygenation.
An extra dose may be considered in remote Northern areas where RSV outbreaks may continue longer than is usual elsewhere. PVZ should be discontinued for the season if a child is hospitalized for RSV infection. If feasible, clinics or appointments should be organized to facilitate vial sharing, to reduce costs. PVZ is contraindicated in individuals with known significant hypersensitivity reaction to PVZ or any component of the product (humanized monoclonal antibody, glycine, histidine). Moderate to severe illness, with or without fever, is a reason to consider deferring PVZ, to avoid superimposing adverse effects from PVZ on the underlying illness, or mistakenly identifying a manifestation of the underlying illness as a complication of PVZ. The decision to delay PVZ depends on the severity and etiology of the underlying disease. Minor illnesses such as the common cold, with or without fever, are not contraindications to use of PVZ. PVZ contains antibody only against RSV and may be co-administered with any other live or inactivated vaccines.
# I. INTRODUCTION
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract illness in young children worldwide 1,2 .
At present the only immunizing agent available for the prevention of serious RSV disease is PVZ, a monoclonal anti-RSV antibody. Several active vaccine candidates are currently undergoing clinical trials in infants, pregnant women and adults 3 . RSV vaccines will not be addressed in this Statement.
In June 2002, Health Canada approved PVZ (Synagis TM ) for the prevention of serious lower respiratory tract disease caused by RSV in infants at high risk of serious RSV disease. In 2003, the National Advisory Committee on Immunization (NACI) published recommendations on the use of PVZ or the prevention of RSV disease 4 . At that time, NACI recommended PVZ be used during the RSV season for premature infants (less than or equal to 32 weeks' gestational age (wGA) who would be less than six months of chronological age at the start of RSV season, children less than 24 months of age with chronic lung disease of prematurity (CLD) requiring oxygen and/or medical therapy in the previous six months or other pulmonary disorders requiring oxygen therapy, and children less than 24 months of age with hemodynamically significant congenital heart disease (hsCHD). PVZ prophylaxis could also be considered for children born at less than 35 wGA who are less than 6 months of age at the start of RSV season and who live in remote northern communities 4 . Since the 2003 statement, NACI recommendations have been modified in the Canadian Immunization Guide (CIG) but no new Statement has been issued. From 2013, in addition to the above recommendations, the CIG stated that PVZ prophylaxis may benefit selected infants between 33 and 35 wGA who are less than 6 months of age at the start of the RSV season and may be considered for infants in this gestational age group who live in rural or remote communities according to an assessment of access to medical care (e.g., requirement for air transportation to hospital facilities) and other factors known to increase risk. In addition, PVZ prophylaxis should be considered for all Inuit children in northern remote communities who are younger than 6 months of age at the start of RSV season, regardless of wGA.
Since the publication of the NACI statement in 2003, there have been a series of updated PVZ guidance documents published by expert committees including the American Academy of Pediatrics (AAP) in 2009 and 2014 [5][6][7] and the Canadian Paediatric Society (CPS) in 2015 8 which have made PVZ prophylaxis recommendations that differ significantly from the 2003 NACI guidance and highlight the need to reassess NACI's recommendations. A summary of current criteria for PVZ eligibility in Canadian provinces and territories and in ten other northern hemisphere countries, "Recommendations for use of Palivizumab in Canada and internationally", is presented in Appendix A.
The purpose of this document is to update previous NACI recommendations for the use of PVZ, taking into consideration recent data on burden of illness due to RSV disease, the efficacy and effectiveness of PVZ in infants at risk of more severe RSV disease and economic implications of PVZ use.
# Guidance Objective:
The objective of this advisory committee statement is to review evidence and develop guidance on strategies to prevent severe consequences of RSV infection in children at high risk of severe RSV disease by administration of monoclonal antibody. SYNCYTIAL VIRUS INFECTION IN INFANTS (2) The effectiveness of PVZ prophylaxis on reducing the complications associated with RSV in infants For details of methodology and results in the document "NACI Literature Review on the Effects of PVZ Prophylaxis on Reducing the Complications Associated with Respiratory Syncytial Virus in Infants" which will be forthcoming. Data are summarized in Section IV.2 of this Statement 12 .
(3) The cost-effectiveness of PVZ prophylaxis for RSV For details of methodology and results see "Cost-Effectiveness of PVZ Prophylaxis for Respiratory Syncytial Virus (RSV): A Systematic Review." Data are summarized in Section V.1 of this Statement.
In addition to these systematic reviews, other literature searches included:
(4) An environmental scan of recommendations for use of PVZ in Canadian provinces and territories and in other Northern hemisphere countries (5) A rapid literature review on the safety of PVZ ( 6) Informal literature reviews when information was needed to address specific questions.
Results of ( 4) and ( 5) are added to this document as Appendices A and B. Information and data from the informal reviews (6) are presented in the text of this document.
In order to develop comprehensive, appropriate immunization program recommendations, NACI considers a number of factors. In addition to critically appraising evidence on burden of disease and vaccine characteristics such as safety, efficacy, immunogenicity and effectiveness, NACI uses a published, peer-reviewed framework and evidence-informed tools to ensure that issues related to ethics, equity, feasibility, and acceptability (EEFA) are systematically assessed and integrated into its guidance 13 . The NACI Secretariat applied this framework with accompanying evidence-informed tools (Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, Acceptability Matrix) to systematically consider these programmatic factors for the development of clear, comprehensive, appropriate recommendations for timely, transparent decision-making. For details on the development and application of NACI's EEFA Framework and evidence-informed tools (including the Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, and Acceptability Matrix), please see https://doi.org/10.1016/j.vaccine.2020.05.051.
For this Statement, NACI reviewed the key questions for the systematic literature reviews as proposed by the RSV Working Group. Following literature searches and critical appraisal of individual studies, proposed recommendations for PVZ use were developed. The RSV Working Group chair and PHAC medical specialist presented the evidence and proposed recommendations to NACI on February 5, 2020. Following thorough review of the evidence and consultation at the NACI meetings of February 5, 2020, September 24, 2020 and October 22, 2021, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text.
# III. EPIDEMIOLOGY
RSV is an enveloped RNA virus belong to the family Paramyxoviridae. There are 2 subgroups based on differences in the G surface protein, and numerous genotypes within these subgroups. Humans are the only source of infection and transmission occurs from direct or indirect exposure to respiratory secretions containing the virus 14 .
RSV infects almost all infants by 2 years of age 1,2 . The most common clinical presentations of RSV in young children requiring hospitalization are bronchiolitis (an acute lower respiratory tract infection associated with tachypnea, cough, and wheezing), and pneumonia 14,15 . Primary infection does not confer complete protective immunity. Reinfections occur throughout life but are usually less severe, mainly presenting as upper respiratory tract illness in older children and adults 14 .
Hospitalization rates are highest in children < 1 year of age and especially in the first 2 months of life 16 . Hospitalization rates per 1000 children per year in high income countries are reported as 26.3 (95% CI 22.8, 30.2), 11.3 (95% CI 6.1, 20.9) and 1.4 (95% CI 0.9, 2.0) for age groups 0-5 months, 6-11 months and 12-59 months respectively 2 . In Canada, similar rates of 20, 10.2, and 4.8 per 1000 per year are reported for children aged < 6 months 15 , <1year, and 1-3 years, respectively 17 . In Ontario, 9% of annual hospital admissions of children <1 year of age were attributed to RSV 17 . The casefatality rate in high income countries is usually <0.5%, with higher rates in infants with co-morbidities 1,18 . Eighty-two percent of deaths in one Canadian study were in children with underlying risk factors for severe RSV disease 19 .
Most children less than 2 years of age hospitalized with RSV infection have no co-morbidities 1,17 , but higher rates and durations of hospitalization and more intensive care unit admissions have been reported in premature infants and in those with CLD or CHD 1,8,17 . Children with other lung diseases not associated with prematurity such as cystic fibrosis 20 or with other chronic conditions including immunodeficiency 21,22 and children living in indigenous communities in the far north 23 may also be at increased risk of severe RSV disease. RSV is being increasingly recognized as an important cause of morbidity and mortality in the elderly 24 .
In temperate climates, RSV causes epidemics every winter. In Canada the RSV season typically begins in October or November and lasts until April or May, with most cases occurring in December through March 25 . Studies of temporal trends in RSV hospitalization rates have shown conflicting results, likely due to differences in testing policies, sensitivity of diagnostic tests used, and criteria for hospitalization 1 . One recent US study reported decreased RSV hospitalization rates from 1997 to 2012 for all infants and for infants with CLD and high risk CHD but not for other high risk infants 26 .
# III.1 Burden of Disease in Specific High Risk Groups
Data from the burden of RSV illness systematic review performed for the development of this statement are summarized and integrated into the relevant sections below. In view of the small numbers of articles identified and heterogeneity in the methodology used and outcomes studied, the interpretation of the findings must be viewed with caution. Information from earlier studies and from the 2018-2020 literature review is also presented here.
The systematic literature review on the burden of RSV disease in young children (BODsr), limited to publications from 2014 to September 2018, and the 2020 updated review yielded no studies of burden of RSV illness in premature infants of <29 wGA. Data from studies of less premature infants are summarized here.
In study-level comparisons, one study of moderate to low certainty of evidence (COE) found similar RSVH rates for infants of 29-32 wGA and 33-36 wGA during their first RSV season (RR 1.20, 95% CI 0.92, 1.56) 27 . Another, also rated as moderate to low COE, found a relative risk of RSVH of 2.05 (95% CI 1. 89, 2.22) between infants of 33-36 wGA and term infants age <24 months 28 . Very low COE was found for RSVH in one study of infants <33 wGA compared to term infants in their first RSV season (RR 3.88, 95% CI 1.13, 13.30) 29 .
Single arm pooled proportions for RSVH (Table 1) were 5.1%, 2.8%, 3.3% and 4.1 for infants of 29 to <33 wGA 27,29 , 32-34 wGA 30 , 32/33 to 35 wGA 27,28,[30][31][32][33][34][35] and 35 wGA 30 respectively. RSVH rate for healthy term infants was 1.2%. Three of four studies in this group reported RSVH during the first year of life (0.8% to 1.5%) 29,36,37 , and one study reported RSVH to age 24 months (1.3%) 28 . 37 , Zomer-Kooijker 2014 36 .
Between-study comparisons using pooled data (all assessed by GRADE at very low COE due to the indirect nature of the evidence) showed RR for RSVH for premature infants versus term infants of 4.3 (95% CI 3.7, 4.8, p=0.000) for infants of 29-32 to <33 wGA and 2.8 (95% CI 2.5, 3.1, P=0.000) for infants of 32-35 wGA. Actual risk differences were 3.9% (95% CI 2.7, 5.1) and 2.1% (95% CI 1.4, 2.8) respectively. The 2020 literature update identified two studies that reported on RSVH in otherwise healthy premature infants. In a multinational RCT assessing efficacy of nirsevimab (a new monoclonal antibody active against RSV), RSVH rates in the 150 days following administration of placebo were 4.3% and 4.0 % in infants of ≥29 to ≤32 wGA and > 32 wGA respectively (ROB low) 38 . RSVH rate during RSV season was 3.4% in infants of 33-35 wGA in a 2015-2017 retrospective cohort study in Quebec by Papenburg et al. (ROB moderate) 39 . In addition, a systematic review, rated by AMSTAR as average, reported on seven observational prospective studies carried out between 2000 and 2008.
The pooled RSVH rate for otherwise healthy infants of 33-<35 wGA was 3.4% or 5.5 per 100 patientseasons 40 .
Earlier literature was reviewed for data about more severely premature infants. RSVH rates for infants during their 1 st RSV season in the placebo arm of a 1996-1997 PVZ RCT were (% and 95% CI) 10.0 43 . Other observational studies, ROB low 44 or moderate [45][46][47] , have reported RSVH rates of 10.4%, 7.7%, 13% and 13.5% in the first year of life for infants born at <29, <28, <29 or ≤30 wGA without other comorbidities. These early preterm infants receive little or no maternal antibody and their narrower airway passages increase their vulnerability to the effects of RSV infection.
(
Infants of 29-32 wGA are also at increased risk of RSVH in comparison to healthy term infants but RSVH rates are lower than those for more premature infants, at 5.7 to 9.9% in their 1 st RSV season (ROB moderate) 45,46 . Infants of 32 or 33 to 35 wGA have reported RSVH rates of 2.8 to 6.5% in their 1st year of life or 1 st RSV season (ROB moderate) 45,48 . In the study of Boyce et al., RSVH rates for premature infants in the 2 nd 6 months of life were similar to those for low risk term infants in the 1 st 6 months (ROB moderate) 43 . In another study, RSVH rates for preterm infants of 32-34 of wGA (20% of whom received PVZ), were similar to those of 1 month old term infants by 4.2 -4.5 months of age (ROB moderate) 49 .
Chronological age is an important risk factor for RSVH (ROB moderate) 16,43,49 Between-study comparisons (all at very low COE) using pooled data showed mean differences in LOS between premature versus term infants of 6.5 days (95% CI 3.9, 9.1, p < 0. 59 .
In earlier literature, premature infants have also been reported to have longer median hospital stays than term infants 60 . In a prospective cohort study in 2008-9, infants of 28 to < 33 wGA with confirmed RSVH had a mean LOS of 7.2 ± 3.3 days (ROB low) 61 .
# III.1.1.3. ICU Admission and Mechanical Ventilation
In the BODsr, one study looked at ICU admission, ICU LOS, mechanical ventilation (MV) and duration of MV in infants of 29-32 versus 33-35 wGA. There was no significant difference in any of these parameters (low to very low COE) 50 .
Single arm pooled proportions of patients hospitalized for RSV that were admitted to ICU were 51.7, 19.1, 31.5 and 13.9 for infants of 29-32 wGA 50 , 32-34 wGA 30 , 32-35 wGA 30,35,50 and 35 wGA 30 , respectively. Rate of ICU admission for hospitalized healthy term infants was 15.8% 37,52,53 . (Table 3) 30,35,50 , respectively. MV rate for healthy term infants was 14.0% 52,53 . (Table 5) 55 .
In earlier literature, premature infants have also been reported to have an increased risk for ICU admission compared to term infants 60 . In a prospective cohort study in 2008-9, 5.9% of infants of 28 to < 33 wGA required admission to the ICU (ROB low) 61 . A later systematic review of studies from 2000-2014, rated as average by AMSTAR, of infants of 33-35 wGA without comorbidities reported that 22.2% of infants required ICU admission for a median of 8.3 days and 12.7% required MV for a median of 4.8 days 40 . Younger age is associated with higher rates of ICU admission. In a report of infants of 32-35 wGA, no infants >6 months of age required intensive care, but 14% of those aged 3 to <6 months and 27% of those aged < 3 months were admitted to ICU (actual ages) 64 .
# III.1.1.4. Mortality
In a meta-analysis of studies from 1990-2007, all-cause mortality during their first RSV season was 0.99% and 0.13% for infants of ≤32 wGA and 32-35 wGA respectively. RSV attributable mortality was 0.03% for the two groups combined (AMSTAR rating average) 74 . In another systematic review of literature from 1975 to 2011, the weighted mean case fatality rate for children aged ≤ 24 months hospitalized with RSV was 1.2% (range, 0-8.3%; median, 0%; n = 10) for preterm infants <37 wGA versus a weighted mean of 0.2% (range 0-1.5%; median, 0.0%; n = 6) for children with no risk factors for severe RSV (AMSTAR rating poor) 66 While prematurity of any degree may increase risk of RSV hospitalization to some extent, providing prophylaxis for all is not feasible. In Canada 7.7-8.0% of births annually are of < 37 wGA 67 and it has been estimated that 5% of the birth cohort may be born at 32-35 wGA 34 . Risk scores have been developed in attempts to identify otherwise healthy premature infants of > 29-30 wGA or > 32 wGA who are at significantly increased risk of severe RSV disease, which are currently used in several Canadian provinces and territories and internationally (see Appendix A below). The risk factors identified as significant and used in these risk scores vary widely. The validity of such scores, especially those validated with data from several years ago or from different geographical settings, has been questioned 7,34,[68][69][70][71] .
Young chronological age during the RSV season is the most consistent risk factor identified. Other factors include environmental and host factors that increase risk of exposure to RSV or of more severe RSV disease. The risk of RSV hospitalization associated with these individual factors has been difficult to determine because of inconsistent results in different studies. Most environmental and host factors increase the risk for RSVH only slightly and their individual contribution to the burden of RSV disease is limited 7,70 . In a multiple logistic-regression analyses of risk factors which included male gender, child care attendance, smoke exposure, lack of breastfeeding, and other children in the house, only preterm birth and young chronologic age independently correlated with more severe RSV disease after adjusting for other covariates 69 .
# III.1.2 Chronic Lung Disease of Prematurity and Other Chronic Lung Diseases
CLD has been defined by the AAP as "born at gestational age of <32 weeks with need for supplemental O2 for at least the first 28 days after birth" 6 . Some studies defined CLD as the need for O2 at 36 weeks post conceptual age. The BODsr and the 2020 updated literature search did not identify any studies of this risk group.
In a systematic review of data to December 2015, rated average by AMSTAR, RSVH rates for children with CLD in the first 2 years of life without prophylaxis were 12-21% with a weighted mean of 16.8%. CLD was associated with a higher rate of RSVH than other high-risk groups and was a significant independent risk factor for RSVH with odds ratios of 2.2 to 7.2 72 . The Canadian Paediatric Society statement reported RSVH of 6.0 to 22.6 % in studies carried out between 1995 and 2009 8 . RSVH rate of 16.8% in the first year of life was reported in a 1992-6 retrospective cohort study (ROB moderate) 42 . RSVH rate was 12.8% for children ≤ 24 months of age with CLD in the control arm of a PVZ RCT (ROB moderate) 48 and 15.7 % for children within 12 months of initial discharge in the control arm of a PVZ observational study (ROB moderate) 44 . A 1989-93 study reported higher rates in the first year of life than in the second (38.8% vs. 7.3%) (ROB moderate) 43 . Winterstein et al. compared RSVH rates in infants with CLD and in healthy term infants with siblings. The peak RSVH rate for those with CLD was 15.3 /1000 patient-seasons at age 9 months. The RSVH rate for infants with CLD at 18.5 months was similar to that of healthy term infants aged 1 month (9/1000 patient-seasons) 73 .
In that study, 42.7% of the infants with CLD had received PVZ.
There are limited data on outcomes other than hospitalization. In the systematic review of Paes, rated by AMSTAR as average, the mean length of hospital stay for RSV was 4-11 days, with one study reporting 29% of those hospitalized admitted to ICU and 24% undergoing mechanical ventilation 72 . In the retrospective cohort study of Stevens et al. (ROB low) the mean LOS was 9.4 days and 9.1% were admitted to ICU 42 . A meta-analysis, rated by AMSTAR as average, reported an all-cause mortality rate of 0.34% during the first RSV season 74 . In a systematic review of literature from 1975 to 2011, the weighted mean case fatality rate for infants age ≤ 24 months hospitalized with RSV was 4.1% (range, 0-10.5%; median, 7.0%; n = 6) for children with CLD (rated by AMSTAR as poor) 66 .
Data on RSV risk in children with chronic lung disease of etiology other than prematurity are limited. The BODsr identified two studies. Increased rates of RSVH were reported in infants < 24 months old with congenital cystic lung disease (CCLD) (8.3%, 95% CI 0.
# III.1.3 Cystic Fibrosis
The BODsr identified two studies of infants with cystic fibrosis (CF). Pooled proportion for RSVH was 12.3% (95% CI 1.3, 30.8) (ROB high) 77,78 . In between-study comparisons, RR for RSVH in comparison to term infants was 10.3 (95% CI 3.3, 31.6, p<0.000) and actual risk difference was 11.1% (95% CI -3.7, 25.9, p=0.140). One study, with a small number of admissions, reported a mean LOS of 47.00 (12.53, 81.47) (ROB moderate) much higher than in previously published studies but not commented on by the authors 77 . The other study (moderate ROB) reported a mean LOS of 10 days
# 78
. Due to a lack of data (standard deviation not reported by Groves et al.), pooling was not conducted from these studies for this outcome.
In the study of Bjornson, the proportion of the population at risk that was admitted to ICU because of RSV was 2.4% (95% CI -0.9, 5.6) (ROB moderate) 77 . Of the 5 admitted to hospital, 2 were admitted to ICU (40%) and one required mechanical ventilation. Mean duration of ICU admission was 5.00 days (95% CI -2.84, 12.84) (ROB moderate) 77 . The other study did not report on ICU admissions 78 .
Earlier reports also indicate that RSVH occurs more frequently in children with cystic fibrosis than in healthy children. In a systematic review rated as average by AMSTAR, rates of RSVH were 6.4-18.1%, 2.5-4.3 times higher than in healthy children. Average LOS was 2-11 days and ICU admission was reported in 12.5 % (1 of 8 hospitalized patients 22 . Another systematic review of PVZ prophylaxis in cystic fibrosis, rated as good by AMSTAR, reported RSVH rates in patients not receiving PVZ of 7.5-11.7% 20
# . SYNCYTIAL VIRUS INFECTION IN INFANTS
# III.1.4 Congenital Heart Disease
Children with hsCHD were at high risk of RSV morbidity and mortality in the era when corrective surgery was usually delayed. As repair early in infancy became the norm, the risk of severe RSV disease is expected to have decreased although data to support this are sparse. A US study showed decreasing RSVH rates before PVZ prophylaxis was recommended for this group of patients 79 .
The BODsr identified one study of children with hsCHD. Using combined data from 1997 and 2000, RSVH incidence per 1000 births of infants with hsCHD was 23 (95% CI 20, 26) (ROB moderate) 79 . Between-study comparison with RSVH rates for healthy term infants could not be made. For other reported hospitalization-related outcomes, only combined data including years after PVZ became available was presented, and therefore these outcomes were excluded from analysis.
In earlier studies, a systematic review of data from 1995 to 2015, rated as average by AMSTAR, reported RSVH rates of 3.8 to 10.2 % in children < 2 years of age with hsCHD 65 . The Canadian Paediatric Society statement reported RSVH rates of 1.3 to 15% in studies carried out between 1992 and 2008 8 . RSVH rates decreases with age. Rates in the placebo arm of a 1998-2002 RCT were 9.7% for all infants (< 24 months old), 12.2% for infants < 6 months old, 7.3% for those 6 to 12 months old and 4.3% for those 1-2 years old (ROB low) 80 . In observational studies, the RSV hospitalization rate in infants with hsCHD is also significantly higher in those aged <12 months than in those aged 12-24 months. In the study identified in the BODsr, reporting on RSVH in the USA from 1997 to 2012 and spanning the pre and post PVZ eras, 85% of hospitalizations occurred in the 1st year of life 79 . Chiu et al. in Taiwan in 2005-10 reported RSVH rates of 4.8% and 2.1% with cyanotic and acyanotic hsCHD respectively in the first year of life and 0.9% and 0.56% in the second year (ROB moderate) 81 . Resch reported a 9.6% hospitalization rate in 2004-08 study including children with hsCHD and nonhemodynamically significant CHD, some of whom received PVZ, with 56 of 58 infections occurring in the 1st year of life 82 . In a study of children with CHD (not necessarily hemodynamically significant) using Medicaid data from 1989-93, estimated RSVH rate was 9.2% in the 1st year and 1.8% in the 2nd year (ROB moderate) 43 .
In the systematic review of Checchia, median LOS for RSVH for children with hsCHD was 7 to 9.7 days. The proportion of hospitalised patients admitted to ICU was 30.4 -46%, median ICU LOS was 10 days and the proportion receiving mechanical ventilation was 30% 65 . In the placebo arm of the1998-2002 RCT, mean LOS was 13.3 days, 38.1% of those hospitalized were admitted to ICU for a mean of 19.2 days and 22.2% required MV for a mean of 25.3 days (ROB low) 80 . In the study of Chu, children with hsCHD (with or without PVZ prophylaxis) hospitalized for RSV had longer mean hospital LOS (12.1 versus 3.4 days, p<0.001), higher rates of MV (21.9% vs 2.3%, p<0.001) and higher rates of respiratory syncytial virus-associated mortality (2.8 versus 0.1%, p<0.001) when compared with children without hsCHD 79 .
Feltes et al. reported RSV-related deaths among hospitalized infants with hsCHD of 0.6% (ROB low) 80 . In a meta-analysis of studies from 1990 to 2007 all-cause mortality rate in the first RSV season was 4.17% and RSV-attributable mortality was 0.62% (AMSTAR rating average) 74 . In a systematic review of literature from 1975 to 2011, the weighted mean case fatality rate for infants age ≤ 24 months hospitalized with RSV was 5.2% (range, 2.0-37.0%; median, 5.9%; n = 7) for children with CHD (AMSTAR rating poor) 66 .
# III.1.5 Down Syndrome
There is evidence that children with Down syndrome have a higher risk of RSVH than healthy children. This increase is partially explained by co-morbidities such as CHD, CLD or prematurity. Excluding children with these comorbidities, risk remains increased. Possible explanations for this include anatomic abnormalities of the upper respiratory tract, airway malacia, swallowing dysfunction, hypotonia and immune dysfunction 83 .
The BODsr did not identify any studies of children with Down syndrome that were limited to those < 2 yr of age. A single observational study of moderate COE comparing RSV outcomes in children with Down syndrome and healthy children < 3 years of age was identified. For children with Down sndrome and no other risk factors for severe RSV, RSVH rate was reported to be 2%, vs 1.1% in healthy controls, but the RSVH data had some inconsistencies and could not be further assessed. The median LOS was 5 days versus 2 days for healthy controls (mean difference 3.00 days, 95% CI 1.95, 4.05) (low COE) 84 .
A meta-analysis published in 2018 of studies to May 2017, rated by AMSTAR as average, reported a pooled odds ratio (OR) 83 . The authors report that in the single study that included only infants with no other risk factors, there was no mortality and LOS, oxygen need, ICU admission and mechanical ventilation did not differ from those reported for the whole group. An earlier systematic review , rated by AMSTAR as average, reported RSVH rates of 3.6 -13.5% in infants with Down syndrome and no other known risk factors for severe RSV. Risk ratio vs healthy infants was 3.5-10.5 and average LOS was 4-5 days 22 .
III.1.6.Immunocompromised Children RSV can cause significant morbidity and mortality in immunocompromised children. Serum and secretory antibodies are important in preventing RSV infection and T cells are required to efficiently clear the virus. There is very little population based data on the burden of RSV disease in this group. Although most infections occur in young children, immunocompromised older children and adults are also at risk of severe RSV disease and death. Morbidity varies by severity of immunocompromised 22 .
The BODsr identified two studies of immunocompromised children. A USA multicenter study in 2004-2012 reported on RSV hospitalization in liver transplant recipients <18 years of age 85 . Multivariate analyses identified age <2 years at transplant as a predictor of RSVH (P < .001). RSVH rate in the first 2 years post-transplant (for all aged <18 yr) was 5.3% (95% CI 4.4, 6.2) (ROB moderate). Between-study comparisons (all at very low COE) showed a RR for RSVH of 4.4 (95% CI 4.0, 4.9, p<0.000) versus healthy term infants. Actual risk difference was 4.1% (95% CI 3.2, 5.04, p=0.000). The proportion of hospitalized patients that were admitted to ICU was 22.2% (95% CI 15.2, 29.2) (ROB low). RR for ICU admission among those hospitalized for RSV was 1.4 (95% CI 0.8, 2.5, p=0.242, very low COE) versus healthy term infants. Actual risk difference was 6.4% (95% CI -7.8, 20.6, p=0.375; very low COE). Of those admitted to hospital, 10.4 % (95% CI 5.2, 15.5), received MV (ROB low). RR for MV amongst those admitted to hospital was 0.7 (95% CI 0.5, 1.1, p=0.156) versus healthy term infants, with actual risk difference of -3.6% (95% CI -11.5, 4.3, p=0.372, all at very low COE) 85 .
The second study was of RSV infections in children less than 18 years of age with sickle cell disease. This single center retrospective study reported a RSVH rate of 63 per 1000 person-years (95% CI 44, 87) for children < 2 years of age (ROB moderate). Other outcomes (LOS, ICU admission, mechanical ventilation), were reported only for all children aged less than 18 years and did not differ significantly from those of healthy term infants age < 2 years 86 .
An earlier systematic review, rated as average by AMSTAR, reported that most RSV infections in haematopoietic stem cell and solid organ transplant recipients occur in the first 2 years after transplant. Immunocompromised children < 2 years of age with RSVH had a median LOS of 7 and 10 days, with ICU admission occurring in 13% and 19.1% and intubation and/or mechanical ventilation in 3% and 14.3%. Overall case fatality rates were 0% and 4.8% 22 . In a Danish study of children less than 2 years old, carried out in 1997-2003, rates of first hospitalization for RSV were 21.3% in children with congenital immunodeficiencies and 8.4% in children with cancer, while the overall rate in the population of this age was 2.8%. Duration of hospitalization was not increased (ROB moderate) 21 .
El Saleeby et al. reported on RSV infections in 58 individuals aged < 21 years with cancer in Tennessee between 1997 and 2005. In multivariate analysis, age ≤ 2 yr and absolute lymphocyte counts of < 100/mm 3 at the time of RSV infection were found to be independent predictors of the development of LRTI, with OR of 9.84 (95% CI 1.95, 49.8) and 7.17 (95% CI 1.17, 44.03) respectively. These factors were also significantly associated with death 87 . In a Seattle study of HSCT recipients, the majority of whom were adults, absolute lymphocyte count of ≤100 / mm3 at the time of symptom onset was a risk factor for RSV disease progression 88 .
# III.1.7 Children Residing in Remote Communities
The BODsr identified two studies of infants in remote communities. Data from the two studies were not pooled due to differences in study design and patient populations.
One study of infants living in Canadian northern Inuit communities, carried out in 2009, (about 20% of the birth cohort, with or without prematurity or co-morbidities) reported an overall RSVH rate of 66.9 admissions per 1000 live births per year among children <1 year of age (ROB high), with regional RSVH rates of 2.0% in the Northwest Territories, 7.5% in Nunavut, and 17.6% in Nunavik. In different areas of Nunavut rates were 19.5%, 9.1% and 3.7% 23 .
The second was a study of healthy term Native American infants living on reservations in southwestern USA 89 . The RSVH rate was 12.8% (95% CI 10.1, 15.5) (ROB high). In between-study comparisons (very low COE), RR for RSVH was 10.7 (95% CI 9.4, 12.1, p<0.000). Actual risk difference was 11.6% (95% CI 8.9, 14.3, p=0.000). Mean LOS was 4.7 days (95% CI 4.2, 5.2) (ROB moderate). Mean difference in LOS versus healthy term infants was 1.2 days (95% CI -0.10, 2.5), p <0.802, very low COE). The proportion of hospitalized patients that were admitted to the ICU (ROB moderate) was 6.3% (95% CI 1.0, 11.6). RR for ICU admission was 0.4 (95% CI 0.04, 1.2, p=0.091). The actual risk difference was -9.5% (95% CI -22.9, 3.9, p=0. 164 ). Mechanical ventilation was required for 2.5% of hospitalized patients (95% CI 0.9, 5.9) (ROB moderate) for a mean duration of 6.5 days (95% CI 3.6, 9.4) (ROB moderate).
The 2020 literature search update did not identify any studies of populations living in remote communities. Subsequent to that search, results of a recent observational study from Nunavik, Quebec became available (ROB high) 90 . RSVH rates for 2013-2019 was 5.0 % for all infants < 1 yr of age (7.3% after adjustment for possible under detection by rapid antigen test compared to PCR), a much lower rate than that reported in 2009 91 . Previous studies indicate that children living in remote northern Inuit communities have high rates of RSV infection. In 2002, 16.6% of Baffin Island infants less than 1 year of age were admitted to Baffin Regional Hospital for RSV (ROB moderate). Rates ranged from 6.3% for infants from Iqaluit to 34.9% for infants from high risk rural communities. For infants of less than 6 months of age, overall RSVH rate was 25% and was 51% in high risk communities 91 . Singleton et al. reported the YK district of Alaska as having the highest rate of RSVH in the world, with 43.9% of premature infants and 14.8% of term infants < 1 year of age hospitalized annually in the pre-PVZ era (ROB high) 92 . These rates are many fold higher than the overall rates of 1-2% for term infants reported in developed countries and the infected infants frequently require air transfer to community hospitals or to tertiary care institutions.
Data on the burden of RSV illness in children living in other aboriginal communities in North America is very limited 93 and there is no information for other remote communities.
# III.1.8 Other High Risk Infants
The BODsr and the 2020 literature search update did not identify any additional groups at risk for severe RSV disease.
# III.2. RSV Infection and Long Term Sequelae: Recurrent Wheezing, Asthma and Pulmonary Function
Several studies have shown RSV LRTI in early life to be associated with recurrent wheezing in childhood. Some studies suggest that post RSV recurrent wheezing is transient, with wheezing decreasing to background levels over the first decade 94 . Whether RSV in infancy predisposes to the development of asthma, or if infants genetically predisposed to develop asthma are at increased risk of severe RSV disease in infancy, is not known 95 but there is some indirect evidence for the latter. In a prospective cohort of healthy term newborns, infants who later developed severe RSV infection and post-RSV wheezing had lower results on pulmonary function tests in the neonatal period than those that did not 36 , and another study showed bronchial hyper-responsiveness in otherwise healthy term neonates who later developed severe bronchiolitis 96 . Genetic factors predisposing to severe RSV have been described 94,95 . An association between early rhinovirus infection and asthma has been reported 95 , as well as an association between asthma and the frequency of respiratory viral infections in early life rather than any specific etiology 97 . A recent World Health Organization review determined that the evidence is inconclusive in establishing a causal association between RSV lower respiratory tract infection and recurrent wheezing in childhood or asthma and that the evidence does not establish that RSV monoclonal antibody will have a substantial effect on these outcomes 98
# . SYNCYTIAL VIRUS INFECTION IN INFANTS
The BODsr identified 6 studies that assessed long term respiratory sequelae of RSV infection in infancy.
A study of children born at 32-35 wGA with or without RSVH at < 12 months of age found small increases in the proportions with parent or physician reported simple wheeze (< 3 episodes within 12 months) (RR 1.4, 95% CI 1.15, 1.60, absolute increase 18%), parent or physician reported recurrent wheezing (≥3 episodes in 12 months) (RR 1.70, 95% CI 1.27, 2.29, absolute increase 19%), or physician reported severe wheeze (≥ 1 hospitalizations or ≥3 medically-attended episodes or on medication for wheeze for 3 consecutive months or 5 cumulative months) (RR 1.59, 95% CI 1.13, 2.24, absolute increase 14%) from 2 to 6 years of age. There was little to no difference in wheezing during the 6 th year, with RR 1. 16 32 .
A study compared infants born at < 33 wGA versus at term for wheezing in the year following RSVH. There was no significant difference in simple, recurrent or severe wheeze between the two groups (RR 0.54, 95% CI 0.18-1.55; RR 0.80, 95% CI 0.04, 16.14; RR 0.00, 95% CI -0.34, 0.34 respectively but numbers with RSV were small) (very low COE) 29 .
A study of wheezing in the first year of life in healthy term infants with RSV infection who did or did not require hospitalization found little or no difference in parent-reported days with wheeze per month between the two groups (mean difference 0.70; 95% CI -0.94, 2.34) (very low COE) 36 .
Relative risk for physician diagnosed asthma at age 7 years among healthy term infants born to mothers with asthma who had RSV versus another respiratory infection in the first year of life was RR 2. 33 99 . Some studies also addressed pulmonary function. There was little to no difference in the proportion of children born at 32-35 wGA with Force Expiratory Volume in one minute (FEV1) Z score ranking of -2 or -1 in the 6 th year of life among those who did or did not have RSVH at age < 12 months (RR 0.83, 95% CI 0.45, 1.53) (COE low). 32 Infants with or without RSVH at age < 24 months were evaluated at age 17-20 or 28-31 years. Prebronchodilator, there was a small decrease in mean percent of predicted FEV1 (mean difference -7.63, 95% CI -11.35, -3.91) and in the mean percent of predicted Forced Vital Capacity (FVC) (mean difference -4.74, 95% CI -7.80, -1.67) (COE low). There was little or no difference in the mean percent of predicted FEV1/FVC (mean difference -3.20, 95% CI -9.07, 2.67) or the mean percent of predicted Maximum Expiratory Flow after 50% of expired FVC (MEF50) (mean difference -4.00 95% CI -14.95, 6.95) (COE very low) 99,100 . There was little to no difference in the change in mean percent predicted FEV1 (mean difference 0.81, 95% CI -0.67, 2.30) (COE low) after administration of bronchodilator. There was very uncertain evidence on the change in mean percent predicted FVC (mean difference 0.60, 95% CI -0.67, 1.87) (COE very low), FEV1/FVC (mean difference -0.20 95% CI -2.71, 2.31) and the change in mean percent of predicted MEF50 (mean difference 3.70, 95% CI -5.42, 12.82) after administration of bronchodilator (COE very low).There was little or no difference for fractional exhaled nitrous oxide between those with or without RSVH at age < 24 month (mean difference -1.00 95% CI -14.49, 12.49) (COE low) 99,100 .
Single arm data showed rates of recurrent wheezing after RSVH in infancy of 12.4% (95% CI 6.3, 18.5; ROB moderate) for parent-reported or physician-diagnosed recurrent wheezing and 8.0% (95% CI 3.0, 13.0) for physician diagnosed severe wheezing at age 6 yr 32 . In other studies rates of physician-diagnosed asthma after RSVH in the first year of life were 26.9% (95% CI 14.9, 39.0; ROB low) at age 7 yr 97 , and 23.3% (95% CI 10.6, 35.9; ROB moderate) at age 28-31 yr 99 .
The 2020 literature review update identified two studies that looked at long term recurrent wheezing or asthma. In a prospective birth cohort study, premature infants of 32-25 wGA were followed up at 6 years of age for parent-reported wheeze within the previous 12 months. Wheeze was reported for 27.7% of children with RSVH in infancy versus 17.6% for those without RSVH (OR 1.80, 95% CI 1.11, 2.85). After adjustment for confounding factors, OR was 1.89 (95% CI 1.06, 3.32). When stratified by atopic predisposition (defined as atopic disease in at least one parent), the difference was significant only for the group without atopic predisposition (ROB high) 101 . A retrospective matched cohort study of term infants without hsCHD, congenital lung disease or respiratory tract anomalies who did or did not have RSV infection in the first year of life assessed asthma or reactive airway disorder, identified from administrative claims databases, in the first 5 years of life. Cumulative incidence of asthma or reactive airway disorder for children with or without a history of RSV infection was 25.2% vs 11.4%, aOR (95% CI) 2.6 (2.5, 2.9), p <.0001; 35.4% vs 16.7%, aOR 2.8 (2.6, 2.9), p <.0001; and 24.4% vs 12.7%, aOR 2.2 (2.0, 2.4), p <.0001 in three administrative databases (ROB high) 102 .
# III.3 RSV Reinfection
Reinfections with RSV occur throughout life. Naturally acquired immunity does not protect against subsequent infection, although it may modify disease severity with the initial infection usually being the most severe infection during childhood [103][104][105] . In addition, two antigenically distinct RSV subgroups, A and B, may circulate during the same season 105,106 . In a study of 30 infants under 2 years of age with bronchopulmonary dysplasia (BPD), one child had two RSVH in the same season (3.3%) 107 . Two prospective studies from Spain of children born at ≤ 32 weeks gestation reported recurrent RSVH in the same season in 6/584 (1.0%) and 9/999 (0.9%) of patients 108,109 . For these reasons, previous statements from NACI 4 and AAP 5 recommended continuation of PVZ if an infant had a breakthrough RSV infection while receiving prophylaxis. However, more recent data suggest that repeat RSV infections in the same season are rare. A study of 240 premature infants of <28 wGA or birth weight <1000 g in Denmark identified only 1 child with two RSVH in the same season (0.4%) 110 . In a placebo-controlled trial of PVZ in children with CHD, only 0.39% of children (3 of 648 in the placebo group and 2 of 639 who received PVZ) had more than 1 RSVH in the same season 80 . In another study of 429 premature infants followed for 1 year, there were no RSV reinfections 111 112 . In another outpatient study of children less than 5 years of age, of 1802 children with RSV respiratory tract infections over 2 seasons only 1 had two infections in the same season, one of RSV-A and one of RSV-B 113 . Because of the rarity of repeat infections in the same season, the AAP (2014) 6 and CPS (2015) 8 now recommend that if a child experiences a breakthrough RSVH while receiving PVZ, monthly prophylaxis should be discontinued.
# III.4 RSV Infection Risk and Siblings of Multiple Births
In a case-control study of preterm infants with BPD, fourteen sets of twins and two sets of triplets were matched with 34 singleton infants for date of birth and gestational age. The risk of developing RSV illness was significantly higher in multiple-birth infants than in singletons (53% vs 24%; p=.01), as were the rate of RSVH (32% vs 18%; p=.05) and the rate of RSV pneumonia (24% vs. 6%, p = 0.05).
After controlling for confounders in a matched logistic multiple regression analysis, multiple birth was still significantly associated only with the development of pneumonia (p=.048) 114 . In another study, Resch and colleagues retrospectively evaluated rates of hospitalization due to respiratory illness in 435 premature infants of 29-36 weeks gestation without chronic lung disease. They found that multiple birth was associated with RSVH (55% vs. 15%, p = 0.013). Multivariate analysis to consider confounding factors was not done 115 .
In contrast, two larger prospective studies of risk factors linked to RSVH, involving a total of 2326 premature infants, found similar proportions of infants of multiple births in the groups with RSVH and in the control groups 71,116 .
In a retrospective study of infants hospitalized with RSV bronchiolitis, twins represented 7.6 % (66/875) of hospitalizations. Of the 53 pairs of twins with at least one twin with RSVH, if one twin was hospitalized the other had a 34% chance of also being hospitalized with bronchiolitis (24% chance of being hospitalized with RSV positive bronchiolitis) during the same period. However, infants in the twin group were younger and had lower gestational age than singletons. In multivariate analysis, being born a twin was not a significant risk factor for RSV disease severity 117 .
# III.5 Healthcare Associated RSV Infections
RSV is frequently transmitted in hospitals, including in neonatal intensive care units 118 . The available data indicates that RSV infection rates during the birth hospitalization do not differ among infants who receive PVZ prophylaxis while in the neonatal unit compared with those who receive PVZ starting at hospital discharge [119][120][121] . These studies were rated as fair (Harris criteria) 122 . The 2003 NACI statement on PVZ did not address the issue of administration of PVZ to in-patients 4 . The 2014 AAP Statement states that infants in a neonatal unit who qualify for prophylaxis may receive a dose 48-72 hours before discharge home or promptly after discharge 6 . The CPS states that for eligible infants being discharged home for the first time during RSV season, PVZ should be started just before discharge 8 . The United Kingdom's Green Book states that infants in neonatal units who are in the appropriate risk groups should begin PVZ 24 to 48 hours before being discharged. 123 To avoid wastage when vials are being opened daily for single infants about to be discharged, coordinating administrations to three times weekly has been suggested 121 .
PVZ has frequently been used to control RSV outbreaks in neonatal units. In some instances PVZ was administered to all exposed infants 118,[124][125][126][127] , in others only to those would have qualified for PVZ as outpatients 118,127,128 . PVZ was started after other infection control measures had failed in some outbreaks 118,124 , and at the time of recognition of the outbreak in others 118,[125][126][127][128] . The incremental role played by PVZ in control of these outbreaks could not be determined 118 . PVZ may be useful when other measures have failed to control an outbreak or when it is anticipated that adherence to infection control recommendations will be poor 118,126 .
Although not addressed in the AAP 2014 or the CPS statements, the 2009 AAP PVZ statement indicates that infants who have begun PVZ prophylaxis earlier in the season and are hospitalized on the date when a dose is due should receive that dose as scheduled 5 . Likewise the UK Green Book states that those infants that have begun a course of PVZ but are subsequently hospitalized should continue to receive it whilst they remain in hospital 123 .
IV. PRODUCT
# IV.1 Preparation Authorized for Use in Canada
The only product currently authorized for use in Canada for prevention of serious RSV disease is PVZ (Synagis®, AbbVie AstraZeneca, Mississauga, Ontario). PVZ is a humanized monoclonal antibody (IgG1κ) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of RSV, a surface protein that is highly conserved among RSV isolates. It is a composite of 95% human and 5% murine amino acid sequences 129 . It was authorized for use in Canada in 2002.
PVZ solution for injection is available in 50 mg/0.5 ml and 100 mg/1 ml single use vials. Non-medicinal ingredients included are chloride, glycine, histidine and water for injection 129 .
# IV.2 Efficacy and Effectiveness
Studies of the efficacy and effectiveness of PVZ in preventing severe consequences of RSV infection in children at high risk of severe RSV disease are reported in the document "NACI Literature Review on the Effects of PVZ Prophylaxis on Reducing the Complications Associated with Respiratory Syncytial Virus in Infants" which will be forthcoming. Results are summarized below. In mixed populations of infants at risk of severe RSV infection, PVZ prophylaxis is associated with reductions of 38 -86% in the risk of RSV-associated hospital admissions, with number needed to treat (NNT) to prevent one hospitalization of 2 to 24. Differences in the health conditions of the mixed populations preclude definitive conclusions about relative benefits for different patient groups. Studies of mixed populations will not be discussed further here, but are included in the Literature Review which will be forthcoming. Twelve studies examined the effect of PVZ prophylaxis on RSVH in premature infants without CLD: a systematic review and meta-analysis of average quality 74 , four RCT reports of good 41,48 or average quality 111,130 , six observational cohort studies of either good 131 , average or fair 27,44,49 , or poor 47,132 quality and one case-control study of fair quality 133 .
The systematic review and meta-analysis of studies from 1990 to 2007 found that compared to no prophylaxis, PVZ use was associated with 72% fewer RSVH in infants born at ≤32 wGA and 74% fewer in infants born at 32-35 wGA 74 . The IMPACT RCT, carried out in 1996, reported a 78% decrease in rate of hospitalization for RSV in premature infants aged ≤ 6 months without CLD who received PVZ, with a NNT of 16 48 . The decrease was 47% for infants ≤ 32 wGA and 72% for those 32-35 wGA 48 . Notario et al. further analyzed the data from the IMpact study by gestational age groups. PVZ resulted in significant reductions in hospitalization rates for infants of 28-31 wGA (73%), 29-32 wGA (80%), 32-34 wGA (82%), and 32-35 wGA (82%), but not for those <29 wGA or 33-35 wGA. The numbers in these two latter groups were small 41 . NNT ranged from 13 to 21 and decreased with increased gestational age. A similar significant protective effect of PVZ prophylaxis was found in a later RCT of infants 33-35 wGA enrolled in 2008-10 (82%. NNT 24) 111 and a small RCT of infants born at ≤32 wGA enrolled in 2009-11 (OR 0.26, NNT 5) 130 .
In the prospective case-control study rated as fair quality, conducted from 2002 to 2006, PVZ effectiveness for prevention of RSVH was 74% of 29-35 wGA infants. Effectiveness was not observed in those < 29 wGA but the numbers were small 133 .
Observational cohort studies had conflicting results about the impact of PVZ prophylaxis on RSVH in premature infants. A retrospective cohort study of fair quality of children born in 2012-2015 found a 38% lower RSVH rate in the first RSV season in infants 29-32 wGA who received PVZ compared to infants receiving no prophylaxis (NNT 53), but no statistically significant difference in RSVH in infants 33-36 wGA who did and did not receive PVZ prophylaxis. However, numbers of children prescribed PVZ and adherence to PVZ prophylaxis in the latter group were low 27 .
In an observational study rated fair quality, PVZ prophylaxis did not significantly reduce RSVH rate for infants of ≤ 28 wGA without CLD enrolled between 2011-2013 compared with a historic control group born in 2000-2008 44 . However, the sample sizes were small.
PVZ was not significantly effective in cohorts of children born at 32-35 wGA in 2002-3 in a study rated as good quality 131 . Another cohort study of infants born at 32-34 wGA from 1995-2004, rated as fair quality, found a significant reduction in RSVH in Texas (OR=0.45, 95% CI 0.26, 0.78, p =.005) but not in Florida (OR=0.81, 95% CI 0.42, 1.58, p =.54) 49 .
In a study rated as poor quality, PVZ prophylaxis was found to significantly reduce RSVH in a cohort of children born at ≤30 wGA in 1999-2004 (1.1 % vs 13.6%, NNT 9) 47 .
# SYNCYTIAL VIRUS INFECTION IN INFANTS
In summary, there is good evidence, based on early RTC, of the efficacy of PVZ in premature infants of 28-35 wGA. The conflicting results of observational studies on infants of 32-36 wGA are difficult to explain, but may in part be due to differences in study design, adherence, location and era. Three studies, one of good and two of fair quality, suggested lack of effect in infants of < 29 wGA but this may be the result of small numbers of infants without CLD in this very premature group 41,44,133 . One observational study of poor quality supported a protective effect in infants of ≤ 30 wGA. In general, it appears there is evidence in support of the effectiveness of PVZ in reducing RSVH in children born prematurely, although the level of prematurity at which PVZ is most effective is not clear from the data.
# IV.2.1.2. Mortality
The only study that examined all-cause mortality was a systematic review and meta-analysis of average quality by Checchia et al. In infants born at ≤32 wGA. PVZ recipients had a significantly reduced risk of all-cause mortality (OR=0.25, 95% CI 0.13, 0.49, p<0.001) compared to recipients of placebo or no intervention, while in infants born at 32-35 weeks' GA, the difference was not significant (OR=0.22, 95% CI 0.03, 1.89, p=0.085) 74 .
It is possible that there may be a differential impact of PVZ prophylaxis on all-cause mortality in this population, showing a protective effect in infants born at ≤32 weeks' GA, but not at lesser levels of prematurity (32-35 weeks' GA). However, these findings are based upon few studies which may have been underpowered to detect difference in mortality in the less premature infants.
# IV.2.1.3 Long Term Sequelae
# IV.2.1.3.1 Recurrent Wheezing and Atopic Asthma
Six reports examined the effect of PVZ prophylaxis on the risk of wheezing in the first few years of life: Two reports of average or fair quality from a RCT 111,134 and four reports from two cohort studies of good 135 , average or fair 136,137 and poor 138 quality. One study 111 investigated parent-reported wheezing only, while the other five investigated physician-diagnosed or both parent-reported and physician-diagnosed wheezing. Three studies found that PVZ prophylaxis in otherwise healthy premature infants born at 33-35 wGA 111,138 or ≤35 wGA 136 , resulted in a significant reduction (46-66%) in the risk of wheezing in children in the first year of life 111 , up to age 3 138 , or up to 2 years after enrollment at age ≤36 months 136 . In another report from the cohort study of Simoes et al., children who had received PVZ prophylaxis had a significantly decreased incidence of physician-diagnosed wheezing 24-months after study enrollment and a significantly longer time to a third physiciandiagnosed wheezing episode compared to children receiving no intervention, but only in children without a family history of asthma or atopy. There was no significant difference in these outcomes in children with a family history of asthma or atopy 135 . A follow-up of the cohort of children born at 33-35 wGA initially assessed for wheezing at age 3 years 138 found that children who had received PVZ prophylaxis had reduced rates of physician-diagnosed recurrent wheezing during the first 6 years of life compared to children who had not received prophylaxis. However, this association was found only in the subgroups of children with a family history of allergy. The authors distinguished atopic asthma (recurrent wheezing and elevated IgE) from recurrent wheezing and found rates of atopic asthma were similar in children who received PVZ and those who did not, regardless of family history of allergy 137 .
On follow-up at age 6 years of the infants enrolled in the Blanken et al. RCT, the difference between PVZ and placebo recipients was significant only for those with parent reported infrequent wheeze (1-3 episodes per year). There was no significant difference in physician diagnosed asthma or the use of asthma medication in the previous 12 months and pulmonary function at 6 years of age did not differ between the groups 134 .
It appears PVZ may have a consistent impact in reducing the incidence of recurrent wheezing in young children in the first few years of life, but the findings are contradictory as to the relative impact of PVZ versus a family history of atopy on subsequent recurrent wheezing in older children. It also is not clear from these studies at what level of prematurity PVZ may be most effective in having a long term impact. The NNT to prevent one case of recurrent wheezing was 7-8 in infants of 48 .
In an observational study rated as fair, PVZ prophylaxis reduced RSVH rate by 86% (NNT 13) in the first 6 months after initial hospital discharge for infants with CLD enrolled between 2011 and 2013 compared with a historic control group born in 2000-2008. By gestational age, reduction was significant for those of ≤28 wGA (89%, NNT 12) and not those 29-35 wGA, but numbers in the latter group were small 44 . An earlier prospective observational cohort study of poor quality of infants born at ≤32 wGA, carried out in 1999-2002 , found PVZ prophylaxis to be associated with a reduced risk of RSVH (RR=0.15, 95% CI 0.05, 0.49, p<0.01; NNT 3) in the 1st RSV 139 . Another prospective observational study of poor quality that included children up to 24 months of age with CLD also reported reduced risk of RSVH (RR=0.28, 95% CI 0.14, 0.58, p<0.007; NNT 8) 46 . In a prospective case-control study, rated as fair quality, of infants ≤35 wGA and <12 months or 12-24 months of age, conducted from 2002 to 2006, there was no significant reduction in hospitalization rate 133 .
The results suggest that PVZ prophylaxis provides a reduction in the risk of RSV-associated hospital admissions in this population, but the influence of gestational age on this benefit is not clear.
# IV.2.2.2 Mortality
A meta-analysis of average quality showed no observed effect of PVZ vs no intervention/placebo on all-cause mortality for preterm CLD (0.22% vs. 0.34%; Peto OR, 0.83; 95% CI 0.13, 5.25), but there were only 3 events in the prophylaxis group and 2 events in the placebo/no intervention group 74 . 144 .
No conclusions on the effectiveness of PVZ prophylaxis in reducing the risk of RSVH in children with cystic fibrosis can be drawn from the findings of these studies. Only the observational study of Groves et al. found a significant preventive effect of PVZ prophylaxis on RSVH 78 . The rate of RSVH in the control group in that study was very high and the number of participants was small. Most studies had small numbers and may have been underpowered to detect an effect. The exception was the large study of Winterstein et al, which used a health care provider administrative database 142 . It may be that some children with cystic fibrosis, e.g, those with significant chronic lung disease in the first 1 or 2 years of life, may benefit. Robinson et al examined the effect of PVZ prophylaxis on the use of oxygen therapy due to RSV in children with cystic fibrosis. No significant difference between the groups was found in the need for oxygen therapy; however, the number of outcomes was small (PVZ prophylaxis group, n=1; placebo intervention group, n=0) 140 . In the study of Bjornson, increased respiratory support, either MV or oxygen therapy, was required by 2.2 % of PVZ recipients and 1.2% of the control group (p 0.58) 77 . In the study of Buchs, no patients required supplemental oxygen or MV 144 .
# IV.2.3.3 All-Cause Mortality
The RCT study examined the effectiveness of PVZ prophylaxis in reducing all-cause mortality in children with cystic fibrosis. However, as there were no deaths identified in either group during the 6 months of follow-up during the study, no conclusion can be drawn about the effect of PVZ prophylaxis on this outcome 140 . A larger cohort study by Fink et al. also reported no difference in all-cause mortality before age 2 years between those who did or did not receive PVZ 145 .
# IV.2.3.4. Long-Term Sequelae
# IV.2.3.4.1 Lung Function
A small historical cohort study of fair quality found no significant difference in lung function (as assessed by measurement of FEV1) between children with cystic fibrosis who had and had not received PVZ was found on follow-up assessments at 6 years of age 78 . The cohort study by Fink et al., rated as of poor quality, also found no difference in FEV1 at age 7 years between those who did or did not receive PVZ 145 .
# IV.2.3.4.2 Growth Parameters
The RCT found no significant differences between the PVZ and placebo groups at 12 month followup with respect to weight gain or weight to height ratio 140 . A small historical cohort study found no significant differences in growth parameters (weight, height, body mass index) at 6 years of age between children who did and did not receive PVZ prophylaxis 78 . The case control study of Buchs et al, also found no significant difference between PVZ recipients and controls in growth in the first 3 years of life 144 .
# IV.2.3.4.3 P. aeruginosa and S aureus Colonization
The RCT found no statistically significant differences in the numbers of children with P. aeruginosa airway colonization in children receiving PVZ compared to those receiving placebo at 12 months follow-up. 140 In the study by Groves et al, the median time to a first isolate of P. aeruginosa was SYNCYTIAL VIRUS INFECTION IN INFANTS significantly shorter in PVZ recipients than in non-recipients and the relative risk of a first isolate during the study period was also significantly increased in PVZ recipients. However, at follow-up at 6 years of age there was no significant difference in chronic P. aeruginosa colonization rates between the two groups 78 . Buchs et al, reported that PVZ prophylaxis had no significant effect on age at first colonization with P. aeruginosa or S. aureus or in the proportion of children colonized with P. aeruginosa by age 3 years. The proportion of infants colonized with S. aureus by age 3 years was significantly increased in the PVZ recipients (97%) in comparison to controls (85%) 144 . Fink et al. also reported no difference in time to first P. aeruginosa colonization between those with or without PVZ prophylaxis 145 .
The results from the these studies appear consistent with no significant differences in the longer term sequelae examined between children with cystic fibrosis who have and have not received PVZ prophylaxis. However, the number of children studied was small. Five studies examined the efficacy or effectiveness of PVZ prophylaxis in children with hsCHD. A good quality RCT carried out in 1998-2002 80 found that children with hsCHD and ≤24 months of age at the start of the RSV season who received PVZ prophylaxis had a significant relative decrease in RSVH compared to children receiving placebo (RD=45%, p=0.003; NNT 23). This was statistically significant in children with acyanotic CHD (RD=58%, p=0.003; NNT 15), but not in children with cyanotic CHD (RD=29%, p=0.285). An observational cohort study of fair quality of infants < 1year of age, with PVZ recipients in 2013-2015 followed prospectively and controls from 2010-15 identified retrospectively found a significant reduction of 49% (NNT 45) for all cases and 65% (NNT 31) for the subgroup with cyanotic hsCHD but a non-significant reduction of 35% for those with acyanotic disease
# 146
. A significant relative risk of 0.28 (72% reduction, NNT 7) in hospitalization for all cases of hsCHD < 1 year of age was reported in a small observational study of fair quality with PVZ recipients enrolled between 2014-16 and historical controls born in 2007-09 147 . An earlier poor quality observational cohort study with PVZ recipients from 2003-07 and historical controls born 1998-03 did not find PVZ prophylaxis to result in a significant reduction in RSVH compared to no intervention in children with CHD who were born at ≤36 w GA and ≤24 months of age at the start of the RSV season (RR=0.58, 95% CI 0.21, 1.65), but the RSVH rate in the control population was very low (2.9%) 148 . In a prospective case-control study of fair quality, carried out from 2002-6, significant PVZ effectiveness was not observed, either in the first or the second year of life 133 .
These studies show conflicting results on the protective effect of PVZ on RSVH in infants with hsCHD. The two studies that did not show a significant effect 133,148 had smaller numbers of participants than two larger studies that showed 45-49% risk reduction 80,146 . One of these studies showed significant protection in children with cyanotic heart disease but not in those with acyanotic heart disease 146 , but the other showed the opposite 80 . The reasons for these discrepancies are not evident but may be due to inadequate sample size to detect a difference in the subgroups. SYNCYTIAL The RCT involving children with hsCHD and ≤24 months of age found PVZ recipients to have a significant relative decrease in the total number of RSVH days/100 children compared to placebo recipients (RD=56%, p=0.003) 80 . For those admitted to hospital because of RSV, mean LOS was 10.8 days for PVZ recipients and 13.3 days for placebo, not significantly different. In the study of Chiu et al, the LOS was not significantly different in patients who did or did not receive PVZ, either for the total group or for those with cyanotic or acyanotic hsCHD 146 .
# IV.2.4.2.2 Admission to and Length of Stay in Intensive Care Unit due to RSV
The RCT of children with hsCHD aged ≤24 months reported that compared to placebo recipients, PVZ recipients had a relative decrease in the number of admissions to ICU but the reduction was not significant (RD=46%, p=0.094) 80 . In the observational cohort studies, Chiu et al, reported no significance differences in rates of admission to ICU in those who received PVZ and those who did not, either for the total group or for those with cyanotic or acyanotic hsCHD, and Harris et al also found no significant difference in rate of admission to ICU. In the three studies, the proportions of infants hospitalized for RSV who required ICU admission were also not significantly different in the groups that received PVZ and those that did not 80,146,148 .
In the RCT the total number of days/100 children in an ICU due to RSV did not differ significantly between PVZ and placebo recipients 80 . In the cohort study of Harris, mean ICU LOS decreased from 14.9 to 10 days but the difference was not significant 148 .
# IV.2.4.2.3 Use of Mechanical Ventilation (MV) due to RSV
The RCT by Feltes et al. found no significant difference in the use of MV, reported as total days/100 children, between children with hsCHD and ≤24 months of age at the start of the RSV season who received PVZ compared to placebo recipients (RD=41%, p=0.282) 80 .
# IV.2.4.2.4. Duration of Oxygen Therapy due to RSV
The RCT found that compared to placebo, children who received PVZ prophylaxis had significantly less total days/100 children on oxygen therapy (RD=73%, p=0.014) 80 .
These results suggest that for children with hsCHD who are hospitalized with RSV infection, having received PVZ does not affect the severity of illness, as manifested by hospital LOS, ICU admission, ICU LOS, or need for MV, although the number of studies is small.
# IV.2.4.3 All-Cause Mortality
Both the RCT by Feltes et al. and the cohort study by Harris et al. examined all-cause mortality in this population 80,148 . In the RCT, there was no significant difference in all-cause mortality between children with hsCHD and ≤24 months of age at the start of the RSV season who received PVZ compared to 150 . After adjusting for hsCHD, insignificant CHD, gestational age, and birth weight, the analysis found that compared to no intervention receipt of PVZ was associated with a statistically significantly 72% reduction in RSVH (IRR=3.63 95% CI 1.52, 8.67, p=0.002; NNT 12). Significant reduction in hospitalization was also found when the analysis was restricted to children with at least one standard risk criteria for RSV prophylaxis (hsCHD, born at ≤35 wGA, CLD) (IRR 3.39 (1.02-11.25)). However, when the analysis was restricted to children with no standard RSV risk criteria, the difference in RSVH between children receiving PVZ prophylaxis and children receiving no intervention was not significant (IRR=6.57 95% CI 0.70, 62.16). The third study, rated as good, reported a decrease in overall RSVH after PVZ prophylaxis was approved in Japan for all children with Down syndrome. For all children, the adjusted odds ratio (aOR) for those receiving PVZ was 0.41 (95% CI 0.18, 0.92, p=0.03) but there were no differences in RSVH in the groups without hsCHD (aOR 0. 43 150 .
The significance of the results from these studies, one of poor quality 150 and the other involving very few children 149 , is unclear, but suggests that PVZ may not benefit children with Down syndrome who do not have other conditions that may warrant PVZ administration. Further studies would be required before conclusions can be drawn on the benefit of PVZ in this population IV.2.6 Infants Residing in Remote Communities IV.2.6.1 RSV-Associated Hospitalizations There were two cohort studies of poor quality that examined this outcome 92,152 . The Banerji et al. study included Inuit children from Nunavut, Canada who were born at either <36 wGA and/or had significant cardiac or respiratory disease and were <6 months of age at the start of the 2009-10 RSV season. Children who received PVZ had significantly fewer RSVH (2/91, 2.2%) compared to PVZ eligible children receiving no intervention (5/10, 50%) (OR=0.04, 95% CI 0.008, 0.26, p=0.0005). The number needed to treat to prevent one RSVH was 2 152 . As not all PVZ eligible infants were identified, the actual reduction rate is likely to be less than that reported. In the study by Singleton et al., RSVH were assessed in Alaskan Aboriginal children before and after introduction of a PVZ program for high risk infants in 1998.There was a significant reduction in RSVH in infants born at ≤36 wGA (relative rate 0.34, 95% CI 0.17, 0.68, p<0.001). After the PVZ program introduction, among high risk infants the rate of first RSVH was 0.55 per 1000 PVZ protected days and 1.07 per 1000 unprotected days (relative rate 0.52; 95% CI 0.28, 0.93). The number needed to treat to prevent one RSVH was 4 92 .
Although Inuit infants residing in remote northern communities are known to be at high risk of RSVH 23 , data on PVZ effectiveness to prevent hospitalization in this group is very limited. After completion of the PVZ effectiveness literature review, the results of a program providing PVZ prophylaxis to healthy term infants less than 3 months of age during RSV season in Nunavik, Quebec became available 90 . The quality of the study was rated as fair. Between November 2016 and June 2019, 73% of 646 eligible healthy term infants received some PVZ but only 37% received all recommended doses on time. PVZ effectiveness was assessed by 1) comparing RSVH in infants who received all doses of PVZ on time and those who received no PVZ and 2) comparing RSVH during PVZ-protected and unprotected days. RSVH occurred in 10/237 infants (4.2%) who received PVZ and in 7/177 (4.0%) of those who did not. PVZ direct effectiveness was calculated to be -6.7% with wide 95% CI of -174.8, 85.5. RSVH rates were 37.6/100,000 PVZ-protected days and 39.1/100,000 unprotected days, for a direct protective effect of 3.8% with 95% CI -1167. Several studies were identified in the literature search on burden of RSV illness that described the impact of the 2014 AAP revised recommendations for PVZ use on RSVH by analyses of sequential time periods before and after implementation of the revised recommendations 6 . These studies did not meet the criteria for the literature review because children who did or did not receive PVZ were not identified, but are summarized here.
In a single tertiary center study from North Dakota, the rate of RSVH per 1,000 children <24 months old was 5.37 in the pre-2014 guideline period (2012-13 and 2013-14 seasons) and 5.78 in the post-2014 guideline period (2014-2015 season) (rate difference of +0.4, 95% CI −1.2, +2, p 0.622). The number of RSV admissions was 194. The number of doses of PVZ administered per 1000 children <24 months of age was 21.7 in the pre-2014 guideline period and 10.3 doses in the post-2014 guideline period, a reduction of 11.4 doses (95% CI 14.3, 8.4, p <0.001) 153 .
Another single center study from Milwaukee looked at numbers of RSVH in infants less than 1 year old born at ≥29-35 wGA and the proportions of all RSV admissions that were in this gestational age group 2 seasons before and two after implementation of the 2014 AAP guidelines (2012-2017). The number of RSVH was 91.There were no significant differences in the number of admissions or the proportion of admissions in this gestational age group before and after implementation of the new guidelines. Duration of hospitalization increased from a median of 5.86 days before to a median of 7.86 days (p 0.02) after implementation but there was no difference in need for ICU, supplemental oxygen, or MV 154 .
A single center study from Ohio looked at RSVH in infants <12 months old before and after implementation of the 2014 guidelines. Of 1063 RSVH, infants born at 29 0/7 -34 6/7 wGA accounted for 7.1% (34/482) in the 2013-4 season and 9.8% (57/581) in 2014-5 season (not significantly different). Infants of 29-34 wGA who were <6 months old constituted 3.5% (17/482) of RSVH in 2013-14 versus 7.1% (41/581) in 2014-15 (P = .01). Among 290/7-346/7 wGA otherwise healthy infants who were <3 months old, oxygen administration (40.0% vs 78.9%; p 0.05), pediatric ICU admission (30.0% vs 68.4%; p 0.04), MV (10.0% vs 52.6%; 0.04), duration of hospitalization (1.8 vs 8.8 days; p 0.04) were all higher in 2014-15. No differences in morbidity were observed between 2013-14 and 2014-15 in premature infants aged 3 to <6 or 6 to <12 months. PVZ eligibility decreased from 32.3% in 2013-14 to 1.8% in 2014-15 (P < .001) 51 .
A large study used commercial and Medicaid databases to assess infants born between July 1, 2011 and June 30, 2016. Infants were categorized as preterm or term and hospitalizations for RSV for infants aged < 6 months identified. Rate ratios comparing hospitalization rates for preterm and term infants were calculated. Seasonal rate ratios prior to the guidance change for preterm versus term infants ranged from 1.6 to 3.4. After the guidance change, seasonal rate ratios ranged from 2.6 to 5.6. In 2014 to 2016, the risk associated with prematurity of 29-34 wGA versus term birth was significantly higher than in 2012 to 2014 (2.00, p<0.0001 for commercially insured infants and 1.46, p<0.0001 for Medicaid insured infants, p<0.0001). PVZ use decreased by 74-97% in different wGA and age groups Another study investigated the effect of the change in recommendations for children with hsCHD. The 2014 AAP guidelines recommended PVZ prophylaxis for those in the first year of life whereas previous guidelines recommended prophylaxis for those < 2 years of age. A US national administrative healthcare database was reviewed to identify children age < 24 months with CHD admitted with RSV in the 2012-2014 and 2014-2016 RSV seasons. There were 644 RSV admissions in the 2012-13 and 2013-2014 seasons and 625 in the 2014-15 and 2015-2016 seasons. There was no change in LOS, ICU admission rate, or in-hospital mortality for children 13-24 months old with CHD after the change in recommendations. There were no deaths in 13-24 month olds, regardless of era. The population studied was not limited to those with hsCHD 157 .
Following publication of the revised recommendations from the AAP in 2014, Italy implemented similar limitations for PVZ use for otherwise healthy premature infants in the fall of 2016. In a population of 284,902 children aged <2 years in one region of Italy, the number of RSVH was 1729. Following the change in policy a reduction in the number of RSVH from 6.3/1000 (95% CI 6.0, 6.7) to 5.5/1000 (95% CI 5.0, 5.9) was observed. There was no significant difference in wGA or age on admission of children admitted with RSV in the 2 seasons before and the season after the change in policy. The number of prescriptions for PVZ decreased by 48% after the change in policy 158 .
A retrospective review of RSVH of children ≤ 1 years of age over three consecutive RSV seasons (2014-15, 2015-16, 2016-2017) was carried out in single tertiary center in Italy. Total RSV admissions for the 3 seasons was 366. The proportion that were preterm increased in the 3 seasons from 6.6%, to 7.3%, to 9.2%, respectively for the 29 -< 36 wGA group, and from 5.1% to 6.4% to 8.3%, respectively, for the 33 -< 36 wGA subgroup. These increases were not statistically significant but sample size was small 159 .
Another retrospective cohort study of RSVH among infants born at 29-35 wGA in the season before (2015-2016) or after (2016-2017) the introduction of more restricted recommendations for PVZ was conducted in three neonatal ICUs in Italy. There were 262 infants enrolled in 2015-16 and 274 in 2016-17. RSVH occurred in 1.9 and 5.1% in infants in 2015-16 and 2016-17 respectively (odds ratio 2.77; 95% CI 0.98, 7.8, p 0.045. The proportion of infants not receiving PVZ increased significantly from 63.7% in 2015-16 to 80.6% in 2016-17(p-value < 0.0001) 160 .
In summary, there is little population-based data on the effect of the 2014 change in AAP recommendations on RSVH of premature infants of 29 to 35/36 wGA. One small single center study reported no difference in overall RSVH rates. A large administrative database study showed a 1.4 to 2.7 fold increase in RSVH rates in premature infants aged < 3 months. Other studies looked at the proportions of children admitted with RSV who were of 29-35 wGA. Two single center studies showed no difference in this proportion. One showed no difference in morbidity of those admitted, while the other reported a shift towards younger age, and higher morbidity in those admitted who were < 3 months old but not in older infants. Another large database study compared ratios of premature to term infants among those admitted with RSV and reported an increase of 1.5 to 2 fold. One study of children with CHD aged 13-24 months showed no increase in morbidity in those hospitalized with RSV. A similar policy change was made in Italy. Two studies there showed no significant impact while a third reported a 2.7 fold increase in RSVH rates in infants of 29 to <36 wGA. However there are important variations in RSVH rates from 1 season to another, and these studies covered only 1 or 2 seasons before and after policy change.
# IV.3 Immunogenicity
# IV.3.1 PVZ Levels
PVZ is a passive immunizing agent. A PVZ serum concentration of ≥ 30 ug/mL was shown to reduce replication of RSV in the lungs of the cotton rat by 99% 161 . Based on this data, ≥40 ug/mL was chosen arbitrarily as the preferred target trough level in clinical trials in infants 48,80,162 . In these studies, 5 doses of 15 mg/kg were given at intervals of 30 days. A pharmacokinetic computer model based on data from 22 clinical trials suggested that this schedule would provide levels above the target trough for 6 months 163 .
The half-life of PVZ is 19-27 days 164 . Trough PVZ levels increase with sequential doses. Mean ± SD trough serum concentrations 30 days after 15 mg/kg doses one, two, three, and four were 37±21 ug/mL, 57± 41 ug/mL, 68±51 ug/mL, and 72±50 ug/mL, respectively 165 . In a study of PVZ in children with CHD, serum concentrations (mean ±SD) before the second and fifth doses were 55.5 ±19 ug/mL and 90.8 ±35 ug/mL. In 139 patients who underwent cardiac bypass, PVZ levels measured just before and the day after bypass were 98.0 ±52 ug/mL and 41.4 ±33 ug/mL, respectively, a decrease of 58% (p=0.0001) 80 . Previous NACI guidance and the AAP state that for children with CHD who will continue to require prophylaxis, a 15 mg/kg dose of PVZ should be given after cardiac bypass 4,6 . The AAP also suggests that if prophylaxis is still indicated, an extra 15 mg/kg dose be considered at the conclusion of extracorporeal membrane oxygenation 6 .
The possibility of giving fewer than 5 doses of PVZ has been explored. A recent modeling study predicted that levels of 30 to 40 ug/mL would be maintained for 181 days if doses 1 and 2 were given 29 days apart and the subsequent 3 doses 38 days apart. With only 4 doses these levels would be maintained for 143 days 166 . The CPS recommends that programs should administer a maximum of 3 to 5 doses, with 4 doses probably being sufficient in all risk groups if PVZ is started only when there is RSV activity in the community, especially if doses 2, 3, and 4 are given 38 days apart 8 . However, administration at 38 day intervals is more complex to implement and may result in more wastage; an interval of 35 days may be more practical. A program in British Columbia gave 4 doses of PVZ with interval of 21-28 days between the first 2 doses and 28-35 days between subsequent doses. RSVH occurred in 10 of 666 infants (1.5 %). All were PVZ breakthrough cases with the exception of one set of twins who were hospitalized 65 days after the 4th dose. Eighteen others (2.7%) were hospitalized for bronchiolitis while receiving PVZ but not tested for RSV. A 3-dose schedule was provided for 514 lower risk children born at 29 to <35 wGA and without chronic lung or CHD. One child was admitted for RSV while receiving PVZ and another was admitted 58 days after the 3rd dose 167 . A further cohort study of 391 children with CHD in British Columbia who received 4 doses of PVZ 2012 through 2016 showed an admission rate for proven or potential (not tested) RSV lower respiratory tract infection of 6.2 per 100 PVZ approvals 168 , a rate similar to the 5.3% observed in PVZ recipients in a clinical trial of 5 monthly doses in children with CHD (respiratory illnesses that were not tested for RSV were excluded) 80 . Only one child had RSVH more than 30 days following the last dose of PVZ. In another SYNCYTIAL VIRUS INFECTION IN INFANTS study, protective neutralizing antibody levels (defined as neutralization titre (NT95) of ≥ 1 in 12 dilution) were present at an average of 55 days (range 28-105 days) after the final dose of PVZ. Protective neutralizing antibody levels were also found in 54% of control infants aged 4-11 months who did not receive PVZ, suggesting that humoral response to subclinical RSV infections may contribute to neutralizing titers that persist after PVZ administration 169 .
Concern has been expressed about the substantial inter-and intra-individual variability in PVZ levels 163,165 and implications for protection if fewer PVZ doses or longer dose intervals are used. Low trough levels after the first dose has led to suggestions for a shorter interval between the first and second doses 170 . Troughs of <40 ug/ml after the first dose were reported in 33% of recipients 164 . In one report, 46% of breakthrough RSV infections occurred in the interval after the first dose 171 but this high rate has not been replicated in other studies. A retrospective review of 42 patients hospitalized with RSV despite PVZ showing a correlation between lower PVZ levels and admission to an ICU. Mean levels were 47.2 ug/mL in those who required ICU care and 98.7 ug/mL in those who did not (P < 0.0001). In multivariate analysis in the above study, including potential confounding factors, the only parameter associated with ICU admission was PVZ level 172 .
# IV.3.2. Dose Schedules and RSV Seasonality
The annual "RSV season" is the period during which the risk of acquiring RSV is sufficiently high to warrant prophylaxis of high risk infants. The season usually starts in October or November in Canada and ends in April or May, with most cases occurring in December through March. The duration of the annual RSV season varies with year and location, and was reported as varying from 13 to 23 weeks in various locations in the USA 7 and from 90 to 181 days in Hamilton, Ontario 173 . Because 5 monthly doses should provide protective levels for > 6 months, a maximum of 5 doses is recommended by the AAP 6 . Use of PVZ can be optimized if local virology laboratory data are used to determine when to begin prophylaxis 173 . Where such data are unavailable, the start date may be determined by paediatric RSVH data, or based on previous seasons. In some areas, 4 monthly doses may be sufficient 174 . In Canada, some programs start routinely in November or December and others use local laboratory and hospitalization data to define the RSV season (see Appendix A). The latter may be more complicated to implement than using fixed dates but may make more efficient use of the product.
Occasional RSVH may be expected before or after the main season in some areas, but maximum benefit from prophylaxis will be achieved during the peak of the season.
# IV.4 Safety
PVZ is generally considered to be a safe product. Since the description of adverse events (AEs) in the NACI 2003 PVZ statement 4
# IV.4.1 Rapid Literature Review
Nine RCTs, two population based cohort studies, 26 descriptive reports from registries or cohorts, and 2 case reports were identified. The most commonly reported AE considered related to PVZ were injection site reactions, fever, nervousness or irritability, cough, rhinitis, and diarrhea. PVZ related serious adverse events (SAEs) were very rare, reported in 1% or less of recipients, with most studies reporting none. Most were hypersensitivity reactions. Three reports of anaphylaxis were identified. PVZ discontinuation because of AEs occurred in 0-2.3% of recipients. There were no deaths attributable to PVZ. Repeated injections of a humanized monoclonal antibody raised concern for the development of immune mediated disease. Studies showed no increased risk of autoimmune disease or atopy in children exposed to PVZ.
# IV.4.2 Data from the Canada Vigilance Program
A review of AEs reported to the Canada Vigilance Program, Health Canada, identified 259 case reports of AE following PVZ, with 237 classified as serious. The most frequent events were respiratory at 137 (53%), of which 113 were infections, mainly reported because of PVZ product failure, followed by hypersensitivity reactions at 23 (9%). Other events reported are expected complications of the underlying conditions for which PVZ is recommended and are consistent with those reported in the product monograph. The role of PVZ in these AEs is unknown as causality was not assessed.
# IV.5 Vaccine Administration
PVZ is given at a dose of 15 mg/kg of body weight by intramuscular injection.
For dose intervals and numbers of doses see Immunogenicity, section IV.3, above.
# IV.6 Storage Requirements
PVZ should be stored between +2 and +8°C in its original container. It should not be frozen. Vials are for single use and do not contain a preservative.
If an entire vial (50 mg or 100 mg) is not required for a patient's monthly injection, physicians should arrange for more than one patient to receive PVZ within 6 hours 4 or on that same clinic day 175 in order to minimize product wastage. Opened vials containing product not used within 6 hours should be discarded and not stored. Weekly clinics for eligible infants in a specific locality facilitate efficient use with minimal wastage.
# IV.7 Simultaneous Administration with Other Vaccines
PVZ is an antibody directed specifically against RSV and does not contain other antibodies or human serum. It is not expected to interfere with the immune response to live or inactivated vaccines 7,129 . Children receiving PVZ should receive all routine childhood vaccines and any other vaccines that may be indicated because of underlying health conditions, following recommended schedules. SYNCYTIAL
# IV.8 Contraindications and Precautions
# Contraindications
Significant hypersensitivity to any component of PVZ is a contraindication to use of this product.
# Precautions
Minor illnesses such as the common cold, with or without fever, are not contraindications to use of PVZ. Moderate to severe illness, with or without fever, is a reason to consider deferring PVZ, to avoid superimposing adverse effects from PVZ on the underlying illness, or mistakenly identifying a manifestation of the underlying illness as a complication of PVZ. The decision to delay PVZ depends on the severity and etiology of the underlying disease.
# V. ECONOMICS V.1 Systematic Review
A systematic review of the cost-effectiveness of PVZ prophylaxis for RSV was conducted. Studies carried out in OECD countries and published from 2000 to 2018 were reviewed. The original review has been published 176 . For the purposes of NACI's decision-making, changes to the reporting and discussion were made to the original review, and can be found as a NACI Supplement entitled "Cost-Effectiveness of PVZ for Respiratory Syncytial Virus (RSV): A Systematic Review" which will be forthcoming. Changes include currency reported in Canadian dollars, a section on Canadian studies, alternate subgroups reported, and additional commentary. Results from the supplement are summarized here. Of 28 studies included in the final analysis, 20 were cost-utility analyses and 8 were cost-effectiveness analyses. Two economic evaluations were trial-based 177,178 , and the rest were considered model-based. Studies were conducted in the US (n=6), Canada (n=5), Netherlands (n=3), the United Kingdom (n=3), Spain (n=3), Austria (n=2), Germany (n=2), and Italy, Mexico, New Zealand, and Sweden (1 each). Base-case analyses were conducted from a health system payer perspective (n=15) or a societal perspective (n=13). Eight of the payer perspective studies performed additional analyses from a societal perspective. The majority of studies were industry sponsored (n=17, 61%). Cost-effectiveness outcomes were reported as ICERs, mostly represented as the incremental cost per additional QALY (n=20) and cost per hospitalization avoided (n=6). ICERs were adjusted to 2017 Canadian dollars (CAD).
PVZ prophylaxis ranged from being a dominant strategy (i.e,less costly and more effective) to having an ICER of $2,975,489/QALY. The wide variation in ICERs depended on the perspective, study setting, population, local RSV epidemiology, healthcare system, and key model input parameters such as rate of reduction in RSVH (39%-96%), estimated RSV-related mortality (1%-8.1%), PVZ costs ($1,099-$2,198 per 100-mg vial), dosage schedules, and vial usage.
# V.1.1 Economic Evaluations with Outcomes Expressed in Cost per Qaly
Data are summarized in Tables 1 and 2. For studies reporting cost-effectiveness in terms of cost per QALY from a health system payer perspective, there were 22 cost-effectiveness estimates for preterm infants, ranging between $6,216 per QALY and $938,623 per QALY 82,[179][180][181][182][183][184][185][186][187][188] . The subgroups with the next highest numbers of estimates were (i) preterm infants stratified by risk factor scores 185,186,189 , (ii) infants with CHD 82,179,181,182,[190][191][192] , and (iii) infants with CLD 82,181,182,187,191 . The proportion of reported cost-effectiveness estimates that fall below different thresholds is shown in Table 1. The largest agreement among reported estimates falling below the commonly used threshold of $50,000/QALY were infants with CLD (n =6 out of 6 studies), preterm infants (n=18/22), and infants with CHD (n=8/10). For premature infants no specific trend was detected between wGA and the ICER. From a societal perspective, PVZ prophylaxis was considered a dominant strategy (i.e,less costly and more effective) in some instances for preterm infants 183,[193][194][195] , term infants in the Canadian Arctic 196 , and infants with CHD 182 . However, there was high heterogeneity in the study design and model parameters among reviewed studies including those that reported PVZ prophylaxis to be a dominant strategy. There does not appear to be a common driver for dominance of PVZ prophylaxis. In other scenarios, ICERs <$200,000/QALY were observed. Generally, one would expect ICERs from a societal perspective to be lower than those from a payer perspective, but this trend was not observed. Payer and societal perspective estimates frequently came from different studies and there was heterogeneity in model designs and differences between setting-specific costs and RSV epidemiology that may account for larger ICERs under a societal perspective.
Twelve of these studies were industry sponsored. It was noted that 50% of all estimates of <$200,000/QALY and 19% of all estimates of >$200,000/QALY were from studies funded by industry (S. Mac Six studies reported cost-effectiveness in terms of cost per hospitalizations avoided (HA) 179,[197][198][199][200][201] . A study of healthy term infants in different regions of the Canadian Arctic compared two scenarios of PVZ prophylaxis for infants who were less than 6 months of age, from a payer perspective. The ICER ranged from being dominant (i.e,less costly and more effective) in specific Arctic regions to $593,250/HA in the Northwest Territories 197 . Also from the payer perspective, a Florida study of preterm infants (<32 wGA), term infants with CHD, CLD, combinations of all three groups and infants with no indications for PVZ) reported ICERs between $413,127/HA (preterm infants) and $2,924,911/HA (infants with no indication) 201 .
From a societal perspective, a study from the Netherlands of preterm infants (< 28 wGA) with additional risk factors (BPD, male sex, birth weight < 2,500 grams) found ICERs ranging between $24,875/HA and $1,572,268/HA depending on the month of the prophylaxis 198 . In a study from Germany of preterm infants (<35 wGA) with additional risk factors, from a societal perspective ICERs ranged between $11,821/HA and $364,462/HA for preterm infants with CLD and risk factors and preterm male infants without CLD and with no siblings in school, respectively 199 . A New Zealand study analyzed cost-effectiveness of prophylaxis in preterm infants (<28, 29-31 wGA) with or without CLD from a societal perspective. The ICERs ranged from $33,376/HA for preterm infants discharged home on oxygen, to $37,213/HA for infants ≤ 28 wGA with no CLD, to $193,859/HA for preterm (29-31 wGA) infants with CLD 200 .
# V.1.3 Economic Evaluations with Outcomes Expressed in Other Ratios
An economic evaluation on term infants with CHD in western Canada found that from a societal perspective, the base-case ICER was $18,155 per one day of hospitalization avoided 148 . A study of preterm infants (< 32 wGA) or with CLD or significant CHD in France found that from a societal perspective, the base-case ICER was $43,856/ ife year (LY) gained and $33,450/LY gained for preterm infants with CLD and preterm infants with CHD, respectively. From a payer perspective, the ICER was $16,368/LY gained for infants with CLD 202 . In a study of preterm infants with CLD in the US, the model used a reduction in incidence of RSV infection, ranging from 50% ($66,494 per RSV infection episode avoided) to 83% reduction (PVZ prophylaxis a dominant strategy, i.e,less costly and more effective) from a payer perspective 178 .
# V.1.4 Economic Evaluations in Canadian Settings
There were five economic evaluations conducted in Canadian settings 148,186,189,196,197 . Populations studied were term infants from the Canadian Arctic 196,197 , preterm infants 186 , infants with CF 189 , and infants with CHD 148 . These studies assumed 4.5 to 6 doses of PVZ per RSV season at a cost of $1,599 -$1,718 (2017 CAD) per 100 mg of PVZ. In the above studies, the effectiveness of PVZ was measured in reduction in RSVH, which ranged between 42% and 96%. Mortality rates were incorporated into two models, at 1% and 8.1% 186,196 . Sequelae were incorporated into two models (in one sequelae of RSV infection, the other sequelae associated with CF) 186,189 . The most influential parameters on the cost-effectiveness outcomes in the five Canadian studies were: RSVH rates 196,197 , cost of PVZ 148,189 , and cost for hospitalization 196,197 186 . For infants less than 24 months of age with CF, PVZ was determined unlikely to be cost-effective from a payer perspective ($693,105/QALY for all and $167,107/QALY for high risk infants) 189 . In the study of PVZ cost-effectiveness in children < 24 months of age with CHD, from a societal perspective the ICER was $18,155/day of hospitalization avoided and considered unlikely to be cost-effective 148 .
These latter three studies may be generalizable to most Canadian provinces given they used PVZ costs ($1,468 -$1,505 per 100 mg vial, original costs) similar to those in other Canadian provinces, dosing schedules close to 5 injections per season (4.5 to 5.39 vials per season), healthcare costs from British Columbia and Ontario, and included model parameters of relevance to the Canadian healthcare system. Studies of cost-effectiveness of PVZ prophylaxis for infants from smaller Canadian provinces (e.g. Maritimes provinces) were lacking. The most frequently reported influential parameters affecting the ICER were the RSVH rates and cost of PVZ used. Reduction in RSVH varied drastically between 39% and 96% depending on the population of interest, and the source of the data. The cost of a 100mg vial of PVZ also ranged between $1,099 and $2,198 (2017 CAD). However, vial usage and dosage scheme only affected the ICERs in four 181,183,195,200 , and three studies 185,187,200 , respectively. In studies addressing drug wastage, ICERs fluctuated up to 50% depending on the assumed vial usage. In a New Zealand study, assuming no vial sharing (entire 100 mg vial is used per injection) increased cost per case averted by up to 50% (i.e,worse value for money) 200 , while another study in Spain concluded a lower ICER (i.e,better value for money) when 50-mg vials were used instead of 100mg 183 . It has been suggested in the literature that vial usage efficiency can be achieved for PVZ 203 . Discounting was also frequently reported as being influential on the ICER. Discount rates varied across studies (3-5%). Currently Canadian guidelines recommend a discount rate of 1.5% for costs and outcomes 204 . The only exceptions were the six studies from the US. Choice of payer or societal perspective may influence the costs and the benefits included in the analysis. Among the studies that used a societal perspective, the following costs outside of the healthcare system were considered: time loss from work due to asthma; indirect costs of nosocomial infections; travel costs (i.e,hotel, transportation); productivity loss (i.e,caregiving, leisure, future productivity of children); and school absenteeism. 183,185,195 .
Despite the similarities in PVZ prophylaxis cost and dosage schedule, estimated reduction rates of RSVH varied from 39% to 96% depending on the infant population, and literature referenced. Sixtyeight percent of the studies (S. Mac personal communication June 2019) used the IMPACT-RSV trial for some of their model parameters, a trial that included Canadian children and concluded that reduction in RSVH was 78% for preterm infants, 39% for children with CLD and 55% overall. While the subgroup of Canadian subjects in that study showed a 40% overall reduction in RSVH, the trend was similar to that seen in US (56%), and UK subjects (64%) 48 . It is noted that the IMPACT-RSV trial was carried out in 1996 and that with changes in the management of prematurity, CLD and CHD, as well as RSV infection, model parameters based on that study may not be appropriate today.
# V.2 Cost-Effectiveness Study in Nunavik, Quebec
In addition to the studies in the systematic review, preliminary results of a cost-effectiveness study in the region of Nunavik, Northern Quebec were reported to NACI on March 13, 2019 (R. Gilca, Institut national de santé publique de Québec, personal communication, Nov. 18 2020) 206 . Starting in the 2016-17 season, healthy full-term infants <3 months of age at the start of the RSV season or born during the RSV season became eligible for up to 3 doses of PVZ. For the 2017-18 season, infants meeting these criteria were eligible for up to 5 doses. The objectives were to estimate the healthcare cost of RSVH in the targeted population and the cost of the PVZ program, and to estimate cost per hospitalization averted.
The analysis below is based on the first 2 years of the program. It is being updated to include 4 years of data and will be published. The conclusions remain unchanged.
# VI. ETHICS, EQUITY, FEASIBILITY AND ACCEPTABILITY (EEFA) CONSIDERATIONS
The peer-reviewed EEFA Framework 13 was applied to this guidance to ensure the systematic consideration of factors critical for comprehensive immunization program decision-making and successful implementation of recommendations. The use of this EEFA Framework empowers the committee to review and balance all of the available evidence and transparently summarize their rationale for appropriate, timely recommendations. The evidence-informed tools associated with the framework (Ethics Integrated Filters, Equity Matrix, Feasibility Matrix, Acceptability Matrix) ensure that issues related to EEFA of expert committee guidance are systematically and adequately integrated.
# Ethics considerations
To support ethics deliberation and decision-making, NACI's Ethics Integrated Filters for core ethical dimensions (respect for persons and communities, beneficence and non-maleficence, justice, trust) and procedural ethical dimensions (accountability, inclusiveness, responsibility, responsiveness, transparency) were applied. NACI followed its established methodology, standard operating procedures (SOP), and conflict of interest guidelines to ensure a robust analysis of evidence, with transparency about knowns and unknowns, as well as certainty of evidence, and to maintain stakeholder trust. In order to respect the right to exercise informed choice, NACI reviewed the best, current evidence available for groups of infants and children at risk of RSV and summarized it for stakeholders throughout this guidance document, including recent data on burden of illness due to RSV disease, the efficacy and effectiveness of PVZ in infants at risk of more severe RSV disease and economic implications of PVZ use. NACI also considered evidence for minimizing the risk of harm and maximizing benefits for all potential key populations in their deliberations. These findings should be interpreted with caution given that some potential concerns were identified regarding availability of evidence; small numbers of articles were identified for some risk groups and situations and there was significant heterogeneity in methodology used and the outcomes studied. Furthermore, with no evidence of lowered mortality rates from RSV or of long term benefit from PVZ, the high cost of PVZ prophylaxis programs must also be balanced against costs of other health care interventions if these other interventions may be compromised by provision of PVZ programs. Therefore, NACI will continue to monitor the evidence related to use of PVZ in different groups, including the cost-effectiveness of PVZ programs and alternative dosage schedules and newer products which may be more costeffective and will update the statement and its recommendations as needed.
# Equity considerations
NACI reviewed the epidemiology of RSV and the results of the systematic review on the burden of RSV disease in young children in high-income countries comparable to Canada (summarized in Section III) to identify distinct inequities associated with COVID-19, potential reasons for these inequities, and suggested interventions to reduce inequities and improve access to vaccine when it becomes available.
The risk of severe RSV illness is influenced by gestational age at birth, underlying health conditions, and age. As it is not feasible to provide PVZ prophylaxis to all infants at some increased risk of RSV disease, in principle it should be provided to high risk groups at equivalent risk of severe disease. Specific recommendations are needed for selective PVZ prophylaxis for identifiable high-risk subgroups of infants and children who are more vulnerable than others to the adverse effects of RSV infection, and whose risk of severe outcome are within a similar range and for whom PVZ prophylaxis has been shown to be effective. However, the limited nature and heterogeneity of the data available makes assessment of degree of risk somewhat arbitrary. For certain very rare conditions, risk of severe RSV illness may be high but epidemiologic data are not available, and the number of children with certain rare diseases may not be sufficient for PVZ effectiveness to be studied. In these circumstances, extrapolation may be made from data on conditions of pathophysiological similarity with documented increased risk of RSV and where PVZ has been shown to be effective. In most provinces and territories, physicians may request PVZ by exception for children that do not meet specific criteria for PVZ. While this permits flexibility for use in children with rare conditions, it may also introduce inequity. Those making requests for exceptions and those assessing these requests must do so fairly, to avoid inequity.
Infants living in remote northern Inuit communities and other remote rural communities may also be at increased risk of severe outcomes resulting from RSV infection. Limited local access to medical care may necessitate medical evacuations requiring air transportation to hospital facilities. Therefore, additional resources may be needed for provision of PVZ prophylaxis and for monitoring and followup of infants living in remote locations. PVZ prophylaxis should also be provided as close to home as possible given that the number and frequency of visits over a short period of time and the strict injection intervals may be a barrier for families due to out-of-pocket expenses if the family has to travel some distance to receive PVZ and/or take time off work for these visits. In these cases, assistance may need to be given to some families so that they can benefit from the PVZ prophylaxis program. NACI will continue to monitor the evidence related to severity of RSV disease in infants with pre-existing conditions and in infants living in remote northern Inuit communities and other remote rural communities.
# Feasibility considerations
Provision of PVZ prophylaxis is complex and integration into existing active vaccination programs is not feasible due to the dosing schedule and the seasonal nature of the disease. In particular, the need for multiple injections over a short time period may create scheduling challenges; up to 4 doses must be given at 28-35 day intervals during the period that the local annual RSV outbreak is underway. Unlike vaccines, PVZ dose depends on weight and precise timing of visits for PVZ administration is crucial for appropriate protection and it is not possible to combine all visits with visits for other vaccines or routine child care. Additionally, PVZ is provided in multi-dose vials which, once opened, must be used within 6 hours or discarded and wasted. where very few children are candidates for PVZ, further increasing the cost. Therefore, important considerations for the implementation of a new PVZ prophylaxis program include limiting prophylaxis to those groups at highest risk of severe outcomes, scheduling specific PVZ clinics during the RSV season, recognizing the potential impact on existing local programs, and involving of local care givers in planning for program implementation.
# Acceptability considerations
Very limited acceptability data are currently available specific to PVZ prophylaxis and the perception of RSV disease in parents or guardians of high risk infants. Likely barriers to acceptability and adherence include:
The number and frequency of visits, especially if families have to travel some distance to receive prophylaxis and it is not possible to combine visits for PVZ with visits for other vaccines or routine health care needs; Out-of-pocket expenses if appointments require long-distance travel to the treatment center and time away from work. Lack of knowledge about the risk of RSV infection in high risk children.
There is some evidence indicating that Indigenous populations in Canada are at higher risk of nonadherence than non-Indigenous populations and that acceptance is lower in remote northern populations 207,208 . Nurses and midwives working with a population in the Canadian North have also expressed concerns regarding lack of data about the efficacy and safety of PVZ in healthy term infants 207 . Low acceptability of PVZ prophylaxis by families may result in decreased adherence to PVZ schedules and diminish effectiveness 209 . Therefore, implementation of a new program should include ongoing education of local health care providers, families and guardians of infants for whom PVZ is indicated, and their active involvement in planning of the intervention. Provision of PVZ in local clinics as close to home as is feasible and sufficient resources to provide assistance for families who may need some additional support to be able to travel to the clinic are also important considerations. SYNCYTIAL
# VII. RECOMMENDATIONS
Following the thorough review of available evidence summarized above, as well as the systematic assessment of ethics, equity, feasibility and acceptability considerations with the peer-reviewed EEFA Framework, NACI makes the following evidence-informed recommendations.
# RECOMMENDATIONS FOR PUBLIC HEALTH PROGRAM LEVEL DECISION-MAKING (i.e,provinces/territories making decisions for publicly funded immunization programs)
In considering these recommendations and for the purposes of publicly funded program implementation, provinces and territories may take into account local programmatic factors (e.g. current programs, resources). Recognizing that there are differences in operational contexts across Canada, jurisdictions may wish to refer to the Management Options Table below for a summary of the relative merits of vaccinating different high risk groups, if prioritization of targeted immunization programs is required for implementation.
# Preterm infants without CHD or CLD: Recommendation 1.1: NACI recommends that PVZ should be offered to infants born at < 30 weeks, 0 days gestation and aged < 6 months at the onset of or during the RSV season. (Strong NACI Recommendation)
NACI concludes that there is fair evidence to recommend PVZ use in this population (Grade B evidence).
# Recommendation 1.2: NACI recommends that PVZ may be considered for infants of 30 to 32 weeks, 6 days gestation aged < 3 months at the onset of or during the RSV season if they are at high risk of exposure to RSV from day care attendance or presence of another preschool child or children in the home. (Discretionary NACI Recommendation)
NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Recommendation 1.3: NACI recommends that PVZ should not be offered to otherwise healthy infants born at or after 33 weeks, 0 days gestation (Strong NACI Recommendation)
NACI concludes that there is fair evidence to recommend against PVZ use in this population (Grade C evidence).
# Summary of evidence and rationale:
There is good evidence that risk of RSVH is higher in premature infants born at lower gestational age, with reported rates of 7.7 to 13.6% in the first year of life for those of < 28 or < 29 wGA [41][42][43][44][45][46][47] . These infants receive little or no maternal antibody and their narrower airway passages increase their vulnerability to the effects of RSV infection.
There is good evidence that infants of 30-32 wGA are also at increased risk of RSVH in comparison to term infants but hospitalization rates are lower, at 5.1 in the systematic review of publications from 2014-2018 (BODsr) (see Section III.1.1.), 5.7 -9.9% in earlier literature 41-43, 45, 46 and 4.3 % in a more recent study 38 . There is fair evidence that RSVH rates for infants of 29-32 and 33-35 wGA are 4.6 and 2.8 times higher than in term infants, respectively (Section III.1.1.). Earlier studies show inconsistent evidence on the risk of RSVH in infants of 32-35 wGA. Rates of 2.85 to 6.5% in the first year of life or first RSV season have been reported 40,45,48 , while two more recent studies reported rates of 4.0 and 3.4% 38,39 . RSVH rate for healthy term infants in the BODsr was 1.2%. There is fair evidence that premature infants hospitalized for RSV have a longer LOS than term infants, with mean difference in LOS between premature and term infants of 7.97 days for infants of 29-32 wGA and 1.06 days for infants of 32/33-35 wGA. There is fair evidence that premature infants with RSVH have a higher rate of ICU admission than term infants, with RR of 4.0 for infants of 29-32 wGA and 3.0 for 32-35 wGA. There is fair evidence that premature infants of 29-35 wGA with RSVH have a higher rate of MV than term infants, with RR of 1.9 for infants of 29-32 wGA and 1.2 for 33-35 wGA.(Section III.1.1) There is fair evidence that chronological age is an important risk factor for RSVH, with most infections occurring in the first 2-3 months of life 16,49 . There is insufficient evidence of the effectiveness of PVZ in reducing risk of RSVH in premature infants born at < 30 wGA. three studies, two rated as good and one as fair, did not show a significant effect on RSVH in this group, but the numbers of participants were small (total 228 for the three studies). One larger study of premature infants born at ≤30 wGA, rated as poor quality, showed a reduction of 92% with NNT of 9. There is good evidence that PVZ is effective in reducing RSVH rates by 38-80% in premature infants of ≤32 wGA without CLD or hsCHD (NNT 53, 5, 17). There is conflicting evidence about the effect of PVZ on RSVH rates in premature infants born at 32-35 wGA without CLD or hsCHD. Two RCT and one observational study showed reductions of 55-82% (NNT 22, 24) and 55%, while 3 observational studies did not show a significant effect. There is fair evidence (one systematic review) of an association between PVZ receipt and lower all-cause mortality in infants born at ≤ 32 wGA but no evidence for an effect of PVZ on RSV specific mortality 74 . ICERs for preterm infants were < $50,000 per QALY in 82% of estimates (payer perspective) and were dominant (i.e,less costly and more effective) in infants of < 32 wGA (societal perspective). No specific trend was detected between wGA thresholds and ICERs, but numbers of estimates in the wGA groups were small. ICERs were <$50,000/QALY in 100% of estimates for infants of < 29wGA, 67% for 29-32 wGA, 100% for <32 wGA and for < 33 wGA and 67% for 32-35 wGA (payer perspective). In one Canadian study, ICERs were < $50,000 per QALY for infants of 32-35 wGA with high or moderate RSV risk scores (payer perspective). Although burden of illness is higher in infants of 30-35 wGA than in term infants and there is good evidence of PVZ effectiveness for those of 30-32 wGA, cost is of concern for PVZ use in these older gestational age groups. In Canada it is estimated that 8% of infants are born prematurely 67 , and that 5% of the birth cohort may be born at 32-35 wGA 34 .
Recommendations are based on providing prophylaxis for the premature infants at highest risk. NACI concludes that there is fair evidence to recommend against PVZ use in this population (Grade C evidence).
# Summary of evidence and rationale:
Most studies of twins and other multiple births have reported similar risks of RSVH in infants of multiple and singleton births, either without 71,116 or after 114,117 adjustment for confounding factors. One study reported a higher rate of RSVH in infants of multiple births but potential confounding factors were not considered 115 .
There are no data on PVZ use in this group.
Evidence is based on review of key studies, without formal quality appraisal. NACI concludes that there is good evidence to recommend PVZ use in this population (Grade A evidence).
# Chronic Lung Disease of Prematurity and other chronic lung diseases
# Summary of evidence and rationale:
RSVH rate for infants with CLD of prematurity in the first 2 years of life is high (12-21%) 42,44,48,72 . For hospitalized patients, high rates of ICU admission (29%) and MV (24%) have been reported 72 . There is good evidence that PVZ reduces RSVH in infants of ≤ 35 wGA with CLD age < 24 m (RD 39%, NNT 21) 48 . There is fair evidence that PVZ reduces the rate of RSVH in infants with CLD during their first 6 months post initial discharge (RD 86% NNT13) 44 and poor evidence in infants with CLD aged < 6 m at onset of RSV season (RD 85%, 72%; NNT 3, 8) 46,139 . There is insufficient evidence of the effect of PVZ in infants with CLD aged < 12 months or 6-12 months. There is no evidence concerning the effect of PVZ on other hospitalization-related outcomes or RSV long term sequelae in infants with CLD. There is insufficient evidence that PVZ has an effect on all-cause mortality or RSV related mortality in children with CLD as numbers studied are insufficient to detect an effect 74 . Studies on cost-effectiveness of PVZ prophylaxis reported ICERs of < $50,000 per QALY in all estimates (payer or society perspective); ICERs for infants discharged home on oxygen were < $50,000 per hospitalization avoided, and < $50,000 per life year gained. NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of evidence and rationale:
There is fair evidence for increased rates of RSVH in infants with chronic lung disease of etiology other than prematurity (congenital cystic lung disease 8.3%, chronic interstitial lung disease 30%, congenital lung and airway malformations 8.3-13.7%, and some neuromuscular conditions that affect ability to clear airway secretions 9.9-15.9%v 21,75,76 . There is no evidence concerning the effect of PVZ on RSV disease in these conditions. It is postulated that infants with CLD of severity comparable to CLD of prematurity may benefit from PVZ. NACI concludes that there is fair evidence to recommend against routine PVZ use in this population (Grade D evidence).
# Cystic fibrosis:
# Summary of evidence and rationale:
RSVH occurs more frequently in children with CF than in healthy children. RSVH in the systematic review was 12.3% (Section III.1.3). There are limited data about other hospitalization related outcomes.
There is inconsistent evidence on the effect of routine administration of PVZ to infants with CF on RSVH, with all but one study showing no effect 77,78,140,[142][143][144] . There is fair evidence that routine administration of PVZ to infants with CF does not significantly affect long term pulmonary function, growth or airway bacterial colonization 78,140,144,145 . One Canadian study estimated an ICER of over $600,000 per QALY (payer perspective) for routine PVZ prophylaxis in infants with cystic fibrosis 189 NACI concludes that there is insufficient evidence to recommend use in this population. (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of evidence and rationale:
There is no evidence on the burden of RSV illness in the subgroup of infants with CF with severe chronic lung disease in infancy. There is no evidence concerning the effect of PVZ prophylaxis on RSV disease in this subgroup.
It is postulated that infants with CF lung disease of severity comparable to CLD of prematurity may benefit from PVZ. NACI concludes that there is good evidence to recommend PVZ use in this population (Grade A evidence)
# Congenital heart disease and other chronic cardiopathy:
# Summary of evidence and rationale:
There is good evidence that children <24 months of age with hsCHD are at increased risk for RSVH with rates of 2.3-10.2% reported 65,79,80 . There is good evidence that the RSVH rates for infants with CHD is significantly higher in the first year of life than the second year 43,79,81 . There is good evidence that PVZ reduces the risk of RSVH in children with hsCHD aged < 24 months (RD 45%, NNT 23) 80 . There is good evidence that PVZ reduces the risk of RSVH in children with hsCHD aged < 6 months (RD 51%, NNT 16) and fair evidence in children aged <12 months (RD 49%-72%, NNT 45, 7) 44,80,147 . There is good evidence that PVZ reduces the overall number of days of hospitalization for RSV in children with hsCHD 80 but not the LOS for those admitted with RSV 80,146 , and good evidence that PVZ does not affect the proportion of hospitalized children admitted to ICU, the duration of ICU stay, or the proportion requiring MV 80,146,148 . There is insufficient evidence on the effect of PVZ on all-cause mortality or RSV mortality in children with hsCHD 80,148 . Studies on cost-effectiveness of PVZ prophylaxis reported ICERs of < $50,000 per QALY in 80% of estimates (payer perspective) and 63% of estimates (societal perspective). An ICER of $18,155 per day of hospitalization avoided was estimated in a Canadian study 148 NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of evidence and rationale:
There is no evidence about the burden of RSV illness or the use of PVZ in this group. It is postulated that infants with cardiac dysfunction of severity similar to that of children with haemodynamically significant CHD may benefit from PVZ. NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of evidence and rationale:
There is no evidence about the burden of RSV illness or the use of PVZ in this group. It is postulated that these infants will have severe cardiac dysfunction and will likely receive immunosuppressive therapy during the RSV season and that they may benefit from PVZ.
Recommendation 4.4: NACI recommends that for children with both haemodynamically significant CHD and chronic lung disease, recommendations for chronic lung disease (above) should be followed. (Strong NACI Recommendation) NACI concludes that there is insufficient evidence to support a recommendation for this population (Grade I evidence)
# Summary of evidence and rationale:
There are no data on burden of RSV illness or effectiveness of PVZ for this group. Chronic lung disease may warrant prophylaxis for a second RSV season whereas hsCHD alone usually will not. NACI concludes that there is fair evidence to recommend against routine PVZ use in this population (Grade D evidence).
# Summary of evidence and rationale
RSVH occurs more frequently in children with Down syndrome without hsCHD, CLD or prematurity than in healthy children. There are limited data about other hospitalization related outcomes 22,83 . Three studies of PVZ prophylaxis in infants with Down syndrome and without hsCHD, CLD or prematurity showed no effect on RSVH [149][150][151] .
# Recommendation 5.2: NACI recommends that PVZ should be offered to children with Down syndrome who qualify for prophylaxis because of hsCHD, chronic lung disease, prematurity or immunodeficiency. (Strong NACI Recommendation)
NACI concludes that there is fair evidence to recommend PVZ use in this population (Grade B evidence).
# Summary of evidence and rationale
See evidence for hsCHD, chronic lung disease, prematurity or immunodeficiency, above. One study found reduction in RSVH rates in infants with Down syndrome who met standard criteria for receipt of PVZ 150 . NACI concludes that there insufficient evidence to recommend routine PVZ prophylaxis in this population. (Grade I evidence). Therefore this recommendation is based on expert opinion. NACI will continue to monitor the evidence as it evolves.
# Immunocompromised Children:
# Summary of evidence and rationale:
Rates of RSVH in such communities vary widely by community and by year 23,[90][91][92] .
There is one study of fair quality showing no effect of PVZ prophylaxis on RSVH in healthy full term infants living in a northern Inuit population in Canada with rate of RSVH in all infants < 1 year of age of 5% 90 .
A qualitative study of PVZ prophylaxis in healthy full term infants living in one northern Inuit population in Canada identified significant acceptability and feasibility issues 207 .
# Recommendation 7.3: NACI recommends that PVZ prophylaxis may be considered for healthy full term infants aged <6 months at the onset of, or during, the RSV season living in remote northern Inuit communities with documented very high RSV hospitalization rates for term infants. (Discretionary NACI Recommendation)
NACI concludes that there is insufficient evidence to make a recommendation for or against PVZ use in healthy term infants living in remote northern Inuit communities with very high RSV hospitalization rates (Grade I evidence). Therefore, this recommendation is based on expert opinion, with consideration of the high burden of illness in these communities and need for air transport if hospitalization or specialized ambulatory care is required. NACI will continue to monitor the evidence as it evolves. SYNCYTIAL VIRUS INFECTION IN INFANTS Summary of evidence and rationale:
Term infants living in some remote northern Inuit communities have very high rates of RSVH and frequently require air transfer to tertiary care institutions 23,91,92 . Rates of RSVH as high as 20% to 50% of all live births have been reported in some remote communities. There are no studies of PVZ prophylaxis in healthy term infants living in remote northern Inuit communities with very high RSVH rates.
Studies of cost-effectiveness of PVZ prophylaxis estimated ICERs of < $50,000 per QALY for term infants residing in select communities in the Eastern Canadian Arctic with high RSV hospitalization rates, whereas PVZ was dominant (i.e,less costly and more effective) in other select communities. However, these estimates used data for PVZ effectiveness from premature infants and effectiveness in term infants is yet to be established 196 . A qualitative study of PVZ prophylaxis in healthy full term infants living in one northern Inuit population in Canada identified significant acceptability and feasibility challenges 207 . NACI concludes that there is insufficient evidence to recommend PVZ use in this population (Grade I evidence). Therefore this recommendation is based on expert opinion.
# Summary of Evidence and Rationale
There is limited evidence on the burden of RSV disease in infants living in other remote aboriginal communities in North America and no evidence for those in other remote communities.
There is no evidence on the effect of PVZ on RSV disease in these communities. One study of motavizumab, another RSV monoclonal antibody, reported a 87% relative reduction in risk of RSVH in healthy term Native American infants living on reservations in southwestern USA 89 .
# Prevention of Subsequent Recurrent Wheezing
# Summary of Evidence and Rationale
It is not known whether RSV in infancy predisposes to the development of asthma, or if infants genetically predisposed to develop asthma are at increased risk of severe RSV disease requiring RSVH in infancy, is not known. Recurrent wheezing in childhood occurs in healthy term infants hospitalized for RSV in infancy in proportions similar to those reported for infants at high risk of RSVH in infancy 29 . Although PVZ administration to infants born at < 36 wGA has an impact on physician diagnosed recurrent wheezing in the first 1-6 years of life (NNT 3 to 15), findings are contradictory as to PVZ effectiveness in the absence or presence of a family history of atopy . There are no data on the effect of early receipt of PVZ on subsequent wheezing or asthma in children over 7 years of age or in adults. NACI concludes that there is fair evidence to recommend against PVZ use in this population (Grade D evidence).
# Use of PVZ in hospitalized infants
# Summary of Evidence and Rationale
Studies showed that RSV infection rates in NICU did not differ when infants received PVZ prophylaxis in the NICU or starting at hospital discharge [119][120][121] .
# Recommendation 9.2: NACI recommends that PVZ prophylaxis may be considered when all other measures to control an RSV outbreak in a NICU have failed. (Discretionary NACI Recommendation)
NACI concludes that there is insufficient evidence to recommend PVZ use in this situation (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of Evidence and Rationale
PVZ, in addition to other infection control measures, has been used to control NICU outbreaks, but the specific role played by PVZ is unclear 118,[124][125][126][127][128] .
# Summary of Evidence and Rationale
Administering the first dose before discharge avoids the need of a visit to a health care facility soon after discharge and may improve adherence. In hospital, to avoid wastage when vials are opened for individual infants, administration may be coordinated to 3 times weekly.
Recommendation 9.4: NACI recommends that an infant who has begun PVZ prophylaxis earlier in the season and is re-hospitalized on the date when a dose is due should receive that dose as scheduled, providing that the admitting institution is able to supply PVZ when due. (Strong NACI Recommendation)
NACI concludes that there is insufficient evidence to recommend PVZ use in this situation (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of Evidence and Rationale
Keeping to the child's existing PVZ schedule avoids the need to reschedule appointments and may improve adherence. NACI concludes that there is fair evidence for this PVZ schedule (Grade B evidence).
# Summary of evidence and rationale:
A dose of 15 mg/kg every 30 days resulted in target serum PVZ levels assumed to be protective based on animal studies 162 . Longer dose intervals have been used based on a PVZ half-life of 19-27 days and observed accumulation of PVZ after the second dose 48,164,166,167 . Evidence is based on review of key studies, without formal quality appraisal. c. An extra dose may also be considered in remote Northern areas where RSV outbreaks may continue longer than is usual elsewhere NACI concludes that there is insufficient evidence to determine the optimum number of PVZ doses (Grade I evidence). Therefore, this recommendation is based on expert opinion.
# Summary of Evidence and Rationale
Studies suggest that 4 doses are sufficient to provide protection throughout the usual RSV season [166][167][168][169] . A study of children undergoing cardiac bypass reported a 58% decrease in PVZ level after bypass 80 . It is assumed that extracorporeal membrane oxygenation may have a similar effect 6 . Dose sparing can be achieved by:
-Starting PVZ only when the local RSV season has begun 173,174 ; -Favoring the longer interval between doses after dose 2; -Organizing clinics or appointments for PVZ administration that facilitate vial sharing.
Evidence is based on review of key studies, without formal quality appraisal.
# Recommendation 10.3: NACI recommends that PVZ should be discontinued for the season if a child is hospitalized because of RSV infection. (Strong NACI Recommendation
). NACI concludes that there is fair evidence that recurrent severe RSV infections in a single season are rare (Grade B evidence).
# Summary of Evidence and Rationale
Reported rates of second episodes of RSVH in the same season vary from in 0% to 1.0% of the cohort studied 80,[108][109][110][111] , except for a rate of 3.3% in a very small study in 1988 107 .
Evidence is based on review of key studies, without formal quality appraisal.
# RECOMMENDATIONS FOR FOR INDIVIDUAL LEVEL DECISION-MAKING
(For example, individuals wishing to prevent RSV disease or a clinician wishing to advise individual patients with conditions not currently included in public health programs about preventing RSV.) PVZ is not readily available for private purchase in Canada, is costly, and cost may or may not be reimbursed by private insurance plans. No specific recommendations are made for individual level decision-making.
# MANAGEMENT OPTIONS TABLE (Recommendations for public health program level decision-making)
Various options for the use of PVZ, and the decision on which options are preferable will depend on the considerations listed below:
# Options
# Considerations Decision Points
Cohorts at risk:
PVZ, a monoclonal antibody that provides temporary passive protection against severe RSV infection, is the only prophylaxis presently available.
PVZ has only been investigated in children < 24 months old with underlying conditions putting them at increased risk for severe RSV illness and is not recommended for healthy term infants or for individuals over 24 months old.
# Epidemiology
Risk of severe RSV illness is influenced by gestational age at birth, underlying health conditions, and age.
Infants are at highest risk of severe RSV disease in their 1st RSV season and especially at age < 3 months.
-Targeting PVZ prophylaxis to infants at highest risk of severe RSV infection permits most efficient use of PVZ -For healthy preterm infants, PVZ is recommended for those <30 wGA as they are at highest risk. -If resources permit, PVZ may be considered for those of 30-32 wGA if they are at high risk of RSV exposure and < 3 months of age.
RSV causes yearly epidemics from winter to early spring -Use of current local data to determine when PVZ prophylaxis should be started permits most efficient use of PVZ.
# Otherwise healthy premature infants:
Otherwise healthy premature infants have increased risk of severe RSV infection in comparison with term infants. Risk of hospitalization is highest in those < 30 wGA (7.7 to 13%) although also increased in those of 29-32 and 33-35 wGA (4.6 and 2-3 times that of term infants).
PVZ was effective in preventing hospitalization in studies of infants of ≤32 wGA (rate decrease 38-74%, NNT 9 to 54 in different studies). For infants of 32-35 wGA rate decreases of 72-83% with NNT of 12-14 were reported but some studies showed no effect. Studies specific to infants of < 29 wGA did not show an effect but numbers studied were very small.
In Canada 7.7-8% of births are at < 37 wGA and an estimated 5% are 32-35 wGA.
Cost-effectiveness studies of PVZ
# Economics:
PVZ is costly, and the main cost of prophylaxis programs is the product itself. Studies reported a wide range of ICERs depending on the population, setting, baseline hospitalization rates, as well as model structure and study design. Estimated ICERs of <$50,000 per QALY have been reported in selected scenarios but dominant (i.e,less costly and more effective) in very few.
Unlike vaccines, PVZ dose varies with weight. Once opened, a vial must be used that day or discarded.
-Arranging for vial-sharing by scheduling a number
# Children with chronic lung disease of prematurity or of other etiology:
Use of PVZ may be individualized depending on the severity of the chronic lung disease (e.g. oxygen dependence)
Children with CLD of prematurity have a 12-21% risk of hospitalization for RSV. PVZ is effective to prevent hospitalization (rate reduction 39% and NNT 21 in the 1 st 2 years of life, 86%, NNT 13 in the 1 st year).
There are data on increased rates of RSV hospitalization in chronic lung disease of other etiologies but PVZ has not been investigated.
There are data that children with cystic fibrosis have an increased risk of RSV hospitalization but studies to date suggest that PVZ is not protective.
# Down syndrome, Immunocompromised and other chronic conditions
Recommendations are based on PVZ effectiveness and risk of severe RSV disease in different risk groups. For certain very rare conditions, risk of severe RSV illness may be high but epidemiologic data are not available.
Likewise, the number of children with certain rare diseases is not sufficient for PVZ effectiveness to be studied.
In these circumstances, extrapolation may be made from data on conditions of pathophysiological similarity with documented increased risk of RSV and PVZ effectiveness.
No studies of cost-effectiveness of PVZ prophylaxis were identified for these populations.
# Use of PVZ for preterm infants of <37 wGA or for term infants living in remote Inuit communities
# Use of PVZ in term infants may be based on local rates of hospitalization of term infants with RSV and costs of transport to distant hospitals
Studies indicate that children living in some remote Inuit communities, including term infants, are at high risk of RSV hospitalization.
Limited data suggests that PVZ reduces RSV hospitalization of infants of <37 wGA living in remote Inuit communities (rate reduction 96%, 66%, NNT 2,4).
One study offering PVZ to term Inuit infants in an area where baseline rate of
# Options
# Considerations Decision Points
RSVH was not very high showed no effect.
Canadian modelling has suggested that PVZ prophylaxis for term infants may be dominant (i.e,less costly and more effective) in remote Inuit communities with very high baseline RSV hospitalization rates. ICERs were <$50,000/QALY in 75% of estimates, but efficacy was based on studies of preterm infants 6. Use of PVZ for term infants living in other remote aboriginal or other remote communities
# Use of PVZ in term infants may be based on local rates of hospitalization of term infants with RSV and costs of transport to distant hospitals
Limited data suggest that RSV hospitalization rates may be increased in other isolated aboriginal communities. There are no data from Canada.
There are no data on PVZ use in these communities. SYNCYTIAL
# Serological correlate of protection:
Determination of the minimum antibody level required to protect against severe RSV infection in humans and development of a commercially available test for RSV antibody would permit more judicious use of costly monoclonal antibody products, as many infants will develop natural antibody during their first or second year of life.
# RSV monoclonal antibody efficacy/effectiveness in infants living in remote communities, especially in Inuit infants in the far North:
There is (good) evidence of a high burden of RSV disease in Inuit infants in the far North but limited data on the effectiveness of PVZ to prevent hospitalization and the need for air transfer.
# Burden of RSV disease in infants with Down syndrome and efficacy/effectiveness of RSV monoclonal antibody to prevent hospitalization in this population:
The literature suggests that infants with Down syndrome without recognized clinical criteria for PVZ prophylaxis may have high rates of RSV hospitalization. The reasons for this susceptibility are not clear but may relate to immunodeficiency in this population. There is very limited data on the use of PVZ infants with Down syndrome.
# Efficacy/effectiveness of RSV monoclonal antibody in otherwise healthy premature infants born at < 29 wGA:
Studies of the efficacy/effectiveness of PVZ prophylaxis in severely premature infants of < 29 wGA failed to show protection, but the numbers of infants studied were very small. Such studies could not be done in countries where PVZ is now recommended for these infants. 1. Development of a RSV surveillance system with data for each province and territory, analogous to FluWatch, could provide timely data on which to determine when RSV monoclonal antibody prophylaxis programs should most efficiently begin and end.
# 2.
Studies of the burden of severe RSV disease in immunocompromised populations, stratified by age group (especially focusing on those ≤ 2 years of age) and by severity of immunosuppression (especially focusing on those with antibody deficiencies, as these individuals may not benefit from RSV vaccines in the future and thus may continue to warrant RSV monoclonal passive prophylaxis).
Ranking Individual Studies, Strength of Recommendations, Grade of Evidence Evidence from controlled trial(s) without randomization.
# II-2
Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.
# II-3
Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
# III
Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.
# Good
A study (including meta-analyses or systematic reviews) that meets all designspecific criteria* well.
# Fair
A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion* but has no known "fatal flaw".
# Poor
A study (including meta-analyses or systematic reviews) that has at least one design-specific* "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations. recommended interval for the second dose was 28 days and for subsequent doses 35 days. In YK the interval for the second dose was 18-24 days and the subsequent doses 28-30 days. The recommended interval in MB was 28 days up to the fourth dose, 35 days between doses 4 and 5 and 42 days between doses 5 and 6.
The maximum number of doses was 5 in 7 PT (AB, NB, NS, PE, ON, QC, SK), 6 in one (MB), 6 with extension based on local epidemiology in one (NU), and 4 in one (NL). In BC the maximum number of doses was 4 for infants of < 29 wGA and those with CLD or hsCHD, and 3 for premature infants of ≥29 wGA and no CLD or hsCHD. Two did not state a maximum (YK, NT).
# International:
Premature infants without chronic lung disease or hemodynamically significant congenial heart disease (hsCHD).
Three countries used gestational age alone with varying wGA limits: < 26 (Sweden), < 29 (US) and <32 (Netherlands). Four countries (Austria, Germany, Italy, Spain) recommended prophylaxis for all infants below a specific wGA (< 28 to <31), and for less premature infants (up to 34 to 36 wGA) using risk scores. Three countries (France, Switzerland, UK) did not provide prophylaxis for prematurity alone.
Chronic lung disease of prematurity (CLD) and other chronic lung conditions All 10 countries recommended prophylaxis for infants with chronic lung disease of prematurity. Eight countries, all but Switzerland and the UK, included those age < 24 months requiring treatment in the previous 6 months, with 5 of these including all infants < 12 months and one including all infants < 6 months old regardless of treatment. Switzerland recommended prophylaxis only for those < 1 year old. The UK recommended prophylaxis using a gestational age and chronological age grid which encompassed infants of ≤ 34 wGA and age 9 to 1.5 months.
Eight countries, all but France and Spain, also recommended prophylaxis for children aged < 1 or < 2 years with other pulmonary conditions, either routinely or on individual assessment. These tracheostomy.
# Congenital heart disease
All ten countries recommended prophylaxis for infants with significant CHD, to age 2 years in France, Spain, and Netherlands, for the first year of life only in Italy, Sweden, Switzerland, and for the first year with consideration of extension to the second year in the US. Germany recommended prophylaxis to age 6 months, with individual consideration for age 6-12 months. The UK included infants of ≤26 to ≤32 wGA and age 1.5 to 6 months based on a grid using these two parameters. Austria recommended prophylaxis until surgical correction or heart transplantation, regardless of age.
# Other clinical conditions:
Other clinical conditions were considered after individual assessment in eight countries (all but France and Spain). These included immunodeficiency of varying degrees in all eight, neurological or neuromuscular conditions without mention of clearance of respiratory secretions in Austria, Germany, Sweden, and Switzerland, trisomy 21
# Results
# Literature Review
# Randomized Controlled Trials
Nine double blind RCTs were identified. Four were placebo controlled 48,80,111,140,141 , two compared lyophilized and liquid forms of PVZ 212,213 and three compared PVZ to otavizumab (MVZ) (another monoclonal antibody directed against respiratory syncytial virus that was not licensed [214][215][216] . Quality for seven was rated as good while one 111 was rated as fair. The ninth was a conference abstract assessed in a systematic review that included additional information and was rated as good.
In the initial PVZ IMPACT RCT of children born at ≤ 35 weeks gestational age (wGA) and aged ≤ 6 months or age ≤ 24 months with bronchopulmonary dysplasia (BPD), rates of AE reported by the blinded investigator as potentially related to the study drug were similar in the PVZ and placebo groups (11% and 10% respectively). There were no significant differences in types of AE, including injection site reactions. There were no SAE. Discontinuation of PVZ because of AE was rare (0.3%). There were 4 (0.4%) deaths in the PVZ group and 5 (1%) with placebo for reasons judged unrelated to the study drug. The number of infants receiving PVZ was 1002 48 .
An RCT of children ≤ 24 months old with hemodynamically significant CHD (hsCHD) reported similar overall rates of AE (96% vs 97%) and AE judged related to study drug by the blinded investigator (7.2% vs 6.9%) in PVZ and placebo groups respectively. There were more SAE in the placebo group (63% vs Results of an RCT of PVZ in children <2 years old with cystic fibrosis were presented as a conference abstract 141 and was the only study in a later systematic review 140 . There were no significant differences in overall rates of AE, SAE, rates of AE related to study drug (5.4% vs 4.4%) or SAE related to study drug (0 vs 2.1%) with PVZ vs placebo respectively. PVZ was discontinued because of SAE in one case. There were no deaths. The number of children receiving PVZ was 92.
An RCT of otherwise healthy premature infants born at 33-35 wGA and aged ≤ 6 months reported only hospitalizations and deaths as AE. Hospitalization rates were higher with placebo than with PVZ (21.9% vs 12.6%, p 0.04) but when hospitalizations for RSV were removed the difference was not significant (19.1% vs 14.0% for placebo vs PVZ). There were no deaths. The number of infants receiving PVZ was 214 111 .
Two RCTs comparing lyophilized and liquid preparations of PVZ in children with chronic lung disease age ≤ 24 months or born at ≤ 35 wGA and age ≤ 6 months 212 or infants born at ≤ 35 wGA 213 found no significant differences in overall rates of AE 213 or SAE 212,213 . SAE occurred in 5.9% and 2.6% of lyophilized PVZ recipients and 8.5% and 3.3% of liquid PVZ recipients in the two studies but none were judged related to the study drugs. There was one death in a child who received lyophilized PVZ that was deemed not related to the study drug 212 . The total numbers of infants exposed to PVZ were 413 212 and 305 213 .
In doses of PVZ. SAE possibly or probably related to PVZ occurred in 10 subjects (0.09%), a rate of 2 per 10,000 doses). SAE were dyspnea or cyanosis with or without fever (4), As well as rash, thrombocytopenia, osteomyelitis, seizure, hypo-responsiveness, and fever with restlessness. There were 3 deaths, one unrelated to PVZ and two not assessable 222 . A later publication reported data from the same registry for 2009-2016, when 12,729 subjects received 63,572 doses. SAE probably related to PVZ were reported in 8 cases (0.06%), or 1.3 per 10,000 doses. These events were described as breathing cessation (2), rash, rash with fever, urticaria, agitation, erythema at injection site, and acute restriction of leg mobility (1 each). There were 9 deaths, none related to PVZ 223 .
An international prospective observational study from 15 A case report described non-fatal anaphylaxis of onset 20 minutes after a dose of PVZ. 239 The child had received 5 doses of PVZ the previous season and one previous dose in the current season). Anaphylaxis has rarely been reported. The manufacturers in 2002 reported 2 cases of anaphylaxis after administration of 2,000,000 doses of PVZ 240 .
In another case report a child developed apnea, bradycardia and oxygen desaturation 8 hours after the 1 st dose of PVZ. The child was found to have parainfluenza virus 1 and rhinovirus/enterovirus in a nasopharyngeal swab. Review of data reported to the Drug Commission of the German Medical Association from 1998 to 2017 revealed 93 reports of apnea/bradycardia, desaturations or cardiorespiratory event after PVZ administration, of which all but 29 were associated with a concurrent infection. There were 3 fatal cases of cardiorespiratory events within 48 hours of PVZ, all without concomitant infection but all with severe CHD. The authors concluded that there was insufficient information to assess the association of cardiorespiratory events after PVZ administration 241 .
3.1.5. Detection and Clinical Significance of Anti-PVZ Antibodies:
In an early study, antibody to PVZ was detected in 1.2 % of PVZ and 2.8% of placebo recipients, suggesting that the binding of PVZ to antibody was non-specific 48 . In subsequent studies, anti-PVZ antibody has been detected in 1.5-5.9% of PVZ recipients 212,213,216,[230][231][232] . Antibody was generally present transiently and at low levels and there was no boosting with subsequent doses or differences in responses between the 1 st and 2 nd year of PVZ exposure 231,232 . Anti-PVZ antibody was not associated with presence or type of AE events including potentially immune-mediated reactions, and did not affect PVZ levels.
# Data From the Canada Vigilance Program
There were 259 unique case reports of AE following PVZ administration to Dec. 31, 2018, of which 237 were considered serious. The most frequent events were respiratory at 137 (53%), of which 113 were infections (mainly reported because of PVZ product failure), followed by hypersensitivity reactions at 23 (9%). Other events reported are expected complications of the underlying conditions for which PVZ is recommended and are consistent with those reported in the product monograph. The role of PVZ in these AE is unknown as causality was not assessed.
# Summary
The most commonly reported AE considered related to PVZ were injection site reactions, fever, nervousness or irritability, cough, rhinitis, and diarrhea. PVZ related SAE were rare, reported in 1% or less of recipients with most studies reporting none. Most were hypersensitivity reactions. Three reports of anaphylaxis were identified. PVZ discontinuation because of AE occurred in 0-2.3% of recipients. There were no deaths attributable to PVZ.
Repeated injections of a humanized monoclonal antibody raises concern for the development of immune mediated disease 217,242 . Studies showed no increased risk of autoimmune disease or atopy in children exposed to PVZ.
# APPENDIX A: CURRENT CRITERIA FOR RECEIPT OF PVZ IN CANADIAN PROVINCES AND TERRITORIES AND INTERNATIONALLY
Eligibility criteria for PVZ (PVZ) prophylaxis were obtained from all Canadian provinces and territories and from 10 northern hemisphere countries. Data are summarized in the table below.
# Canada:
Premature infants without chronic lung disease or hemodynamically significant congenital heart disease (hsCHD). NACI in 2003 recommended PVZ prophylaxis for infants of ≤ 32 weeks gestational age (wGA) and age < 6 months at the start of the RSV season. The current Canadian Immunization Guide (CIG) states that selected infants of 33-35 wGA may also benefit, based on local considerations. The Canadian Paediatric Society (CPS) in 2015 stated that it is reasonable but not essential to offer prophylaxis to premature infants born at < 30 wGA and aged <6 months.
Six provinces and territories (PT) followed the current CIG recommendations for infants ≤ 32 wGA and selected infants of 33-35 wGA (AB, MB, NB, NT, ON, SK). All 6 PT used defined risk scores to determine eligibility for this group, but the risk criteria and scoring systems used varied across all PT. Two PT offered prophylaxis for those ≤ 29 wGA and for those 29-35 wGA with risk factors (BC, YT). One territory offered PVZ for all < 36 wGA (NU).Only one province followed the NACI recommendation (QC). Three provinces followed the CPS recommendation of prophylaxis for those < 30 wGA (NL, NS, PE).
# Chronic lung disease of prematurity (CLD) and other chronic lung conditions
In 2003, NACI recommended PVZ for children age < 24 months at the start of the RSV season with CLD requiring therapy in the previous 6 months or with other pulmonary disorders requiring oxygen therapy, while the current CIG only mentions children with CLD. CPS recommends prophylaxis for those with CLD of age < 12 months at the start of the RSV season who require ongoing treatment, but for their second RSV season only if still requiring supplemental oxygen or weaned off oxygen in the previous 3 months. Children with cystic fibrosis, upper airway obstruction, or chronic pulmonary disorders other than CLD should not be offered prophylaxis routinely, but it may be considered for those < 24 months old who are on home oxygen or have had a prolonged hospitalization for severe pulmonary disease.
Eight PT followed the NACI recommendation of prophylaxis for children with CLD (AB, MB, NB, NS, ON, PE, QC, SK) while in three PT infants were eligible only to age 12 months (BC, NL, YT). In one territory all infants with CLD and age < 12 months old and those 12-24 months requiring treatment the previous 3 months were eligible (NU) while in another selected infants with CHD who were < 36 wGA and age < 24 months were eligible only a case-by-case basis (NT).
Nine PT provided prophylaxis for other chronic pulmonary conditions for infants of age <24 months (8) or <12 months (1), with some PT requiring individual assessment. Conditions included cystic fibrosis (7), congenital lung or airway abnormalities (4), and neuromuscular conditions affecting ability 99 to clear airway secretions (5). Other conditions included were requirement for home respiratory support (O2, mechanical ventilation, tracheostomy, CPAP) and other severe pulmonary disability.
Congenital heart disease included cystic fibrosis in 5 countries, neuromuscular conditions interfering with clearing of respiratory secretions in 2, congenital anomalies of the respiratory tract or lung in 4, and other conditions such as chronic pulmonary conditions requiring long term need for oxygen therapy, mechanical ventilation or NACI in 2003 and the current CIG recommend prophylaxis for children with hsCHD and age < 24 months. CPS recommends prophylaxis for those of age <12 months only.
Six PT offered prophylaxis for children with hsCHD aged < 24 months (AB, NB, NT, NS, PE, SK), 4 for those < 12 months and for 12-24 months after individual assessment (BC, MB, ON, YK). Three limited prophylaxis to the first 12 months (NL, NU, QC).
# Other clinical conditions:
CPS states that prophylaxis may be considered for children < 24 months old with Down syndrome or immunodeficiency if they are on home oxygen, have had a prolonged hospitalization for severe pulmonary disease, or are severely immunocompromised.
Ten PT listed other clinical criteria for prophylaxis, some requiring individual assessment. Seven offered prophylaxis for Down syndrome (1 requiring additional comorbidity); eight for immunodeficiency (degree of severity varied), and one for neuromuscular conditions without mention of clearance of respiratory secretions.
In four PT, prophylaxis was offered to siblings of a multiple birth if one sibling qualified for prophylaxis (AB, BC, ON, YK), in all but one (ON) only if infants were premature. In one province, all infants of a multiple birth (other than twins), who were of ≤ 35 6/7 wGA and < 3 months old were eligible for prophylaxis (AB). In another, a twin of an approved child may be eligible after assessment (NT).
In all but two PT (NB, YK), protocols stated that other medical conditions may be considered on request after individual assessment. "May be administered" in text; summary says "Recommended" < 29 0/7 wGA and <12 m old at start of RSV season (states that some experts believe that given small increase in risk even if born <29 wGA, PVZ is not justified) "May be considered" in text; summary says "Recommended" <32 0/7 wGA with CLD of prematurity (defined as requirement for >21% oxygen for at least the first 28 days after birth, 1 st yr of life. 2. Methods
# Rapid literature Review
A rapid literature review of the safety of PVZ was conducted using the following sources:
-A systematic review of PVZ safety published in 2013 (rated average by AMSTAR) was used to identify studies published before 2013 211 . These studies were reviewed. -A literature search, based on the research question below, was conducted. The search strategy was developed with a Health Canada librarian (LG), included publications from 2013 onwards and was performed on April 24, 2019. The detailed search strategy is presented below. Because of time constraints, the literature search was limited to two bibliographic databases (MEDLINE and EMBASE) -Studies cited in the references obtained in the search that were not included in (1) or (2) were also reviewed.
Screening, eligibility assessment, data extraction and quality assessment were completed by a single reviewer. A data summary table with ratings of the quality of the evidence using NACI's standard methodology (Table B) was produced (Table C). Results from the accepted studies were synthesized narratively. Articles retrieved in the Health Canada literature search were loaded into RefWorks (ProQuest LLC, Ann Arbor, MI) and uploaded to DistillerSR (Evidence Partners, Ottawa, Canada). Duplicate records were removed. Records were screened by title and abstract. The full texts for articles that were relevant based on the inclusion and exclusion criteria, or that had insufficient information to exclude, were retrieved and assessed for eligibility through full-text screening.
Studies were included if they met the following criteria: -The study involved administration of PVZ intramuscularly to children.
# -
The study presented data on safety or AE. (If PVZ was administered but these were not mentioned in the abstract, the study was nevertheless included for full text review as studies could include safety data without reference in the abstract).
# Good
A study (including meta-analyses or systematic reviews) that meets all design-specific criteria* well.
# Fair
A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion* but has no known "fatal flaw".
# Poor
A study (including meta-analyses or systematic reviews) that has at least one designspecific* "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
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Prevalence of RhD expresssion varies by ethnicity. RhD negative phenotype is seen in 18% of Caucasian, 7.3% of African and 2% of Asian individuals. Individuals who are RhD negative lack RhD antigen expression on the red cell surface and either lack the RHD gene altogether or have an altered RHD gene which does not result in antigen expression (absent D antigen).
A small subset of the population have a variant RhD antigen (referred to as partial D and weak D). An estimated 0.2% -1.0% of Caucasians have variant D phenotypes . Variant D phenotypes are more common in those with an African ethnic background. Patients with partial D or weak D antigens can have weaker reactions with standard serological testing or RhD typing reactions that vary with different testing reagents or methods.
Recognizing individuals with variant D is important as all subtypes of partial D and some subtypes of weak D are at risk for alloimmunization when exposed to a wild-type RhD antigen (present in the majority of RhD positive persons). Weak D types 1, 2, 3 or 4 are identified in 61% of individuals with a variant D upon RHD genotyping in Canada, with an overall prevalence of weak D in pre-natal patients of 0.4% . Individuals with a weak D type 1, 2 or 3 are not at risk of forming anti-D and therefore can be managed safely as RhD-positive, i.e. can be transfused with RhD positive red blood cells (RBC) and do not require perinatal Rh immunoglobulin (RhIg). On the other hand, persons with most other weak D types, and those with partial D antigens are at risk for alloimmunization and should be treated as RhD negative, i.e. receive only RhD negative RBCs and receive perinatal RhIg. Expert opinion on the management of prenatal patients with weak D type 4.0 varies. Providing these individuals with RhIg prophylaxis during pregnancy and RhD negative RBCs for transfusion is the most cautious approach until additional data is available . Unfortunately, routine serological testing is unable to differentiate patients with weak D Type 1, 2 and 3 from the other D variants and RHD genotyping must be performed in order to establish the risk for alloimmunization and the requirement for RhIg prophylaxis.
In 2015 the College of American Pathology and AABB issued a Joint Statement recommending RHD Genotyping for Pregnant Women and Other Females of Childbearing Potential with a Serologic Weak D Phenotype in the United States .
We propose a standardized approach for RhD blood group determination in pregnant patients with an aim to minimize risks of alloimmunization with anti-D and reduce inappropriate utilization of RhIg and RhD-negative blood components.
# SECTION 2.0: CURRENT STATE IN CANADA
Currently, in Canada there is no national standard on further investigation and management of patients who present with a weak D phenotype on pre-transfusion or prenatal testing. A few provinces have developed guidance documents (for e.g., British Columbia and Quebec) . Depending on the individual institutional policy, such patients may be labeled RhD positive, RhD negative or RhD indeterminate. If a female patient with Partial D is erroneously labeled as RhD positive, she may be transfused with RhD positive RBCs and not be offered perinatal RhIg, possibly leading to alloimmunization and HDFN. On the other hand, a female patient with weak D Type 1, 2 or 3 may be erroneously labeled as RhD negative and receive unnecessary perinatal RhIG. Such practice also leads to unnecessary utilization of RhD negative RBCs when RhD positive RBCs could be transfused safely. In Canada if all pregnant women with a variant D phenotype were identified and their RHD genotype determined, an estimated 900 prenatal women who are currently managed as RhD-negative could be managed as RhD positive, avoiding 1800 injections of RhIg annually .
RHD genotyping is offered by the Canadian Blood Services for prenatal patients with discrepant, weak or inconclusive serological RhD test results when results may modify management. Moreover, RBC genotyping may be offered by other local qualified and accredited laboratories. Best practices dictate that the genotyping report should include interpretation of the results and recommendations on RhIg candidacy and assigned RhD group for RBC transfusion. Depending on location, the decision to perform genotyping is determined by local institutional policies. A recent Canadian Survey indicates that most Canadian laboratories refer samples from prenatal women for RHD genotyping when variant D phenotype is suspected. However, about 20% of institutions report that they do not obtain genotyping results in this setting.
# SECTION 3.0: RECOMMENDATIONS
To provide safe and appropriate care for prenatal patients with variant D phenotype and to standardize care across Canada, we recommend that:
1) Prenatal patients with discrepant, weak or inconclusive serological RhD test results should be further investigated with RHD genotyping to determine RhIg candidacy and optimal red blood cell RhD type for transfusion.
This practice is unlikely to result in a significant cost increment in terms of RHD testing for the provinces since it is already an established practice in some provinces, and survey data indicates that 80% of institutions currently perform this testing . Prenatal patients with a variant D phenotype are rare (0.4 %) . Since the majority of patients with variant D phenotype have Weak D types 1, 2 or 3 and can be regarded as Rh positive, any increased cost of testing will likely be outweighed by the savings derived from avoiding unnecessary RhIG.
2) Prenatal patients who type as RhD negative or who are determined to have variant D other than weak D Type 1, 2, and 3 should be considered candidates for perinatal RhIg administration and should be transfused with RhD negative blood components.
Individuals with a weak D type 1, 2 or 3 are not at risk of forming anti-D and therefore can be managed safely as RhD-positive, i.e. can be transfused with RhD positive red blood cells (RBC) and do not require perinatal Rh immunoglobulin (RhIg).
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#
Prevalence of RhD expresssion varies by ethnicity. RhD negative phenotype is seen in 18% of Caucasian, 7.3% of African and 2% of Asian individuals. Individuals who are RhD negative lack RhD antigen expression on the red cell surface and either lack the RHD gene altogether or have an altered RHD gene which does not result in antigen expression (absent D antigen).
A small subset of the population have a variant RhD antigen (referred to as partial D and weak D). An estimated 0.2% -1.0% of Caucasians have variant D phenotypes [3]. Variant D phenotypes are more common in those with an African ethnic background. Patients with partial D or weak D antigens can have weaker reactions with standard serological testing or RhD typing reactions that vary with different testing reagents or methods.
Recognizing individuals with variant D is important as all subtypes of partial D and some subtypes of weak D are at risk for alloimmunization when exposed to a wild-type RhD antigen (present in the majority of RhD positive persons). Weak D types 1, 2, 3 or 4 are identified in 61% of individuals with a variant D upon RHD genotyping in Canada, with an overall prevalence of weak D in pre-natal patients of 0.4% [5]. Individuals with a weak D type 1, 2 or 3 are not at risk of forming anti-D and therefore can be managed safely as RhD-positive, i.e. can be transfused with RhD positive red blood cells (RBC) and do not require perinatal Rh immunoglobulin (RhIg). On the other hand, persons with most other weak D types, and those with partial D antigens are at risk for alloimmunization and should be treated as RhD negative, i.e. receive only RhD negative RBCs and receive perinatal RhIg. Expert opinion on the management of prenatal patients with weak D type 4.0 varies. Providing these individuals with RhIg prophylaxis during pregnancy and RhD negative RBCs for transfusion is the most cautious approach until additional data is available [4]. Unfortunately, routine serological testing is unable to differentiate patients with weak D Type 1, 2 and 3 from the other D variants and RHD genotyping must be performed in order to establish the risk for alloimmunization and the requirement for RhIg prophylaxis.
In 2015 the College of American Pathology and AABB issued a Joint Statement recommending RHD Genotyping for Pregnant Women and Other Females of Childbearing Potential with a Serologic Weak D Phenotype in the United States [3].
We propose a standardized approach for RhD blood group determination in pregnant patients with an aim to minimize risks of alloimmunization with anti-D and reduce inappropriate utilization of RhIg and RhD-negative blood components.
# SECTION 2.0: CURRENT STATE IN CANADA
Currently, in Canada there is no national standard on further investigation and management of patients who present with a weak D phenotype on pre-transfusion or prenatal testing. A few provinces have developed guidance documents (for e.g., British Columbia and Quebec) [8.9]. Depending on the individual institutional policy, such patients may be labeled RhD positive, RhD negative or RhD indeterminate. If a female patient with Partial D is erroneously labeled as RhD positive, she may be transfused with RhD positive RBCs and not be offered perinatal RhIg, possibly leading to alloimmunization and HDFN. On the other hand, a female patient with weak D Type 1, 2 or 3 may be erroneously labeled as RhD negative and receive unnecessary perinatal RhIG. Such practice also leads to unnecessary utilization of RhD negative RBCs when RhD positive RBCs could be transfused safely. In Canada if all pregnant women with a variant D phenotype were identified and their RHD genotype determined, an estimated 900 prenatal women who are currently managed as RhD-negative could be managed as RhD positive, avoiding 1800 injections of RhIg annually [5,6].
RHD genotyping is offered by the Canadian Blood Services for prenatal patients with discrepant, weak or inconclusive serological RhD test results when results may modify management. Moreover, RBC genotyping may be offered by other local qualified and accredited laboratories. Best practices dictate that the genotyping report should include interpretation of the results and recommendations on RhIg candidacy and assigned RhD group for RBC transfusion. Depending on location, the decision to perform genotyping is determined by local institutional policies. A recent Canadian Survey [7] indicates that most Canadian laboratories refer samples from prenatal women for RHD genotyping when variant D phenotype is suspected. However, about 20% of institutions report that they do not obtain genotyping results in this setting.
# SECTION 3.0: RECOMMENDATIONS
To provide safe and appropriate care for prenatal patients with variant D phenotype and to standardize care across Canada, we recommend that:
1) Prenatal patients with discrepant, weak or inconclusive serological RhD test results should be further investigated with RHD genotyping to determine RhIg candidacy and optimal red blood cell RhD type for transfusion.
This practice is unlikely to result in a significant cost increment in terms of RHD testing for the provinces since it is already an established practice in some provinces, and survey data indicates that 80% of institutions currently perform this testing [7]. Prenatal patients with a variant D phenotype are rare (0.4 %) [5]. Since the majority of patients with variant D phenotype have Weak D types 1, 2 or 3 and can be regarded as Rh positive, any increased cost of testing will likely be outweighed by the savings derived from avoiding unnecessary RhIG.
2) Prenatal patients who type as RhD negative or who are determined to have variant D other than weak D Type 1, 2, and 3 should be considered candidates for perinatal RhIg administration and should be transfused with RhD negative blood components.
Individuals with a weak D type 1, 2 or 3 are not at risk of forming anti-D and therefore can be managed safely as RhD-positive, i.e. can be transfused with RhD positive red blood cells (RBC) and do not require perinatal Rh immunoglobulin (RhIg).
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a86dbdaeb9d1b7b6632813cb02e3ea5b6512dcaa
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An appropriate treatment and a follow-up of the infected patient; A recommendation to abstain from sexual contact until the end of treatment AND until the symptoms are resolved 2 : w In case of doubt regarding abstinence, a recommendation to use barrier methods for all types of sexual contact (genital, oral-genital, anal or oral-anal).Partners should be contacted if they had sexual contact with the infected patient: Most recent partner and regular partners, regardless of the presence or absence of symptoms.A sample for M. genitalium; A treatment for M. genitalium if microbiological test results indicate the presence of M. genitalium; A clinical assessment including identifying risk factors for other STBBI; Screening for other STBBI based on the risk factors identified. Consult the tool ITSS à rechercher selon les facteurs de risque décelés. 1. For cases of suspected sexual abuse, refer to the Guide d'intervention médicosociale pour répondre aux besoins des victimes d'agression sexuelle. 2. In the event of noncompliance with the abstinence instruction, consult an experienced colleague to determine the appropriate management.# ANTIBIOTIC RESISTANCE
M. genitalium resistance to different antibiotics is increasing rapidly, and the recommended treatments might eventually be modified as susceptibility patterns evolve based on the mutations that confer resistance to the antibiotics used for treatment. Practitioners need to be vigilant because:
Resistance to azithromycin is well established; Resistance to fluoroquinolones is on the rise.
# GENERAL INFORMATION
When a person presents with a syndrome consistent with an STBBI and screens negative for C. trachomatis and N.
gonorrhoeae and an appropriate syndromic treatment for the syndrome has proven ineffective, it is important to consider the possibility of the presence of other pathogenic agents or chronic conditions.
Non-chlamydial/non-gonococcal infections can have different etiologies, such as M. genitalium. This optimal usage guide applies to individuals for whom appropriate microbiological testing has been performed AND whose results show the presence of M. genitalium. For further details, see the practice guideline entitled Prélèvements et analyses de laboratoire pour la recherche de Mycoplasma genitalium.
It should be noted that a confirmed M. genitalium infection is not a notifiable disease.
This optimal usage guide is intended for primary care physicians. It is provided for information purposes only and should not replace the judgment of the clinician who performs activities reserved under a statute or a regulation. The recommendations concern persons 14 years of age and older 1 . They were developed using a systematic process and are supported by the scientific literature and the knowledge and experience of Québec clinicians and experts. For further details, go to the section Guides d'usage optimal at inesss.qc.ca.
# MEDICATION FREE OF CHARGE
For persons who are registered with the Québec health insurance plan (RAMQ) and have a valid health insurance card, claim slip or temporary proof of eligibility for medication, enter on the prescription the code K (for the infected patient) or L (for sexual partners).
# MANAGEMENT CONFIRMED mycoplasma genitalium infection
Stay up to date at inesss.qc.ca
# MYCOPLASMA GENITALIUM INFECTION
# TREATMENT PRINCIPLES
When the screening results for macrolide or fluoroquinolone resistance mutations are known, antibiotic resistance should be considered when choosing a treatment for M. genitalium. Since the use of azithromycin can induce macrolide resistance, retreatment with azithromycin in a multi-day dosing regimen should not be prescribed to individuals who did not respond to this antibiotic during the initial treatment of a syndrome consistent with an STBBI. The use of moxifloxacin as first-line therapy in all cases of confirmed M. genitalium infection is not recommended as the other treatment options are limited. Sequential treatment with doxycycline before azithromycin or moxifloxacin (depending on macrolide resistance) is recommended. Doxycycline appears to reduce the M. genitalium bacterial load, which seems to promote the action of azithromycin and moxifloxacin.
# TREATMENT
# Suspected or confirmed fluoroquinolone resistance
Doxycycline- 100 mg PO BID x 7 days followed by azithromycin 1 1 g PO initial dose followed by 500 mg PO daily x 3 days (total of 2.5 g) Doxycycline- 100 mg PO BID x 7 days followed by moxifloxacin 1,2 400 mg PO daily x 7 days Consult an experienced colleague.
For example, pristinamycin could be prescribed. This antibiotic is available through Health Canada's Special Access Program (SAP) for drugs.
- If doxycycline has been used as first-line therapy for an uncomplicated infection and the microbiology test results indicated the presence of M. genitalium, azithromycin or moxifloxacin should be administered as soon as possible after doxycycline. Doxycycline should not be repeated if the interval between the completion of doxycycline therapy and the initiation of azithromycin or moxifloxacin is less than 14 days.
# COMPLICATED INFECTIONS: PELVIC INFLAMMATORY DISEASE (PID) OR EPIDIDYMITIS/EPIDIDYMO-ORCHITIS
Consult an experienced colleague. The antibiotic combination to be used should include: Moxifloxacin 1, 2 400 mg PO daily x 14 days
# CURRENT SEXUAL PARTNER OF THE INFECTED PATIENT EMPIRICAL TREATMENT
Same antibiotic therapy as for the patient, unless the resistance data call for a different approach.
# PREGNANT OR BREASTFEE-DING WOMAN UNCOMPLICATED INFECTIONS: CERVICITIS OR URETHRITIS (INFECTED PATIENT) COMPLICATED INFECTIONS: PID (INFECTED PATIENT) EMPIRICAL TREATMENT (CURRENT SEXUAL PARTNER OF THE INFECTED PATIENT)
Consult an experienced colleague.
# TESTS OF CURE
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An appropriate treatment and a follow-up of the infected patient; A recommendation to abstain from sexual contact until the end of treatment AND until the symptoms are resolved 2 : w In case of doubt regarding abstinence, a recommendation to use barrier methods for all types of sexual contact (genital, oral-genital, anal or oral-anal).Partners should be contacted if they had sexual contact with the infected patient: Most recent partner and regular partners, regardless of the presence or absence of symptoms.A sample for M. genitalium; A treatment for M. genitalium if microbiological test results indicate the presence of M. genitalium; A clinical assessment including identifying risk factors for other STBBI; Screening for other STBBI based on the risk factors identified. Consult the tool ITSS à rechercher selon les facteurs de risque décelés. 1. For cases of suspected sexual abuse, refer to the Guide d'intervention médicosociale pour répondre aux besoins des victimes d'agression sexuelle. 2. In the event of noncompliance with the abstinence instruction, consult an experienced colleague to determine the appropriate management.# ANTIBIOTIC RESISTANCE
M. genitalium resistance to different antibiotics is increasing rapidly, and the recommended treatments might eventually be modified as susceptibility patterns evolve based on the mutations that confer resistance to the antibiotics used for treatment. Practitioners need to be vigilant because:
Resistance to azithromycin is well established; Resistance to fluoroquinolones is on the rise.
# GENERAL INFORMATION
When a person presents with a syndrome consistent with an STBBI and screens negative for C. trachomatis and N.
gonorrhoeae and an appropriate syndromic treatment for the syndrome has proven ineffective, it is important to consider the possibility of the presence of other pathogenic agents or chronic conditions.
Non-chlamydial/non-gonococcal infections can have different etiologies, such as M. genitalium. This optimal usage guide applies to individuals for whom appropriate microbiological testing has been performed AND whose results show the presence of M. genitalium. For further details, see the practice guideline entitled Prélèvements et analyses de laboratoire pour la recherche de Mycoplasma genitalium.
It should be noted that a confirmed M. genitalium infection is not a notifiable disease.
This optimal usage guide is intended for primary care physicians. It is provided for information purposes only and should not replace the judgment of the clinician who performs activities reserved under a statute or a regulation. The recommendations concern persons 14 years of age and older 1 . They were developed using a systematic process and are supported by the scientific literature and the knowledge and experience of Québec clinicians and experts. For further details, go to the section Guides d'usage optimal at inesss.qc.ca.
# MEDICATION FREE OF CHARGE
For persons who are registered with the Québec health insurance plan (RAMQ) and have a valid health insurance card, claim slip or temporary proof of eligibility for medication, enter on the prescription the code K (for the infected patient) or L (for sexual partners).
# MANAGEMENT CONFIRMED mycoplasma genitalium infection
Stay up to date at inesss.qc.ca
# MYCOPLASMA GENITALIUM INFECTION
# TREATMENT PRINCIPLES
When the screening results for macrolide or fluoroquinolone resistance mutations are known, antibiotic resistance should be considered when choosing a treatment for M. genitalium. Since the use of azithromycin can induce macrolide resistance, retreatment with azithromycin in a multi-day dosing regimen should not be prescribed to individuals who did not respond to this antibiotic during the initial treatment of a syndrome consistent with an STBBI. The use of moxifloxacin as first-line therapy in all cases of confirmed M. genitalium infection is not recommended as the other treatment options are limited. Sequential treatment with doxycycline before azithromycin or moxifloxacin (depending on macrolide resistance) is recommended. Doxycycline appears to reduce the M. genitalium bacterial load, which seems to promote the action of azithromycin and moxifloxacin.
# TREATMENT
# Suspected or confirmed fluoroquinolone resistance
Doxycycline* 100 mg PO BID x 7 days followed by azithromycin 1 1 g PO initial dose followed by 500 mg PO daily x 3 days (total of 2.5 g) Doxycycline* 100 mg PO BID x 7 days followed by moxifloxacin 1,2 400 mg PO daily x 7 days Consult an experienced colleague.
For example, pristinamycin could be prescribed. This antibiotic is available through Health Canada's Special Access Program (SAP) for drugs.
#
* If doxycycline has been used as first-line therapy for an uncomplicated infection and the microbiology test results indicated the presence of M. genitalium, azithromycin or moxifloxacin should be administered as soon as possible after doxycycline. Doxycycline should not be repeated if the interval between the completion of doxycycline therapy and the initiation of azithromycin or moxifloxacin is less than 14 days.
# COMPLICATED INFECTIONS: PELVIC INFLAMMATORY DISEASE (PID) OR EPIDIDYMITIS/EPIDIDYMO-ORCHITIS
Consult an experienced colleague. The antibiotic combination to be used should include: Moxifloxacin 1, 2 400 mg PO daily x 14 days
# CURRENT SEXUAL PARTNER OF THE INFECTED PATIENT EMPIRICAL TREATMENT
Same antibiotic therapy as for the patient, unless the resistance data call for a different approach.
# PREGNANT OR BREASTFEE-DING WOMAN UNCOMPLICATED INFECTIONS: CERVICITIS OR URETHRITIS (INFECTED PATIENT) COMPLICATED INFECTIONS: PID (INFECTED PATIENT) EMPIRICAL TREATMENT (CURRENT SEXUAL PARTNER OF THE INFECTED PATIENT)
Consult an experienced colleague.
# TESTS OF CURE
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# LIST OF ABBREVIATIONS
Fibrinogen replacement in the setting of acquired hypofibrinogenemia plays an important role in management of massive bleeding post cardiac surgery, trauma and obstetrical hemorrhage among others. However, there continues to be a lack of evidence firmly guiding fibrinogen replacement product choice as well as ongoing uncertainties as to the optimal target and dose.
Fibrinogen concentrate (FC), plasma (including both frozen plasma (FP) and fresh frozen plasma (FFP)), and cryoprecipitate are currently used to treat acquired hypofibrinogenemia.
There are two FC products currently available in Canada: RiaSTAP (CSL Behring) and FIBRYGA (Octapharma) (1,2). Both are licensed for treatment of acute bleeding episodes and perioperative prophylaxis in adult and pediatric patients with congenital afibrinogenemia and hypofibrinogenemia. FIBRYGA is also licensed as a complementary therapy during the management of uncontrolled severe bleeding in patients with acquired fibrinogen deficiency during surgical interventions (2). The use of fibrinogen concentrates in acquired hypofibrinogenemia is supported by studies, including a high-quality randomized trial in bleeding patients undergoing cardiovascular surgery (3).
According to data provided by the manufacturers, in addition to fibrinogen, fibrinogen concentrates contain trace amounts of the other substances, such as FXIII and fibronectin. These substances are not listed as active ingredients in the product monograph and the concentrations in the final product may vary. As such, their clinical relevance, if any, is unknown. Furthermore, both fibrinogen concentrates appear to have similar efficacy in improving clot firmness in a dilutional hypofibrinogenemia model in vitro (4).
The major difference between these products is related to the product storage: FIBRYGA is stored at room temperature for up to 36 months whereas RiaSTAP is stored in a refrigerator for up to 60 months (1,2).
Plasma is indicated for replacement of multiple clotting factor deficiencies and should not be used solely for fibrinogen replacement. FP and FFP are considered equivalent in terms of clinical effectiveness. The additional risks of plasma transfusion include transfusion associated circulatory overload (TACO), transfusion related acute lung injury (TRALI) and allergic reactions.
Cryoprecipitate is prepared from slowly thawed FP and is indicated for replacement of fibrinogen in patients with congenital and acquired fibrinogen deficiency (quantitative or qualitative) in the setting of bleeding or an increased risk of bleeding (ex. impending major surgery).
Currently, there is no evidence of superiority of one fibrinogen replacement source over the others in terms of clinical effectiveness. However, fibrinogen concentrate is pathogen inactivated and has a preferred safety profile in terms of transmissible disease risk as compared to frozen plasma and cryoprecipitate. Furthermore, fibrinogen concentrate offers many logistical advantages, including a more precise fibrinogen dose, simpler preparation (without need for thawing and with capability for bedside reconstitution), and efficiency of administration.
# SECTION 2.0: FIBRINOGEN CONCENTRATE DOSING
Fibrinogen content of the above-mentioned products is as follows (1,2,5-7):
- FC = 0.9 -1. In a bleeding obstetrical patient with acquired hypofibrinogenemia, fibrinogen replacement is indicated when fibrinogen level is less than 2.0 g/L (8,9). In a massively bleeding or preoperative patient with acquired hypofibrinogenemia, fibrinogen should be replaced when the level is less than 1.5 g/L (10-12).
Options for fibrinogen replacement in adult patients with acquired hypofibrinogenemia include the following: FC: 2-4 g Cryoprecipitate: 10 units (1 unit/10 kg) FP or FFP: 3-4 units (10-15 mL/kg)
In neonates and pediatric patients, it is recommended to consult with the product monograph and a specialist with expertise in managing pediatric/neonatal coagulopathy prior to administration of fibrinogen concentrates. In published studies (13)(14) of acquired hypofibrinogenemia in neonatal or pediatric populations, fibrinogen concentrate dosing has ranged between 30-60 mg/kg.
Following administration of a fibrinogen replacement therapy, repeat bloodwork should be completed within 60 minutes to assess the degree of fibrinogen increment. The expected increment is approximately 0.5-1.0 g/L (3,7,14).
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# LIST OF ABBREVIATIONS
Fibrinogen replacement in the setting of acquired hypofibrinogenemia plays an important role in management of massive bleeding post cardiac surgery, trauma and obstetrical hemorrhage among others. However, there continues to be a lack of evidence firmly guiding fibrinogen replacement product choice as well as ongoing uncertainties as to the optimal target and dose.
Fibrinogen concentrate (FC), plasma (including both frozen plasma (FP) and fresh frozen plasma (FFP)), and cryoprecipitate are currently used to treat acquired hypofibrinogenemia.
There are two FC products currently available in Canada: RiaSTAP (CSL Behring) and FIBRYGA (Octapharma) (1,2). Both are licensed for treatment of acute bleeding episodes and perioperative prophylaxis in adult and pediatric patients with congenital afibrinogenemia and hypofibrinogenemia. FIBRYGA is also licensed as a complementary therapy during the management of uncontrolled severe bleeding in patients with acquired fibrinogen deficiency during surgical interventions (2). The use of fibrinogen concentrates in acquired hypofibrinogenemia is supported by studies, including a high-quality randomized trial in bleeding patients undergoing cardiovascular surgery (3).
According to data provided by the manufacturers, in addition to fibrinogen, fibrinogen concentrates contain trace amounts of the other substances, such as FXIII and fibronectin. These substances are not listed as active ingredients in the product monograph and the concentrations in the final product may vary. As such, their clinical relevance, if any, is unknown. Furthermore, both fibrinogen concentrates appear to have similar efficacy in improving clot firmness in a dilutional hypofibrinogenemia model in vitro (4).
The major difference between these products is related to the product storage: FIBRYGA is stored at room temperature for up to 36 months whereas RiaSTAP is stored in a refrigerator for up to 60 months (1,2).
Plasma is indicated for replacement of multiple clotting factor deficiencies and should not be used solely for fibrinogen replacement. FP and FFP are considered equivalent in terms of clinical effectiveness. The additional risks of plasma transfusion include transfusion associated circulatory overload (TACO), transfusion related acute lung injury (TRALI) and allergic reactions.
Cryoprecipitate is prepared from slowly thawed FP and is indicated for replacement of fibrinogen in patients with congenital and acquired fibrinogen deficiency (quantitative or qualitative) in the setting of bleeding or an increased risk of bleeding (ex. impending major surgery).
Currently, there is no evidence of superiority of one fibrinogen replacement source over the others in terms of clinical effectiveness. However, fibrinogen concentrate is pathogen inactivated and has a preferred safety profile in terms of transmissible disease risk as compared to frozen plasma and cryoprecipitate. Furthermore, fibrinogen concentrate offers many logistical advantages, including a more precise fibrinogen dose, simpler preparation (without need for thawing and with capability for bedside reconstitution), and efficiency of administration.
# SECTION 2.0: FIBRINOGEN CONCENTRATE DOSING
Fibrinogen content of the above-mentioned products is as follows (1,2,5-7):
FC = 0.9 -1. In a bleeding obstetrical patient with acquired hypofibrinogenemia, fibrinogen replacement is indicated when fibrinogen level is less than 2.0 g/L (8,9). In a massively bleeding or preoperative patient with acquired hypofibrinogenemia, fibrinogen should be replaced when the level is less than 1.5 g/L (10-12).
Options for fibrinogen replacement in adult patients with acquired hypofibrinogenemia include the following: FC: 2-4 g Cryoprecipitate: 10 units (1 unit/10 kg) FP or FFP: 3-4 units (10-15 mL/kg)
In neonates and pediatric patients, it is recommended to consult with the product monograph and a specialist with expertise in managing pediatric/neonatal coagulopathy prior to administration of fibrinogen concentrates. In published studies (13)(14) of acquired hypofibrinogenemia in neonatal or pediatric populations, fibrinogen concentrate dosing has ranged between 30-60 mg/kg.
Following administration of a fibrinogen replacement therapy, repeat bloodwork should be completed within 60 minutes to assess the degree of fibrinogen increment. The expected increment is approximately 0.5-1.0 g/L (3,7,14).
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a673e72a61bd13239fc197d08bde0acc20cb0eb4
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# THROMBOPHILIA: HOMOCYSTEINEMIA AND METHYLENE TETRAHYDROFOLATE REDUCTASE GENE MUTATION OBJECTIVES:
- To review the clinical relevance of testing for homocysteinemia and methylene tetrahydrofolate reductase (MTHFR) gene mutations.
- To discuss the evidence for reducing homocysteine levels for vascular protection and prevention of venous thromboembolism (VTE).
# BACKGROUND:
Homocysteine is an amino acid not found in food but obtained from the conversion of dietary methionine. Homocysteine can be converted back into methionine or metabolized into cysteine through pathways involving several enzymes and the cofactors folic acid, vitamin B12 and vitamin B6. Normal plasma concentrations of homocysteine range from 5-15 µmol/L.
Mild to moderate hyperhomocysteinemia ranging between 15-30 µmol/L is common and can be seen in 5-12% of the general population. The causes of mild to moderate elevations in homocysteine include enzyme defects, renal insufficiency, hypothyroidism, alcoholism, some drugs (such as methotrexate, phenytoin, carbamazepine, isoniazid), and deficiencies of vitamin B12 or folic acid. These levels of homocysteine are associated with atherosclerosis and increased risk of stroke, ischemic heart disease and peripheral arterial disease. Observational studies have shown an inconsistent or weak association with first episode or recurrent VTE. Hyperhomocysteinemia has been associated with obstetric complications but the importance and significance of this association remain unclear.
Methylene tetrahydrofolate reductase (MTHFR) gene mutation is one of the most common enzymatic defects that may lead to elevation of homocysteine levels. MTHFR is required for the regeneration of methionine from homocysteine. The genetic mutation, which results from a single nucleotide substitution at position 677 (C677T), produces a form of MTHFR that has decreased activity. As a consequence, homocysteine cannot be reconverted to methionine, and homocysteine levels increase. Approximately 40% and 10% of the general population are heterozygous carriers and homozygous for this mutation, respectively. The significance of the MTHFR mutation in the absence of hyperhomocysteinemia is unclear.
Homocystinuria is a rare genetic disease that is usually diagnosed in childhood. It causes very high levels of homocysteine and severe clinical manifestations including premature vascular disease and VTE. This condition is not addressed in this guide.
# DIAGNOSIS:
VTE:
It is unclear if identifying individuals with hyperhomocysteinemia in the evaluation of VTE is clinically relevant because interventions for decreasing homocysteine level in such individuals do not reduce their risk of first or recurrent VTE. Therefore, testing for hyperhomocysteinemia and MTHFR mutations in patients with VTE is not recommended.
# Cardiovascular outcomes:
The clinical relevance of measuring homocysteine levels is also unclear when evaluating risk of atherosclerotic events. Homocysteine-lowering therapy has not been shown to reduce the risk of myocardial infarction or total cardiovascular death in clinical trials. Reductions in stroke have been demonstrated with B vitamin supplementation. Patients with normal levels of homocysteine were not excluded in all trials, but mean baseline levels of homocysteine were elevated. The patients in these trials had other traditional cardiovascular risk factors. Testing for MTHFR mutations is not recommended.
# MANAGEMENT:
B vitamin supplementation (folic acid, vitamin B6, and vitamin B12, either alone or in some combination) may lower homocysteine levels within a few weeks. However, clinical trials have not demonstrated that decreasing the levels of homocysteine reduces recurrent VTE, even in patients with high baseline levels. Based on currently available data, treating hyperhomocysteinemia in patients with VTE is not recommended.
B vitamin supplementation has also not demonstrated benefit in reducing myocardial infarction or cardiovascular death. There has been a suggestion that B vitamin supplementation may reduce the risk of stroke, particularly if a patient has an eGFR above 50 mL/min/1.73m 2 ; however, a benefit has not been conclusively demonstrated. Furthermore, no benefit in stroke reduction is found when analyzing the subgroup of patients with an eGFR below 50 mL/min/1.73m 2 .
B vitamin supplementation for primary prevention of cardiovascular disease is also not recommended in areas where there is prevalent folate-fortification of grains. In regions where folate-fortification of grains is uncommon, then vitamin supplementation can be considered in those patients with other atherosclerotic risk factors with the aim of reducing risk of stroke. The Chinese Stroke Prevention Trial (CSPPT), a primary prevention study conducted in China on subjects for whom folic acid supplementation had not been implemented, found a reduction in stroke (0.7% absolute risk reduction) with the addition of folic acid to enalapril in patients with hypertension compared with the use of enalapril alone.
The optimal management of adverse obstetric outcome in patients with hyperhomocysteinemia is not known.
# PEDIATRICS:
The MTHFR mutation in combination with hyperhomocysteinemia is reported to be associated with stroke in children. Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# Date of Version: 31January2022
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
|
# THROMBOPHILIA: HOMOCYSTEINEMIA AND METHYLENE TETRAHYDROFOLATE REDUCTASE GENE MUTATION OBJECTIVES:
• To review the clinical relevance of testing for homocysteinemia and methylene tetrahydrofolate reductase (MTHFR) gene mutations.
• To discuss the evidence for reducing homocysteine levels for vascular protection and prevention of venous thromboembolism (VTE).
# BACKGROUND:
Homocysteine is an amino acid not found in food but obtained from the conversion of dietary methionine. Homocysteine can be converted back into methionine or metabolized into cysteine through pathways involving several enzymes and the cofactors folic acid, vitamin B12 and vitamin B6. Normal plasma concentrations of homocysteine range from 5-15 µmol/L.
Mild to moderate hyperhomocysteinemia ranging between 15-30 µmol/L is common and can be seen in 5-12% of the general population. The causes of mild to moderate elevations in homocysteine include enzyme defects, renal insufficiency, hypothyroidism, alcoholism, some drugs (such as methotrexate, phenytoin, carbamazepine, isoniazid), and deficiencies of vitamin B12 or folic acid. These levels of homocysteine are associated with atherosclerosis and increased risk of stroke, ischemic heart disease and peripheral arterial disease. Observational studies have shown an inconsistent or weak association with first episode or recurrent VTE. Hyperhomocysteinemia has been associated with obstetric complications but the importance and significance of this association remain unclear.
Methylene tetrahydrofolate reductase (MTHFR) gene mutation is one of the most common enzymatic defects that may lead to elevation of homocysteine levels. MTHFR is required for the regeneration of methionine from homocysteine. The genetic mutation, which results from a single nucleotide substitution at position 677 (C677T), produces a form of MTHFR that has decreased activity. As a consequence, homocysteine cannot be reconverted to methionine, and homocysteine levels increase. Approximately 40% and 10% of the general population are heterozygous carriers and homozygous for this mutation, respectively. The significance of the MTHFR mutation in the absence of hyperhomocysteinemia is unclear.
Homocystinuria is a rare genetic disease that is usually diagnosed in childhood. It causes very high levels of homocysteine and severe clinical manifestations including premature vascular disease and VTE. This condition is not addressed in this guide.
# DIAGNOSIS:
VTE:
It is unclear if identifying individuals with hyperhomocysteinemia in the evaluation of VTE is clinically relevant because interventions for decreasing homocysteine level in such individuals do not reduce their risk of first or recurrent VTE. Therefore, testing for hyperhomocysteinemia and MTHFR mutations in patients with VTE is not recommended.
# Cardiovascular outcomes:
The clinical relevance of measuring homocysteine levels is also unclear when evaluating risk of atherosclerotic events. Homocysteine-lowering therapy has not been shown to reduce the risk of myocardial infarction or total cardiovascular death in clinical trials. Reductions in stroke have been demonstrated with B vitamin supplementation. Patients with normal levels of homocysteine were not excluded in all trials, but mean baseline levels of homocysteine were elevated. The patients in these trials had other traditional cardiovascular risk factors. Testing for MTHFR mutations is not recommended.
# MANAGEMENT:
B vitamin supplementation (folic acid, vitamin B6, and vitamin B12, either alone or in some combination) may lower homocysteine levels within a few weeks. However, clinical trials have not demonstrated that decreasing the levels of homocysteine reduces recurrent VTE, even in patients with high baseline levels. Based on currently available data, treating hyperhomocysteinemia in patients with VTE is not recommended.
B vitamin supplementation has also not demonstrated benefit in reducing myocardial infarction or cardiovascular death. There has been a suggestion that B vitamin supplementation may reduce the risk of stroke, particularly if a patient has an eGFR above 50 mL/min/1.73m 2 ; however, a benefit has not been conclusively demonstrated. Furthermore, no benefit in stroke reduction is found when analyzing the subgroup of patients with an eGFR below 50 mL/min/1.73m 2 .
B vitamin supplementation for primary prevention of cardiovascular disease is also not recommended in areas where there is prevalent folate-fortification of grains. In regions where folate-fortification of grains is uncommon, then vitamin supplementation can be considered in those patients with other atherosclerotic risk factors with the aim of reducing risk of stroke. The Chinese Stroke Prevention Trial (CSPPT), a primary prevention study conducted in China on subjects for whom folic acid supplementation had not been implemented, found a reduction in stroke (0.7% absolute risk reduction) with the addition of folic acid to enalapril in patients with hypertension compared with the use of enalapril alone.
The optimal management of adverse obstetric outcome in patients with hyperhomocysteinemia is not known.
# PEDIATRICS:
The MTHFR mutation in combination with hyperhomocysteinemia is reported to be associated with stroke in children. Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# Date of Version: 31January2022
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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# Increased Risk Donor Toolkit
# Toolkit Purpose
This toolkit was developed to summarize recommendations on the use of Increased Risk Donors (IRDs) for organ transplantation as well as to provide useful information and guidance that could help Ontario increase organ utilization and improve access to organ transplantation for patients. It is intended for use by transplant physicians, hospital administration and transplant programs who are directly or indirectly involved with patient care in a transplant setting. This toolkit includes recommended tools and templates to support transplant programs in providing information to patients on the use of increased risk donors for transplantation.
The objectives of this toolkit are to: Educate all healthcare providers along the transplant continuum about IRDs; Provide guidance to healthcare administrators about incorporating IRDs into their clinical and administrative processes; Provide information to healthcare providers to educate patients about IRDs; Provide tools to support informed patient consent at the time of transplant.
# Toolkit Development Process
In March 2013, the Canadian Society of Transplantation (CST) and the Canadian National Transplant Research Program (CNTRP) held a conference and developed a framework guidance document that outlines recommendations for utilization of IRDs in Canada. The conference included experts from Canada in organ and tissue donation and transplantation, transplant infectious diseases, laboratory medicine, and epidemiology. Additional content expertise was provided by Health Canada, several major Canadian Organ Procurement Organizations (OPOs), and Canadian Blood Services (CBS). This toolkit is based on the recommendations developed by the CST/CNTRP Increased Risk Donor Working Group (2014) published in the journal Transplantation (CST/CNTRP Increased Risk Donor Working Group, 2014).
The process for the development of this toolkit included: Detailed review of CST and CNTRP recommendations; Literature research on current practices; Review of TGLN policies and procedures; Consultation sessions with transplant medical leads;
In 2017, TGLN's Infectious Disease Lead, Dr. Atul Humar, presented an algorithm that would increase the utilization of Hepatitis C Virus (HCV) positive organs based on new evidence on the efficacy of treatments for HCV (Feld, et al., 2015). Based on consensus from the Organ Specific Working Group representatives to move forward with the new algorithm, amendments to this version of the toolkit have been made to address the utilization of both HCV antibody positive, Nucleic Acid Testing (NAT) negative and HCV NAT positive donors in select populations.
# Introduction to Increased Risk Donors
# What is an Increased Risk Donor?
Increased Risk Donors (IRDs) are donors who may or may not test positive for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), and HCV and/or identify certain lifestyle behaviours that are of higher risk who may transmit infectious diseases to transplant recipients. Donors who test negative for HIV, HBV, or HCV are still at risk for transmitting HIV, HCV, or HBV to recipients, due to a window period of time where the infection(s) is not detectable.
For the purpose of classification, the risk profile for HCV antibody positive, NAT negative donors who also have NAT negative results for HIV and HBV is similar to those who test negative for infections but identify with certain lifestyle behaviours. The risk associated with this donor profile is low due to treatment or spontaneous clearance, as evidenced by the NAT method, which is more specific and yields results earlier than other tests (Maylin, et al., 2008). Some exceptions to this may occur in the setting of liver transplant from donors who are HCV antibody positive / NAT negative.
For more information on NAT, see Section 3.1.2 and "The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation" in the American Journal of Transplantation (Levitsky, et al., 2017).
# Donation Protocols for Increased Risk Donors
TGLN is responsible for determining the safety of deceased organs for transplantation through donor screening, donor testing, and donor suitability assessment as per the Health Canada requirements for the Safety of Human Cells, Tissues, and Organs for Transplantation regulations (CTO regulations). All persons are considered to be a potential organ donor, regardless of age, health status, or social behavior. Potential donors that are referred to TGLN are assessed on an individual basis and go through a screening process as well as medical suitability testing to determine if organs are safe for transplantation. As part of the screening process, the family and/or close friends of every potential donor is asked a series of detailed questions about the social medical history of their loved one, and the donor's lifestyle is considered to assess the potential for the transmission of infectious disease to the recipient. Potential donors with identified increased risk behaviors may be eligible to donate, via a process of "exceptional distribution". Exceptional distribution is permitted if another standard organ is not immediately available, and the transplant physician has authorized the use of the organ based on their clinical judgment. The transplant program communicates the risk to the potential recipient so they can make an informed decision about whether to consent to accepting the offered organ.
The CTO regulations relating to exceptional distribution can be found in Appendix A.
# Criteria for Increased Risk Behaviour
Behavioural risk factors for HIV, HCV and HBV are assessed by a history and physical examination of the donor. Table 1 outlines the behaviours that are considered increased risk by the Canadian Standards Association. or with a person known or suspected to have HIV, or clinically active HBV or clinically active HCV; f) persons who have been exposed, in the preceding 12 months*, to known or suspected HIV-, HBV-, and/or HCV-infected blood through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane; g) persons who have been in youth correctional facility, jail, or prison for more than 72 consecutive hours in the preceding 12 months; h) persons who within 12 months- preceding donation have undergone tattooing, ear piercing, or body piercing in which sterile procedures were not used (e.g., contaminated instruments and/or ink were used, or shared instruments that had not been sterilized between uses were used); and i) persons who have had close contact within 12 months preceding donation with another person having clinically active HBV or clinically active HCV infection (e.g., living in the same household, where sharing of kitchen and bathroom facilities occurs regularly). - The 12 month period specified in Items f) and h) may be reduced to 6 months if nucleic acid testing (NAT) is used for the detection of HIV, HBV, and HCV.
# E.2:
The assessment of donors less than 11 years of age shall include the following risk factors and risk behaviours associated with HIV, HBV, and HCV: a) persons who have been exposed, in the preceding 12 months*, to known or suspected HIV-, HBV-, and/or HCV-infected blood through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane; b) persons who within 12 months- of donation have undergone tattooing, ear piercing, or body piercing in which sterile procedures were not used (e.g., contaminated instruments and/or ink were used, or shared instruments that had not been sterilized between uses were used); c) persons who have had close contact within 12 months preceding donation with another person having clinically active viral hepatitis (e.g., living in the same household, where sharing of kitchen and bathroom facilities occurs regularly); d) persons who have been breastfed within the past 12 months † of donation by women with or a risk for HIV, HBV, and/or HCV; and e) persons less than 18 months of age who are born to women with or at risk for HIV, HBV, and/or HCV infection. - The 12 month period specified in Items a) and b) may be reduced to 6 months if NAT is used for the detection of HIV-1, HBV, and HCV. † It is only necessary to assess donors less than five years of age against the criteria in Item d).
Source: Canadian Standards Association, 2017.
# Risk Assessment of Increased Risk Donor Organs
# Infectious Disease Testing
# General Donor Testing Requirements
In order to evaluate the safety of organs for transplantation, TGLN facilitates infectious disease testing for all potential donors. STAT pre-transplant serological testing is required for:
- human immunodeficiency virus I/II (HIV I/II); human T-cell lymphotropic virus (HTLV I/II); venereal disease research lab test (VDRL); hepatitis B surface antigen (HBsAg); hepatitis C virus (HCV); antibody to hepatitis B core antigen (anti-HBcAb); cytomegalovirus (CMV); and, West Nile virus (WNV) between May to October.
Additionally, retrospective (non-STAT) testing is required for: Epstein Barr virus (EBV); Toxoplasmosis IgG (toxo) for all potential heart donors For pediatric cases, maternal serology is required if the potential pediatric donor is ≤ 18 months of age and/or has been breast-fed within the last 12 months.
Test results are documented in the TGLN donor chart and reported to the appropriate transplant program(s) at the time of offer. Positive results do not automatically preclude donation as exceptional distribution may be considered. If the potential donor is assessed as being an increased risk, Nucleic Acid Testing (NAT) should be performed in addition to the required pre-transplant STAT serological testing.
# Nucleic Acid Testing
NAT is a method of testing for diseases in an individual's blood and it is the recommended method of infectious disease testing for living and deceased donors. It detects viruses earlier than other screening methods; thus, narrowing the detection window period of HIV, HCV, and HBV infections. Figure 1 below outlines the difference in pathogen detection window periods between serology and NAT testing methods. NAT aims to reduce the risk to the recipients in contracting diseases from organs that are recovered from deceased organ donors; in particular those donors that have been identified as having increased risk behavior. In general, NAT should be performed on deceased organ donors in circumstances where a decision is made to use exceptional distribution protocols from a donor with a history of increased risk behavior.
TGLN has implemented a process for requesting NAT testing for donors with confirmation of increased risk criteria having occurred as per Health Canada guidelines, especially if increased risk behaviors have occurred within the serology window period. Additionally, NAT should be requested for donors for which there is no way to confirm whether or not increased risk criteria has occurred in serology testing window period and who also have physical evidence of recent risk exposure. The process for requesting individual NAT testing based on the patient assessment can be found in Appendix B.
# Risk of Infection from Increased Risk Donor Organs
The potential risk for transmission of an infectious disease is the most important consideration in conducting a risk vs. benefit analysis when organs from IRDs become available. Residual risk estimates have been published based primarily on U.S. epidemiologic data. A systematic review of prevalence and incidence studies was conducted to determine the risk in a Canadian population (CST/CNTRP Increased Risk Donor Working Group, 2014).
Estimates of residual risk are provided in Tables 2 and Table 3 below per 10,000 donors if enzyme-linked immunosorbent assay (ELISA) or NAT is used for screening. Furthermore, the estimate is converted to a ratio to provide a number that can be more easily conveyed to patients during the informed consent process. Risk estimates assume the behaviour(s) occurred right up until the moment of donation. Additional factors may need to be considered when determining the actual risk to the patient, such as length of hospitalization prior to donation with risk generally decreasing as duration of hospitalization increases. The diagram below shows the recommended sequence of activities in the IRD organ utilization process. Information and guidance on each of the activities are outlined in the following section.
# Guidance for Increased Risk Donor Organ Utilization 1) CONSIDER USE OF IRD ORGANS FOR SELECT TRANSPLANT PATIENTS
The number of organs and tissue needed in Ontario continues to be higher than the number available. When determining the risks vs. benefits of an organ from an IRD, physicians should consider the following facts: There is a shortage of organs and tissue that can be used for transplant; There are nearly 1,500 Ontarians waiting to get life-saving organ transplants; Every three days, someone dies while waiting for an organ transplant; The waiting times for organ transplants can be up to several years depending on the organ.
Given the significant discrepancy between donor organ supply and demand, the use of organs from IRDs should be considered for some patients. Using these organs offers an opportunity for shortening wait times while providing good outcomes. Furthermore, utilizing NAT testing during the screening process can further reduce the risk of disease transmission.
Physicians should consider the following factors when identifying potential candidates for organ transplant from an IRD: 1. Estimated time the patient may be on the wait list if he/she waits until the next offer.
- Estimated wait-list mortality if he/she waits until the next offer.
- Risk of becoming too sick that a transplant may not be possible.
Ultimately, the transplant physician must determine that the benefits of transplanting a particular patient with an IRD organ are greater than the risks. Otherwise, the patient should continue to wait for an organ from a standard donor.
# 2) CONSIDER USE OF HCV Ab +ve and NAT +ve ORGANS FOR SELECT TRANSPLANT PATIENTS
The HCV Donor Algorithm below outlines how donor organs should be considered for allocation. The Algorithm assumes that HIV NAT and HBV NAT results are also negative. *Risk of transmission may be higher in liver patients (Bari, et al., 2017) Use of HCV NAT positive organs should be considered in the following settings according to the order specified below. HCV NAT negative donors that are currently being treated for HCV or have only recently completed their HCV treatment should also be considered at the same risk level as NAT positive donors.
# HCV Donor Algorithm
- Preferentially use in HCV NAT positive recipients 2. Consider using in clinical trials evaluating the use of HCV NAT positive organs in NAT negative recipients 3. Consider use in selected cases of urgent need and special recipient considerations at the individual physician's discretion Stringent informed consent must be obtained and the availability of appropriate HCV drugs to treat transmission is mandatory. These recipients will be screened and monitored by transplant programs.
# 3) DISCUSSION OF IRD OPTIONS AT TIME OF LISTING
Information on the use of organs from IRDs should be provided to potential recipients at the time of listing and again at the time of offer. The discussion should take place with the transplant physician, although other members of the team may also be involved. The goal of the discussion is to ensure the patient is given the information, support and time needed to understand the option to accept an IRD organ and to make a decision that best reflects the patient's wishes.
The information provided to patients should be accurate and non-leading and the risk should be contextualized in a clear and understandable manner. In the discussion, the transplant physician should ensure, at a minimum, that the patient understands the: Patient benefits of accepting an IRD organ vs. waiting for a standard organ; Risk of acquiring an infectious disease; Support available throughout and after the transplant; Post-transplant monitoring and testing requirements; Impact to wait list status from declining option; The difference between willingness to consider an offer and offer acceptance.
Although a patient may decline this option at the time of listing, this could be reassessed throughout the waiting period and again at the time of offer as the patient's health status may change over time. The patient's decision should be noted in the medical chart and reviewed with the patient on a regular basis.
# 4) RECEIVING OFFER OF ORGAN FROM IRD
Organs from IRDs will be offered to transplant programs via a process of exceptional distribution. TGLN, as source establishment, is permitted to offer exceptionally distributed organs, if the following conditions are met: an organ that has been determined safe for transplantation is not immediately available; the transplant physician authorizes the exceptional distribution; the transplant establishment obtains the informed consent of the recipient.
The organ(s) are distributed to a transplant program based on reasons related to the benefit of the recipient. Organs distributed via exceptional distribution are of a known risk, and adverse event reporting and investigation are not necessitated in the event of any reactions due to this known risk. TGLN will offer the organ(s) as per the allocation algorithm and indicate it as an exceptional distribution case. When making the offer to transplant programs, TGLN will ensure that the transplant physician is aware of the reason(s) for the exceptional distribution.
Exceptional distribution requires the transplant physician to authorize the use of the organ and obtain informed consent from the recipient (see following section). The decision by the transplant physician around utilization or non-utilization may take into account the timing of increased risk behaviour, the window period for the specific test used, the status of the recipient as well as other recipient-specific circumstances.
If the transplant physician decides to accept the IRD organ, TGLN will request and document the transplant physician's justification for accepting the organ in the Notice of Exceptional Distribution form (see Appendix C) and the clinical notes. TGLN will ensure that the TGLN portion of the form is complete and send the form to the transplant program Medical Director where it will be completed and returned to TGLN. TGLN will place a copy of the completed form in the TGLN donor chart.
# 5) OBTAIN INFORMED CONSENT AT TIME OF TRANSPLANT
Obtaining appropriate informed consent for potential recipients of organs from IRDs is essential. The informed consent must be obtained before the transplant takes place. To support the practitioner in providing their patient with accurate and timely information at the time of consent, a Frequently Asked Questions (FAQ) document for IRD and HCV NAT +ve donors have been developed. The information in the FAQ provides an overview of the risk and benefits in utilizing IRD and HCV NAT +ve donor organs.
A recommended template for a standardized informed consent script for IRD and HCV NAT +ve donors that can be read at the time of listing and of offer are provided in the Appendices. This script may be modified as needed to align with hospital specific practices. Standardizing the informed consent process may contribute to an increased utilization of organs.
It is essential to document the informed consent process. Hospital requirements may vary as to the format of documentation in the medical record and hospital specific protocols should be followed. A sample IRD Organ Informed Consent Form and HCV Positive Organ Informed Consent Form are also included in the Appendices.
# 6) FOLLOW-UP TESTING OF TRANSPLANT PATIENT
If organs from IRDs are utilized, post-transplant monitoring and testing of recipients is recommended for early detection of potential transmissions. Since delayed seroconversion may occur, post-transplant screening with NAT for HIV and HCV is recommended along with NAT or HBsAg testing for HBV. A potential proposed algorithm for testing is shown below in Table 5. In the unlikely case that the patient acquires an infection from the IRD organ, the infectious disease specialists should treat the patient as required.
# Suggested IRD Protocol Development Guidelines
Utilization of IRDs may require formal changes to clinical and administrative processes within hospitals, including education of healthcare providers. Every hospital has different processes and procedures to implementing new protocols. The additional and potential use of HCV NAT positive donor organs in a select population of patients should be reconsidered within these protocols. Suggested guidelines for development of IRD protocols are:
- Review hospital based protocol development, approval, and implementation guidelines a. Typically, each hospital has protocol development guidelines. Refer to these prior to initiating the development or revision of existing protocols to ensure the IRD utilization protocol reflects the process required for your facility. b. Consider who should be involved and what the current process is in your hospital to initiate protocol development.
# Identify existing exceptional distribution protocols
a. Locate and review existing protocols on the use of IRDs; determine when the last revisions were completed.
# Review recommended IRD utilization process steps and compare with existing protocols
a. Identify any inconsistencies between existing and recommended process steps. b. Identify any information that may require revisions or changes in practices within the protocols. c. Review sample protocols, which have been provided as guidelines to integrate content requirements.
- Draft protocols to reflect all steps of the process, including the IRD utilization process identified by TGLN a. Draft IRD protocols to reflect donation process steps. b. Incorporate hospital-specific IRD practices.
# Proceed with hospital-specific process for approval and implementation of IRD utilization protocols
a. Follow hospital-specific process for revision, approval, and implementation of IRD protocols.
- Proceed with Steps 1 through 5 above to include hospital-specific process for NAT Testing in IRD, and HCV positive (Ab or NAT) organ recipients based on the approved policy for testing
# Conclusion
One donor can save up to eight lives and improve the lives of up to 75 people. Yet, there is a constant shortage of organs and tissue available for transplantation, and the demand for organs and tissue needed in Ontario continues to exceed the available supply. This document is intended to support transplant physicians and programs in the use of organs from IRDs so that more organ transplants can be given to patients who need them.
The use of organs from IRDs should be performed in a safe and ethical manner. This includes rigorous informed consent of potential recipients and appropriate testing of donors. It is recommended that transplant programs discuss their protocols with hospital senior leadership before finalizing policies to ensure that they are aligned with hospital requirements. Overall, a more standardized approach across Ontario and the rest of Canada should lead to optimized utilization practices and a significant increase in the number of organ transplants.
Patient FAQ -Getting an Organ from an Increased Risk Donor
# WHAT IS AN INCREASED RISK DONOR ORGAN?
This is an organ from a donor who identifies certain lifestyle behaviours that are of higher risk of transmitting infectious diseases to transplant recipients. These donors may test negative for infections, but they may still be a risk for spreading Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), and Hepatitis B Virus (HBV) to transplant patients, due to a window period where the infection(s) cannot be detected from the tests. Organs are considered an increased risk if the donor has identified the following behaviours: persons who have injected non-medical drugs into the blood, muscles, or under the skin in the last 5 years; men who have had sex with another man in the last 12 months; persons who have had sex in exchange for money or drugs in the last 5 years; persons who have had sex with any persons described above or with a person who has or may have HIV, HBV or HCV infection in the last 12 months; persons with a history of intranasal cocaine use in the last 6 months (unless they test HCV NAT negative); persons who have been in contact with the blood and/or bodily fluids of a person who has or may have HIV, HBV, and/ or HCV in the last 12 months; persons who have been in youth correctional facility, jail, or prison for more than 72 hours in the last 12 months; persons with a tattoo or piercing where sterile procedures were not used in the last 12 months; and, persons who have had close contact with another person having clinically active viral hepatitis (e.g., living in the same house where kitchen and bathroom are shared) in the last 12 months.
You might be offered an organ from a deceased donor that has an increased risk of passing on infections, such as HIV, HBV, and HCV. You will be informed if this is an increased risk organ when it is offered to you.
# WHAT IS THE DIFFERENCE BETWEEN AN ORGAN FROM AN INCREASED RISK DONOR AND ONE FROM A STANDARD DONOR?
The increased risk from the donor does not affect how well the organ will work. It means that the donor engaged in activities before their death that increase the chances of having an infection. All donors are screened for infectious diseases. This includes testing for HIV, Hepatitis B, and Hepatitis C. Even with negative test results, there is still a very small chance that an organ from an increased risk donor has an infection such as HIV or Hepatitis. There are treatments available for these diseases but they are not curable.
On average, increased risk donors tend to be of younger age with better organ function.
# WHY WOULD I THINK ABOUT ACCEPTING AN ORGAN FROM AN INCREASED RISK DONOR?
Deciding to accept an organ from an IRD may increase your chance of getting a transplant. These are the facts: There is a constant shortage of organs and tissue that can be used for transplant. There are nearly 1,500 Ontarians waiting to get life-saving organ transplants. Every three days, someone dies while waiting for an organ transplant. The waiting times for organ transplants can be up to several years depending on the organ.
You will only be offered an increased risk organ if a transplant doctor at your hospital feels that the benefits of transplanting you with the organ are greater than the risk. Otherwise the organ will not be offered to you. A transplant doctor will speak to you about the risks and benefits of accepting the increased risk organ versus waiting for another organ.
# HOW WILL I KNOW IF I DEVELOP AN INFECTION?
If you decide to accept the organ, you will be monitored after your transplant to be sure that you did not get an infection. In the unlikely case that you do get an infection, treatments are available. The infectious disease doctors will treat you, if needed.
# WHO DECIDES IF I SHOULD ACCEPT AN INCREASED RISK ORGAN?
The decision to accept the increased risk organ is YOURS. The right choice for you depends on the state of your health. You need to talk about this with your medical team and all your doctors. The best answer for you may change if the state of your health changes.
If you have questions about organs from IRDs, talk with a member of your healthcare team while you are waiting for your transplant. If you are offered an organ from an increased risk donor, it will be helpful to have already thought about this information.
# IF I DO NOT AGREE TO ACCEPT AN INCREASED RISK ORGAN, WILL IT HURT MY CHANCES OF GETTING A STANDARD ORGAN?
No. Everyone has a different level of how much risk they are willing to accept for themselves. The decision to accept the organ is yours. If you decide NOT to accept the organ, you will NOT lose your place on the waiting list.
You will only be offered the consideration of an HCV positive organ if a transplant doctor at your hospital has identified you in one of the three categories of patients listed above, you have consented, and appropriate HCV drugs to treat transmission are available.
Otherwise, the organ will not be offered to you. A transplant doctor will speak to you about the risks and benefits of accepting the HCV positive donor organ versus waiting for another organ.
# E. WHAT ARE THE RISKS OF RECEIVING AN HCV POSITIVE ORGAN AND HOW WILL I KNOW IF I DEVELOP AN INFECTION?
In the case of HCV NAT positive donors, if you decide to accept the organ, there is a 100% chance you will get HCV. The infectious disease doctors in partnership with the transplant physicians will treat you accordingly based on the access to drug coverage and perform regular blood tests.
# F. WHO DECIDES IF I SHOULD ACCEPT AN HCV POSITIVE ORGAN?
The decision to accept the HCV positive organ is YOURS. The right choice for you depends on the state of your health. You need to talk about this with your medical team and all your doctors. The best answer for you may change if the state of your health changes.
If you have questions, talk with a member of your healthcare team while you are waiting for your transplant.
If you are offered an HCV positive organ from a donor, it is because you consented to consider this type of organ at the time of listing.
# G. IF I DO NOT AGREE TO ACCEPT AN HCV POSITIVE DONOR ORGAN, WILL IT HURT MY CHANCES OF GETTING A STANDARD ORGAN?
No. Everyone has a different level of how much risk they are willing to accept for themselves. The decision to accept the organ is yours. If you decide NOT to accept the organ, you will NOT lose your place on the waiting list.
# Appendix A: CTO Regulations for Exceptional Distribution
CTO Regulations: Exceptional Distribution 40. A source establishment may distribute cells, tissues or organs that have not been determined safe for transplantation if all of the following conditions are met:
(a) a cell, tissue or organ that has been determined safe for transplantation is not immediately available; (b) the transplant physician or dentist, based on their clinical judgment, authorizes the exceptional distribution; and (c) the transplant establishment obtains the informed consent of the recipient. 41. (1) A source establishment that distributes cells, tissues or organs under section 40 must keep a copy of the notice of exceptional distribution in its records.
(2) The transplant establishment must keep a copy of the notice of exceptional distribution in its records.
(3) A notice of exceptional distribution must contain all of the following information:
(a) the name of the transplanted cell, tissue or organ; (b) the provisions of these Regulations with which the cell, tissue or organ is not in compliance at the time of its distribution; (c) the justification for the distribution that formed the basis for the transplant physician's or dentist's decision to authorize it; (d) the name of the source establishment that distributed the cell, tissue or organ;
(e) the name of the transplant establishment and of the transplant physician or dentist who authorized the distribution; and (f) the time and date of the written authorization of the distribution and a copy of the authorization signed by the transplant physician or dentist. 42. A source establishment that distributes a cell, tissue or organ under section 40 before the donor suitability assessment is complete must, after the distribution, complete the assessment, carry out any other appropriate follow-up testing and notify the relevant transplant establishment of the results.
Source: Safety of Human Cells, Tissues and Organs for Transplantation Regulations, 2015.
# Appendix B: Individual NAT Testing Algorithm
# Appendix C: Notice of Exceptional Distribution Form
# Appendix D: Patient FAQ on Getting an Organ from an IRD
The information in the following FAQ should be provided to the patient at the time of transplant assessment or listing and can also be used at the time of offer to ensure understanding of the risks and benefits of accepting an IRD organ. Patient FAQs, scripts, and forms for getting an HCV Ab+ or HCV NAT +ve donor organ follow in the next section.
# Appendix E: Template for Standardized Informed Consent Script for IRD Organs
The following script may be read, as written, to the patient at the time of the organ offer. The patient should be encouraged to ask questions to ensure that s/he understands and appreciates the content. The patient must verbally confirm that he/she is accepting this offer. The patient's affirmation should be documented in the patient's chart as applicable. Please see Appendix G to I for the patient FAQ, script, and form for getting an HCV NAT +ve donor organ.
# Script for Obtaining Informed Consent
You are being offered an organ from a deceased donor that the Canadian Standards Association guidelines defines as being at increased risk for transmitting infections, such as HIV, HBV, and HCV. There is always some risk with every donor. Please think back to discussions you have had about the risks in accepting an organ. The increased risk does not affect how well the organ works. Instead, we mean that this donor engaged in behaviors before their death that increase their chances of having an infection. You need to balance the slightly increased risk of accepting this organ with the likely benefits of being transplanted at this time instead of waiting for another organ. This donor has already had two types of screening for infections. They had required testing for HIV, hepatitis B, and Hepatitis C. They also had special testing for HIV, Hepatitis C, and Hepatitis B. All of the NAT test results were negative. Even with negative test results, there is still a very small chance that this donor has an infection such as HIV or hepatitis.
Based on information on similar donors with the same behaviors and negative test results, your risk of getting an infection may be in the range of: (only read statistics pertaining to this donor's specific behavior from Table 2, and Table 3. It is not necessary to name the behaviour, only the level of risk. If the donor has tested HCV antibody positive and NAT negative and all history is unknown, or there are no high risk behaviours, read out the highest risk rate which is IV Drug Use (liver patients are exceptions, who may be a higher risk).
A transplant physician at your hospital has carefully looked at information about this donor. She/he recommends that you consider this organ. In his/her opinion, the potential benefits of accepting the organ outweigh the risks of getting an infection from this donor. If you decide to accept this organ, you will be monitored after your transplant to be sure that you did not get an infection. IF you get an infection, treatments are available. The infectious disease doctors will treat you, if needed. Everyone has a different level of how much risk they are willing to accept for themselves The decision to accept this organ is yours. If you decide NOT to accept the organ, you will not lose your place on the waiting list.
# Do you have any questions?
Additional points may be discussed with the patient depending on type of transplant (e.g. kidney vs. non-kidney) and other factors. These points include: 1. Estimated time the patient may be on the wait list if he/she waits until the next offer 2. Estimated wait-list mortality if he/she waits until the next offer 3. Risk of becoming so sick a transplant may not be possible Note: A separate standardized informed consent template may be needed for kidney vs. non-kidney recipients given the availability of dialysis for support of end stage renal failure patients. Increased Risk Donor (IRD) organs may not meet the strict criteria of a standard organ donor.
# Appendix F: Sample IRD Organ Informed Consent Form
IRDs identify certain lifestyle behaviors that are of an increased risk of spreading illnesses to patients compared to standard donors.
Please take your time to make your decision about accepting an IRD organ. Feel free to ask questions.
Patient Sign-Off I, the undersigned, have been informed about the purpose, procedures, possible benefits and risks of accepting an IRD organ, and I have received a copy of this informed consent document. I have been given the opportunity to ask questions and I have been told that I can ask questions in the future. All my questions have been answered to my satisfaction. As a representative of this transplant program, I have explained the purpose, the procedures, the possible benefits and the risks that are involved with an organ from an Increased Risk Donor (IRD). Any questions that have been raised have been answered to the best of my knowledge. You are waiting for an organ transplant Your doctor feels that you will benefit from having an IRD organ. An IRD organ may allow you to be transplanted sooner, rather than waiting a longer period of time for a standard criteria organ.
# Appendix G: Patient FAQ on Getting an Organ from a HCV NAT Positive Donor or HCV Antibody Positive (with Recent Antiviral Treatment)
The information in the following FAQ should be provided to the patient at the time of transplant assessment or listing and can be used again at the time of offer to ensure understanding of the risks and benefits of accepting a Hepatitis C Virus (HCV) NAT positive organ.
# WHAT DETERMINES AN HCV POSITIVE ORGAN?
Hepatitis C is a virus that enters through a person's blood stream and can affect the liver. This is an organ from a donor who has tested negative for Human Immunodeficiency Virus (HIV), and Hepatitis B Virus (HBV) and fits one of the following two profiles:
A. HCV antibody positive, NAT negative results with recent or unknown history of treatment:
The donor is currently on HCV treatment, less than 12 weeks have elapsed since completion of HCV treatment, or HCV treatment history is unknown.
# B. Donor NAT test results are positive for HCV
A patient may be asked to consider an organ from a deceased donor that is HCV NAT positive by either of the above definitions if they fit into one of the following categories:
1) HCV NAT positive recipient 2) Participant in clinical trials for HCV NAT negative recipients 3) Selected cases and special recipient considerations
The risk of transmission from a donor who tested HCV NAT positive is 100%.
# C. WHAT IS THE DIFFERENCE BETWEEN AN HCV POSITIVE ORGAN AND A STANDARD DONOR ORGAN?
An organ that comes from an HCV positive donor does not affect how well the organ will work (however, the risk of transmission may be higher for liver recipients). The difference is that by receiving an HCV positive organ, a treatment protocol will be required. The evidence shows that HCV treatments are effective in 95-99% of the HCV population (Feld, et al., 2015;Levitsky, et al., 2017). New therapies called direct acting antivirals (DAAs) are pills that act on the virus itself to get rid of it from the body.
The new treatment requires a shorter time (between 8 to 24 weeks), has reduced side effects, and appears to be effective at all stages of the disease.
After your surgery, an infectious disease physician or hepatologist may also be involved in your care and you will require some additional blood work at 2 weeks, 6 weeks, 1 month, 3 months, and 1 year to track the Hepatitis C virus in your blood. All other care and the transplant surgery will be the same.
# D. WHY WOULD I THINK ABOUT ACCEPTING AN HCV POSITIVE ORGAN?
Deciding to accept an organ from an HCV positive donor may increase your chance of getting a transplant. These are the facts: There is a constant shortage of organs and tissue that can be used for transplant. There are nearly 1,500 Ontarians waiting to get life-saving organ transplants. Every three days, someone dies while waiting for an organ transplant. The waiting times for organ transplants can be up to several years depending on the organ.
# Appendix H: Template for Standardized Informed Consent Script for HCV Antibody Positive (with Recent Antiviral Treatment) and HCV NAT Positive Donor Organs
The following script may be read, as written, to the patient at the time of the organ listing and again at offer. Please note that once a patient has consented and the program has accepted the organ, the "Notice of Exceptional Distribution" will still need to be completed. The patient should be encouraged to ask questions to ensure that s/he understands and appreciates the content. The patient must verbally confirm that he/she is accepting this offer. The patient's affirmation should be documented in the patient's chart as applicable.
# Script for Obtaining Informed Consent
You are being offered an organ from a deceased donor that has tested positive for the Hepatitis C Virus (HCV). We look at the combination of two types of testing and the history of any recent treatments for HCV in the donor to determine whether the donor organ classifies as HCV+. If you get HCV, treatments are available and the infectious disease doctors will treat you if needed.
The results for this donor indicate they are negative for HIV and HBV, and are (choose 1 of the following): a) Considered HCV positive due to a positive HCV NAT result b) Considered HCV positive due to a recent history of HCV antiviral treatment in the donor and a positive HCV antibody result You are being considered to receive an organ from a deceased donor who is HCV positive because you fit one of the following categories: 1. HCV NAT positive recipient 2. Participant in a clinical trial for HCV NAT negative recipients 3. Selected cases and special recipient considerations
There is always some risk with every donor and the risk of transmission may be higher in liver patients (Bari, et al., 2017). You need to balance the risk of accepting this organ with the likely benefits of being treated effectively post-transplant instead of waiting for another organ.
A transplant physician at your hospital has carefully looked at information about this donor. She/he recommends that you consider this organ. In his/her opinion, the potential benefits of accepting the organ outweigh the risks of getting an infection from this donor. If you decide to accept this organ, you will be monitored after your transplant for your viral status. The hepatologist or infectious disease doctors will treat you if needed. Everyone has a different level of how much risk they are willing to take. The decision to accept this organ is yours. If you decide NOT to accept the organ, you will not lose your place on the waiting list.
# Do you have any questions?
Additional points may be discussed with the patient depending on type of transplant (e.g. kidney vs. non-kidney) and other factors. These points include: 1. Estimated time the patient may be on the wait list if he/she waits until the next offer 2. Estimated wait-list mortality if he/she waits until the next offer 3. Risk of becoming so sick a transplant may not be possible Note: A separate standardized informed consent template may be needed for kidney vs. non-kidney recipients given the availability of dialysis for support of end stage renal failure patients. HCV positive organs may not meet the strict criteria of a standard organ donor. The donor organ has tested either HCV Nucleic Acid Testing (NAT) positive OR HCV antibody (Ab) positive with a history of recent or unknown treatment.
Please take your time to make your decision about accepting an HCV donor organ. Feel free to ask questions.
Patient Sign-Off I, the undersigned, have been informed about the purpose, procedures, possible benefits and risks of accepting an HCV positive donor organ, and I have received a copy of this informed consent document. I have been given the opportunity to ask questions and I have been told that I can ask questions in the future. All my questions have been answered to my satisfaction.
Yes, I am willing to accept an organ from an HCV Antibody (Ab) positive, NAT negative donor with a history of recent or unknown treatment Yes, I am willing to accept an organ from an HCV NAT positive donor You are waiting for an organ transplant Your doctor feels that you will benefit from having an HCV donor organ. An HCV donor organ may allow you to be transplanted sooner, rather than waiting a longer period of time for a standard criteria organ.
# Glossary of Terms
HCV Antibody Test: A blood test that detects antibodies to Hepatitis C Virus (HCV) in the blood and identifies if HCV is currently in the blood or was in the blood in the past. The HCV Antibody Test cannot determine if the infection is acute or long-term (chronic).
Canadian National Transplant Research Program: a national initiative designed to increase organ and tissue donation in Canada and enhance the survival and quality of life of Canadians who receive transplants.
Canadian Society of Transplantation: the professional organization for physicians, surgeons, scientists and allied health professionals dedicated to leading, advancing, and advocating for patient care, research, and education in donation and transplantation in Canada.
Canadian Standards Association: a not-for-profit standards organization which develops and published standards in a variety of areas and provides training and advisory services.
Direct Acting Antivirals (DAA): Direct Acting Antivirals are Hepatitis C Virus (HCV) treatments that are made up of different combinations of drugs and target the virus in the blood.
Exceptional Distribution: the process and conditions under sections 40 to 42 of the CTO regulations whereby a source establishment may distribute cells, tissues or organs that have not been determined safe for transplantation.
Enzyme-Linked Immunosorbent Assay (ELISA): is a common laboratory technique which is used to measure the concentration of an analyte (usually antibodies or antigens) in solution.
Hepatitis B Virus (HBV): a DNA virus belonging to the Hepadnaviridae family of viruses. The virus causes the disease hepatitis B, a viral infection that attacks the liver and can cause both acute and chronic disease.
Hepatitis C Virus (HCV): a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The virus causes the disease Hepatitis C, a bloodborne virus that can cause both acute and chronic hepatitis infection.
Human Immunodeficiency Virus (HIV): a retrovirus that infects cells of the immune system, destroying or impairing their function.
Increased Risk Behaviour: certain lifestyle behaviours that are of higher risk of transmitting infectious diseases to transplant recipients.
Increased Risk Donor (IRD): organ or tissue donor who identifies certain lifestyle behaviours that meet the criteria for being a higher risk of transmitting infectious diseases to transplant recipients.
Informed Consent: process for getting permission before conducting a healthcare intervention on a person.
Nucleic Acid Testing (NAT): a molecular technique used to detect a virus or a bacterium. It detects viruses earlier than other screening methods; thus, narrowing the detection window period.
# Public Health Ontario Laboratory (PHOL):
The provincial laboratory of Public Health Ontario (PHO), which is a governing body who strives to prevent illness and improve health through scientific evidence and expert guidance that shapes policy and practices in Ontario. There are 11 laboratory sites in Ontario.
Residual Risk: the risk of infectious disease transmission when the screening test is negative.
Serology: a blood test to detect serum antibodies or antibody-like substances that appear specifically in association with certain diseases.
Source Establishment: entity responsible for the processing of cells, tissues and organs, whether the processing is carried out by the source establishment itself or by another establishment, and for determining whether the cells, tissues and organs are safe for transplantation.
# Sustained Virologic Response (SVR):
When the Hepatitis C Virus (HCV) is not detected in the blood after a certain amount of time (12 weeks) after completing treatment, sustained virologic response (SVR) is achieved.
Trillium Gift of Life Network (TGLN): a not-for-profit agency of the Government of Ontario that plans, promotes, coordinates and supports organ and tissue donation and transplantation across Ontario.
Window Period: the time between first infection and when a test can reliably detect that infection.
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# Increased Risk Donor Toolkit
# Toolkit Purpose
This toolkit was developed to summarize recommendations on the use of Increased Risk Donors (IRDs) for organ transplantation as well as to provide useful information and guidance that could help Ontario increase organ utilization and improve access to organ transplantation for patients. It is intended for use by transplant physicians, hospital administration and transplant programs who are directly or indirectly involved with patient care in a transplant setting. This toolkit includes recommended tools and templates to support transplant programs in providing information to patients on the use of increased risk donors for transplantation.
The objectives of this toolkit are to: Educate all healthcare providers along the transplant continuum about IRDs; Provide guidance to healthcare administrators about incorporating IRDs into their clinical and administrative processes; Provide information to healthcare providers to educate patients about IRDs; Provide tools to support informed patient consent at the time of transplant.
# Toolkit Development Process
In March 2013, the Canadian Society of Transplantation (CST) and the Canadian National Transplant Research Program (CNTRP) held a conference and developed a framework guidance document that outlines recommendations for utilization of IRDs in Canada. The conference included experts from Canada in organ and tissue donation and transplantation, transplant infectious diseases, laboratory medicine, and epidemiology. Additional content expertise was provided by Health Canada, several major Canadian Organ Procurement Organizations (OPOs), and Canadian Blood Services (CBS). This toolkit is based on the recommendations developed by the CST/CNTRP Increased Risk Donor Working Group (2014) published in the journal Transplantation (CST/CNTRP Increased Risk Donor Working Group, 2014).
The process for the development of this toolkit included: Detailed review of CST and CNTRP recommendations; Literature research on current practices; Review of TGLN policies and procedures; Consultation sessions with transplant medical leads;
In 2017, TGLN's Infectious Disease Lead, Dr. Atul Humar, presented an algorithm that would increase the utilization of Hepatitis C Virus (HCV) positive organs based on new evidence on the efficacy of treatments for HCV (Feld, et al., 2015). Based on consensus from the Organ Specific Working Group representatives to move forward with the new algorithm, amendments to this version of the toolkit have been made to address the utilization of both HCV antibody positive, Nucleic Acid Testing (NAT) negative and HCV NAT positive donors in select populations.
# Introduction to Increased Risk Donors
# What is an Increased Risk Donor?
Increased Risk Donors (IRDs) are donors who may or may not test positive for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), and HCV and/or identify certain lifestyle behaviours that are of higher risk who may transmit infectious diseases to transplant recipients. Donors who test negative for HIV, HBV, or HCV are still at risk for transmitting HIV, HCV, or HBV to recipients, due to a window period of time where the infection(s) is not detectable.
For the purpose of classification, the risk profile for HCV antibody positive, NAT negative donors who also have NAT negative results for HIV and HBV is similar to those who test negative for infections but identify with certain lifestyle behaviours. The risk associated with this donor profile is low due to treatment or spontaneous clearance, as evidenced by the NAT method, which is more specific and yields results earlier than other tests (Maylin, et al., 2008). Some exceptions to this may occur in the setting of liver transplant from donors who are HCV antibody positive / NAT negative.
For more information on NAT, see Section 3.1.2 and "The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation" in the American Journal of Transplantation (Levitsky, et al., 2017).
# Donation Protocols for Increased Risk Donors
TGLN is responsible for determining the safety of deceased organs for transplantation through donor screening, donor testing, and donor suitability assessment as per the Health Canada requirements for the Safety of Human Cells, Tissues, and Organs for Transplantation regulations (CTO regulations). All persons are considered to be a potential organ donor, regardless of age, health status, or social behavior. Potential donors that are referred to TGLN are assessed on an individual basis and go through a screening process as well as medical suitability testing to determine if organs are safe for transplantation. As part of the screening process, the family and/or close friends of every potential donor is asked a series of detailed questions about the social medical history of their loved one, and the donor's lifestyle is considered to assess the potential for the transmission of infectious disease to the recipient. Potential donors with identified increased risk behaviors may be eligible to donate, via a process of "exceptional distribution". Exceptional distribution is permitted if another standard organ is not immediately available, and the transplant physician has authorized the use of the organ based on their clinical judgment. The transplant program communicates the risk to the potential recipient so they can make an informed decision about whether to consent to accepting the offered organ.
The CTO regulations relating to exceptional distribution can be found in Appendix A.
# Criteria for Increased Risk Behaviour
Behavioural risk factors for HIV, HCV and HBV are assessed by a history and physical examination of the donor. Table 1 outlines the behaviours that are considered increased risk by the Canadian Standards Association. or with a person known or suspected to have HIV, or clinically active HBV or clinically active HCV; f) persons who have been exposed, in the preceding 12 months*, to known or suspected HIV-, HBV-, and/or HCV-infected blood through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane; g) persons who have been in youth correctional facility, jail, or prison for more than 72 consecutive hours in the preceding 12 months; h) persons who within 12 months* preceding donation have undergone tattooing, ear piercing, or body piercing in which sterile procedures were not used (e.g., contaminated instruments and/or ink were used, or shared instruments that had not been sterilized between uses were used); and i) persons who have had close contact within 12 months preceding donation with another person having clinically active HBV or clinically active HCV infection (e.g., living in the same household, where sharing of kitchen and bathroom facilities occurs regularly). * The 12 month period specified in Items f) and h) may be reduced to 6 months if nucleic acid testing (NAT) is used for the detection of HIV, HBV, and HCV.
# E.2:
The assessment of donors less than 11 years of age shall include the following risk factors and risk behaviours associated with HIV, HBV, and HCV: a) persons who have been exposed, in the preceding 12 months*, to known or suspected HIV-, HBV-, and/or HCV-infected blood through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane; b) persons who within 12 months* of donation have undergone tattooing, ear piercing, or body piercing in which sterile procedures were not used (e.g., contaminated instruments and/or ink were used, or shared instruments that had not been sterilized between uses were used); c) persons who have had close contact within 12 months preceding donation with another person having clinically active viral hepatitis (e.g., living in the same household, where sharing of kitchen and bathroom facilities occurs regularly); d) persons who have been breastfed within the past 12 months † of donation by women with or a risk for HIV, HBV, and/or HCV; and e) persons less than 18 months of age who are born to women with or at risk for HIV, HBV, and/or HCV infection. * The 12 month period specified in Items a) and b) may be reduced to 6 months if NAT is used for the detection of HIV-1, HBV, and HCV. † It is only necessary to assess donors less than five years of age against the criteria in Item d).
Source: Canadian Standards Association, 2017.
# Risk Assessment of Increased Risk Donor Organs
# Infectious Disease Testing
# General Donor Testing Requirements
In order to evaluate the safety of organs for transplantation, TGLN facilitates infectious disease testing for all potential donors. STAT pre-transplant serological testing is required for:
human immunodeficiency virus I/II (HIV I/II); human T-cell lymphotropic virus (HTLV I/II); venereal disease research lab test (VDRL); hepatitis B surface antigen (HBsAg); hepatitis C virus (HCV); antibody to hepatitis B core antigen (anti-HBcAb); cytomegalovirus (CMV); and, West Nile virus (WNV) between May to October.
Additionally, retrospective (non-STAT) testing is required for: Epstein Barr virus (EBV); Toxoplasmosis IgG (toxo) for all potential heart donors For pediatric cases, maternal serology is required if the potential pediatric donor is ≤ 18 months of age and/or has been breast-fed within the last 12 months.
Test results are documented in the TGLN donor chart and reported to the appropriate transplant program(s) at the time of offer. Positive results do not automatically preclude donation as exceptional distribution may be considered. If the potential donor is assessed as being an increased risk, Nucleic Acid Testing (NAT) should be performed in addition to the required pre-transplant STAT serological testing.
# Nucleic Acid Testing
NAT is a method of testing for diseases in an individual's blood and it is the recommended method of infectious disease testing for living and deceased donors. It detects viruses earlier than other screening methods; thus, narrowing the detection window period of HIV, HCV, and HBV infections. Figure 1 below outlines the difference in pathogen detection window periods between serology and NAT testing methods. NAT aims to reduce the risk to the recipients in contracting diseases from organs that are recovered from deceased organ donors; in particular those donors that have been identified as having increased risk behavior. In general, NAT should be performed on deceased organ donors in circumstances where a decision is made to use exceptional distribution protocols from a donor with a history of increased risk behavior.
TGLN has implemented a process for requesting NAT testing for donors with confirmation of increased risk criteria having occurred as per Health Canada guidelines, especially if increased risk behaviors have occurred within the serology window period. Additionally, NAT should be requested for donors for which there is no way to confirm whether or not increased risk criteria has occurred in serology testing window period and who also have physical evidence of recent risk exposure. The process for requesting individual NAT testing based on the patient assessment can be found in Appendix B.
# Risk of Infection from Increased Risk Donor Organs
The potential risk for transmission of an infectious disease is the most important consideration in conducting a risk vs. benefit analysis when organs from IRDs become available. Residual risk estimates have been published based primarily on U.S. epidemiologic data. A systematic review of prevalence and incidence studies was conducted to determine the risk in a Canadian population (CST/CNTRP Increased Risk Donor Working Group, 2014).
Estimates of residual risk are provided in Tables 2 and Table 3 below per 10,000 donors if enzyme-linked immunosorbent assay (ELISA) or NAT is used for screening. Furthermore, the estimate is converted to a ratio to provide a number that can be more easily conveyed to patients during the informed consent process. Risk estimates assume the behaviour(s) occurred right up until the moment of donation. Additional factors may need to be considered when determining the actual risk to the patient, such as length of hospitalization prior to donation with risk generally decreasing as duration of hospitalization increases. The diagram below shows the recommended sequence of activities in the IRD organ utilization process. Information and guidance on each of the activities are outlined in the following section.
# Guidance for Increased Risk Donor Organ Utilization 1) CONSIDER USE OF IRD ORGANS FOR SELECT TRANSPLANT PATIENTS
The number of organs and tissue needed in Ontario continues to be higher than the number available. When determining the risks vs. benefits of an organ from an IRD, physicians should consider the following facts: There is a shortage of organs and tissue that can be used for transplant; There are nearly 1,500 Ontarians waiting to get life-saving organ transplants; Every three days, someone dies while waiting for an organ transplant; The waiting times for organ transplants can be up to several years depending on the organ.
Given the significant discrepancy between donor organ supply and demand, the use of organs from IRDs should be considered for some patients. Using these organs offers an opportunity for shortening wait times while providing good outcomes. Furthermore, utilizing NAT testing during the screening process can further reduce the risk of disease transmission.
Physicians should consider the following factors when identifying potential candidates for organ transplant from an IRD: 1. Estimated time the patient may be on the wait list if he/she waits until the next offer.
2. Estimated wait-list mortality if he/she waits until the next offer.
3. Risk of becoming too sick that a transplant may not be possible.
Ultimately, the transplant physician must determine that the benefits of transplanting a particular patient with an IRD organ are greater than the risks. Otherwise, the patient should continue to wait for an organ from a standard donor.
# 2) CONSIDER USE OF HCV Ab +ve and NAT +ve ORGANS FOR SELECT TRANSPLANT PATIENTS
The HCV Donor Algorithm below outlines how donor organs should be considered for allocation. The Algorithm assumes that HIV NAT and HBV NAT results are also negative. *Risk of transmission may be higher in liver patients (Bari, et al., 2017) Use of HCV NAT positive organs should be considered in the following settings according to the order specified below. HCV NAT negative donors that are currently being treated for HCV or have only recently completed their HCV treatment should also be considered at the same risk level as NAT positive donors.
# HCV Donor Algorithm
1. Preferentially use in HCV NAT positive recipients 2. Consider using in clinical trials evaluating the use of HCV NAT positive organs in NAT negative recipients 3. Consider use in selected cases of urgent need and special recipient considerations at the individual physician's discretion Stringent informed consent must be obtained and the availability of appropriate HCV drugs to treat transmission is mandatory. These recipients will be screened and monitored by transplant programs.
# 3) DISCUSSION OF IRD OPTIONS AT TIME OF LISTING
Information on the use of organs from IRDs should be provided to potential recipients at the time of listing and again at the time of offer. The discussion should take place with the transplant physician, although other members of the team may also be involved. The goal of the discussion is to ensure the patient is given the information, support and time needed to understand the option to accept an IRD organ and to make a decision that best reflects the patient's wishes.
The information provided to patients should be accurate and non-leading and the risk should be contextualized in a clear and understandable manner. In the discussion, the transplant physician should ensure, at a minimum, that the patient understands the: Patient benefits of accepting an IRD organ vs. waiting for a standard organ; Risk of acquiring an infectious disease; Support available throughout and after the transplant; Post-transplant monitoring and testing requirements; Impact to wait list status from declining option; The difference between willingness to consider an offer and offer acceptance.
Although a patient may decline this option at the time of listing, this could be reassessed throughout the waiting period and again at the time of offer as the patient's health status may change over time. The patient's decision should be noted in the medical chart and reviewed with the patient on a regular basis.
# 4) RECEIVING OFFER OF ORGAN FROM IRD
Organs from IRDs will be offered to transplant programs via a process of exceptional distribution. TGLN, as source establishment, is permitted to offer exceptionally distributed organs, if the following conditions are met: an organ that has been determined safe for transplantation is not immediately available; the transplant physician authorizes the exceptional distribution; the transplant establishment obtains the informed consent of the recipient.
The organ(s) are distributed to a transplant program based on reasons related to the benefit of the recipient. Organs distributed via exceptional distribution are of a known risk, and adverse event reporting and investigation are not necessitated in the event of any reactions due to this known risk. TGLN will offer the organ(s) as per the allocation algorithm and indicate it as an exceptional distribution case. When making the offer to transplant programs, TGLN will ensure that the transplant physician is aware of the reason(s) for the exceptional distribution.
Exceptional distribution requires the transplant physician to authorize the use of the organ and obtain informed consent from the recipient (see following section). The decision by the transplant physician around utilization or non-utilization may take into account the timing of increased risk behaviour, the window period for the specific test used, the status of the recipient as well as other recipient-specific circumstances.
If the transplant physician decides to accept the IRD organ, TGLN will request and document the transplant physician's justification for accepting the organ in the Notice of Exceptional Distribution form (see Appendix C) and the clinical notes. TGLN will ensure that the TGLN portion of the form is complete and send the form to the transplant program Medical Director where it will be completed and returned to TGLN. TGLN will place a copy of the completed form in the TGLN donor chart.
# 5) OBTAIN INFORMED CONSENT AT TIME OF TRANSPLANT
Obtaining appropriate informed consent for potential recipients of organs from IRDs is essential. The informed consent must be obtained before the transplant takes place. To support the practitioner in providing their patient with accurate and timely information at the time of consent, a Frequently Asked Questions (FAQ) document for IRD and HCV NAT +ve donors have been developed. The information in the FAQ provides an overview of the risk and benefits in utilizing IRD and HCV NAT +ve donor organs.
A recommended template for a standardized informed consent script for IRD and HCV NAT +ve donors that can be read at the time of listing and of offer are provided in the Appendices. This script may be modified as needed to align with hospital specific practices. Standardizing the informed consent process may contribute to an increased utilization of organs.
It is essential to document the informed consent process. Hospital requirements may vary as to the format of documentation in the medical record and hospital specific protocols should be followed. A sample IRD Organ Informed Consent Form and HCV Positive Organ Informed Consent Form are also included in the Appendices.
# 6) FOLLOW-UP TESTING OF TRANSPLANT PATIENT
If organs from IRDs are utilized, post-transplant monitoring and testing of recipients is recommended for early detection of potential transmissions. Since delayed seroconversion may occur, post-transplant screening with NAT for HIV and HCV is recommended along with NAT or HBsAg testing for HBV. A potential proposed algorithm for testing is shown below in Table 5. In the unlikely case that the patient acquires an infection from the IRD organ, the infectious disease specialists should treat the patient as required.
# Suggested IRD Protocol Development Guidelines
Utilization of IRDs may require formal changes to clinical and administrative processes within hospitals, including education of healthcare providers. Every hospital has different processes and procedures to implementing new protocols. The additional and potential use of HCV NAT positive donor organs in a select population of patients should be reconsidered within these protocols. Suggested guidelines for development of IRD protocols are:
1. Review hospital based protocol development, approval, and implementation guidelines a. Typically, each hospital has protocol development guidelines. Refer to these prior to initiating the development or revision of existing protocols to ensure the IRD utilization protocol reflects the process required for your facility. b. Consider who should be involved and what the current process is in your hospital to initiate protocol development.
# Identify existing exceptional distribution protocols
a. Locate and review existing protocols on the use of IRDs; determine when the last revisions were completed.
# Review recommended IRD utilization process steps and compare with existing protocols
a. Identify any inconsistencies between existing and recommended process steps. b. Identify any information that may require revisions or changes in practices within the protocols. c. Review sample protocols, which have been provided as guidelines to integrate content requirements.
4. Draft protocols to reflect all steps of the process, including the IRD utilization process identified by TGLN a. Draft IRD protocols to reflect donation process steps. b. Incorporate hospital-specific IRD practices.
# Proceed with hospital-specific process for approval and implementation of IRD utilization protocols
a. Follow hospital-specific process for revision, approval, and implementation of IRD protocols.
6. Proceed with Steps 1 through 5 above to include hospital-specific process for NAT Testing in IRD, and HCV positive (Ab or NAT) organ recipients based on the approved policy for testing
# Conclusion
One donor can save up to eight lives and improve the lives of up to 75 people. Yet, there is a constant shortage of organs and tissue available for transplantation, and the demand for organs and tissue needed in Ontario continues to exceed the available supply. This document is intended to support transplant physicians and programs in the use of organs from IRDs so that more organ transplants can be given to patients who need them.
The use of organs from IRDs should be performed in a safe and ethical manner. This includes rigorous informed consent of potential recipients and appropriate testing of donors. It is recommended that transplant programs discuss their protocols with hospital senior leadership before finalizing policies to ensure that they are aligned with hospital requirements. Overall, a more standardized approach across Ontario and the rest of Canada should lead to optimized utilization practices and a significant increase in the number of organ transplants.
Patient FAQ -Getting an Organ from an Increased Risk Donor
# WHAT IS AN INCREASED RISK DONOR ORGAN?
This is an organ from a donor who identifies certain lifestyle behaviours that are of higher risk of transmitting infectious diseases to transplant recipients. These donors may test negative for infections, but they may still be a risk for spreading Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), and Hepatitis B Virus (HBV) to transplant patients, due to a window period where the infection(s) cannot be detected from the tests. Organs are considered an increased risk if the donor has identified the following behaviours: persons who have injected non-medical drugs into the blood, muscles, or under the skin in the last 5 years; men who have had sex with another man in the last 12 months; persons who have had sex in exchange for money or drugs in the last 5 years; persons who have had sex with any persons described above or with a person who has or may have HIV, HBV or HCV infection in the last 12 months; persons with a history of intranasal cocaine use in the last 6 months (unless they test HCV NAT negative); persons who have been in contact with the blood and/or bodily fluids of a person who has or may have HIV, HBV, and/ or HCV in the last 12 months; persons who have been in youth correctional facility, jail, or prison for more than 72 hours in the last 12 months; persons with a tattoo or piercing where sterile procedures were not used in the last 12 months; and, persons who have had close contact with another person having clinically active viral hepatitis (e.g., living in the same house where kitchen and bathroom are shared) in the last 12 months.
You might be offered an organ from a deceased donor that has an increased risk of passing on infections, such as HIV, HBV, and HCV. You will be informed if this is an increased risk organ when it is offered to you.
# WHAT IS THE DIFFERENCE BETWEEN AN ORGAN FROM AN INCREASED RISK DONOR AND ONE FROM A STANDARD DONOR?
The increased risk from the donor does not affect how well the organ will work. It means that the donor engaged in activities before their death that increase the chances of having an infection. All donors are screened for infectious diseases. This includes testing for HIV, Hepatitis B, and Hepatitis C. Even with negative test results, there is still a very small chance that an organ from an increased risk donor has an infection such as HIV or Hepatitis. There are treatments available for these diseases but they are not curable.
On average, increased risk donors tend to be of younger age with better organ function.
# WHY WOULD I THINK ABOUT ACCEPTING AN ORGAN FROM AN INCREASED RISK DONOR?
Deciding to accept an organ from an IRD may increase your chance of getting a transplant. These are the facts: There is a constant shortage of organs and tissue that can be used for transplant. There are nearly 1,500 Ontarians waiting to get life-saving organ transplants. Every three days, someone dies while waiting for an organ transplant. The waiting times for organ transplants can be up to several years depending on the organ.
You will only be offered an increased risk organ if a transplant doctor at your hospital feels that the benefits of transplanting you with the organ are greater than the risk. Otherwise the organ will not be offered to you. A transplant doctor will speak to you about the risks and benefits of accepting the increased risk organ versus waiting for another organ.
# HOW WILL I KNOW IF I DEVELOP AN INFECTION?
If you decide to accept the organ, you will be monitored after your transplant to be sure that you did not get an infection. In the unlikely case that you do get an infection, treatments are available. The infectious disease doctors will treat you, if needed.
# WHO DECIDES IF I SHOULD ACCEPT AN INCREASED RISK ORGAN?
The decision to accept the increased risk organ is YOURS. The right choice for you depends on the state of your health. You need to talk about this with your medical team and all your doctors. The best answer for you may change if the state of your health changes.
If you have questions about organs from IRDs, talk with a member of your healthcare team while you are waiting for your transplant. If you are offered an organ from an increased risk donor, it will be helpful to have already thought about this information.
# IF I DO NOT AGREE TO ACCEPT AN INCREASED RISK ORGAN, WILL IT HURT MY CHANCES OF GETTING A STANDARD ORGAN?
No. Everyone has a different level of how much risk they are willing to accept for themselves. The decision to accept the organ is yours. If you decide NOT to accept the organ, you will NOT lose your place on the waiting list.
You will only be offered the consideration of an HCV positive organ if a transplant doctor at your hospital has identified you in one of the three categories of patients listed above, you have consented, and appropriate HCV drugs to treat transmission are available.
Otherwise, the organ will not be offered to you. A transplant doctor will speak to you about the risks and benefits of accepting the HCV positive donor organ versus waiting for another organ.
# E. WHAT ARE THE RISKS OF RECEIVING AN HCV POSITIVE ORGAN AND HOW WILL I KNOW IF I DEVELOP AN INFECTION?
In the case of HCV NAT positive donors, if you decide to accept the organ, there is a 100% chance you will get HCV. The infectious disease doctors in partnership with the transplant physicians will treat you accordingly based on the access to drug coverage and perform regular blood tests.
# F. WHO DECIDES IF I SHOULD ACCEPT AN HCV POSITIVE ORGAN?
The decision to accept the HCV positive organ is YOURS. The right choice for you depends on the state of your health. You need to talk about this with your medical team and all your doctors. The best answer for you may change if the state of your health changes.
If you have questions, talk with a member of your healthcare team while you are waiting for your transplant.
If you are offered an HCV positive organ from a donor, it is because you consented to consider this type of organ at the time of listing.
# G. IF I DO NOT AGREE TO ACCEPT AN HCV POSITIVE DONOR ORGAN, WILL IT HURT MY CHANCES OF GETTING A STANDARD ORGAN?
No. Everyone has a different level of how much risk they are willing to accept for themselves. The decision to accept the organ is yours. If you decide NOT to accept the organ, you will NOT lose your place on the waiting list.
# Appendix A: CTO Regulations for Exceptional Distribution
CTO Regulations: Exceptional Distribution 40. A source establishment may distribute cells, tissues or organs that have not been determined safe for transplantation if all of the following conditions are met:
(a) a cell, tissue or organ that has been determined safe for transplantation is not immediately available; (b) the transplant physician or dentist, based on their clinical judgment, authorizes the exceptional distribution; and (c) the transplant establishment obtains the informed consent of the recipient. 41. (1) A source establishment that distributes cells, tissues or organs under section 40 must keep a copy of the notice of exceptional distribution in its records.
(2) The transplant establishment must keep a copy of the notice of exceptional distribution in its records.
(3) A notice of exceptional distribution must contain all of the following information:
(a) the name of the transplanted cell, tissue or organ; (b) the provisions of these Regulations with which the cell, tissue or organ is not in compliance at the time of its distribution; (c) the justification for the distribution that formed the basis for the transplant physician's or dentist's decision to authorize it; (d) the name of the source establishment that distributed the cell, tissue or organ;
(e) the name of the transplant establishment and of the transplant physician or dentist who authorized the distribution; and (f) the time and date of the written authorization of the distribution and a copy of the authorization signed by the transplant physician or dentist. 42. A source establishment that distributes a cell, tissue or organ under section 40 before the donor suitability assessment is complete must, after the distribution, complete the assessment, carry out any other appropriate follow-up testing and notify the relevant transplant establishment of the results.
Source: Safety of Human Cells, Tissues and Organs for Transplantation Regulations, 2015.
# Appendix B: Individual NAT Testing Algorithm
# Appendix C: Notice of Exceptional Distribution Form
# Appendix D: Patient FAQ on Getting an Organ from an IRD
The information in the following FAQ should be provided to the patient at the time of transplant assessment or listing and can also be used at the time of offer to ensure understanding of the risks and benefits of accepting an IRD organ. Patient FAQs, scripts, and forms for getting an HCV Ab+ or HCV NAT +ve donor organ follow in the next section.
# Appendix E: Template for Standardized Informed Consent Script for IRD Organs
The following script may be read, as written, to the patient at the time of the organ offer. The patient should be encouraged to ask questions to ensure that s/he understands and appreciates the content. The patient must verbally confirm that he/she is accepting this offer. The patient's affirmation should be documented in the patient's chart as applicable. Please see Appendix G to I for the patient FAQ, script, and form for getting an HCV NAT +ve donor organ.
# Script for Obtaining Informed Consent
You are being offered an organ from a deceased donor that the Canadian Standards Association guidelines defines as being at increased risk for transmitting infections, such as HIV, HBV, and HCV. There is always some risk with every donor. Please think back to discussions you have had about the risks in accepting an organ. The increased risk does not affect how well the organ works. Instead, we mean that this donor engaged in behaviors before their death that increase their chances of having an infection. You need to balance the slightly increased risk of accepting this organ with the likely benefits of being transplanted at this time instead of waiting for another organ. This donor has already had two types of screening for infections. They had required testing for HIV, hepatitis B, and Hepatitis C. They also had special testing for HIV, Hepatitis C, and Hepatitis B. All of the NAT test results were negative. Even with negative test results, there is still a very small chance that this donor has an infection such as HIV or hepatitis.
Based on information on similar donors with the same behaviors and negative test results, your risk of getting an infection may be in the range of: (only read statistics pertaining to this donor's specific behavior from Table 2, and Table 3. It is not necessary to name the behaviour, only the level of risk. If the donor has tested HCV antibody positive and NAT negative and all history is unknown, or there are no high risk behaviours, read out the highest risk rate which is IV Drug Use (liver patients are exceptions, who may be a higher risk).
A transplant physician at your hospital has carefully looked at information about this donor. She/he recommends that you consider this organ. In his/her opinion, the potential benefits of accepting the organ outweigh the risks of getting an infection from this donor. If you decide to accept this organ, you will be monitored after your transplant to be sure that you did not get an infection. IF you get an infection, treatments are available. The infectious disease doctors will treat you, if needed. Everyone has a different level of how much risk they are willing to accept for themselves The decision to accept this organ is yours. If you decide NOT to accept the organ, you will not lose your place on the waiting list.
# Do you have any questions?
Additional points may be discussed with the patient depending on type of transplant (e.g. kidney vs. non-kidney) and other factors. These points include: 1. Estimated time the patient may be on the wait list if he/she waits until the next offer 2. Estimated wait-list mortality if he/she waits until the next offer 3. Risk of becoming so sick a transplant may not be possible Note: A separate standardized informed consent template may be needed for kidney vs. non-kidney recipients given the availability of dialysis for support of end stage renal failure patients. Increased Risk Donor (IRD) organs may not meet the strict criteria of a standard organ donor.
# Appendix F: Sample IRD Organ Informed Consent Form
IRDs identify certain lifestyle behaviors that are of an increased risk of spreading illnesses to patients compared to standard donors.
Please take your time to make your decision about accepting an IRD organ. Feel free to ask questions.
Patient Sign-Off I, the undersigned, have been informed about the purpose, procedures, possible benefits and risks of accepting an IRD organ, and I have received a copy of this informed consent document. I have been given the opportunity to ask questions and I have been told that I can ask questions in the future. All my questions have been answered to my satisfaction. As a representative of this transplant program, I have explained the purpose, the procedures, the possible benefits and the risks that are involved with an organ from an Increased Risk Donor (IRD). Any questions that have been raised have been answered to the best of my knowledge. You are waiting for an organ transplant Your doctor feels that you will benefit from having an IRD organ. An IRD organ may allow you to be transplanted sooner, rather than waiting a longer period of time for a standard criteria organ.
# Appendix G: Patient FAQ on Getting an Organ from a HCV NAT Positive Donor or HCV Antibody Positive (with Recent Antiviral Treatment)
The information in the following FAQ should be provided to the patient at the time of transplant assessment or listing and can be used again at the time of offer to ensure understanding of the risks and benefits of accepting a Hepatitis C Virus (HCV) NAT positive organ.
# WHAT DETERMINES AN HCV POSITIVE ORGAN?
Hepatitis C is a virus that enters through a person's blood stream and can affect the liver. This is an organ from a donor who has tested negative for Human Immunodeficiency Virus (HIV), and Hepatitis B Virus (HBV) and fits one of the following two profiles:
A. HCV antibody positive, NAT negative results with recent or unknown history of treatment:
The donor is currently on HCV treatment, less than 12 weeks have elapsed since completion of HCV treatment, or HCV treatment history is unknown.
# B. Donor NAT test results are positive for HCV
A patient may be asked to consider an organ from a deceased donor that is HCV NAT positive by either of the above definitions if they fit into one of the following categories:
1) HCV NAT positive recipient 2) Participant in clinical trials for HCV NAT negative recipients 3) Selected cases and special recipient considerations
The risk of transmission from a donor who tested HCV NAT positive is 100%.
# C. WHAT IS THE DIFFERENCE BETWEEN AN HCV POSITIVE ORGAN AND A STANDARD DONOR ORGAN?
An organ that comes from an HCV positive donor does not affect how well the organ will work (however, the risk of transmission may be higher for liver recipients). The difference is that by receiving an HCV positive organ, a treatment protocol will be required. The evidence shows that HCV treatments are effective in 95-99% of the HCV population (Feld, et al., 2015;Levitsky, et al., 2017). New therapies called direct acting antivirals (DAAs) are pills that act on the virus itself to get rid of it from the body.
The new treatment requires a shorter time (between 8 to 24 weeks), has reduced side effects, and appears to be effective at all stages of the disease.
After your surgery, an infectious disease physician or hepatologist may also be involved in your care and you will require some additional blood work at 2 weeks, 6 weeks, 1 month, 3 months, and 1 year to track the Hepatitis C virus in your blood. All other care and the transplant surgery will be the same.
# D. WHY WOULD I THINK ABOUT ACCEPTING AN HCV POSITIVE ORGAN?
Deciding to accept an organ from an HCV positive donor may increase your chance of getting a transplant. These are the facts: There is a constant shortage of organs and tissue that can be used for transplant. There are nearly 1,500 Ontarians waiting to get life-saving organ transplants. Every three days, someone dies while waiting for an organ transplant. The waiting times for organ transplants can be up to several years depending on the organ.
# Appendix H: Template for Standardized Informed Consent Script for HCV Antibody Positive (with Recent Antiviral Treatment) and HCV NAT Positive Donor Organs
The following script may be read, as written, to the patient at the time of the organ listing and again at offer. Please note that once a patient has consented and the program has accepted the organ, the "Notice of Exceptional Distribution" will still need to be completed. The patient should be encouraged to ask questions to ensure that s/he understands and appreciates the content. The patient must verbally confirm that he/she is accepting this offer. The patient's affirmation should be documented in the patient's chart as applicable.
# Script for Obtaining Informed Consent
You are being offered an organ from a deceased donor that has tested positive for the Hepatitis C Virus (HCV). We look at the combination of two types of testing and the history of any recent treatments for HCV in the donor to determine whether the donor organ classifies as HCV+. If you get HCV, treatments are available and the infectious disease doctors will treat you if needed.
The results for this donor indicate they are negative for HIV and HBV, and are (choose 1 of the following): a) Considered HCV positive due to a positive HCV NAT result b) Considered HCV positive due to a recent history of HCV antiviral treatment in the donor and a positive HCV antibody result You are being considered to receive an organ from a deceased donor who is HCV positive because you fit one of the following categories: 1. HCV NAT positive recipient 2. Participant in a clinical trial for HCV NAT negative recipients 3. Selected cases and special recipient considerations
There is always some risk with every donor and the risk of transmission may be higher in liver patients (Bari, et al., 2017). You need to balance the risk of accepting this organ with the likely benefits of being treated effectively post-transplant instead of waiting for another organ.
A transplant physician at your hospital has carefully looked at information about this donor. She/he recommends that you consider this organ. In his/her opinion, the potential benefits of accepting the organ outweigh the risks of getting an infection from this donor. If you decide to accept this organ, you will be monitored after your transplant for your viral status. The hepatologist or infectious disease doctors will treat you if needed. Everyone has a different level of how much risk they are willing to take. The decision to accept this organ is yours. If you decide NOT to accept the organ, you will not lose your place on the waiting list.
# Do you have any questions?
Additional points may be discussed with the patient depending on type of transplant (e.g. kidney vs. non-kidney) and other factors. These points include: 1. Estimated time the patient may be on the wait list if he/she waits until the next offer 2. Estimated wait-list mortality if he/she waits until the next offer 3. Risk of becoming so sick a transplant may not be possible Note: A separate standardized informed consent template may be needed for kidney vs. non-kidney recipients given the availability of dialysis for support of end stage renal failure patients. HCV positive organs may not meet the strict criteria of a standard organ donor. The donor organ has tested either HCV Nucleic Acid Testing (NAT) positive OR HCV antibody (Ab) positive with a history of recent or unknown treatment.
Please take your time to make your decision about accepting an HCV donor organ. Feel free to ask questions.
Patient Sign-Off I, the undersigned, have been informed about the purpose, procedures, possible benefits and risks of accepting an HCV positive donor organ, and I have received a copy of this informed consent document. I have been given the opportunity to ask questions and I have been told that I can ask questions in the future. All my questions have been answered to my satisfaction.
Yes, I am willing to accept an organ from an HCV Antibody (Ab) positive, NAT negative donor with a history of recent or unknown treatment Yes, I am willing to accept an organ from an HCV NAT positive donor You are waiting for an organ transplant Your doctor feels that you will benefit from having an HCV donor organ. An HCV donor organ may allow you to be transplanted sooner, rather than waiting a longer period of time for a standard criteria organ.
# Glossary of Terms
HCV Antibody Test: A blood test that detects antibodies to Hepatitis C Virus (HCV) in the blood and identifies if HCV is currently in the blood or was in the blood in the past. The HCV Antibody Test cannot determine if the infection is acute or long-term (chronic).
Canadian National Transplant Research Program: a national initiative designed to increase organ and tissue donation in Canada and enhance the survival and quality of life of Canadians who receive transplants.
Canadian Society of Transplantation: the professional organization for physicians, surgeons, scientists and allied health professionals dedicated to leading, advancing, and advocating for patient care, research, and education in donation and transplantation in Canada.
Canadian Standards Association: a not-for-profit standards organization which develops and published standards in a variety of areas and provides training and advisory services.
Direct Acting Antivirals (DAA): Direct Acting Antivirals are Hepatitis C Virus (HCV) treatments that are made up of different combinations of drugs and target the virus in the blood.
Exceptional Distribution: the process and conditions under sections 40 to 42 of the CTO regulations whereby a source establishment may distribute cells, tissues or organs that have not been determined safe for transplantation.
Enzyme-Linked Immunosorbent Assay (ELISA): is a common laboratory technique which is used to measure the concentration of an analyte (usually antibodies or antigens) in solution.
Hepatitis B Virus (HBV): a DNA virus belonging to the Hepadnaviridae family of viruses. The virus causes the disease hepatitis B, a viral infection that attacks the liver and can cause both acute and chronic disease.
Hepatitis C Virus (HCV): a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The virus causes the disease Hepatitis C, a bloodborne virus that can cause both acute and chronic hepatitis infection.
Human Immunodeficiency Virus (HIV): a retrovirus that infects cells of the immune system, destroying or impairing their function.
Increased Risk Behaviour: certain lifestyle behaviours that are of higher risk of transmitting infectious diseases to transplant recipients.
Increased Risk Donor (IRD): organ or tissue donor who identifies certain lifestyle behaviours that meet the criteria for being a higher risk of transmitting infectious diseases to transplant recipients.
Informed Consent: process for getting permission before conducting a healthcare intervention on a person.
Nucleic Acid Testing (NAT): a molecular technique used to detect a virus or a bacterium. It detects viruses earlier than other screening methods; thus, narrowing the detection window period.
# Public Health Ontario Laboratory (PHOL):
The provincial laboratory of Public Health Ontario (PHO), which is a governing body who strives to prevent illness and improve health through scientific evidence and expert guidance that shapes policy and practices in Ontario. There are 11 laboratory sites in Ontario.
Residual Risk: the risk of infectious disease transmission when the screening test is negative.
Serology: a blood test to detect serum antibodies or antibody-like substances that appear specifically in association with certain diseases.
Source Establishment: entity responsible for the processing of cells, tissues and organs, whether the processing is carried out by the source establishment itself or by another establishment, and for determining whether the cells, tissues and organs are safe for transplantation.
# Sustained Virologic Response (SVR):
When the Hepatitis C Virus (HCV) is not detected in the blood after a certain amount of time (12 weeks) after completing treatment, sustained virologic response (SVR) is achieved.
Trillium Gift of Life Network (TGLN): a not-for-profit agency of the Government of Ontario that plans, promotes, coordinates and supports organ and tissue donation and transplantation across Ontario.
Window Period: the time between first infection and when a test can reliably detect that infection.
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To outline the evidence, indications and guidance relating to the use of thrombolytic and endovascular therapy for the early management of acute ischemic stroke (AIS).Thrombolytic therapy is highly effective in AIS. Recombinant tissue plasminogen activator (rt-PA), the most well-studied agent used in this setting, has demonstrated efficacy in the treatment of AIS in 9 randomized trials involving more than 6,700 patients over more than 20 years. Thrombolytic therapy with rt-PA has been shown to improve the likelihood of favourable outcome in AIS, despite a small increased risk of serious bleeding. Therapy is time-sensitive, with the benefits of therapy decreasing successively with longer delays from onset to treatment. The benefit is greatest when rt-PA is administered within the first 3 hours after symptom onset, with a less robust risk-vs-benefit balance up to 4.5 hours. Treatment benefits of rt-PA are preserved across the spectrum of age and clinical severity of disabling deficits. The most serious risks of thrombolytic therapy are intracranial hemorrhage (ICH, affecting up to 6% with variable trial-dependent definitions), major extracranial hemorrhage, and angioedema (up to 5%). Approximately 2% of rt-PA-associated intracranial hemorrhages are fatal.#
Evidence-based guidelines support the use of thrombolytic therapy with rt-PA for carefully selected patients with disabling AIS and its use is considered standard of care in this setting. An effective stroke protocol demands highly coordinated input from paramedics and a pre-notified emergency department team, collaboration from radiology to ensure emergent brain imaging to confirm eligibility, as well as the availability of physicians trained in acute stroke and thrombolytic therapy. If patients may be eligible for thrombolysis, they should have an emergent head CT at the time of hospital arrival. The target median door-to-rt-PA time is less than 30 minutes.
Recent evidence supports the use of advanced neuroimaging to select individuals who may benefit from rt-PA beyond the 4.5 hour window or individuals with unknown time of onset (e.g. those who have a disabling deficit without evidence of established parenchymal ischemic changes, or a small ischemic core on MRI). Current Canadian best practice guidelines recommend consultation with a stroke specialist cases where thrombolysis will be administered past 4.5 hours from known time of onset.
The role of tenecteplase as an alternative to rt-PA (at doses of 0.25 mg/kg or 0.50 mg/kg as a single bolus dose) for thrombolysis in acute ischemic stroke is under active investigation. There are no current Canadian recommendations for use of tenecteplase at this time for individuals with acute ischemic stroke, but multiple clinical trials examining use of the 0.25 mg/kg dose for this indication are ongoing.
Endovascular thrombectomy is indicated in selected patients with a proximal intracranial artery occlusion and may be used both in those who have received rt-PA, as well as in those who are not eligible for rt-PA. The strongest evidence for benefit exists for treatment within 6 hours of onset of stroke symptoms, although selected candidates who may benefit from late revascularization (i.e. up to 24 hours after onset) may be identified through advanced neuroimaging.
In some regions of the country, a stroke bypass system exists in which patients who may have AIS are transported to the nearest stroke center to facilitate rapid expert treatment, with bypass of the closest hospital if they meet established criteria. In most provinces, Telestroke is a rapidly developing service to connect remote centers with physicians who have expertise in stroke .
# PATIENT SELECTION FOR THROMBOLYTIC THERAPY IN AIS:
Inclusion criteria: Patients ≥18 years of age with a diagnosis of disabling AIS with time of onset <4.5 hours. If rt-PA administration is considered after 4.5 h, consultation with a physician with stroke expertise should be obtained. For adolescents, decision to administer alteplase should be based on clinical judgment, presenting symptoms, and patient age and, if possible, consultation with a pediatric stroke specialist.
# Absolute Exclusion Criteria:
- Any source of active hemorrhage or any condition that could increase the risk of major hemorrhage after thrombolytic administration - Any hemorrhage on brain imaging
# Relative Exclusion Criteria (requiring clinical judgement):
# A. History
- History of intracranial hemorrhage - Stroke, serious head injury or spinal trauma in the preceding 3 months - Recent major surgery, such as cardiac, thoracic, abdominal, or orthopedic in previous 14 days - Arterial puncture at a non-compressible site in the previous 7 days
# B. Clinical
- Symptoms suggestive of subarachnoid hemorrhage - Stroke symptoms due to another non-ischemic acute neurological condition such as seizure with post-ictal Todd's paralysis or focal neurological signs due to severe hypo-or hyperglycemia - Hypertension refractory to antihypertensive treatment such that target blood pressure <180/105 cannot be achieved or maintained - Currently prescribed and taking a direct oral anticoagulant (DOAC). In centres with access to specialized tests of DOAC levels and reversal agents, thrombolysis could be considered, and decisions made based on individual patient characteristics, in consultation with hematology specialists, patients and their families. Otherwise, endovascular treatment should be considered if the patient is otherwise eligible.
# C. Laboratory
- Blood glucose concentration below 2.7 mmol/L or above 22.2 mmol/L - Elevated activated partial-thromboplastin time (aPTT)
- International Normalized Ratio (INR) > 1.7
# D. CT or MRI Findings
- CT showing early signs of extensive infarction
# THROMBOLYTIC AGENT DOSING IN AIS:
The recommended dose of rt-PA for AIS is 0.9 mg/kg (maximum 90 mg) infused over 60 minutes, with 10% of the total dose administered as an initial IV bolus over 1 minute. Anticoagulants and antiplatelet agents may increase the risk of bleeding complications and are not recommended within 24 hours of rt-PA administration.
# MONITORING OF PATIENTS WHO RECEIVED THROMBOLYTIC THERAPY FOR AIS:
The patient should be observed in a monitored setting with frequent neurologic and vital signs assessments as well as cardiac monitoring. The clinician must be ready to recognize and manage possible complications. Complications include systemic and intracranial bleeding, angioedema and rarely serious anaphylaxis reactions. There is insufficient evidence to support the use of fresh frozen plasma, prothrombin complex concentrates, or platelets for rt-PA related bleeding; however, cryoprecipitate and tranexamic acid are recommended in addition to supportive care.
# ENDOVASCULAR THERAPY:
Endovascular therapy (EVT) may be used in eligible patients alone or in combination with thrombolysis. There is very strong evidence from multiple randomized trials demonstrating benefit of EVT in individuals with proximal intracranial occlusions in the anterior circulation (internal carotid artery and proximal middle cerebral artery as well as individuals with tandem cervical carotid and intracranial occlusions) with moderate-to-severe neurological deficits. The majority of patients from contemporary EVT trials were treated within 6 hours of stroke onset, and shorter times from onset to recanalization are associated with better functional outcomes. Most participants in these trials also received rt-PA. Two trials have demonstrated benefit of EVT in individuals treated up to 24 hours from time of last seen well who are carefully selected individuals based on small ischemic cores with advanced CT or MR perfusion imaging. Individuals with larger branch anterior occlusions and significant neurological deficits also benefit from EVT, though the evidence is less robust and treatment decisions are individualized in this group. The benefit of EVT in individuals with milder neurological deficits and proximal large artery occlusions is the subject of ongoing clinical trials; treatment decisions also remain individualized in this group at present. Trials examining EVT for basilar occlusions, which are associated with high rates of death and dependence, have not demonstrated as robust a benefit for EVT as in anterior circulation occlusions. However, interpretation of existing data is complicated by both enrolment biases and crossover to treatment from control participants. Current guidelines recommend EVT for basilar occlusions.
Treatment decision-making regarding suitability for EVT is generally a collaborative effort between the neuro-interventionalist and stroke physician. Decision-making takes into account the patient's pre-morbid status, current neurological deficits, burden of ischemic core on neuroimaging, and vascular access. Transport logistics are also often germane to treatment decisions as EVT is performed only at comprehensive stroke centres. Success of EVT requires the coordination of pre-hospital and hospital systems, rapid neurovascular imaging and expertise in neurointervention, and access to stroke unit care.
# SPECIAL CONSIDERATIONS:
Pediatrics: There are little safety and efficacy data in patients under 18 years of age with AIS. Physicians with expertise in pediatric stroke should manage these patients where possible. When this is not possible, a combination of a neonatologist/pediatrician and an adult neurologist, supported by consultation with an experienced specialist in pediatric stroke, is recommended.
Pregnancy: There have been no empiric studies of IV rt-PA in pregnant women presenting with AIS; however, it is reasonable to consider giving rt-PA to a pregnant women with disabling AIS who meets existing criteria for treatment and pregnancy should not be considered to be a contraindication for EVT. Although there are fetal risks to these interventions, given the very high morbidity and mortality associated with AIS due to large vessel occlusion, maternal care for disabling stroke should not be delayed or deferred on the basis of pregnancy. Treatment options for pregnant women with AIS should promptly be considered in consultation with an interdisciplinary team with expertise in neurology, obstetrics and gynecology, maternal-fetal medicine, and interventional radiology where possible and available.
# REFERENCES:
Boulanger Powers WJ, et al on behalf of the American Heart Association Stroke Council. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019;50:e344-e418.
# Date of version: 06September2020
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any
medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To outline the evidence, indications and guidance relating to the use of thrombolytic and endovascular therapy for the early management of acute ischemic stroke (AIS).Thrombolytic therapy is highly effective in AIS. Recombinant tissue plasminogen activator (rt-PA), the most well-studied agent used in this setting, has demonstrated efficacy in the treatment of AIS in 9 randomized trials involving more than 6,700 patients over more than 20 years. Thrombolytic therapy with rt-PA has been shown to improve the likelihood of favourable outcome in AIS, despite a small increased risk of serious bleeding. Therapy is time-sensitive, with the benefits of therapy decreasing successively with longer delays from onset to treatment. The benefit is greatest when rt-PA is administered within the first 3 hours after symptom onset, with a less robust risk-vs-benefit balance up to 4.5 hours. Treatment benefits of rt-PA are preserved across the spectrum of age and clinical severity of disabling deficits. The most serious risks of thrombolytic therapy are intracranial hemorrhage (ICH, affecting up to 6% with variable trial-dependent definitions), major extracranial hemorrhage, and angioedema (up to 5%). Approximately 2% of rt-PA-associated intracranial hemorrhages are fatal.#
Evidence-based guidelines support the use of thrombolytic therapy with rt-PA for carefully selected patients with disabling AIS and its use is considered standard of care in this setting. An effective stroke protocol demands highly coordinated input from paramedics and a pre-notified emergency department team, collaboration from radiology to ensure emergent brain imaging to confirm eligibility, as well as the availability of physicians trained in acute stroke and thrombolytic therapy. If patients may be eligible for thrombolysis, they should have an emergent head CT at the time of hospital arrival. The target median door-to-rt-PA time is less than 30 minutes.
Recent evidence supports the use of advanced neuroimaging to select individuals who may benefit from rt-PA beyond the 4.5 hour window or individuals with unknown time of onset (e.g. those who have a disabling deficit without evidence of established parenchymal ischemic changes, or a small ischemic core on MRI). Current Canadian best practice guidelines recommend consultation with a stroke specialist cases where thrombolysis will be administered past 4.5 hours from known time of onset.
The role of tenecteplase as an alternative to rt-PA (at doses of 0.25 mg/kg or 0.50 mg/kg as a single bolus dose) for thrombolysis in acute ischemic stroke is under active investigation. There are no current Canadian recommendations for use of tenecteplase at this time for individuals with acute ischemic stroke, but multiple clinical trials examining use of the 0.25 mg/kg dose for this indication are ongoing.
Endovascular thrombectomy is indicated in selected patients with a proximal intracranial artery occlusion and may be used both in those who have received rt-PA, as well as in those who are not eligible for rt-PA. The strongest evidence for benefit exists for treatment within 6 hours of onset of stroke symptoms, although selected candidates who may benefit from late revascularization (i.e. up to 24 hours after onset) may be identified through advanced neuroimaging.
In some regions of the country, a stroke bypass system exists in which patients who may have AIS are transported to the nearest stroke center to facilitate rapid expert treatment, with bypass of the closest hospital if they meet established criteria. In most provinces, Telestroke is a rapidly developing service to connect remote centers with physicians who have expertise in stroke [ https://www.strokebestpractices.ca/recommendations/telestroke].
# PATIENT SELECTION FOR THROMBOLYTIC THERAPY IN AIS:
Inclusion criteria: Patients ≥18 years of age with a diagnosis of disabling AIS with time of onset <4.5 hours. If rt-PA administration is considered after 4.5 h, consultation with a physician with stroke expertise should be obtained. For adolescents, decision to administer alteplase should be based on clinical judgment, presenting symptoms, and patient age and, if possible, consultation with a pediatric stroke specialist.
# Absolute Exclusion Criteria:
• Any source of active hemorrhage or any condition that could increase the risk of major hemorrhage after thrombolytic administration • Any hemorrhage on brain imaging
# Relative Exclusion Criteria (requiring clinical judgement):
# A. History
• History of intracranial hemorrhage • Stroke, serious head injury or spinal trauma in the preceding 3 months • Recent major surgery, such as cardiac, thoracic, abdominal, or orthopedic in previous 14 days • Arterial puncture at a non-compressible site in the previous 7 days
# B. Clinical
• Symptoms suggestive of subarachnoid hemorrhage • Stroke symptoms due to another non-ischemic acute neurological condition such as seizure with post-ictal Todd's paralysis or focal neurological signs due to severe hypo-or hyperglycemia • Hypertension refractory to antihypertensive treatment such that target blood pressure <180/105 cannot be achieved or maintained • Currently prescribed and taking a direct oral anticoagulant (DOAC). In centres with access to specialized tests of DOAC levels and reversal agents, thrombolysis could be considered, and decisions made based on individual patient characteristics, in consultation with hematology specialists, patients and their families. Otherwise, endovascular treatment should be considered if the patient is otherwise eligible.
# C. Laboratory
• Blood glucose concentration below 2.7 mmol/L or above 22.2 mmol/L • Elevated activated partial-thromboplastin time (aPTT)
• International Normalized Ratio (INR) > 1.7
# D. CT or MRI Findings
• CT showing early signs of extensive infarction
# THROMBOLYTIC AGENT DOSING IN AIS:
The recommended dose of rt-PA for AIS is 0.9 mg/kg (maximum 90 mg) infused over 60 minutes, with 10% of the total dose administered as an initial IV bolus over 1 minute. Anticoagulants and antiplatelet agents may increase the risk of bleeding complications and are not recommended within 24 hours of rt-PA administration.
# MONITORING OF PATIENTS WHO RECEIVED THROMBOLYTIC THERAPY FOR AIS:
The patient should be observed in a monitored setting with frequent neurologic and vital signs assessments as well as cardiac monitoring. The clinician must be ready to recognize and manage possible complications. Complications include systemic and intracranial bleeding, angioedema and rarely serious anaphylaxis reactions. There is insufficient evidence to support the use of fresh frozen plasma, prothrombin complex concentrates, or platelets for rt-PA related bleeding; however, cryoprecipitate and tranexamic acid are recommended in addition to supportive care.
# ENDOVASCULAR THERAPY:
Endovascular therapy (EVT) may be used in eligible patients alone or in combination with thrombolysis. There is very strong evidence from multiple randomized trials demonstrating benefit of EVT in individuals with proximal intracranial occlusions in the anterior circulation (internal carotid artery and proximal middle cerebral artery as well as individuals with tandem cervical carotid and intracranial occlusions) with moderate-to-severe neurological deficits. The majority of patients from contemporary EVT trials were treated within 6 hours of stroke onset, and shorter times from onset to recanalization are associated with better functional outcomes. Most participants in these trials also received rt-PA. Two trials have demonstrated benefit of EVT in individuals treated up to 24 hours from time of last seen well who are carefully selected individuals based on small ischemic cores with advanced CT or MR perfusion imaging. Individuals with larger branch anterior occlusions and significant neurological deficits also benefit from EVT, though the evidence is less robust and treatment decisions are individualized in this group. The benefit of EVT in individuals with milder neurological deficits and proximal large artery occlusions is the subject of ongoing clinical trials; treatment decisions also remain individualized in this group at present. Trials examining EVT for basilar occlusions, which are associated with high rates of death and dependence, have not demonstrated as robust a benefit for EVT as in anterior circulation occlusions. However, interpretation of existing data is complicated by both enrolment biases and crossover to treatment from control participants. Current guidelines recommend EVT for basilar occlusions.
Treatment decision-making regarding suitability for EVT is generally a collaborative effort between the neuro-interventionalist and stroke physician. Decision-making takes into account the patient's pre-morbid status, current neurological deficits, burden of ischemic core on neuroimaging, and vascular access. Transport logistics are also often germane to treatment decisions as EVT is performed only at comprehensive stroke centres. Success of EVT requires the coordination of pre-hospital and hospital systems, rapid neurovascular imaging and expertise in neurointervention, and access to stroke unit care.
# SPECIAL CONSIDERATIONS:
Pediatrics: There are little safety and efficacy data in patients under 18 years of age with AIS. Physicians with expertise in pediatric stroke should manage these patients where possible. When this is not possible, a combination of a neonatologist/pediatrician and an adult neurologist, supported by consultation with an experienced specialist in pediatric stroke, is recommended.
Pregnancy: There have been no empiric studies of IV rt-PA in pregnant women presenting with AIS; however, it is reasonable to consider giving rt-PA to a pregnant women with disabling AIS who meets existing criteria for treatment and pregnancy should not be considered to be a contraindication for EVT. Although there are fetal risks to these interventions, given the very high morbidity and mortality associated with AIS due to large vessel occlusion, maternal care for disabling stroke should not be delayed or deferred on the basis of pregnancy. Treatment options for pregnant women with AIS should promptly be considered in consultation with an interdisciplinary team with expertise in neurology, obstetrics and gynecology, maternal-fetal medicine, and interventional radiology where possible and available.
# REFERENCES:
Boulanger Powers WJ, et al on behalf of the American Heart Association Stroke Council. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019;50:e344-e418.
# Date of version: 06September2020
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any
#
medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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This guidance is intended for nephrologists and other healthcare providers. It is based on known evidence as of April 18, 2023. The risk of mortality from COVID-19 disease appears to be higher in patients with kidney disease. In a UK National Health Service study using a living risk predictor algorithm (QCOVID) for the risk of hospital admission and mortality due to COVID-19, chronic kidney disease (CKD) patients stage 5 (with or without dialysis or transplant) were found to be at increased risk of complications. 1 Other risk factors included patients on oral steroids or immunosuppressive agents. The majority of these patients had multi-morbidities (including diabetes, heart disease, lung diseases) and many were over the age of 70. Compounding these risk factors is the need for hemodialysis patients to travel to and receive dialysis care three times per week at hospital or community-based dialysis units where social distancing is more difficult and multiple exchanges with care teams and other patients occur.#
Is COVID-19 immunization recommended for people with kidney disease? COVID-19 vaccines should be encouraged for people with kidney disease and are not contraindicated, including those who have had a COVID-19 infection. This recommendation is based on the following review:
- The National Advisory Committee on Immunization recommends that immunosuppressed individuals may be offered the vaccine if the benefits of vaccine outweigh the potential risks. 2 - Patients with kidney disease have an increased risk of hospitalization and death related to COVID-19 infection. 1 - The Canadian Society of Nephrology supports the use of COVID-19 immunization in this population and has advocated to all provinces and the federal government for the urgent prioritization of dialysis patients for COVID-19 vaccinations. 3 - Aside from a very rare risk of an allergic reaction (only a handful of people to date), there is no concern that the vaccine will cause kidney patients harm. There is only uncertainty regarding its effectiveness for those who are immunosuppressed.
COVID-19 Vaccines for People with Kidney Disease Updated: April 18, 2023
While data specific to the safety and efficacy of COVID-19 vaccines in people with kidney disease is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 4 The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization.
Is the COVID-19 vaccine efficacious and safe for people with kidney disease?
People living with chronic kidney disease, including those on dialysis, are less likely to mount an adequate immune response to the COVID-19 vaccines, which puts them at higher risk for COVID-19 infection and severe complication. 5 There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 6 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose.
There are currently no known factors that would predispose individuals with chronic kidney disease to different or more frequent adverse events associated with the vaccines when compared to the general population.
Are there any specific contraindications or exceptions for kidney patients?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 7 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
There are no specific contraindications or exceptions for those with kidney disease. Health-care providers of those who have had a kidney transplant should refer to the clinical guidance on COVID-19 vaccines for people who have received an organ transplant.
COVID-19 Vaccines for People with Kidney Disease Updated: April 18, 2023
Are there specific recommendations or considerations for safe and/or most effective administration?
# Patients on kidney transplant waiting list
For those on the kidney transplant waiting list, there are some considerations related to immunization timing. It is recommended that immunization proceed as quickly as possible, given that the response to the vaccine is likely diminished in the immediate post-transplant period. Thus, completing immunization prior to transplant will be important for those high on the waiting list or those highly sensitized patients.
# Patients on immunosuppressive therapy
People who take immunosuppressant/immunomodulating therapy were excluded in COVID-19 vaccine trials. Therefore, it is unknown if the COVID-19 vaccines are as efficacious in those who take immunosuppressants compared to those who are not considered immunosuppressed.
Kidney patients who take immunosuppressants (with or without transplants) should be informed there are not yet studies that examine the direct benefit and safety of COVID-19 immunization in this population, and that these recommendations/clinical guidance are based on extrapolation of data from other viral infections, immunology of immunizations and from expert opinion.
The benefits of immunization are considered to outweigh the potential risks. Immunization is recommended in this group, preferably once 'induction' therapy has been completed.
People who may have severe systemic disease (lupus, vasculitis, etc.) who need to receive immunosuppressive therapy (Rituximab, Prednisone 20 mg/day or greater, Cyclophosphamide, Plasma Exchange) should complete that course of treatment before receiving the vaccine and should not delay treatment of their life threatening condition in order to be immunized. See special considerations for Rituximab and Prednisone below.
In general, it is preferred that patients complete immunization before starting high-dose immunosuppressive therapy, if possible, based on the timing of the treatments and the availability of vaccines at the time. This should ideally be at least 14 days after the second dose of any of the vaccines. *Life-saving or prolonging therapy should not be delayed solely for the purposes of completing immunization.
Any other timing would require case-by-case assessment based on: a. Risk of morbidity related to COVID-19 infection (including local prevalence of the pandemic, comorbidities that confer higher risk categories in general population, etc.). b. Suboptimal immunity protection due to insufficient time between immunization and immunosuppressive therapy. The following considerations and recommendations for HD care should be taken into account as hemodialysis patients begin receiving vaccination against COVID-19:
- COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. - For new hemodialysis patients requiring TB screening:
- Blood samples may be sent for IGRA testing if the patient has not had a COVID-19 vaccine dose in the last 28 days. o IGRA testing should be deferred until 28 days after the most recent COVID-19 vaccine dose.
# Special considerations for immunotherapy: Rituximab and Prednisone
Patients receiving these agents may have a blunted immune response to vaccines in general that can extend to up to six months following treatment completion.
- For patients on rituximab, COVID-19 immunization should ideally be timed four to five months after their last infusion and 2 to 4 weeks prior to their next infusion, when possible, in order to optimize vaccine response. However, in patients that require immediate infusion or who are unable to optimize timing of infusion product and vaccine, treatment is paramount. Patients should be counselled to get the vaccine as soon as it is available to them, but to not delay rituximab treatment for the sake of a vaccine appointment. - For patients on prednisone 20mg/day or higher (or equivalents), consider waiting until the prednisone dose is tapered to below 20mg/day to receive both vaccine doses, but only if the time needed to taper the prednisone dose below 20mg/day is short. Pediatric patients on high-dose steroids should consult with their pediatric rheumatologist to decide on the best time to receive the vaccine. 12
|
This guidance is intended for nephrologists and other healthcare providers. It is based on known evidence as of April 18, 2023. The risk of mortality from COVID-19 disease appears to be higher in patients with kidney disease. In a UK National Health Service study using a living risk predictor algorithm (QCOVID) for the risk of hospital admission and mortality due to COVID-19, chronic kidney disease (CKD) patients stage 5 (with or without dialysis or transplant) were found to be at increased risk of complications. 1 Other risk factors included patients on oral steroids or immunosuppressive agents. The majority of these patients had multi-morbidities (including diabetes, heart disease, lung diseases) and many were over the age of 70. Compounding these risk factors is the need for hemodialysis patients to travel to and receive dialysis care three times per week at hospital or community-based dialysis units where social distancing is more difficult and multiple exchanges with care teams and other patients occur.#
Is COVID-19 immunization recommended for people with kidney disease? COVID-19 vaccines should be encouraged for people with kidney disease and are not contraindicated, including those who have had a COVID-19 infection. This recommendation is based on the following review:
• The National Advisory Committee on Immunization recommends that immunosuppressed individuals may be offered the vaccine if the benefits of vaccine outweigh the potential risks. 2 • Patients with kidney disease have an increased risk of hospitalization and death related to COVID-19 infection. 1 • The Canadian Society of Nephrology supports the use of COVID-19 immunization in this population and has advocated to all provinces and the federal government for the urgent prioritization of dialysis patients for COVID-19 vaccinations. 3 • Aside from a very rare risk of an allergic reaction (only a handful of people to date), there is no concern that the vaccine will cause kidney patients harm. There is only uncertainty regarding its effectiveness for those who are immunosuppressed.
COVID-19 Vaccines for People with Kidney Disease Updated: April 18, 2023
2
While data specific to the safety and efficacy of COVID-19 vaccines in people with kidney disease is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 4 The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization.
Is the COVID-19 vaccine efficacious and safe for people with kidney disease?
People living with chronic kidney disease, including those on dialysis, are less likely to mount an adequate immune response to the COVID-19 vaccines, which puts them at higher risk for COVID-19 infection and severe complication. 5 There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 6 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose.
There are currently no known factors that would predispose individuals with chronic kidney disease to different or more frequent adverse events associated with the vaccines when compared to the general population.
Are there any specific contraindications or exceptions for kidney patients?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 7 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
There are no specific contraindications or exceptions for those with kidney disease. Health-care providers of those who have had a kidney transplant should refer to the clinical guidance on COVID-19 vaccines for people who have received an organ transplant.
COVID-19 Vaccines for People with Kidney Disease Updated: April 18, 2023
3
Are there specific recommendations or considerations for safe and/or most effective administration?
# Patients on kidney transplant waiting list
For those on the kidney transplant waiting list, there are some considerations related to immunization timing. It is recommended that immunization proceed as quickly as possible, given that the response to the vaccine is likely diminished in the immediate post-transplant period. Thus, completing immunization prior to transplant will be important for those high on the waiting list or those highly sensitized patients.
# Patients on immunosuppressive therapy
People who take immunosuppressant/immunomodulating therapy were excluded in COVID-19 vaccine trials. Therefore, it is unknown if the COVID-19 vaccines are as efficacious in those who take immunosuppressants compared to those who are not considered immunosuppressed.
Kidney patients who take immunosuppressants (with or without transplants) should be informed there are not yet studies that examine the direct benefit and safety of COVID-19 immunization in this population, and that these recommendations/clinical guidance are based on extrapolation of data from other viral infections, immunology of immunizations and from expert opinion.
The benefits of immunization are considered to outweigh the potential risks. Immunization is recommended in this group, preferably once 'induction' therapy has been completed.
People who may have severe systemic disease (lupus, vasculitis, etc.) who need to receive immunosuppressive therapy (Rituximab, Prednisone 20 mg/day or greater, Cyclophosphamide, Plasma Exchange) should complete that course of treatment before receiving the vaccine and should not delay treatment of their life threatening condition in order to be immunized. See special considerations for Rituximab and Prednisone below.
In general, it is preferred that patients complete immunization before starting high-dose immunosuppressive therapy, if possible, based on the timing of the treatments and the availability of vaccines at the time. This should ideally be at least 14 days after the second dose of any of the vaccines. *Life-saving or prolonging therapy should not be delayed solely for the purposes of completing immunization.
Any other timing would require case-by-case assessment based on: a. Risk of morbidity related to COVID-19 infection (including local prevalence of the pandemic, comorbidities that confer higher risk categories in general population, etc.). b. Suboptimal immunity protection due to insufficient time between immunization and immunosuppressive therapy. The following considerations and recommendations for HD care should be taken into account as hemodialysis patients begin receiving vaccination against COVID-19:
• COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. [8][9][10][11] • For new hemodialysis patients requiring TB screening:
o Blood samples may be sent for IGRA testing if the patient has not had a COVID-19 vaccine dose in the last 28 days. o IGRA testing should be deferred until 28 days after the most recent COVID-19 vaccine dose.
# Special considerations for immunotherapy: Rituximab and Prednisone
Patients receiving these agents may have a blunted immune response to vaccines in general that can extend to up to six months following treatment completion.
• For patients on rituximab, COVID-19 immunization should ideally be timed four to five months after their last infusion and 2 to 4 weeks prior to their next infusion, when possible, in order to optimize vaccine response. However, in patients that require immediate infusion or who are unable to optimize timing of infusion product and vaccine, treatment is paramount. Patients should be counselled to get the vaccine as soon as it is available to them, but to not delay rituximab treatment for the sake of a vaccine appointment. • For patients on prednisone 20mg/day or higher (or equivalents), consider waiting until the prednisone dose is tapered to below 20mg/day to receive both vaccine doses, but only if the time needed to taper the prednisone dose below 20mg/day is short. Pediatric patients on high-dose steroids should consult with their pediatric rheumatologist to decide on the best time to receive the vaccine. 12
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# Introduction
The COVID-19 pandemic is a public health crisis with wide reaching health care implications due to illnesses from the disease itself, social and physical distancing restrictions, and the deferral or indefinite postponement of non-urgent clinical care and procedures. As physical and social distancing measures have been implemented to curb the spread of COVID-19, healthcare has been upended with the deferral or cancellation of in-person visits and health care providers have had to rapidly adapt their clinical practice. During this time, drug production sites and supply chains have also been disrupted. Consequently, Canadian people and couples who want to avoid a pregancy at this time are at increased risk of developing an unmet need for family planning due to lack of access to contraceptive care or methods. Compounding this, social isolation may increase unintended pregnancy through exposure to unprotected intercourse, reproductive coercion, and intimate personal violence.
Ideally, contraception provision would be practised in accordance with the Canadian Contraception Consensus guidelines, including recommendations for screening, duration of use, follow-up assessments, and the provision of long-acting reversible contraception (LARC) methods as firstline contraception methods. During pandemic situations, provision of family planning services must be adapted in an evidence-based fashion. This document provides interim guidance to affirm best practices and provide expert consensus on strategies to maintain contraceptive access during the COVID-19 pandemic or other periods of major social disruption.
# Recommendations and Summary Statements
# The unmet need for contraception increases during periods of social disruption,
including pandemics. Health care providers should facilitate continued access to contraception during this time.
Access to safe, voluntary family planning is a human right. 1,2 During social disruptions, including wartime conflict and pandemics, there is an increased and unmet need for contraception, leading to increased rates of unintended pregnancy and its associated outcomes. 3,4 Individuals may lack access to contraception and thus have unprotected intercourse as well as be at increased risk of intimate partner violence, reproductive coercion, and unwanted or unplanned intercourse.
It is essential to have ongoing access to a choice of effective contraceptives through the provision of information, counselling, and services (including emergency contraception). 5 Given the elevated risk of adverse outcomes of pregnancy, and the humanitarian need to ensure access to birth control, the UNFPA considers access to contraception "life-saving" during a pandemic. 5 Healthcare providers should facilitate ongoing access to contraception, including offering virtual visits to initiate, improve, and continue contraceptive methods.
# During the COVID-19 pandemic, contraceptive care may be offered virtually (telephone encounter, video encounter) or in person depending on the needs of the individual and in line with other health authority recommendations
To facilitate access to contraception while respecting physical and social distancing guidance, contraception counselling can be performed virtually to determine acceptable contraceptive options for an individual patient. Some contraceptive methods can be initiated without the need for an in-person assessment, including barrier methods, the POP, DMPA, and in some instances combined hormonal contraception (in the absence of contraindications). Initiation of other methods, such as long acting reversible contraceptives (LARC), may need to be deferred if the clinical resources for insertion are not readily available, the patient has known or suspected COVID-19 infection, or is in a high risk category for COVID-19 infection.
# Long-Acting Reversible Contraception (LARC) provides reliable contraception that
is resistant to fluctuations in healthcare access during a pandemic. LARC placement is an essential medical service and women who would benefit from a LARC method should be able to access placement or insertion appointments.
In Canada, intrauterine contraception (IUC) is the only LARC method available at this time.
Women may have had a contraceptive implant inserted in another country but the single rod etonogestrel implant is not currently available in Canada. IUCs include levonorgestrel intrauterine systems (LNG-IUS) and copper intrauterine devices (Cu-IUD). IUCs provide effective reversible contraception for up to (and in some cases beyond) 5 years. 6 LARC methods are the most effective way to prevent unintended pregnancy but it may not be possible for all clinicians to maintain access to IUC placement or implant insertion (when available) during a pandemic or period of social disruption.
Health care providers who currently provide IUC care are encouraged to continue offering this service if feasible. Clinics should follow local public health guidelines to screen patients prior to appointments, have access to appropriate personal protective equipment (PPE), wash and disinfect clinical areas as required, and adhere to scrupulous hand-washing protocols. Health care providers should have a robust system for assessing and ensuring follow-up for patients they are able to see. If IUC placement is not possible during the pandemic, contraceptives that can be self-administered should be offered as a bridge to delayed IUC insertion. A short-acting reversible contraceptive (SARC) can be initiated immediately in the absence of contraindications to method use.
Health care providers should make particular efforts to maintain IUC access (through provision or referral) for patients at higher risk of unintended pregnancy and its complications, including those with a history of unintended pregnancy, those at risk of reproductive coercion or intimate partner violence, those with contraindications to estrogencontaining contraception, and patients for whom a short-acting contraceptive method (including barriers) is contraindicated or unlikely to provide reliable contraception. .
# Intrauterine contraception (IUC) may be safely continued beyond its approved duration of use. Appointments for IUC removal or replacement can be deferred up to 12 months, depending on the specific device and duration of use.
Routine IUC replacements and removals should be postponed if possible and IUC users should be counselled on the safety and effectiveness of extended IUC use. Extended use of an IUC is safe beyond the approved duration of use, however there may be small effects on effectiveness. Although each device is approved for certain durations of use, most are effective for longer than the manufacturers' recommendations 6,7 and immediate replacement at the end of this time period is not necessary.
There is good evidence to support exended use of the LNG-IUS 52 mg (Mirena®) for up to 7 years in women who are > 25 years old at the time of insertion. 7,8,9,10,11,12,13 There is limited experience with extended use of the LNG-IUS 13.5 mg (Jaydess®) and the LNG-IUS 19.5 mg (Kyleena®). Although the risk of pregnancy is likely to be small, women using the 13.5 mg and 19.5 mg LNG-IUS's should be advised to use a second method of contraception, such as barrier methods, POP, or CHC (if no contraindications) once the approved duration of use has passed. 14 Most copper IUDs are effective for longer than their approved duration of use. Although the product monograph indicates a duration of use of 30 months for certain Cu-IUDs, evidence from clinical trials indicates that these may be used for up to 5 years. 15 There is good evidence to support the use of copper IUDs with 380mm 2 of copper for at least 12 years, 7,8,12,16 and likely until menopause if it is inserted over the age of 35. For those 5year copper IUDs with less than 380mm 2 of copper, there is likely effectiveness beyond five years, however a second method of contraception may be beneficial. POP and CHCs (if no contraindications exist) can be initiated with an IUD or IUS in situ until a removal appointment can be arranged. 14 Given the extended duration of effectiveness for many IUCs, patients who require initial IUC placement should be prioritized over those requiring IUC replacements during periods of social disruption. The etonogestrel subdermal implant is approved for three years of use. There is reliable evidence that etonogestrel implants remain effective beyond three years with studies showing excellent effectiveness at 4 and 5 years. 17 7, 13, 18 If a patient wishes to continue using an etonogestel implant, appointment for removal or replacement (once available) can be deferred. Although etonogestrel serum levels may still be above the minimum level required for ovulation inhibition beyond five years, women who have had the implant for more than five years should be advised to use another method of contraception due to potential variation among women. 19 6. Progestin-only contraception, including progestin-only pills (POPs) and depot medroxyprogesterone acetate (DMPA), may be safely initiated and continued without an in-person assessment.
Progestin-only contraception is effective and safe for the vast majority of women. When taken within the appropriate 3-hour time window, the progestin-only pill has similar efficacy to combined hormonal contraceptives. There are very few contraindications to the use of progestin-only contraception; these include current or recent progesterone-receptor positive breast cancer, severe liver cirrhosis, and hepatic adenoma (benign or malignant). 20 A virtual encounter may be used in place of an in-person assessment to initiate progestin-only contraceptives. Progestin-only contraception can be continued (re-prescribed) without a physical examination. Both DMPA and the POP can be initiated at any time during a woman's menstrual cycle. Back-up contraception should be used for at least 7 days after DMPA initiation or at least 48 hours after POP initiation (POP). 20 7. DMPA can be administered every 14 weeks by any healthcare provider trained to provide intramuscular (IM) injections.
In Canada, DMPA is approved and available as a 150 mg dose given as an intramuscular (IM) injection every 3 months (every 12 to 13 weeks), usually in an office setting. The 104 mg DMPA subcutaneous (sc) formulation is not available in Canada. DMPA IM maintains its effectiveness up to 14 weeks after the last injection. 20,21,22 Women may not be able to readily access their regular health care provider's office to receive their DMPA injection thus limiting contraceptive use and choice. Health care providers who did not initally prescribe DMPA may be asked to perform the injection. Regulatory bodies should consider removing barriers and allowing allied health professionals already trained in the provision of IM injections, such as pharmacists and midwives, to provide intramuscular DMPA injections thereby improving access. There should be no limit on the duration of DMPA use among women of reproductive age who are otherwise eligible to use this method. 20 8. It is reasonable to initiate estrogen-containing contraception without a blood pressure assessment in women who are otherwise at low risk of cardiovascular disease and have no contraindications to the use of combined hormonal contraception (CHC). A blood pressure should be assessed as soon as it is clinically feasible.
Estrogen-containing contraception may be continued and the prescription refilled without a blood pressure assessment if the woman has not developed any contraindications or adverse events during its use. A follow-up blood pressure should be obtained when feasible.
In healthy women < 35 years old with no other cardiovascular risk factors, the risk of occult hypertension is low. While a blood pressure assessment is recommended prior to initiating estrogen-containing pills, patches, or rings, 23,24 it can be deferred during a pandemic provided that the patient is otherwise healthy and has no contraindications to the use of combined hormonal contraception (CHC). If a patient has a home blood-pressure cuff, or a close contact who can perform a blood pressure, this can replace an in-office reading. A documented blood pressure within the past year is a sufficient screen for hypertension. Public blood pressure cuffs should not be used while physical and social isolation recommendations are in place.
An attempt to obtain a blood pressure measurement should be made within three months of CHC initiation. In patients > 35 years of age or younger patients with minor cardiovascular risk factors for whom estrogen containing contraceptives would still be considered acceptable, a blood pressure should be obtained within three months even if previously screened. Otherwise, continuation (re-prescribing) of estrogen-containing contraception can be performed by virtual visit or pharmacy refill without a blood pressure assessment.
# Contraceptive patches can be changed every 9 days. A single vaginal contraceptive ring can be used continuously for up to 4 weeks.
Both the contraceptive patch and the vaginal contraceptive ring can be used in an off-label fashion beyond their approved duration of use. 24 This recommendation may become more applicable in the event of drug shortages or limited ability to pay for contraception due to loss of income or extended health benefits. Pharmacokinetic studies indicate that the patch maintains ovulation inhibitory levels of hormones throughout 9 days of use, 25 while the ring maintains inhibitory levels for at least 28 days of use. 26 The hormone-free interval for the patch or the ring should NOT exceed seven days.
# Emergency contraception is an essential medical service for which timely access must be maintained.
Women should be reminded about the availability of emergency contraception (EC). Hormonal EC options include LNG-EC and UPA-EC (Ella®). Both should be taken within 5 days of unprotected intercourse (UPI). LNG-EC is more effective the sooner it is taken and can be obtained at a pharmacy without a prescription (either over-the counter or behind-the counter depending on the pharmacy and jurisdiction). UPA-EC requires a prescription and is more effective than LNG-EC, especially at days 4 and 5 after UPI. The copper IUD is the most effective EC method, can be inserted up to 7 days after UPI, and in addition provides ongoing contraception. 27 Copper IUD placement for emergency contraception should be considered an essential medical service.
Virtual encounters (telephone or video consultation) can be used for EC counselling. If hormonal EC is chosen, consider quick-starting another method of contraception such as a progestin-only pill or a combined hormonal contraceptive (in the absence of contraindications), and calling the prescription to a pharmacy. 14 Timing of starting contraception after hormonal EC will depend on whether LNG-EC or UPA-EC was taken. 28 Emergency copper IUD placements can be arranged when and where it is appropriate.
# Emergency contraception should be discussed (LNG-EC, UPA-EC, copper IUD) and proactive prescriptions (UPA-EC) provided. Women should be aware of the possibility of drug shortages and possible alternatives to their current method of contraception.
Proactive prescription of UPA-EC should be considered for all patients using less reliable forms of contraception (SARC, barrier methods, withdrawal, natural family planning) or no method of contraception. If a patient feels uncomfortable initiating long acting reversible contraception given physical distancing recommendations and desires fewer in-person visits for safety, she should be counselled on short-acting and barrier methods of contraception.
A prescription for UPA-EC could be provided until an in-person encounter can occur.
Due to disrupted production sites and supply chains, medication shortages may occur. 29 Although health care providers should provide enough refills to reduce required visits to medical offices and pharmacies, pharmacies may limit prescriptions to a 30-day supply.
Patients may wish to explore and consider other contraceptive methods, including barrier contraception, in addition to their current method.
- Women and couples who are awaiting a permanent contraception procedure should be reminded to use an effective, reversible method of contraception at this time and until the procedure can be performed.
The COVID-19 crisis requires the indefinite postponement of scheduled non-urgent procedures, including permanent contraception procedures. 30 Women waiting for a date for surgery or a consultation for permanent contraception are at risk of unintended pregnancy if they are not using an effective method of birth control. It is advisable to inform these individuals that these procedures have been postponed indefinitely and remind them to use an effective contraceptive method until the procedure can be performed. 31 Counselling on other contraceptive options can be performed by virtual encounter (telephone or video conferencing).
- Women who are positive for COVID-19 infection can continue any form of contraception that has already been initiated, including combined hormonal contraceptives, regardless of illness severity.
# Asymptomatic and mild illness not requiring hospitalization
There is currently no available evidence associating asymptomatic and mild COVID-19 illnesses not requiring hospitalization with an increased venous thromboembolism (VTE) risk. 32,33 In this context, any form of contraception, including estrogen-containing combined hormonal contraceptives, can be continued without modification.
# Moderate to severe illness requiring hospitalization
Moderate and severe COVID-19 illnesses requiring hospitalization are associated with an increased VTE risk, up to 17% incidence of any VTE and 7.1% incidence of pulmonary embolism (PE). 34 Study populations were often older, mostly male and had risk factors for VTE, limiting generalizability to healthy, reproductive age women. Current recommendations are to prophylactically anti-coagulate everyone hospitalized with a COVID-19 illness. 35 Non-hormonal contraceptives (copper intrauterine device) and progesterone-only methods of contraception (POP, LNG-IUS, DMPA and progestin implants) are not associated with an increased risk of VTE 20 and require no modification to their ongoing use in women with moderate to severe COVID-19 illness requiring hospitalization.
Combined oral contraceptives (COCs) are associated with a 2-to 3-fold increase in VTE compared to non-users, with the highest risk in the first year of use. 24 Baseline risk of VTE in reproductive age women not using COCs is 4-5/10,000-woman years, compared to 10/10,000 woman years in COC users. This is in comparison to the relative risk of 6.7 of VTE in pregnancy and 115.1 in the postpartum period. 24 Contextualizing this risk against the risk of a pregnancy complicated by COVID-19 illness is crucial. In pregnant women with a COVID-19 illness, current data show a 7-10% rate of ICU admission, 3.4% rate of mechanical ventilation and 1% maternal mortality rate. 36 The rate of VTE in pregnant women with COVID-19 is not established yet, with only a handful of case reports so far. 37,38,39,40 Given the elevated risk of VTE associated with pregnancy and postpartum compared to CHC use, as well as the risks of pregnancy complicated by COVID-19 illness, continued use of CHCs (pill, patch or ring) in women with moderate to severe COVID-19 illness requiring hospitalization represents a balanced harm reduction approach.
# Asymptomatic and mild illness not requiring hospitalization
There is currently no available evidence associating asymptomatic and mild COVID-19 illnesses not requiring hospitalization with an increased venous thromboembolism (VTE) risk. 32,33 In this context, initiating any form of contraception, including estrogen-containing combined hormonal contraceptives, is safe. The usual Medical Eligibility Criteria for each method apply. As outlined earlier in this guideline, women initiating combined hormonal contraceptives (pill, patch, ring) who are otherwise at low risk of cardiovascular disease, can initiate without a blood pressure assessment. A blood pressure should be assessed as soon as it is clinically feasible.
# Moderate to severe illness requiring hospitalization
Non-hormonal contraceptives (copper intrauterine device) and progesterone-only methods of contraception (POP, LNG-IUS, DMPA and progestin implants) are not associated with an increased risk of VTE 20 and can be initiated in women with moderate to severe COVID-19 illness requiring hospitalization.
As outlined above, COC use is associated with a 2-to 3-fold increase in VTE risk from baseline, with the highest risk within the first year of use. While women with COVID-19 who have already initiated this as their chosen form of contraception may continue instead of stopping and re-starting CHCs, women who are choosing to initiate contraception at the time of moderate to severe COVID-19 illness requiring hospitalization should consider nonhormonal or progesterone-only methods first.
The risk of VTE associated with moderate to severe COVID-19 illness requiring hospitalization returns to baseline at discharge from hospital. 41 Current recommendations are to halt prophylactic anti-coagulation at the time of discharge. 35,42 Given this return to baseline VTE risk, women desiring to initiate combined hormonal contraception or transition from another method can do so safely at this time.
# Women who are positive for COVID-19 infection can use any form of emergency contraception, regardless of illness severity.
There are no absolute contraindications to the use of emergency contraception aside from pregnancy and hypersensitivity. 43 Even women with contraindications to the use of CHCs can safely use hormonal EC methods. 43 Women with any severity of COVID-19 illness can safely use any of the currently available methods for emergency contraception in Canada.
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# Introduction
The COVID-19 pandemic is a public health crisis with wide reaching health care implications due to illnesses from the disease itself, social and physical distancing restrictions, and the deferral or indefinite postponement of non-urgent clinical care and procedures. As physical and social distancing measures have been implemented to curb the spread of COVID-19, healthcare has been upended with the deferral or cancellation of in-person visits and health care providers have had to rapidly adapt their clinical practice. During this time, drug production sites and supply chains have also been disrupted. Consequently, Canadian people and couples who want to avoid a pregancy at this time are at increased risk of developing an unmet need for family planning due to lack of access to contraceptive care or methods. Compounding this, social isolation may increase unintended pregnancy through exposure to unprotected intercourse, reproductive coercion, and intimate personal violence.
Ideally, contraception provision would be practised in accordance with the Canadian Contraception Consensus guidelines, including recommendations for screening, duration of use, follow-up assessments, and the provision of long-acting reversible contraception (LARC) methods as firstline contraception methods. During pandemic situations, provision of family planning services must be adapted in an evidence-based fashion. This document provides interim guidance to affirm best practices and provide expert consensus on strategies to maintain contraceptive access during the COVID-19 pandemic or other periods of major social disruption.
# Recommendations and Summary Statements
# The unmet need for contraception increases during periods of social disruption,
including pandemics. Health care providers should facilitate continued access to contraception during this time.
Access to safe, voluntary family planning is a human right. 1,2 During social disruptions, including wartime conflict and pandemics, there is an increased and unmet need for contraception, leading to increased rates of unintended pregnancy and its associated outcomes. 3,4 Individuals may lack access to contraception and thus have unprotected intercourse as well as be at increased risk of intimate partner violence, reproductive coercion, and unwanted or unplanned intercourse.
It is essential to have ongoing access to a choice of effective contraceptives through the provision of information, counselling, and services (including emergency contraception). 5 Given the elevated risk of adverse outcomes of pregnancy, and the humanitarian need to ensure access to birth control, the UNFPA considers access to contraception "life-saving" during a pandemic. 5 Healthcare providers should facilitate ongoing access to contraception, including offering virtual visits to initiate, improve, and continue contraceptive methods.
# During the COVID-19 pandemic, contraceptive care may be offered virtually (telephone encounter, video encounter) or in person depending on the needs of the individual and in line with other health authority recommendations
To facilitate access to contraception while respecting physical and social distancing guidance, contraception counselling can be performed virtually to determine acceptable contraceptive options for an individual patient. Some contraceptive methods can be initiated without the need for an in-person assessment, including barrier methods, the POP, DMPA, and in some instances combined hormonal contraception (in the absence of contraindications). Initiation of other methods, such as long acting reversible contraceptives (LARC), may need to be deferred if the clinical resources for insertion are not readily available, the patient has known or suspected COVID-19 infection, or is in a high risk category for COVID-19 infection.
# Long-Acting Reversible Contraception (LARC) provides reliable contraception that
is resistant to fluctuations in healthcare access during a pandemic. LARC placement is an essential medical service and women who would benefit from a LARC method should be able to access placement or insertion appointments.
In Canada, intrauterine contraception (IUC) is the only LARC method available at this time.
Women may have had a contraceptive implant inserted in another country but the single rod etonogestrel implant is not currently available in Canada. IUCs include levonorgestrel intrauterine systems (LNG-IUS) and copper intrauterine devices (Cu-IUD). IUCs provide effective reversible contraception for up to (and in some cases beyond) 5 years. 6 LARC methods are the most effective way to prevent unintended pregnancy but it may not be possible for all clinicians to maintain access to IUC placement or implant insertion (when available) during a pandemic or period of social disruption.
Health care providers who currently provide IUC care are encouraged to continue offering this service if feasible. Clinics should follow local public health guidelines to screen patients prior to appointments, have access to appropriate personal protective equipment (PPE), wash and disinfect clinical areas as required, and adhere to scrupulous hand-washing protocols. Health care providers should have a robust system for assessing and ensuring follow-up for patients they are able to see. If IUC placement is not possible during the pandemic, contraceptives that can be self-administered should be offered as a bridge to delayed IUC insertion. A short-acting reversible contraceptive (SARC) can be initiated immediately in the absence of contraindications to method use.
Health care providers should make particular efforts to maintain IUC access (through provision or referral) for patients at higher risk of unintended pregnancy and its complications, including those with a history of unintended pregnancy, those at risk of reproductive coercion or intimate partner violence, those with contraindications to estrogencontaining contraception, and patients for whom a short-acting contraceptive method (including barriers) is contraindicated or unlikely to provide reliable contraception. .
# Intrauterine contraception (IUC) may be safely continued beyond its approved duration of use. Appointments for IUC removal or replacement can be deferred up to 12 months, depending on the specific device and duration of use.
Routine IUC replacements and removals should be postponed if possible and IUC users should be counselled on the safety and effectiveness of extended IUC use. Extended use of an IUC is safe beyond the approved duration of use, however there may be small effects on effectiveness. Although each device is approved for certain durations of use, most are effective for longer than the manufacturers' recommendations 6,7 and immediate replacement at the end of this time period is not necessary.
There is good evidence to support exended use of the LNG-IUS 52 mg (Mirena®) for up to 7 years in women who are > 25 years old at the time of insertion. 7,8,9,10,11,12,13 There is limited experience with extended use of the LNG-IUS 13.5 mg (Jaydess®) and the LNG-IUS 19.5 mg (Kyleena®). Although the risk of pregnancy is likely to be small, women using the 13.5 mg and 19.5 mg LNG-IUS's should be advised to use a second method of contraception, such as barrier methods, POP, or CHC (if no contraindications) once the approved duration of use has passed. 14 Most copper IUDs are effective for longer than their approved duration of use. Although the product monograph indicates a duration of use of 30 months for certain Cu-IUDs, evidence from clinical trials indicates that these may be used for up to 5 years. 15 There is good evidence to support the use of copper IUDs with 380mm 2 of copper for at least 12 years, 7,8,12,16 and likely until menopause if it is inserted over the age of 35. For those 5year copper IUDs with less than 380mm 2 of copper, there is likely effectiveness beyond five years, however a second method of contraception may be beneficial. POP and CHCs (if no contraindications exist) can be initiated with an IUD or IUS in situ until a removal appointment can be arranged. 14 Given the extended duration of effectiveness for many IUCs, patients who require initial IUC placement should be prioritized over those requiring IUC replacements during periods of social disruption. The etonogestrel subdermal implant is approved for three years of use. There is reliable evidence that etonogestrel implants remain effective beyond three years with studies showing excellent effectiveness at 4 and 5 years. 17 7, 13, 18 If a patient wishes to continue using an etonogestel implant, appointment for removal or replacement (once available) can be deferred. Although etonogestrel serum levels may still be above the minimum level required for ovulation inhibition beyond five years, women who have had the implant for more than five years should be advised to use another method of contraception due to potential variation among women. 19 6. Progestin-only contraception, including progestin-only pills (POPs) and depot medroxyprogesterone acetate (DMPA), may be safely initiated and continued without an in-person assessment.
Progestin-only contraception is effective and safe for the vast majority of women. When taken within the appropriate 3-hour time window, the progestin-only pill has similar efficacy to combined hormonal contraceptives. There are very few contraindications to the use of progestin-only contraception; these include current or recent progesterone-receptor positive breast cancer, severe liver cirrhosis, and hepatic adenoma (benign or malignant). 20 A virtual encounter may be used in place of an in-person assessment to initiate progestin-only contraceptives. Progestin-only contraception can be continued (re-prescribed) without a physical examination. Both DMPA and the POP can be initiated at any time during a woman's menstrual cycle. Back-up contraception should be used for at least 7 days after DMPA initiation or at least 48 hours after POP initiation (POP). 20 7. DMPA can be administered every 14 weeks by any healthcare provider trained to provide intramuscular (IM) injections.
In Canada, DMPA is approved and available as a 150 mg dose given as an intramuscular (IM) injection every 3 months (every 12 to 13 weeks), usually in an office setting. The 104 mg DMPA subcutaneous (sc) formulation is not available in Canada. DMPA IM maintains its effectiveness up to 14 weeks after the last injection. 20,21,22 Women may not be able to readily access their regular health care provider's office to receive their DMPA injection thus limiting contraceptive use and choice. Health care providers who did not initally prescribe DMPA may be asked to perform the injection. Regulatory bodies should consider removing barriers and allowing allied health professionals already trained in the provision of IM injections, such as pharmacists and midwives, to provide intramuscular DMPA injections thereby improving access. There should be no limit on the duration of DMPA use among women of reproductive age who are otherwise eligible to use this method. 20 8. It is reasonable to initiate estrogen-containing contraception without a blood pressure assessment in women who are otherwise at low risk of cardiovascular disease and have no contraindications to the use of combined hormonal contraception (CHC). A blood pressure should be assessed as soon as it is clinically feasible.
Estrogen-containing contraception may be continued and the prescription refilled without a blood pressure assessment if the woman has not developed any contraindications or adverse events during its use. A follow-up blood pressure should be obtained when feasible.
In healthy women < 35 years old with no other cardiovascular risk factors, the risk of occult hypertension is low. While a blood pressure assessment is recommended prior to initiating estrogen-containing pills, patches, or rings, 23,24 it can be deferred during a pandemic provided that the patient is otherwise healthy and has no contraindications to the use of combined hormonal contraception (CHC). If a patient has a home blood-pressure cuff, or a close contact who can perform a blood pressure, this can replace an in-office reading. A documented blood pressure within the past year is a sufficient screen for hypertension. Public blood pressure cuffs should not be used while physical and social isolation recommendations are in place.
An attempt to obtain a blood pressure measurement should be made within three months of CHC initiation. In patients > 35 years of age or younger patients with minor cardiovascular risk factors for whom estrogen containing contraceptives would still be considered acceptable, a blood pressure should be obtained within three months even if previously screened. Otherwise, continuation (re-prescribing) of estrogen-containing contraception can be performed by virtual visit or pharmacy refill without a blood pressure assessment.
# Contraceptive patches can be changed every 9 days. A single vaginal contraceptive ring can be used continuously for up to 4 weeks.
Both the contraceptive patch and the vaginal contraceptive ring can be used in an off-label fashion beyond their approved duration of use. 24 This recommendation may become more applicable in the event of drug shortages or limited ability to pay for contraception due to loss of income or extended health benefits. Pharmacokinetic studies indicate that the patch maintains ovulation inhibitory levels of hormones throughout 9 days of use, 25 while the ring maintains inhibitory levels for at least 28 days of use. 26 The hormone-free interval for the patch or the ring should NOT exceed seven days.
# Emergency contraception is an essential medical service for which timely access must be maintained.
Women should be reminded about the availability of emergency contraception (EC). Hormonal EC options include LNG-EC and UPA-EC (Ella®). Both should be taken within 5 days of unprotected intercourse (UPI). LNG-EC is more effective the sooner it is taken and can be obtained at a pharmacy without a prescription (either over-the counter or behind-the counter depending on the pharmacy and jurisdiction). UPA-EC requires a prescription and is more effective than LNG-EC, especially at days 4 and 5 after UPI. The copper IUD is the most effective EC method, can be inserted up to 7 days after UPI, and in addition provides ongoing contraception. 27 Copper IUD placement for emergency contraception should be considered an essential medical service.
Virtual encounters (telephone or video consultation) can be used for EC counselling. If hormonal EC is chosen, consider quick-starting another method of contraception such as a progestin-only pill or a combined hormonal contraceptive (in the absence of contraindications), and calling the prescription to a pharmacy. 14 Timing of starting contraception after hormonal EC will depend on whether LNG-EC or UPA-EC was taken. 28 Emergency copper IUD placements can be arranged when and where it is appropriate.
# Emergency contraception should be discussed (LNG-EC, UPA-EC, copper IUD) and proactive prescriptions (UPA-EC) provided. Women should be aware of the possibility of drug shortages and possible alternatives to their current method of contraception.
Proactive prescription of UPA-EC should be considered for all patients using less reliable forms of contraception (SARC, barrier methods, withdrawal, natural family planning) or no method of contraception. If a patient feels uncomfortable initiating long acting reversible contraception given physical distancing recommendations and desires fewer in-person visits for safety, she should be counselled on short-acting and barrier methods of contraception.
A prescription for UPA-EC could be provided until an in-person encounter can occur.
Due to disrupted production sites and supply chains, medication shortages may occur. 29 Although health care providers should provide enough refills to reduce required visits to medical offices and pharmacies, pharmacies may limit prescriptions to a 30-day supply.
Patients may wish to explore and consider other contraceptive methods, including barrier contraception, in addition to their current method.
12. Women and couples who are awaiting a permanent contraception procedure should be reminded to use an effective, reversible method of contraception at this time and until the procedure can be performed.
The COVID-19 crisis requires the indefinite postponement of scheduled non-urgent procedures, including permanent contraception procedures. 30 Women waiting for a date for surgery or a consultation for permanent contraception are at risk of unintended pregnancy if they are not using an effective method of birth control. It is advisable to inform these individuals that these procedures have been postponed indefinitely and remind them to use an effective contraceptive method until the procedure can be performed. 31 Counselling on other contraceptive options can be performed by virtual encounter (telephone or video conferencing).
13. Women who are positive for COVID-19 infection can continue any form of contraception that has already been initiated, including combined hormonal contraceptives, regardless of illness severity.
# Asymptomatic and mild illness not requiring hospitalization
There is currently no available evidence associating asymptomatic and mild COVID-19 illnesses not requiring hospitalization with an increased venous thromboembolism (VTE) risk. 32,33 In this context, any form of contraception, including estrogen-containing combined hormonal contraceptives, can be continued without modification.
# Moderate to severe illness requiring hospitalization
Moderate and severe COVID-19 illnesses requiring hospitalization are associated with an increased VTE risk, up to 17% incidence of any VTE and 7.1% incidence of pulmonary embolism (PE). 34 Study populations were often older, mostly male and had risk factors for VTE, limiting generalizability to healthy, reproductive age women. Current recommendations are to prophylactically anti-coagulate everyone hospitalized with a COVID-19 illness. 35 Non-hormonal contraceptives (copper intrauterine device) and progesterone-only methods of contraception (POP, LNG-IUS, DMPA and progestin implants) are not associated with an increased risk of VTE 20 and require no modification to their ongoing use in women with moderate to severe COVID-19 illness requiring hospitalization.
Combined oral contraceptives (COCs) are associated with a 2-to 3-fold increase in VTE compared to non-users, with the highest risk in the first year of use. 24 Baseline risk of VTE in reproductive age women not using COCs is 4-5/10,000-woman years, compared to 10/10,000 woman years in COC users. This is in comparison to the relative risk of 6.7 of VTE in pregnancy and 115.1 in the postpartum period. 24 Contextualizing this risk against the risk of a pregnancy complicated by COVID-19 illness is crucial. In pregnant women with a COVID-19 illness, current data show a 7-10% rate of ICU admission, 3.4% rate of mechanical ventilation and 1% maternal mortality rate. 36 The rate of VTE in pregnant women with COVID-19 is not established yet, with only a handful of case reports so far. 37,38,39,40 Given the elevated risk of VTE associated with pregnancy and postpartum compared to CHC use, as well as the risks of pregnancy complicated by COVID-19 illness, continued use of CHCs (pill, patch or ring) in women with moderate to severe COVID-19 illness requiring hospitalization represents a balanced harm reduction approach.
# Asymptomatic and mild illness not requiring hospitalization
There is currently no available evidence associating asymptomatic and mild COVID-19 illnesses not requiring hospitalization with an increased venous thromboembolism (VTE) risk. 32,33 In this context, initiating any form of contraception, including estrogen-containing combined hormonal contraceptives, is safe. The usual Medical Eligibility Criteria for each method apply. As outlined earlier in this guideline, women initiating combined hormonal contraceptives (pill, patch, ring) who are otherwise at low risk of cardiovascular disease, can initiate without a blood pressure assessment. A blood pressure should be assessed as soon as it is clinically feasible.
# Moderate to severe illness requiring hospitalization
Non-hormonal contraceptives (copper intrauterine device) and progesterone-only methods of contraception (POP, LNG-IUS, DMPA and progestin implants) are not associated with an increased risk of VTE 20 and can be initiated in women with moderate to severe COVID-19 illness requiring hospitalization.
As outlined above, COC use is associated with a 2-to 3-fold increase in VTE risk from baseline, with the highest risk within the first year of use. While women with COVID-19 who have already initiated this as their chosen form of contraception may continue instead of stopping and re-starting CHCs, women who are choosing to initiate contraception at the time of moderate to severe COVID-19 illness requiring hospitalization should consider nonhormonal or progesterone-only methods first.
The risk of VTE associated with moderate to severe COVID-19 illness requiring hospitalization returns to baseline at discharge from hospital. 41 Current recommendations are to halt prophylactic anti-coagulation at the time of discharge. 35,42 Given this return to baseline VTE risk, women desiring to initiate combined hormonal contraception or transition from another method can do so safely at this time.
# Women who are positive for COVID-19 infection can use any form of emergency contraception, regardless of illness severity.
There are no absolute contraindications to the use of emergency contraception aside from pregnancy and hypersensitivity. 43 Even women with contraindications to the use of CHCs can safely use hormonal EC methods. 43 Women with any severity of COVID-19 illness can safely use any of the currently available methods for emergency contraception in Canada.
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# Background
Bladder cancer is the fourth most common cancer among men and accounts for 8% of all new male cancer cases. Urinary bladder cancer is less common among women (ranked 11th) and accounts for less than 3% of all new female cancer cases. Statistics Canada estimates that in 2022 there will be approximately 13,300 new cases of bladder cancer and 2,500 deaths associated with bladder cancer in Canada. 1 Upper tract disease represents approximately 5-10% of all urothelial malignancies. 2 Upper tract tumours can be graded, in order to distinguish those with a low risk or recurrence from those with a high risk. The grading system was developed by the World Health Organization (WHO) in 2004. 3 Papillary urothelial neoplasms of low malignant potential (PUNLMP) have a low rate of recurrence (36%) and stage progression (3.7%) as compared to low grade papillary urothelial carcinomas (50% and 10%, respectively). High grade papillary urothelial carcinomas have a high rate of recurrence and stage progression. The progression rate ranges from 15 to 40%. 4,5 Guideline Questions 1. What staging investigations are required for patients with upper tract tumours? 2. What are the appropriate treatment options (i.e., surgery, systemic therapy, etc.) for patients with upper tract tumours? 3. What is a reasonable follow-up strategy for patients who have completed treatment for upper tract tumours?
# Search Strategy
This guideline was reviewed and endorsed by the Alberta Provincial Genitourinary Tumour Team. Members of the Alberta Provincial Genitourinary Tumour Team include medical oncologists, radiation oncologists, urologists, pathologists, nurses, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Genitourinary Tumour Team and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Utilization Unit Handbook.
This guideline was originally developed in April, 2013 and updated in December 2020.
# Target Population
These guideline recommendations apply to adult patients with transitional cell carcinoma (urothelial carcinoma) of the ureter and/or renal pelvis.
# Recommendations
# Staging
# Discussion
Due to the small number of patients that present with primary transitional cell carcinoma (TCC) of the ureter and renal pelvis, there is a lack of high level evidence (i.e., randomized controlled trials) to inform the treatment strategies for this disease. For this reason, many of the recommendations are based on findings from studies involving patients with TCC of the bladder. Physicians should take into account specific clinical characteristics of each patient with regard to renal function, comorbidities, tumour location, stage and grade when determining the optimal treatment for their patients. 7
# Surgery
If the tumour is operable, surgical excision is recommended. Nephroureterectomy with cuff of bladder excision is recommended, or if possible, a nephron-sparing procedure for low-grade disease. Lymph node dissection is recommended in high-grade cases. An analysis of the SEER database compared the cancer-specific mortality of patients with pT1-4 (any N, M0) disease who underwent a nephroureterectomy with a bladder cuff excision versus those who had a nephroureterectomy alone.
The results indicated that the cancer-specific mortality was higher at 2 and 5 years among patients in the nephroureterectomy only group (17.7% and 28.1% versus 12.2% and 22.4%). However, patients that underwent bladder cuff excision were significantly younger. 8 A single institution retrospective study, comparing outcomes associated with nephroureterectomy versus nephron-sparing endoscopic surgery, among 96 patients with upper tract TCC, showed that the 5-year overall survival rate was comparable between treatment groups (i.e., 72% for nephroureterectomy and 75% for nephronsparing approach). Patients with low grade disease treated with a nephron-sparing approach had a higher 5-year metastases-free survival (94% versus 88%) and 5-year cancer-specific survival (100% versus 89%), along with a lower complication rate (9.3% versus 29%). The authors concluded that endoscopic management provides cancer related and overall survival equivalent to that of nephroureterectomy in patients with low-grade disease. 9 An abstract presented at the American Urological Association meeting in May 2012 analyzed the outcomes of 1029 patients with upper tract TCC from the Canadian UTUC database. 10 In multivariate analyses, no differences were found in overall survival or disease-specific survival based on surgical approach (extravesical management, open bladder cuff excision or endoscopic management). Furthermore, open bladder cuff excision was found to reduce tumour recurrence compared with extravesical management (HR=0.628, 95% CI 0.491-0.801, p=0.0002). 10
# Neoadjuvant Therapy
Cases in which systemic therapy is being considered should be brought to and discussed at local tumour board meetings. Neoadjuvant chemotherapy can be considered in high grade patients, if the degree of invasiveness can be established prior to surgery. There is no strong evidence that neoadjuvant chemotherapy is effective in the treatment of TCC of the renal pelvis and ureter due to the rarity of the disease and lack of literature. 7,11 A retrospective comparative study comparing patients with biopsy-proven high-grade disease who received neoadjuvant chemotherapy followed by nephrouterectomy with patients who underwent initial nephroureterectomy (N=150) demonstrated significant downstaging with neoadjuvant chemotherapy (p =.004). The incidence of tumors classified as pathologic T2 (pT2) or as pT3 or higher was significantly lower in the study group (pT2, 65.4% vs 48.8%; P = .043; pT3 or higher, 47.7% vs 27.9%; P = .029). 12 Based on this data, the European Guidelines on Upper Tract Urothelial Carcinomas recommend this strategy. 12 Furthermore, because of the comparable etiology between TCC of the bladder and that of the upper tract, findings from studies involving patients with invasive bladder cancer can be extrapolated to patients with highgrade upper tract urothelial carcinoma. 13,14 A meta-analysis by the Advanced Bladder Cancer (ABC) Meta-analysis Collaboration (2005) of 11 trials (N=3005) found a significant survival benefit with platinum-based combination chemotherapy (HR=0.86, 95% CI 0.77-0.95, p=.003), equivalent to a 5% absolute improvement in survival at 5 years. A significant disease-free survival benefit was also noted in those patients that received neoadjuvant platinum-based chemotherapy (HR=0.78, 95% CI 0.71-0.86, p<.0001). 15 Another meta-analysis of eight trials of neoadjuvant cisplatinum-based combination chemo-therapy for TCC of the bladder published similar results; the pooled HR was 0.87 (95%, CI 0.78-0.96, p=.006), consistent with an absolute overall survival benefit of 6.5%. 16 A more recent retrospective study that included patients with upper tract TCC who received neoadjuvant chemotherapy following by laparoscopic nephroureterectomy showed that, as compared to nephroureterectomy alone, neoadjuvant chemotherapy was associated with a significantly higher complete response rate (15% versus 1.7%); however, complications were higher in the neoadjuvant chemotherapy group (58% versus 45%). 17 Similar results have been reported elsewhere. 18
# Adjuvant Therapy
The open-label phase 3 POUT trial compared adjuvant chemotherapy to surveillance after nephroureterectomy with curative intent in UTUC patients. Chemotherapy was cisplatin or carboplatin (for GFR <50 mL/min) plus gemcitabine. A total of N=261 patients were enrolled from 57 sites. Adjuvant chemotherapy significantly improved disease-free survival (HR: 0.45; 95%CI: 0.330-0.68; p<0.001) after a median follow-up of 30.3 months. Treatment associated adverse events were reported in 44% of patients who underwent chemotherapy. 19 T4b Extravesical tumor invades pelvic wall, abdominal wall
|
# Background
Bladder cancer is the fourth most common cancer among men and accounts for 8% of all new male cancer cases. Urinary bladder cancer is less common among women (ranked 11th) and accounts for less than 3% of all new female cancer cases. Statistics Canada estimates that in 2022 there will be approximately 13,300 new cases of bladder cancer and 2,500 deaths associated with bladder cancer in Canada. 1 Upper tract disease represents approximately 5-10% of all urothelial malignancies. 2 Upper tract tumours can be graded, in order to distinguish those with a low risk or recurrence from those with a high risk. The grading system was developed by the World Health Organization (WHO) in 2004. 3 Papillary urothelial neoplasms of low malignant potential (PUNLMP) have a low rate of recurrence (36%) and stage progression (3.7%) as compared to low grade papillary urothelial carcinomas (50% and 10%, respectively). High grade papillary urothelial carcinomas have a high rate of recurrence and stage progression. The progression rate ranges from 15 to 40%. 4,5 Guideline Questions 1. What staging investigations are required for patients with upper tract tumours? 2. What are the appropriate treatment options (i.e., surgery, systemic therapy, etc.) for patients with upper tract tumours? 3. What is a reasonable follow-up strategy for patients who have completed treatment for upper tract tumours?
# Search Strategy
This guideline was reviewed and endorsed by the Alberta Provincial Genitourinary Tumour Team. Members of the Alberta Provincial Genitourinary Tumour Team include medical oncologists, radiation oncologists, urologists, pathologists, nurses, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Genitourinary Tumour Team and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Utilization Unit Handbook.
This guideline was originally developed in April, 2013 and updated in December 2020.
# Target Population
These guideline recommendations apply to adult patients with transitional cell carcinoma (urothelial carcinoma) of the ureter and/or renal pelvis.
# Recommendations
# Staging
# Discussion
Due to the small number of patients that present with primary transitional cell carcinoma (TCC) of the ureter and renal pelvis, there is a lack of high level evidence (i.e., randomized controlled trials) to inform the treatment strategies for this disease. For this reason, many of the recommendations are based on findings from studies involving patients with TCC of the bladder. Physicians should take into account specific clinical characteristics of each patient with regard to renal function, comorbidities, tumour location, stage and grade when determining the optimal treatment for their patients. 7
# Surgery
If the tumour is operable, surgical excision is recommended. Nephroureterectomy with cuff of bladder excision is recommended, or if possible, a nephron-sparing procedure for low-grade disease. Lymph node dissection is recommended in high-grade cases. An analysis of the SEER database compared the cancer-specific mortality of patients with pT1-4 (any N, M0) disease who underwent a nephroureterectomy with a bladder cuff excision versus those who had a nephroureterectomy alone.
The results indicated that the cancer-specific mortality was higher at 2 and 5 years among patients in the nephroureterectomy only group (17.7% and 28.1% versus 12.2% and 22.4%). However, patients that underwent bladder cuff excision were significantly younger. 8 A single institution retrospective study, comparing outcomes associated with nephroureterectomy versus nephron-sparing endoscopic surgery, among 96 patients with upper tract TCC, showed that the 5-year overall survival rate was comparable between treatment groups (i.e., 72% for nephroureterectomy and 75% for nephronsparing approach). Patients with low grade disease treated with a nephron-sparing approach had a higher 5-year metastases-free survival (94% versus 88%) and 5-year cancer-specific survival (100% versus 89%), along with a lower complication rate (9.3% versus 29%). The authors concluded that endoscopic management provides cancer related and overall survival equivalent to that of nephroureterectomy in patients with low-grade disease. 9 An abstract presented at the American Urological Association meeting in May 2012 analyzed the outcomes of 1029 patients with upper tract TCC from the Canadian UTUC database. 10 In multivariate analyses, no differences were found in overall survival or disease-specific survival based on surgical approach (extravesical management, open bladder cuff excision or endoscopic management). Furthermore, open bladder cuff excision was found to reduce tumour recurrence compared with extravesical management (HR=0.628, 95% CI 0.491-0.801, p=0.0002). 10
# Neoadjuvant Therapy
Cases in which systemic therapy is being considered should be brought to and discussed at local tumour board meetings. Neoadjuvant chemotherapy can be considered in high grade patients, if the degree of invasiveness can be established prior to surgery. There is no strong evidence that neoadjuvant chemotherapy is effective in the treatment of TCC of the renal pelvis and ureter due to the rarity of the disease and lack of literature. 7,11 A retrospective comparative study comparing patients with biopsy-proven high-grade disease who received neoadjuvant chemotherapy followed by nephrouterectomy with patients who underwent initial nephroureterectomy (N=150) demonstrated significant downstaging with neoadjuvant chemotherapy (p =.004). The incidence of tumors classified as pathologic T2 (pT2) or as pT3 or higher was significantly lower in the study group (pT2, 65.4% vs 48.8%; P = .043; pT3 or higher, 47.7% vs 27.9%; P = .029). 12 Based on this data, the European Guidelines on Upper Tract Urothelial Carcinomas recommend this strategy. 12 Furthermore, because of the comparable etiology between TCC of the bladder and that of the upper tract, findings from studies involving patients with invasive bladder cancer can be extrapolated to patients with highgrade upper tract urothelial carcinoma. 13,14 A meta-analysis by the Advanced Bladder Cancer (ABC) Meta-analysis Collaboration (2005) of 11 trials (N=3005) found a significant survival benefit with platinum-based combination chemotherapy (HR=0.86, 95% CI 0.77-0.95, p=.003), equivalent to a 5% absolute improvement in survival at 5 years. A significant disease-free survival benefit was also noted in those patients that received neoadjuvant platinum-based chemotherapy (HR=0.78, 95% CI 0.71-0.86, p<.0001). 15 Another meta-analysis of eight trials of neoadjuvant cisplatinum-based combination chemo-therapy for TCC of the bladder published similar results; the pooled HR was 0.87 (95%, CI 0.78-0.96, p=.006), consistent with an absolute overall survival benefit of 6.5%. 16 A more recent retrospective study that included patients with upper tract TCC who received neoadjuvant chemotherapy following by laparoscopic nephroureterectomy showed that, as compared to nephroureterectomy alone, neoadjuvant chemotherapy was associated with a significantly higher complete response rate (15% versus 1.7%); however, complications were higher in the neoadjuvant chemotherapy group (58% versus 45%). 17 Similar results have been reported elsewhere. 18
# Adjuvant Therapy
The open-label phase 3 POUT trial compared adjuvant chemotherapy to surveillance after nephroureterectomy with curative intent in UTUC patients. Chemotherapy was cisplatin or carboplatin (for GFR <50 mL/min) plus gemcitabine. A total of N=261 patients were enrolled from 57 sites. Adjuvant chemotherapy significantly improved disease-free survival (HR: 0.45; 95%CI: 0.330-0.68; p<0.001) after a median follow-up of 30.3 months. Treatment associated adverse events were reported in 44% of patients who underwent chemotherapy. 19 T4b Extravesical tumor invades pelvic wall, abdominal wall
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In this guideline update, we highlight important and new findings related to pharmacological therapy of chronic obstructive pulmonary disease (COPD) that should change clinical practice and improve disease management. We present updated evidence, recommendations and expert clinical remarks on maintenance pharmacotherapy in patients with stable COPD. The diagnosis and nonpharmacological therapy of COPD are out-of-scope for this update. In patients with COPD who have persistent shortness of breath, exercise intolerance and/or poor health status despite using inhaled LAMA or LABA monotherapy, we recommend augmenting treatment to LAMA/LABA dual therapy. In patients with high-risk exacerbations, LAMA/LABA is the preferred choice to ICS/LABA except in patients with previous exacerbations who have higher peripheral eosinophilia. There is no role for ICS monotherapy; when indicated, ICS should only be used in combination with bronchodilators. Treatment "step up" in COPD is proposed as a practical construct supported by evidence that inhaled combined therapy is superior to monotherapy and triple therapy to dual therapy in certain patient populations. Because the superiority of inhaled triple or dual bronchodilator therapy may not be achieved in every patient, "step down" may be considered for some patients (not at high risk for future exacerbations), but should be done with close medical supervision, as the risk of clinical deterioration is real and continues to exist. The decision of changing a therapy should always occur after a complete evaluation of the patient and the potential benefit to a change in therapy; as well as an assessment of any adverse effects of the therapy, and with a review of patient adherence, inhaler technique and patient preferences. Pharmacological therapy plays a foundational role in therapy, but it should never be the sole treatment in managing COPD patients. Clinicians should always combine and optimize pharmacological and nonpharmacological therapies with the dual goals of reducing symptoms and preventing acute exacerbations of COPD (AECOPD).
# R ESUM E
La pr esente mise a jour des lignes directrices met de l'avant de nouveaux r esultats importants sur le traitement pharmacologique de la maladie pulmonaire obstructive chronique (MPOC) qui devraient modifier la pratique clinique et am eliorer la prise en charge de la maladie. Nous pr esentons une mise a jour des donn ees probantes et des recommandations, et des observations cliniques d'experts sur la pharmacoth erapie d'entretien pour les patients dont la MPOC est stable. La pr esente mise a jour ne porte pas sur le diagnostic et le traitement non pharmacologique de la MPOC. Chez les patients ayant une MPOC et dont l'essoufflement, l'intol erance a l'effort et la d et erioration de l' etat de sant e persistent malgr e une monoth erapie d'antimuscarinique a longue dur ee d'action (AMLA) ou de bêta 2 -agoniste a longue dur ee d'action (BALA), nous recommandons une progression du traitement vers une bith erapie AMLA/BALA. Chez les patients pr esentant un risque elev e d'exacerbations, il faut privil egier une bith erapie AMLA/BALA plutôt qu'une association de corticost eroïde en inhalation (CSI)/BALA, sauf chez les patients ayant d ej a subi des exacerbations et dont le nombre d' eosinophiles de sang p eriph erique est elev e. Il n'y a pas lieu de recourir a la monoth erapie de CSI; lorsqu'ils sont indiqu es, les CSI doiventêtre utilis es uniquement
# Introduction
Since the last published Canadian Thoracic Society (CTS) position statement on the pharmacotherapy in patients with chronic obstructive pulmonary disease (COPD) in 2017, 1 several important publications have necessitated an update to the current approach. This document is intended to guide best practice in light of recent research.
In clinical practice, an integrated, comprehensive approach to care should include: a diagnosis of COPD confirmed with spirometry; clinical evaluation of the patient; and comprehensive management, which includes nonpharmacological and pharmacological interventions (Figure 1).
The diagnosis of COPD should be considered in patients at risk of developing this disease. Patients' smoking history should be the main focus as it remains the most important risk factor. However, clinicians should be aware of an increased risk of COPD in individuals reporting a past medical history of asthma and/or severe childhood respiratory disease. Additionally, patients who have been exposed to passive smoke and/or to indoor biomass fuel are also at increased risk for the development of COPD. 2 This includes individuals from developing countries where indoor biomass exposure is the leading cause of COPD. Physicians should also be attentive to patients presenting with "exacerbationlike respiratory events" in the office or emergency setting, which may be an initial presentation of previously undiagnosed COPD. These events are common in undiagnosed COPD (22% in undiagnosed compared to 40% in diagnosed COPD) and have substantial impact on health service utilization, such as emergency department (ED) visits and hospital admissions. 3 An exacerbation-like respiratory event can be a trigger (opportunity) for patients to come to the attention of the healthcare system and for clinicians to consider the diagnosis of COPD and/or to optimize disease management.
Recent robust population data have confirmed that many individuals with COPD remain undiagnosed, but symptomatic, with an increased risk of exacerbations, pneumonia and death. 4 However, undiagnosed COPD, but asymptomatic, can also have exacerbations and pneumonia. 4 These patients who are "asymptomatic" may have adapted their lives to the limitations associated with their disease and may not want to reflect upon changes that occur to them as being a problem, that is, denial. If the physician uses probing questions, then symptoms may be better determined. This reality calls into question the validity of current recommendations for diagnosis of COPD that suggest targeted testing with spirometry only for symptomatic individuals.
It is important to remind physicians that spirometry is essential for the diagnosis of COPD, that is, a fixed postbronchodilator ratio of the FEV 1 /FVC of <0.70 or < the lower limit of normal (LLN) ratio (i.e., less than the lower fifth percentile of the reference value from a healthy population). Recent results support the use of fixed ratio less than 0.70 as appropriate to identify individuals at risk of clinically significant COPD. 5,6 However, more than a single postbronchodilator spirometric assessment may be necessary for diagnosing COPD for patients with mild airway obstruction at baseline. 7 We suggest post-bronchodilator FEV 1 /FVC ratio should be confirmed by a repeat spirometry on a separate occasion if the value is between 0.6 and 0.8, because the ratio may change as a result of biological variation. Findings, however, indicate that if the initial post-bronchodilator FEV 1 /FVC ratio is less than 0.6 it is very unlikely to rise above 0.7 spontaneously. While the diagnosis of COPD is confirmed by a reduced FEV 1 /FVC ratio < 0.7, the severity of airflow obstruction in COPD should be assessed by the degree of reduction in the postbronchodilator FEV 1 (% predicted).
Non-pharmacological therapy is complementary to inhaled or oral medication and should be a foundational aspect of the comprehensive management of COPD. Physicians must ensure patients have the proper support to live in a smoke free environment, receive appropriate vaccinations, adhere to prescribed medication (including using proper inhaler technique), receive self-management education and coaching, remain physically active and be referred to and complete pulmonary rehabilitation. 1,8,9 In a recent survey by the COPD Foundation, 10 patients reported gaps such as not receiving information after diagnosis of COPD, and receiving almost no education on self-management skills. Patients wished they had mastered these skills sooner to recognize early signs of an exacerbation and what to do about it, to stay active, and to cope with episodes of anxiety and dyspnea.
In this guideline update, we highlight important and new findings related to pharmacological therapy that should change clinical practice and improve disease management. We present updated evidence and recommendations, and expert clinical remarks on maintenance pharmacotherapy in patients with stable COPD. The diagnosis and non-pharmacological therapy of COPD are out-of-scope for this update.
# Objectives
The overall objective of this CTS clinical practice guideline is to help clinicians to match their therapeutic decisions to the clinical status of each patient. This is a step toward personalizing therapy based on increasing individual characterization.
The specific objective is to provide clinical guidance with evidence-based recommendations and expert-informed clinical remarks to optimize maintenance pharmacological therapy for patients with COPD.
# Target patient population
The update applies to all individuals with stable COPD.
# Key definitions
Bronchodilators open up the airways in the lungs by relaxing airway smooth muscle. They also reduce lung hyperinflation. Bronchodilator medications can be short-or longacting. Different types of short-or long-acting bronchodilators work in different ways.
Short-acting bronchodilators can be either SABAs (shortacting beta agonists) or SAMAs (short-acting muscarinic antagonists). Long-acting bronchodilators can be either LABAs (longacting beta2 agonists) or LAMAs (long-acting muscarinic antagonists).
Acute Exacerbations of COPD (AECOPD): Exacerbations are "event-based" occurrences; that is, respiratory symptom(s) that worsen beyond the normal day-to-day variability and may require the use of antibiotics and/or systemic corticosteroids and/or healthcare services. The varying levels of exacerbation severity are: mild (worsening or new respiratory symptoms without a change in prescribed medications); moderate (prescribed antibiotic and/or oral corticosteroids); and severe (requiring a hospital admission or ED visit).
We have chosen to reconsider the classification of exacerbations into low-and high-risk of future exacerbations to align with patients enrolled in recently published randomized clinical trials. This was a necessary decision considering that the recommendations made in the guideline are evidence based.
Low-and high-risk of future exacerbations: Patients are considered to be at: low-risk of exacerbations if they had 1 moderate exacerbation in the last year and did not require an ED visit or hospitalization high-risk of exacerbations if they had !2 moderate or !1 severe exacerbation in the last year requiring a hospital admission/ED visit.
Stable COPD: Patients are considered to have "stable COPD" in all clinical states other than during the period of an AECOPD. However, patients with "stable COPD" may have progressive symptoms and/or have experienced an exacerbation.
Symbol "/" for combination therapy: The symbol "/" refers to: combination products (in the same device) and combination regimens (in separate devices). Single or multiple inhalers for combination therapy represent the clinical reality of different approaches to manage patients for a variety of considerations, such as access to medication, response to treatment, medical conditions other than COPD and patient preference.
# Methodology
This guideline was developed in accordance with the CTS guideline development process. 11 The panel used the AGREE II checklist to guide the development of the guideline. 12
# Guideline panel composition
The COPD guideline panel comprised 12 experts: six respirologists with experience in COPD management, research and research methodology including three clinicians/epidemiologists; two primary care physicians appointed by the College of Family Physicians of Canada; and one pharmacist. All author conflicts of interests are available at https:// cts-sct.ca/guideline-library/.
# Key clinical questions
The key clinical questions were developed using the Patient/ population; Intervention or interventions; Comparison groups; Outcome or outcomes of interest (PICO) method. The PICO questions were based on the last published CTS position statement on the pharmacotherapy in patients with COPD in 2017. 1 We identified new evidence for PICO questions 1 and 2 but no new evidence to support an update of PICO 3 on Asthma COPD overlap (ACO). We did not include new interventions or de novo clinical questions in this review.
# Literature search and screening of abstracts
This update includes all new research publications from the end-date of the literature search for the 2017 CTS position statement on pharmacotherapy in patients with chronic obstructive pulmonary disease. 1 An initial search was conducted through the CTS/McMaster Plus database with selected relevant manuscripts included with publication dates through October 31, 2018. A dedicated literature search and additional articles were found by reviewing the references in included articles and based on authors' knowledge of other relevant publications. See Appendix 1 for details of the search strategy and a flow chart of search results and articles reviewed. We indexed the studies according to the PICO questions and made them available to the guideline panel on a dedicated software platform for manual assignment to individual reviewers.
For each PICO question, two panel members scrutinized titles and abstracts to decide whether the article was relevant (JB/PH-PICO 1; MB/DM-PICO 2). Where opinions differed, the two panel members resolved the conflict by discussion. Upon reaching consensus on the list of relevant abstracts, we obtained and reviewed copies of the full articles of all relevant and possibly relevant articles. The chosen inclusion and exclusion criteria (Appendix 1) were documented at both the abstract and full-text review stages.
# Study selection criteria
We excluded studies if they were not related to maintenance pharmacotherapy in patients with stable, moderate to very-severe COPD. We included only randomized clinical trials and systematic reviews for further review and inclusion. The same pairs of reviewers who scrutinized titles and abstracts also assessed inclusion/exclusion criteria (Appendix 1) for full-text articles. The Cochrane Risk of Bias Tool for randomized clinical trials was used to assess the risk of bias in individual studies. The Documentation and Appraisal Review (DART) tool was used to assess the quality of systematic reviews addressing a variety of research designs.
# Critical appraisal of identified studies
We compiled data from all articles relevant to each PICO question into evidence tables (available at: / guideline-library/). The entire panel discussed each PICO question via webinars in June 2019, at which time, all evidence tables were reviewed. Accordingly, we established group consensus on the quality and strength of the evidence addressing each clinical question according to the GRADE criteria (Appendix 1). 13 In instances where there was insufficient evidence but a recommendation was still warranted, a suggestion was developed and "consensus-based (CB)" replaced the grade.
# Synthesis of evidence-base and clinical judgment of risk-versus-benefit
For each clinical question, we considered the strength and directness of the evidence supporting an intervention or treatment approach. For each therapeutic approach, we also considered: the potential health benefit to the patient; the morbidity and mortality impact on the overall COPD population; risks/harms; the burden placed on the patient; and the cost-effectiveness (these are the factors categorized under the "Contextualization and Deliberations" domain of the guidelines). 14 We also included informed clinical remarks with PICO clinical questions and recommendations, in an effort to compliment recommendations with practical clinical advice. Some of these remarks are not based on strong evidence, but represent the consensus opinions of panel members based on expertise.
# Update of recommendations and classification
We used recommendations in the 2015 Prevention of Acute Exacerbations of COPD -American College of Chest Physicians, the Canadian Thoracic Society Guideline document 15 Following open and extensive discussions and evidence review for each PICO question, the entire panel proposed wording updates to each prior recommendation pertaining to that PICO question, and where applicable, a change to the strength of the recommendation to reflect newly published literature. We based strength of the recommendation on the GRADE quality of evidence 13 (Appendix 1), and our synthesis of clinical judgment. The CTS Canadian Respiratory Guidelines Committee (CRGC) Chair then vetted the recommendations to optimize language with a view to improving likelihood of uptake. 16,17 Recommendations were then voted upon by electronic survey using a six-point voting scale, whereby it was defined a priori that a recommendation would only be accepted if each panel member voted for option 1, 2 or 3 (wholeheartedly agree, agree or can support). For a recommendation to be accepted, it had to be voted on by 75% of the eligible panel members and achieve ratings 1, 2 or 3 by 80% of the voting panelists. In the event of a failure to reach 80% of votes with ratings 1, 2 or 3, another period of discussion ensued, whereby dissenting opinions were heard and considered. The recommendation was revised and followed by a second round of voting by electronic survey using a three-point scale, for which acceptance of a recommendation required a majority (80%) of panelists to choose option 1 or 2 (Appendix 1). Throughout this process all recommendations achieved acceptance, with no recommendation requiring a second round of voting.
# Review and approval process
The CTS independently invited formal review of the update by an external (non-CTS) content expert. The lead author responded to the comments and made corresponding changes. Two members of the CRGC then completed their own review and provided further feedback for consideration. Upon acceptance, the Committee recommended approval of the guideline to the CTS Executive Committee.
# Living guideline/future updates
The guideline will be formally reviewed every three years or sooner to determine the need for and nature of any updates, in accordance with the CTS Living Guideline Model (details available at /). Authors and/or the CTS COPD Assembly Steering Committee members will also use the continuously updated McMaster Plus database, whereby they will receive alerts when new articles pertaining to these PICO questions are published (starting from the last date of the literature search conducted for this guideline). This will serve to prompt members to consider timely guideline updates with evolving evidence and will facilitate formal literature reviews.
Summary PICO 1: Improving symptoms, exercise tolerance, physical activity and health status in stable COPD patients Among respiratory symptoms, shortness of breath (dyspnea) on exertion is the most debilitating symptom COPD patients experience. 18 Since disease progression reduces patients' capacity to exercise and, therefore, affects the ability to perform the activities of daily life, 19,20 they consider relief of this symptom to be one of the most important outcomes in the management of their disease. 21 Shortness of breath also contributes to the established extra-pulmonary manifestations of COPD, including anxiety, depression, 22 cardiovascular disease 23 and peripheral locomotor muscle deconditioning. 24 Importantly, it is strongly associated with increased morbidity and mortality in adults with COPD. 25,26 Persistent shortness of breath is associated with increased exacerbation risk. 26,27 Dyspnea and exacerbation are not independent or dichotomous outcomes and they are often present in the same patient. Alleviating shortness of breath is a key goal of COPD management.
Inhaled bronchodilators are the mainstay medications in the pharmacologic management of COPD. There are two main classes of bronchodilators: B 2 -adrenoreceptor agonists and muscarinic antagonists, both in long-and short-acting forms. They can be used as monotherapy, combined as dual bronchodilators or combined with ICS for maintenance treatment. Bronchodilators enhance the neuromechanical coupling of the respiratory system and delay the onset of mechanical constraints, providing relief from exertional shortness of breath with concomitant improvement in exercise tolerance in patients with COPD. 28 This section discusses the optimal use of inhaled and oral pharmacologic maintenance therapies shown to improve shortness of breath, exercise tolerance, physical activity and health status in stable COPD patients.
# Key evidence
Based on this review for PICO 1, recommendations 1, 3, 7 and 8 remain unchanged, while recommendations 2, 4 and 5 have a change in GRADE assessment due to new research findings, and 2, 5 and 6 are revised based on evidence from published literature. See Appendix 2 detailing the upgrades and revisions from 2017.
As stated in the previous position statement, use of LAMA or LABA monotherapy is endorsed to reduce shortness of breath, improve exercise tolerance and improve health status in patients with stable COPD. Although LAMA is often preferred to LABA in monotherapy, the evidence of its superiority comes primarily from studies in which the main outcome was to prevent COPD exacerbations. In patients with COPD who have persistent shortness of breath, exercise intolerance and/or poor health status despite using inhaled LAMA or LABA monotherapy, we recommend augmenting treatment to LAMA/LABA dual therapy. Patients should be routinely monitored and evaluated for their response after any change in their therapy, as many have persisting symptoms with an impact on their well-being. 29 In terms of improving physical activity, the evidence suggests that combining a self-management behavioral intervention with exercise and pharmacologic interventions has the largest effect on physical activity and symptom improvement. A self-management behavioral intervention is more likely to help patients change their behavior and can lead to long-term adoption of a more physically active lifestyle. 30,31 For patients who remain symptomatic and have poor exercise tolerance or health status despite being on LAMA/ LABA combination therapy, the evidence supports patients enrolling in a pulmonary rehabilitation program. 32 For patients who remain symptomatic and have poor health status despite these interventions, a clinician should consider "step up" to triple therapy (LAMA/LABA/ICS), although each individual should be evaluated for risk/benefit of adding ICS in these circumstances. Evidence for its benefit has been demonstrated primarily in patients who have a high risk of exacerbations. 33,34 For PICO 1, data is lacking with respect to withdrawal or "step down" from LAMA/LABA/ICS to LAMA/LABA dual therapy or from dual therapy to monotherapy. We continue to support guidance from the previous position statement. 1 The consensus was that, in patients with COPD with no improvement in shortness of breath, exercise tolerance or health status despite the use of triple inhaled therapy or inhaled LAMA/LABA dual therapy, clinicians may cautiously consider "step down" treatment for some patients. These patients need to be monitored carefully with close clinical follow-ups to detect any signs of clinical deterioration after medication "step down."
As per previous guidelines, oral therapies such as theophylline, phosphodiesterase-4-inhibitor, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines or phosphodiesterase-5-inhibitor demonstrate no evidence of conferring additional benefit in patients already on combination longacting bronchodilators. We reiterate that ICS monotherapy, as a lone intervention, has no place in treating COPD patients. If there is an indication for ICS therapy or the patient has asthma in addition to COPD, then ICS should be prescribed in a combination inhaler with long-acting bronchodilator(s). 1.8
# Consensus
We recommend against treatment with ICS monotherapy in stable COPD patients.
When indicated, ICS should ideally be administered in a combination therapy in COPD patients.
Stable COPD: Patients are considered to have "stable COPD" in all clinical states other than during the period of an acute exacerbation of COPD (AECOPD). However, patients with "stable COPD" may have progressive symptoms and/or have experienced an exacerbation. Bronchodilators open up the airways in the lungs by relaxing airway smooth muscle. They also reduce lung hyperinflation. Bronchodilator medications can be shortor long-acting. Different types of short-or long-acting bronchodilators work in different ways.
Short-acting bronchodilators can be either SABAs (short-acting beta agonists) or SAMAs (short-acting muscarinic antagonists).
Long-acting bronchodilators can be either LABAs (long-acting beta2 agonists) or LAMAs (long-acting muscarinic antagonists).
Symbol "/" for combination therapy: The symbol "/" refers to: combination products (in the same device) and combination regimens (in separate devices). Single or multiple inhalers for combination therapy represent the clinical reality of different approaches to manage patients for a variety of considerations, such as access to medication, response to treatment, medical conditions other than COPD and patient preference. Exacerbations: Exacerbations are "event-based" occurrences; that is, respiratory symptom(s) that worsen beyond the normal day-to-day variability and may require the use of antibiotics and/or systemic corticosteroids and/or healthcare services. The varying levels of exacerbation severity are: mild (worsening or new respiratory symptoms without a change in prescribed medications); moderate (prescribed antibiotic and/or oral corticosteroids); and severe (requiring a hospital admission or ED visit).
Low-and high-risk of future exacerbations: Patients are considered to be at:
Low-risk of exacerbations if they had 1 moderate exacerbation in the last year and did not require an ED visit or hospitalization.
High-risk of exacerbations if they had Summary PICO 2: Preventing acute exacerbations in stable COPD patients
In Canada, AECOPD continues to be the most frequent cause of acute hospitalization in adults, 120 and is associated with the highest total hospital cost of care (2016)(2017). The cost of hospitalizations related to COPD is more than 30% higher than that of the next most expensive health condition (heart failure). 121 AECOPDs are a gateway to poor outcomes and adverse consequences. They accelerate lung function decline, dramatically reduce quality of life, and are strong predictors of future AECOPDs. They are acute, trajectory-changing manifestations of a chronic disease associated with increased mortality. COPD is the third leading cause of death worldwide. 125,126 A fundamental and achievable goal of therapy in managing stable COPD is to reduce the occurrence and severity of AECOPDs. Furthermore, providing appropriate preventive therapy for patients at increased risk of exacerbation increases the likelihood of reducing and preventing ED visits and hospital admissions. In patients with severe COPD, reducing AECOPD may also reduce mortality. 33 This section discusses the optimal use of inhaled and oral pharmacologic maintenance therapies shown to prevent AECOPD in patients with stable COPD, not the treatment of acute exacerbations.
# Key evidence
Based on this review for PICO 2, recommendations 3 and 10 remain unchanged, while recommendations 1, 2, 4, 5, 6, 7, 8 and 9 have a change in GRADE assessment due to new research findings. Recommendations 5, 6, 7, 9 and 11 are revised based on evidence from published literature. See Appendix 2 detailing the upgrades and revisions from 2017.
A significant change is the use of either an ICS/LABA or LAMA/LABA as a first step in patients with high risk of AECOPD. Although ICS/LABA or LAMA/LABA is a viable inhaled therapeutic option in this setting, LAMA/LABA is the preferred choice except in patients with previous exacerbations who have higher peripheral eosinophilia (Figure 2). In this case, ICS/LABA could be the favored therapy as stated by the evidence described in the Discussion section of this guideline. Monotherapy with either LAMA or LABA is not the optimal initial maintenance treatment for patients who experience or are at high risk of AECOPD. Acknowledging the significant adverse consequences of AECOPD, consider inhaled therapy with either ICS/LABA or LAMA/LABA as the acceptable minimum maintenance therapy for this high risk population. It is important to remember that in real life practice, it is the exception to treat a patient only to prevent exacerbations; the vast majority of time we optimize bronchodilator therapy to improve a patient's dyspnea.
Similar to our analysis in PICO 1, we conclude that there is no role for ICS monotherapy and ICS should only be used in combination with bronchodilators. ICS/LABA and LAMA/ LABA/ICS are the only current single inhaler options. Health Canada has not approved an inhaled ICS for monotherapy use in COPD. Furthermore, in prior studies, the monotherapy ICS arm underperformed compared to combination ICS/ LABA, and post-hoc analysis suggested increased mortality in the ICS monotherapy participants. 127 Administering ICS with LAMA/LABA in separate inhalers has not been studied in COPD. 120,122,123 When combination ICS/LABA or LAMA/ LABA/ICS is used, high doses of ICS 122 are not typically necessary to achieve optimum benefit in COPD, as shown by a relatively flat dose-response curve 128 and greater incidence of adverse effect with higher inhaled ICS doses. 129 There remains clinical uncertainty regarding potential "step down" of therapy 90,123 in patients with a history of a high risk of future AECOPD. Evidence from a randomized clinical trial involving participants with COPD receiving combination ICS/LABA with LAMA in separate inhalers who underwent stepwise ICS withdrawal suggests the intervention is not associated with a significantly increased risk of exacerbation over a short term of follow up. 130 However, in this study the initial baseline exacerbation rate was low, about one-third of participants had not previously required inhaled triple therapy before recruitment, there was a statistically significant reduction in FEV 1 (43 mL, p ¼ 0.001) after ICS withdrawal, and the number of deaths was numerically small but higher in the ICS withdrawal group (n ¼ 40) compared to the ICS continuation group (n ¼ 34). More recently, another randomized clinical trial of patients with COPD with low risk of AECOPD on long-term triple inhaled therapy with direct de-escalation to LAMA/LABA led to a small decrease in lung function as a primary endpoint, with no difference in exacerbation rate. However, the primary study endpoint was not met, with confidence limits for trough FEV 1 exceeding the non-inferiority margin of À50 mL. Further analysis of these studies revealed a higher rate of exacerbation in patients with !300 blood eosinophils/lL, suggesting that, as a biomarker, blood eosinophil at !300/lL in patients with previous AECOPD could be useful to predict a favorable response to ICS when combined with long-acting bronchodilator(s). However, no RCT has compared ICS/LABA versus LABA/LAMA in patients with high risk of and blood eosinophil at !300/lL, with exacerbation as a primary endpoint.
Given these findings and acknowledging the negative impact of AECOPD, reductions in lung function and the potential adverse consequences of therapy, we continue to support guidance from the previous CTS guidance document 123 that the clinical phenotype should drive pharmacotherapy for patients with COPD. If therapy was started without a clear indication (such as the use of an ICS in a patient with no history of exacerbations), you may consider initiating a "step down." However, if therapy was started according to recommendations (such as the use of LAMA/LABA/ICS in a patient with moderate-severe COPD with poor quality of life and history of frequent and/or severe AECOPD) and treatment has been effective, a "step down" is NOT recommended. Given the potential for serious negative consequences of AECOPD, including hospitalization and death, we believe that de-escalation should only be considered in patients at low risk of morbidity and mortality, and this after a period of considerable stability. Moreover, while awaiting objective documentation supporting the safety of this approach, if you decide to "step down," we highly recommend monitoring your patients carefully with regular clinical assessments that includes the monitoring of lung function and re-occurrence of AECOPD.
As noted, the incidence of pneumonia is higher with maintenance therapy of ICS-containing inhaled medicines, especially in COPD patients with severe and very severe disease. However, these are also the patients who benefit most from an ICS-containing regimen. Debate still ensues as to an intra-class difference between fixed combinations of inhaled corticosteroid/long acting b 2 agonist regarding the risk of pneumonia and pneumonia-related events in treating patients with COPD. 131 However, the clinical significance of increased pneumonia in COPD patients who use ICS remains unclear, since there is no concurrent documented increase risk of mortality in this group. 131 Results from a large clinical trial 33 confirmed a higher incidence of pneumonia with ICS-combination therapy, but this was accompanied by significant improvements in lung function and quality of life and significant reductions in exacerbations and mortality, which are endpoints of significant importance.
As stated in the previous position statement, if patients with COPD continue to experience exacerbations despite being on optimal long-acting inhaled therapy, consider adding a daily macrolide (e.g. Azithromycin) as maintenance therapy in appropriate patients who have normal QT interval on ECG and no evidence of either colonization or acute infection with atypical mycobacterium. Also consider oral Roflumilast or oral N-acetylcysteine (600 mg po BID) in those having a clinical phenotype by history in keeping with chronic bronchitis. In recommendation 2.11 in this update, recent evidence supports not using theophylline in patients who are on long-acting inhaled therapy. We reiterate that systemic corticosteroids should not be used for maintenance pharmacotherapy in stable COPD. COPD pharmacotherapy promoting an approach that aligns treatment decisions with symptom burden and risk of future exacerbations. To learn more about the Asthma-COPD Overlap (ACO) treatment algorithm, refer to the CTS position statement on the pharmacotherapy in patients with COPD in 2017. 1 mMRC is a modified (0-4 scale) version of the MRC breathlessness scale which was used in previous CTS guidelines. The mMRC aligns with the Global Initiative for Chronic Obstructive Airways Disease (GOLD) 2019 report. SABD prn (as needed) should accompany all recommended therapies. Solid arrows indicate step up therapy to optimally manage symptoms of dyspnea and/or activity limitation, as well as prevention of AECOPD where appropriate. Dashed arrows indicate potential step down of therapy, with caution and with close monitoring of patient symptoms, exacerbations and lung function. Symbol "/" refers to combination products (in the same device) and combination regimens (in separate devices). ICS should ideally be administered in a combination inhaler.
†Patients are considered at Low Risk of AECOPD with 1 moderate AECOPD in the last year (moderate AECOPD is an event with prescribed antibiotic and/or oral corticosteroids), and did not require hospital admission/ED visit; or at High Risk of AECOPD with !2 moderate AECOPD or !1 severe exacerbation in the last year (severe AECOPD is an event requiring hospitalization or ED visit). Ã Blood eosinophil !300/mL in patients with previous AECOPD may be useful to predict a favorable response to ICS combination inhaler. ‡Oral Therapies ¼ Roflumilast, N-acetylcysteine, daily dose Azithromycin could be considered with patients with high risk AECOPD despite on optimal long-acting inhaled therapy. Oral corticosteroids as maintenance therapy are not indicated in COPD.
# 1B
We recommend oral N-acetylcysteine (600 mg po BID) for patients with chronic bronchitis and a high risk of AECOPD despite optimal long-acting inhaled therapy.
# 2A
We suggest macrolide maintenance therapy for patients with a high risk of AECOPD despite optimal long-acting inhaled therapy.
Weigh the benefits against the risks of potential microbial resistance, hearing impairment and QT-prolonging drug interactions.
# 2B
We suggest that oral slow-release theophylline should not be used, as it does not prevent AECOPD in patients on optimal long-acting inhaled therapy. 123,190 Stable COPD: Patients are considered to have "stable COPD" in all clinical states other than during the period of an acute exacerbation of COPD (AECOPD). However, patients with "stable COPD" may have progressive symptoms and/or have experienced an exacerbation. SABD prn (as needed) should accompany all recommended therapies. Bronchodilators open up the airways in the lungs by relaxing airway smooth muscle. They also reduce lung hyperinflation. Bronchodilator medications can be short-or long-acting. Different types of short-or long-acting bronchodilators work in different ways.
Short-acting bronchodilators can be either SABAs (short-acting beta agonists) or SAMAs (short-acting muscarinic antagonists). Long-acting bronchodilators can be either LABAs (long-acting beta2 agonists) or LAMAs (long-acting muscarinic antagonists).
Symbol "/" for combination therapy: The symbol "/" refers to: combination products (in the same device) and combination regimens (in separate devices). Single or multiple inhalers for combination therapy represent the clinical reality of different approaches to manage patients for a variety of considerations, such as access to medication, response to treatment, medical conditions other than COPD and patient preference. Exacerbations: Exacerbations are "event-based" occurrences; that is, respiratory symptom(s) that worsen beyond the normal day-to-day variability and may require the use of antibiotics and/or systemic corticosteroids and/or healthcare services. The varying levels of exacerbation severity are: mild (worsening or new respiratory symptoms without a change in prescribed medications); moderate (prescribed antibiotic and/or oral corticosteroids); and severe (requiring a hospital admission or ED visit).
Low-and high-risk of future exacerbations: Patients are considered to be at:
Low-risk of exacerbations if they had 1 moderate exacerbation in the last year and did not require an ED visit or hospitalization.
High-risk of exacerbations if they had !2 moderate or !1 severe exacerbation in the last year requiring a hospital admission/ED visit.
Oral Therapies are Roflumilast, N-acetylcysteine or daily dose Azithromycin. Oral corticosteroids as maintenance therapy are not indicated in COPD. Optimal long-acting inhaled therapy is therapy that has been tailored to the patient's exacerbation history, in accordance with Figure 2. Abbreviations: PICO, Patient/population -Intervention or interventions -Comparison groups -Outcome or outcomes of interest; COPD, chronic obstructive pulmonary disease; BID, bis in die (twice a day); ICS, inhaled corticosteroid; ED, emergency department; SABD prn, short-acting bronchodilator as needed.
# Discussion
Since the 2017 CTS pharmacotherapy position statement, there have been several important clinical trials that have necessitated an update. In this guideline we have incorporated new evidence from published large multicenter clinical trials and systematic reviews that have an impact on clinicians' approach to the medical management of patients living with COPD. We have summarized our updated recommendations in Tables 1 and 2 and included a comparison of 2017 and 2019 recommendations in Appendix 2.
An updated COPD pharmacologic algorithm (Figure 2) that reflects these updates was also derived.
The treatment propositions presented in this updated Guideline, in particular the approach of a treatment "step up" and "step down" are pragmatic and intended to provide meaningful guidance for clinicians. Most research trials were not strictly designed to assess such a therapeutic approach. However, treatment "step up" in COPD is a practical construct with wide appeal that is supported by evidence that inhaled combined therapy is superior to monotherapy and triple therapy to dual therapy in certain patient populations. Because the superiority of inhaled triple or dual bronchodilator therapy may not be achieved in every patient, "step down" may be considered for some patients, but should only be done with close medical supervision, as the risk of clinical deterioration is real and continues to exist.
There are several important considerations in the management of COPD that are not addressed by the PICO questions in this guideline document. We have therefore provided a commentary of selected topics in this discussion. A full review of these clinical issues may be undertaken in subsequent guideline development.
# Choice of inhaler device
The choice of the inhaler device and/or the decision to use single or multiple devices for combination therapy remains a subject of clinical interest and controversy. Very few studies have compared combination products in the same device compared to separate devices. In the only randomized clinical trial examining this issue, a single-inhaler LAMA/ LABA/ICS was compared to an ICS/LABA and LAMA in separate devices; this study demonstrated non-inferiority between the two treatment strategies. 191 There is no study that has been performed in COPD comparing LABA or combined LAMA/LABA with ICS in single and separate devices. Although the use of single or multiple devices for combination therapy is a clinical reality, properly designed trials or real-life data are lacking in COPD.
# Choice of bronchodilator combination
Another topic is the question clinicians may have with respect to the equivalence or superiority of the various combined long-acting bronchodilators (LAMA/LABA). Few comparative efficacy trials compared combination long-acting bronchodilator therapy; those that did showed between-treatment differences in FEV 1 that were small and of uncertain clinical significance. 192,193 Interval for changing inhaler therapy
The decision to change a therapy should always occur after a complete evaluation of the patient and the potential benefit of a change in therapy; as well as an assessment of any adverse effects of the therapy, and with a review of patient adherence, inhaler technique and preferences. Although there is no absolute interval time at which the evaluation should be performed following a change in therapy, 6 months after initiating a long acting bronchodilator and 12 months after initiating a combination regimen with an ICS are suggested timeframes.
# Peripheral blood eosinophils in COPD
While peripheral blood eosinophil counts have demonstrated reasonable repeatability over a year in a population-based cohort of COPD patients in primary care, 194 practical uncertainty remains regarding the exact cut-off level of sputum or blood eosinophils for predicting therapeutic response in COPD. Despite this uncertainty, peripheral blood eosinophil counts may play a role in certain clinical settings. New information is incorporated into this update with respect to blood eosinophils as a potential biomarker for use in COPD patients known to have exacerbations to prevent future exacerbations. A consistent pattern of results from randomized clinical trials conducted in COPD patients at risk of exacerbations has emerged. Lower eosinophil counts (<100 eosinophils/mL) predict a lower or no response to ICS containing regimens in terms of preventing exacerbation. ICS containing regimens will benefit in reducing the likelihood of exacerbations in the magnitude of effect being greater at higher eosinophil counts, particularly !300 eosinophils/lL. 156 This provides a measure of probability of response to ICS containing regimen in patients who had previous exacerbations, aligning with a more personalized approach.
# Mortality
Reducing mortality has been a long-standing goal of therapy in COPD. Older studies have revealed mortality-reducing trends with inhaled therapy 127,195 but statistical significance was not achieved. Although there is still no definitive answer, more recent evidence from a large randomized controlled trial study demonstrated significant relative reduction in all-cause mortality during treatment with regimens that included inhaled ICS/LABA or triple therapy (LAMA/ LABA/ICS) compared to LAMA/LABA for COPD patients with high risk of exacerbations. Despite a higher incidence of study-reported pneumonia in the ICS-containing treatment regimens, mortality was reduced by 42% in favor of LAMA/LABA/ICS vs. LAMA/LABA (unadjusted p ¼ 0.01), and 39% in favor of ICS/LABA vs LAMA/LABA (unadjusted p ¼ 0.02). An analysis of adjudicated cause-specific death during treatment demonstrated fewer deaths from both respiratory and cardiovascular etiologies in the ICS-containing regimens. This topic requires further attention, but mortality is an important outcome that should have our consideration in clinical decision.
# Dissemination and implementation
Our guideline will be disseminated through traditional channels including this publication, through the CTS website and social media channels, and through an accompanying slide deck that will be used to present this content to various target groups across the country. It is also anticipated that we will produce a separate implementation document that will include key indicators of appropriate care and practical guidance for healthcare system change. Our goal is to monitor the impact of these actionable recommendations through their ability to correct knowledge gaps and improve actual behaviors within the target user groups. On a population level, we also believe that monitoring the frequency of COPD ED visits, hospital admissions and re-admissions would be relevant metrics to assess the success of this guideline. For messages targeting nonexperts, we will seek to tailor messages and produce corresponding educational content, in collaboration with key stakeholders such as provincial lung associations, RESPIPLUS and RESPTREC.
# Conclusion
This update is an important step toward optimizing the pharmacologic management of COPD. Recommendations enable better-personalized therapy based on more specific individual characteristics. The update further highlights the intent and benefit of therapy in both improving symptoms and activity limitations, and reducing the risk of AECOPD. Areas of debate still require further study, including approach to treatment "step down" targeting specific group of patients, blood eosinophil use and its cut off, and use of single or multiple inhalers for combination therapy, but recent evidence has strengthened many recommendations to optimize management of COPD. In summary, pharmacological therapy plays a foundational role in therapy, but it should never be the sole treatment in managing COPD patients. Clinicians should always combine and optimize pharmacological and non-pharmacological therapies with the dual goals of reducing symptoms and preventing AECOPD. bers of the CTS CRGC for their input and guidance. We would like to acknowledge with sincere appreciation our expert reviewer, Marc Miravitlles from the Pneumonlogy Department, University Hospital Vall d'Hebron, Ciber de Enfermedales Respiratorias (CIBERES), Barcelona, Spain.
# Editorial independence
The CTS COPD guideline panel is accountable to the CTS Canadian Respiratory Guidelines Committee and the CTS Board of Directors. The CTS COPD guideline panel is functionally and editorially independent from any funding sources of the CTS and does not receive any direct funding from external sources. The CTS receives unrestricted grants that are combined into a central operating account to facilitate the knowledge translation activities of the CTS Assemblies and its guideline panels. No funders played a role in the collection, review, analysis or interpretation of the scientific literature or in any decisions regarding the key messages presented in this document.
# Disclosures
Members of the CTS COPD Guideline Panel declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy. Individual member conflict of interest statements are posted at /. Evidence for at least one critical outcome from observational studies, case series or randomized controlled trials, with serious flaws or indirect evidence.
# ORCID
Recommendation can apply to most patients in many circumstances. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect, and may well change the estimate.
Weak recommendation, high-quality evidence 2A Benefits closely balanced with risks and burden.
Consistent evidence from randomized controlled trials without important limitations, or exceptionally strong evidence from observational studies.
The best action may differ depending on circumstances or patient or societal values. Further research is unlikely to change our confidence in the estimate of effect.
Weak recommendation, moderate-quality evidence 2B Benefits closely balanced with risks and burden.
Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence from observational studies.
Best action may differ depending on circumstances or patient or societal values.
Higher-quality research may well have an important impact on our confidence in the estimate of effect, and may change the estimate.
Weak recommendation, low-or very-lowquality evidence 2C Uncertainty in the estimates of benefits, risks and burden; benefits, risk and burden may be closely balanced.
Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials, with serious flaws or indirect evidence.
Other alternatives may be equally reasonable.
Higher-quality research is likely to have an important impact on our confidence in the estimate of effect, and may well change the estimate.
# Consensus-based unchanged
# Recommendation revised
New clinical remark Rec 7 -There is insufficient or equivocal evidence in stable COPD patients to determine whether the addition of an oral therapy, such as theophyllines, phosphodiesterase-4-inhibitors, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines or phosphodiesterase-5inhibitors, confers additional benefit to inhaled LAMA or LABA monotherapy, or LAMA plus LABA dual therapy in reducing dyspnea, improving exercise tolerance and activity levels or improving health status. (Grade 2C).
There is insufficient or equivocal evidence to determine whether the addition of an oral therapy, such as theophyllines, phosphodiesterase-4inhibitors, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines or phosphodiesterase-5-inhibitors confers additional benefit to LAMA or LABA monotherapy, or LAMA/LABA dual therapy in reducing dyspnea, improving exercise tolerance and activity levels and/ or improving health status.
# GRADE 2C
unchanged Recommendation not updated (continued)
|
#
In this guideline update, we highlight important and new findings related to pharmacological therapy of chronic obstructive pulmonary disease (COPD) that should change clinical practice and improve disease management. We present updated evidence, recommendations and expert clinical remarks on maintenance pharmacotherapy in patients with stable COPD. The diagnosis and nonpharmacological therapy of COPD are out-of-scope for this update. In patients with COPD who have persistent shortness of breath, exercise intolerance and/or poor health status despite using inhaled LAMA or LABA monotherapy, we recommend augmenting treatment to LAMA/LABA dual therapy. In patients with high-risk exacerbations, LAMA/LABA is the preferred choice to ICS/LABA except in patients with previous exacerbations who have higher peripheral eosinophilia. There is no role for ICS monotherapy; when indicated, ICS should only be used in combination with bronchodilators. Treatment "step up" in COPD is proposed as a practical construct supported by evidence that inhaled combined therapy is superior to monotherapy and triple therapy to dual therapy in certain patient populations. Because the superiority of inhaled triple or dual bronchodilator therapy may not be achieved in every patient, "step down" may be considered for some patients (not at high risk for future exacerbations), but should be done with close medical supervision, as the risk of clinical deterioration is real and continues to exist. The decision of changing a therapy should always occur after a complete evaluation of the patient and the potential benefit to a change in therapy; as well as an assessment of any adverse effects of the therapy, and with a review of patient adherence, inhaler technique and patient preferences. Pharmacological therapy plays a foundational role in therapy, but it should never be the sole treatment in managing COPD patients. Clinicians should always combine and optimize pharmacological and nonpharmacological therapies with the dual goals of reducing symptoms and preventing acute exacerbations of COPD (AECOPD).
# R ESUM E
La pr esente mise a jour des lignes directrices met de l'avant de nouveaux r esultats importants sur le traitement pharmacologique de la maladie pulmonaire obstructive chronique (MPOC) qui devraient modifier la pratique clinique et am eliorer la prise en charge de la maladie. Nous pr esentons une mise a jour des donn ees probantes et des recommandations, et des observations cliniques d'experts sur la pharmacoth erapie d'entretien pour les patients dont la MPOC est stable. La pr esente mise a jour ne porte pas sur le diagnostic et le traitement non pharmacologique de la MPOC. Chez les patients ayant une MPOC et dont l'essoufflement, l'intol erance a l'effort et la d et erioration de l' etat de sant e persistent malgr e une monoth erapie d'antimuscarinique a longue dur ee d'action (AMLA) ou de bêta 2 -agoniste a longue dur ee d'action (BALA), nous recommandons une progression du traitement vers une bith erapie AMLA/BALA. Chez les patients pr esentant un risque elev e d'exacerbations, il faut privil egier une bith erapie AMLA/BALA plutôt qu'une association de corticost eroïde en inhalation (CSI)/BALA, sauf chez les patients ayant d ej a subi des exacerbations et dont le nombre d' eosinophiles de sang p eriph erique est elev e. Il n'y a pas lieu de recourir a la monoth erapie de CSI; lorsqu'ils sont indiqu es, les CSI doiventêtre utilis es uniquement
# Introduction
Since the last published Canadian Thoracic Society (CTS) position statement on the pharmacotherapy in patients with chronic obstructive pulmonary disease (COPD) in 2017, 1 several important publications have necessitated an update to the current approach. This document is intended to guide best practice in light of recent research.
In clinical practice, an integrated, comprehensive approach to care should include: a diagnosis of COPD confirmed with spirometry; clinical evaluation of the patient; and comprehensive management, which includes nonpharmacological and pharmacological interventions (Figure 1).
The diagnosis of COPD should be considered in patients at risk of developing this disease. Patients' smoking history should be the main focus as it remains the most important risk factor. However, clinicians should be aware of an increased risk of COPD in individuals reporting a past medical history of asthma and/or severe childhood respiratory disease. Additionally, patients who have been exposed to passive smoke and/or to indoor biomass fuel are also at increased risk for the development of COPD. 2 This includes individuals from developing countries where indoor biomass exposure is the leading cause of COPD. Physicians should also be attentive to patients presenting with "exacerbationlike respiratory events" in the office or emergency setting, which may be an initial presentation of previously undiagnosed COPD. These events are common in undiagnosed COPD (22% in undiagnosed compared to 40% in diagnosed COPD) and have substantial impact on health service utilization, such as emergency department (ED) visits and hospital admissions. 3 An exacerbation-like respiratory event can be a trigger (opportunity) for patients to come to the attention of the healthcare system and for clinicians to consider the diagnosis of COPD and/or to optimize disease management.
Recent robust population data have confirmed that many individuals with COPD remain undiagnosed, but symptomatic, with an increased risk of exacerbations, pneumonia and death. 4 However, undiagnosed COPD, but asymptomatic, can also have exacerbations and pneumonia. 4 These patients who are "asymptomatic" may have adapted their lives to the limitations associated with their disease and may not want to reflect upon changes that occur to them as being a problem, that is, denial. If the physician uses probing questions, then symptoms may be better determined. This reality calls into question the validity of current recommendations for diagnosis of COPD that suggest targeted testing with spirometry only for symptomatic individuals.
It is important to remind physicians that spirometry is essential for the diagnosis of COPD, that is, a fixed postbronchodilator ratio of the FEV 1 /FVC of <0.70 or < the lower limit of normal (LLN) ratio (i.e., less than the lower fifth percentile of the reference value from a healthy population). Recent results support the use of fixed ratio less than 0.70 as appropriate to identify individuals at risk of clinically significant COPD. 5,6 However, more than a single postbronchodilator spirometric assessment may be necessary for diagnosing COPD for patients with mild airway obstruction at baseline. 7 We suggest post-bronchodilator FEV 1 /FVC ratio should be confirmed by a repeat spirometry on a separate occasion if the value is between 0.6 and 0.8, because the ratio may change as a result of biological variation. Findings, however, indicate that if the initial post-bronchodilator FEV 1 /FVC ratio is less than 0.6 it is very unlikely to rise above 0.7 spontaneously. While the diagnosis of COPD is confirmed by a reduced FEV 1 /FVC ratio < 0.7, the severity of airflow obstruction in COPD should be assessed by the degree of reduction in the postbronchodilator FEV 1 (% predicted).
Non-pharmacological therapy is complementary to inhaled or oral medication and should be a foundational aspect of the comprehensive management of COPD. Physicians must ensure patients have the proper support to live in a smoke free environment, receive appropriate vaccinations, adhere to prescribed medication (including using proper inhaler technique), receive self-management education and coaching, remain physically active and be referred to and complete pulmonary rehabilitation. 1,8,9 In a recent survey by the COPD Foundation, 10 patients reported gaps such as not receiving information after diagnosis of COPD, and receiving almost no education on self-management skills. Patients wished they had mastered these skills sooner to recognize early signs of an exacerbation and what to do about it, to stay active, and to cope with episodes of anxiety and dyspnea.
In this guideline update, we highlight important and new findings related to pharmacological therapy that should change clinical practice and improve disease management. We present updated evidence and recommendations, and expert clinical remarks on maintenance pharmacotherapy in patients with stable COPD. The diagnosis and non-pharmacological therapy of COPD are out-of-scope for this update.
# Objectives
The overall objective of this CTS clinical practice guideline is to help clinicians to match their therapeutic decisions to the clinical status of each patient. This is a step toward personalizing therapy based on increasing individual characterization.
The specific objective is to provide clinical guidance with evidence-based recommendations and expert-informed clinical remarks to optimize maintenance pharmacological therapy for patients with COPD.
# Target patient population
The update applies to all individuals with stable COPD.
# Key definitions
Bronchodilators open up the airways in the lungs by relaxing airway smooth muscle. They also reduce lung hyperinflation. Bronchodilator medications can be short-or longacting. Different types of short-or long-acting bronchodilators work in different ways.
Short-acting bronchodilators can be either SABAs (shortacting beta agonists) or SAMAs (short-acting muscarinic antagonists). Long-acting bronchodilators can be either LABAs (longacting beta2 agonists) or LAMAs (long-acting muscarinic antagonists).
Acute Exacerbations of COPD (AECOPD): Exacerbations are "event-based" occurrences; that is, respiratory symptom(s) that worsen beyond the normal day-to-day variability and may require the use of antibiotics and/or systemic corticosteroids and/or healthcare services. The varying levels of exacerbation severity are: mild (worsening or new respiratory symptoms without a change in prescribed medications); moderate (prescribed antibiotic and/or oral corticosteroids); and severe (requiring a hospital admission or ED visit).
We have chosen to reconsider the classification of exacerbations into low-and high-risk of future exacerbations to align with patients enrolled in recently published randomized clinical trials. This was a necessary decision considering that the recommendations made in the guideline are evidence based.
Low-and high-risk of future exacerbations: Patients are considered to be at: low-risk of exacerbations if they had 1 moderate exacerbation in the last year and did not require an ED visit or hospitalization high-risk of exacerbations if they had !2 moderate or !1 severe exacerbation in the last year requiring a hospital admission/ED visit.
Stable COPD: Patients are considered to have "stable COPD" in all clinical states other than during the period of an AECOPD. However, patients with "stable COPD" may have progressive symptoms and/or have experienced an exacerbation.
Symbol "/" for combination therapy: The symbol "/" refers to: combination products (in the same device) and combination regimens (in separate devices). Single or multiple inhalers for combination therapy represent the clinical reality of different approaches to manage patients for a variety of considerations, such as access to medication, response to treatment, medical conditions other than COPD and patient preference.
# Methodology
This guideline was developed in accordance with the CTS guideline development process. 11 The panel used the AGREE II checklist to guide the development of the guideline. 12
# Guideline panel composition
The COPD guideline panel comprised 12 experts: six respirologists with experience in COPD management, research and research methodology including three clinicians/epidemiologists; two primary care physicians appointed by the College of Family Physicians of Canada; and one pharmacist. All author conflicts of interests are available at https:// cts-sct.ca/guideline-library/.
# Key clinical questions
The key clinical questions were developed using the Patient/ population; Intervention or interventions; Comparison groups; Outcome or outcomes of interest (PICO) method. The PICO questions were based on the last published CTS position statement on the pharmacotherapy in patients with COPD in 2017. 1 We identified new evidence for PICO questions 1 and 2 but no new evidence to support an update of PICO 3 on Asthma COPD overlap (ACO). We did not include new interventions or de novo clinical questions in this review.
# Literature search and screening of abstracts
This update includes all new research publications from the end-date of the literature search for the 2017 CTS position statement on pharmacotherapy in patients with chronic obstructive pulmonary disease. 1 An initial search was conducted through the CTS/McMaster Plus database with selected relevant manuscripts included with publication dates through October 31, 2018. A dedicated literature search and additional articles were found by reviewing the references in included articles and based on authors' knowledge of other relevant publications. See Appendix 1 for details of the search strategy and a flow chart of search results and articles reviewed. We indexed the studies according to the PICO questions and made them available to the guideline panel on a dedicated software platform for manual assignment to individual reviewers.
For each PICO question, two panel members scrutinized titles and abstracts to decide whether the article was relevant (JB/PH-PICO 1; MB/DM-PICO 2). Where opinions differed, the two panel members resolved the conflict by discussion. Upon reaching consensus on the list of relevant abstracts, we obtained and reviewed copies of the full articles of all relevant and possibly relevant articles. The chosen inclusion and exclusion criteria (Appendix 1) were documented at both the abstract and full-text review stages.
# Study selection criteria
We excluded studies if they were not related to maintenance pharmacotherapy in patients with stable, moderate to very-severe COPD. We included only randomized clinical trials and systematic reviews for further review and inclusion. The same pairs of reviewers who scrutinized titles and abstracts also assessed inclusion/exclusion criteria (Appendix 1) for full-text articles. The Cochrane Risk of Bias Tool for randomized clinical trials was used to assess the risk of bias in individual studies. The Documentation and Appraisal Review (DART) tool was used to assess the quality of systematic reviews addressing a variety of research designs.
# Critical appraisal of identified studies
We compiled data from all articles relevant to each PICO question into evidence tables (available at: https://cts-sct.ca/ guideline-library/). The entire panel discussed each PICO question via webinars in June 2019, at which time, all evidence tables were reviewed. Accordingly, we established group consensus on the quality and strength of the evidence addressing each clinical question according to the GRADE criteria (Appendix 1). 13 In instances where there was insufficient evidence but a recommendation was still warranted, a suggestion was developed and "consensus-based (CB)" replaced the grade.
# Synthesis of evidence-base and clinical judgment of risk-versus-benefit
For each clinical question, we considered the strength and directness of the evidence supporting an intervention or treatment approach. For each therapeutic approach, we also considered: the potential health benefit to the patient; the morbidity and mortality impact on the overall COPD population; risks/harms; the burden placed on the patient; and the cost-effectiveness (these are the factors categorized under the "Contextualization and Deliberations" domain of the guidelines). 14 We also included informed clinical remarks with PICO clinical questions and recommendations, in an effort to compliment recommendations with practical clinical advice. Some of these remarks are not based on strong evidence, but represent the consensus opinions of panel members based on expertise.
# Update of recommendations and classification
We used recommendations in the 2015 Prevention of Acute Exacerbations of COPD -American College of Chest Physicians, the Canadian Thoracic Society Guideline document 15 Following open and extensive discussions and evidence review for each PICO question, the entire panel proposed wording updates to each prior recommendation pertaining to that PICO question, and where applicable, a change to the strength of the recommendation to reflect newly published literature. We based strength of the recommendation on the GRADE quality of evidence 13 (Appendix 1), and our synthesis of clinical judgment. The CTS Canadian Respiratory Guidelines Committee (CRGC) Chair then vetted the recommendations to optimize language with a view to improving likelihood of uptake. 16,17 Recommendations were then voted upon by electronic survey using a six-point voting scale, whereby it was defined a priori that a recommendation would only be accepted if each panel member voted for option 1, 2 or 3 (wholeheartedly agree, agree or can support). For a recommendation to be accepted, it had to be voted on by 75% of the eligible panel members and achieve ratings 1, 2 or 3 by 80% of the voting panelists. In the event of a failure to reach 80% of votes with ratings 1, 2 or 3, another period of discussion ensued, whereby dissenting opinions were heard and considered. The recommendation was revised and followed by a second round of voting by electronic survey using a three-point scale, for which acceptance of a recommendation required a majority (80%) of panelists to choose option 1 or 2 (Appendix 1). Throughout this process all recommendations achieved acceptance, with no recommendation requiring a second round of voting.
# Review and approval process
The CTS independently invited formal review of the update by an external (non-CTS) content expert. The lead author responded to the comments and made corresponding changes. Two members of the CRGC then completed their own review and provided further feedback for consideration. Upon acceptance, the Committee recommended approval of the guideline to the CTS Executive Committee.
# Living guideline/future updates
The guideline will be formally reviewed every three years or sooner to determine the need for and nature of any updates, in accordance with the CTS Living Guideline Model (details available at https://cts-sct.ca/guideline-library/methodology/). Authors and/or the CTS COPD Assembly Steering Committee members will also use the continuously updated McMaster Plus database, whereby they will receive alerts when new articles pertaining to these PICO questions are published (starting from the last date of the literature search conducted for this guideline). This will serve to prompt members to consider timely guideline updates with evolving evidence and will facilitate formal literature reviews.
Summary PICO 1: Improving symptoms, exercise tolerance, physical activity and health status in stable COPD patients Among respiratory symptoms, shortness of breath (dyspnea) on exertion is the most debilitating symptom COPD patients experience. 18 Since disease progression reduces patients' capacity to exercise and, therefore, affects the ability to perform the activities of daily life, 19,20 they consider relief of this symptom to be one of the most important outcomes in the management of their disease. 21 Shortness of breath also contributes to the established extra-pulmonary manifestations of COPD, including anxiety, depression, 22 cardiovascular disease 23 and peripheral locomotor muscle deconditioning. 24 Importantly, it is strongly associated with increased morbidity and mortality in adults with COPD. 25,26 Persistent shortness of breath is associated with increased exacerbation risk. 26,27 Dyspnea and exacerbation are not independent or dichotomous outcomes and they are often present in the same patient. Alleviating shortness of breath is a key goal of COPD management.
Inhaled bronchodilators are the mainstay medications in the pharmacologic management of COPD. There are two main classes of bronchodilators: B 2 -adrenoreceptor agonists and muscarinic antagonists, both in long-and short-acting forms. They can be used as monotherapy, combined as dual bronchodilators or combined with ICS for maintenance treatment. Bronchodilators enhance the neuromechanical coupling of the respiratory system and delay the onset of mechanical constraints, providing relief from exertional shortness of breath with concomitant improvement in exercise tolerance in patients with COPD. 28 This section discusses the optimal use of inhaled and oral pharmacologic maintenance therapies shown to improve shortness of breath, exercise tolerance, physical activity and health status in stable COPD patients.
# Key evidence
Based on this review for PICO 1, recommendations 1, 3, 7 and 8 remain unchanged, while recommendations 2, 4 and 5 have a change in GRADE assessment due to new research findings, and 2, 5 and 6 are revised based on evidence from published literature. See Appendix 2 detailing the upgrades and revisions from 2017.
As stated in the previous position statement, use of LAMA or LABA monotherapy is endorsed to reduce shortness of breath, improve exercise tolerance and improve health status in patients with stable COPD. Although LAMA is often preferred to LABA in monotherapy, the evidence of its superiority comes primarily from studies in which the main outcome was to prevent COPD exacerbations. In patients with COPD who have persistent shortness of breath, exercise intolerance and/or poor health status despite using inhaled LAMA or LABA monotherapy, we recommend augmenting treatment to LAMA/LABA dual therapy. Patients should be routinely monitored and evaluated for their response after any change in their therapy, as many have persisting symptoms with an impact on their well-being. 29 In terms of improving physical activity, the evidence suggests that combining a self-management behavioral intervention with exercise and pharmacologic interventions has the largest effect on physical activity and symptom improvement. A self-management behavioral intervention is more likely to help patients change their behavior and can lead to long-term adoption of a more physically active lifestyle. 30,31 For patients who remain symptomatic and have poor exercise tolerance or health status despite being on LAMA/ LABA combination therapy, the evidence supports patients enrolling in a pulmonary rehabilitation program. 32 For patients who remain symptomatic and have poor health status despite these interventions, a clinician should consider "step up" to triple therapy (LAMA/LABA/ICS), although each individual should be evaluated for risk/benefit of adding ICS in these circumstances. Evidence for its benefit has been demonstrated primarily in patients who have a high risk of exacerbations. 33,34 For PICO 1, data is lacking with respect to withdrawal or "step down" from LAMA/LABA/ICS to LAMA/LABA dual therapy or from dual therapy to monotherapy. We continue to support guidance from the previous position statement. 1 The consensus was that, in patients with COPD with no improvement in shortness of breath, exercise tolerance or health status despite the use of triple inhaled therapy or inhaled LAMA/LABA dual therapy, clinicians may cautiously consider "step down" treatment for some patients. These patients need to be monitored carefully with close clinical follow-ups to detect any signs of clinical deterioration after medication "step down."
As per previous guidelines, oral therapies such as theophylline, phosphodiesterase-4-inhibitor, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines or phosphodiesterase-5-inhibitor demonstrate no evidence of conferring additional benefit in patients already on combination longacting bronchodilators. We reiterate that ICS monotherapy, as a lone intervention, has no place in treating COPD patients. If there is an indication for ICS therapy or the patient has asthma in addition to COPD, then ICS should be prescribed in a combination inhaler with long-acting bronchodilator(s). 1.8
# Consensus
We recommend against treatment with ICS monotherapy in stable COPD patients.
When indicated, ICS should ideally be administered in a combination therapy in COPD patients.
Stable COPD: Patients are considered to have "stable COPD" in all clinical states other than during the period of an acute exacerbation of COPD (AECOPD). However, patients with "stable COPD" may have progressive symptoms and/or have experienced an exacerbation. Bronchodilators open up the airways in the lungs by relaxing airway smooth muscle. They also reduce lung hyperinflation. Bronchodilator medications can be shortor long-acting. Different types of short-or long-acting bronchodilators work in different ways.
Short-acting bronchodilators can be either SABAs (short-acting beta agonists) or SAMAs (short-acting muscarinic antagonists).
Long-acting bronchodilators can be either LABAs (long-acting beta2 agonists) or LAMAs (long-acting muscarinic antagonists).
Symbol "/" for combination therapy: The symbol "/" refers to: combination products (in the same device) and combination regimens (in separate devices). Single or multiple inhalers for combination therapy represent the clinical reality of different approaches to manage patients for a variety of considerations, such as access to medication, response to treatment, medical conditions other than COPD and patient preference. Exacerbations: Exacerbations are "event-based" occurrences; that is, respiratory symptom(s) that worsen beyond the normal day-to-day variability and may require the use of antibiotics and/or systemic corticosteroids and/or healthcare services. The varying levels of exacerbation severity are: mild (worsening or new respiratory symptoms without a change in prescribed medications); moderate (prescribed antibiotic and/or oral corticosteroids); and severe (requiring a hospital admission or ED visit).
Low-and high-risk of future exacerbations: Patients are considered to be at:
Low-risk of exacerbations if they had 1 moderate exacerbation in the last year and did not require an ED visit or hospitalization.
High-risk of exacerbations if they had Summary PICO 2: Preventing acute exacerbations in stable COPD patients
In Canada, AECOPD continues to be the most frequent cause of acute hospitalization in adults, 120 and is associated with the highest total hospital cost of care (2016)(2017). The cost of hospitalizations related to COPD is more than 30% higher than that of the next most expensive health condition (heart failure). 121 AECOPDs are a gateway to poor outcomes and adverse consequences. [122][123][124] They accelerate lung function decline, dramatically reduce quality of life, and are strong predictors of future AECOPDs. They are acute, trajectory-changing manifestations of a chronic disease associated with increased mortality. COPD is the third leading cause of death worldwide. 125,126 A fundamental and achievable goal of therapy in managing stable COPD is to reduce the occurrence and severity of AECOPDs. Furthermore, providing appropriate preventive therapy for patients at increased risk of exacerbation increases the likelihood of reducing and preventing ED visits and hospital admissions. In patients with severe COPD, reducing AECOPD may also reduce mortality. 33 This section discusses the optimal use of inhaled and oral pharmacologic maintenance therapies shown to prevent AECOPD in patients with stable COPD, not the treatment of acute exacerbations.
# Key evidence
Based on this review for PICO 2, recommendations 3 and 10 remain unchanged, while recommendations 1, 2, 4, 5, 6, 7, 8 and 9 have a change in GRADE assessment due to new research findings. Recommendations 5, 6, 7, 9 and 11 are revised based on evidence from published literature. See Appendix 2 detailing the upgrades and revisions from 2017.
A significant change is the use of either an ICS/LABA or LAMA/LABA as a first step in patients with high risk of AECOPD. Although ICS/LABA or LAMA/LABA is a viable inhaled therapeutic option in this setting, LAMA/LABA is the preferred choice except in patients with previous exacerbations who have higher peripheral eosinophilia (Figure 2). In this case, ICS/LABA could be the favored therapy as stated by the evidence described in the Discussion section of this guideline. Monotherapy with either LAMA or LABA is not the optimal initial maintenance treatment for patients who experience or are at high risk of AECOPD. Acknowledging the significant adverse consequences of AECOPD, consider inhaled therapy with either ICS/LABA or LAMA/LABA as the acceptable minimum maintenance therapy for this high risk population. It is important to remember that in real life practice, it is the exception to treat a patient only to prevent exacerbations; the vast majority of time we optimize bronchodilator therapy to improve a patient's dyspnea.
Similar to our analysis in PICO 1, we conclude that there is no role for ICS monotherapy and ICS should only be used in combination with bronchodilators. ICS/LABA and LAMA/ LABA/ICS are the only current single inhaler options. Health Canada has not approved an inhaled ICS for monotherapy use in COPD. Furthermore, in prior studies, the monotherapy ICS arm underperformed compared to combination ICS/ LABA, and post-hoc analysis suggested increased mortality in the ICS monotherapy participants. 127 Administering ICS with LAMA/LABA in separate inhalers has not been studied in COPD. 120,122,123 When combination ICS/LABA or LAMA/ LABA/ICS is used, high doses of ICS 122 are not typically necessary to achieve optimum benefit in COPD, as shown by a relatively flat dose-response curve 128 and greater incidence of adverse effect with higher inhaled ICS doses. 129 There remains clinical uncertainty regarding potential "step down" of therapy 90,123 in patients with a history of a high risk of future AECOPD. Evidence from a randomized clinical trial involving participants with COPD receiving combination ICS/LABA with LAMA in separate inhalers who underwent stepwise ICS withdrawal suggests the intervention is not associated with a significantly increased risk of exacerbation over a short term of follow up. 130 However, in this study the initial baseline exacerbation rate was low, about one-third of participants had not previously required inhaled triple therapy before recruitment, there was a statistically significant reduction in FEV 1 (43 mL, p ¼ 0.001) after ICS withdrawal, and the number of deaths was numerically small but higher in the ICS withdrawal group (n ¼ 40) compared to the ICS continuation group (n ¼ 34). More recently, another randomized clinical trial of patients with COPD with low risk of AECOPD on long-term triple inhaled therapy with direct de-escalation to LAMA/LABA led to a small decrease in lung function as a primary endpoint, with no difference in exacerbation rate. However, the primary study endpoint was not met, with confidence limits for trough FEV 1 exceeding the non-inferiority margin of À50 mL. Further analysis of these studies revealed a higher rate of exacerbation in patients with !300 blood eosinophils/lL, suggesting that, as a biomarker, blood eosinophil at !300/lL in patients with previous AECOPD could be useful to predict a favorable response to ICS when combined with long-acting bronchodilator(s). However, no RCT has compared ICS/LABA versus LABA/LAMA in patients with high risk of and blood eosinophil at !300/lL, with exacerbation as a primary endpoint.
Given these findings and acknowledging the negative impact of AECOPD, reductions in lung function and the potential adverse consequences of therapy, we continue to support guidance from the previous CTS guidance document 123 that the clinical phenotype should drive pharmacotherapy for patients with COPD. If therapy was started without a clear indication (such as the use of an ICS in a patient with no history of exacerbations), you may consider initiating a "step down." However, if therapy was started according to recommendations (such as the use of LAMA/LABA/ICS in a patient with moderate-severe COPD with poor quality of life and history of frequent and/or severe AECOPD) and treatment has been effective, a "step down" is NOT recommended. Given the potential for serious negative consequences of AECOPD, including hospitalization and death, we believe that de-escalation should only be considered in patients at low risk of morbidity and mortality, and this after a period of considerable stability. Moreover, while awaiting objective documentation supporting the safety of this approach, if you decide to "step down," we highly recommend monitoring your patients carefully with regular clinical assessments that includes the monitoring of lung function and re-occurrence of AECOPD.
As noted, the incidence of pneumonia is higher with maintenance therapy of ICS-containing inhaled medicines, especially in COPD patients with severe and very severe disease. However, these are also the patients who benefit most from an ICS-containing regimen. Debate still ensues as to an intra-class difference between fixed combinations of inhaled corticosteroid/long acting b 2 agonist regarding the risk of pneumonia and pneumonia-related events in treating patients with COPD. 131 However, the clinical significance of increased pneumonia in COPD patients who use ICS remains unclear, since there is no concurrent documented increase risk of mortality in this group. 131 Results from a large clinical trial 33 confirmed a higher incidence of pneumonia with ICS-combination therapy, but this was accompanied by significant improvements in lung function and quality of life and significant reductions in exacerbations and mortality, which are endpoints of significant importance.
As stated in the previous position statement, if patients with COPD continue to experience exacerbations despite being on optimal long-acting inhaled therapy, consider adding a daily macrolide (e.g. Azithromycin) as maintenance therapy in appropriate patients who have normal QT interval on ECG and no evidence of either colonization or acute infection with atypical mycobacterium. Also consider oral Roflumilast or oral N-acetylcysteine (600 mg po BID) in those having a clinical phenotype by history in keeping with chronic bronchitis. In recommendation 2.11 in this update, recent evidence supports not using theophylline in patients who are on long-acting inhaled therapy. We reiterate that systemic corticosteroids should not be used for maintenance pharmacotherapy in stable COPD. COPD pharmacotherapy promoting an approach that aligns treatment decisions with symptom burden and risk of future exacerbations. To learn more about the Asthma-COPD Overlap (ACO) treatment algorithm, refer to the CTS position statement on the pharmacotherapy in patients with COPD in 2017. 1 mMRC is a modified (0-4 scale) version of the MRC breathlessness scale which was used in previous CTS guidelines. The mMRC aligns with the Global Initiative for Chronic Obstructive Airways Disease (GOLD) 2019 report. SABD prn (as needed) should accompany all recommended therapies. Solid arrows indicate step up therapy to optimally manage symptoms of dyspnea and/or activity limitation, as well as prevention of AECOPD where appropriate. Dashed arrows indicate potential step down of therapy, with caution and with close monitoring of patient symptoms, exacerbations and lung function. Symbol "/" refers to combination products (in the same device) and combination regimens (in separate devices). ICS should ideally be administered in a combination inhaler.
†Patients are considered at Low Risk of AECOPD with 1 moderate AECOPD in the last year (moderate AECOPD is an event with prescribed antibiotic and/or oral corticosteroids), and did not require hospital admission/ED visit; or at High Risk of AECOPD with !2 moderate AECOPD or !1 severe exacerbation in the last year (severe AECOPD is an event requiring hospitalization or ED visit). Ã Blood eosinophil !300/mL in patients with previous AECOPD may be useful to predict a favorable response to ICS combination inhaler. ‡Oral Therapies ¼ Roflumilast, N-acetylcysteine, daily dose Azithromycin could be considered with patients with high risk AECOPD despite on optimal long-acting inhaled therapy. Oral corticosteroids as maintenance therapy are not indicated in COPD.
# 1B
We recommend oral N-acetylcysteine (600 mg po BID) for patients with chronic bronchitis and a high risk of AECOPD despite optimal long-acting inhaled therapy.
123,177-185 2.10
# 2A
We suggest macrolide maintenance therapy for patients with a high risk of AECOPD despite optimal long-acting inhaled therapy.
Weigh the benefits against the risks of potential microbial resistance, hearing impairment and QT-prolonging drug interactions.
# 2B
We suggest that oral slow-release theophylline should not be used, as it does not prevent AECOPD in patients on optimal long-acting inhaled therapy. 123,190 Stable COPD: Patients are considered to have "stable COPD" in all clinical states other than during the period of an acute exacerbation of COPD (AECOPD). However, patients with "stable COPD" may have progressive symptoms and/or have experienced an exacerbation. SABD prn (as needed) should accompany all recommended therapies. Bronchodilators open up the airways in the lungs by relaxing airway smooth muscle. They also reduce lung hyperinflation. Bronchodilator medications can be short-or long-acting. Different types of short-or long-acting bronchodilators work in different ways.
Short-acting bronchodilators can be either SABAs (short-acting beta agonists) or SAMAs (short-acting muscarinic antagonists). Long-acting bronchodilators can be either LABAs (long-acting beta2 agonists) or LAMAs (long-acting muscarinic antagonists).
Symbol "/" for combination therapy: The symbol "/" refers to: combination products (in the same device) and combination regimens (in separate devices). Single or multiple inhalers for combination therapy represent the clinical reality of different approaches to manage patients for a variety of considerations, such as access to medication, response to treatment, medical conditions other than COPD and patient preference. Exacerbations: Exacerbations are "event-based" occurrences; that is, respiratory symptom(s) that worsen beyond the normal day-to-day variability and may require the use of antibiotics and/or systemic corticosteroids and/or healthcare services. The varying levels of exacerbation severity are: mild (worsening or new respiratory symptoms without a change in prescribed medications); moderate (prescribed antibiotic and/or oral corticosteroids); and severe (requiring a hospital admission or ED visit).
Low-and high-risk of future exacerbations: Patients are considered to be at:
Low-risk of exacerbations if they had 1 moderate exacerbation in the last year and did not require an ED visit or hospitalization.
High-risk of exacerbations if they had !2 moderate or !1 severe exacerbation in the last year requiring a hospital admission/ED visit.
Oral Therapies are Roflumilast, N-acetylcysteine or daily dose Azithromycin. Oral corticosteroids as maintenance therapy are not indicated in COPD. Optimal long-acting inhaled therapy is therapy that has been tailored to the patient's exacerbation history, in accordance with Figure 2. Abbreviations: PICO, Patient/population -Intervention or interventions -Comparison groups -Outcome or outcomes of interest; COPD, chronic obstructive pulmonary disease; BID, bis in die (twice a day); ICS, inhaled corticosteroid; ED, emergency department; SABD prn, short-acting bronchodilator as needed.
# Discussion
Since the 2017 CTS pharmacotherapy position statement, there have been several important clinical trials that have necessitated an update. In this guideline we have incorporated new evidence from published large multicenter clinical trials and systematic reviews that have an impact on clinicians' approach to the medical management of patients living with COPD. We have summarized our updated recommendations in Tables 1 and 2 and included a comparison of 2017 and 2019 recommendations in Appendix 2.
An updated COPD pharmacologic algorithm (Figure 2) that reflects these updates was also derived.
The treatment propositions presented in this updated Guideline, in particular the approach of a treatment "step up" and "step down" are pragmatic and intended to provide meaningful guidance for clinicians. Most research trials were not strictly designed to assess such a therapeutic approach. However, treatment "step up" in COPD is a practical construct with wide appeal that is supported by evidence that inhaled combined therapy is superior to monotherapy and triple therapy to dual therapy in certain patient populations. Because the superiority of inhaled triple or dual bronchodilator therapy may not be achieved in every patient, "step down" may be considered for some patients, but should only be done with close medical supervision, as the risk of clinical deterioration is real and continues to exist.
There are several important considerations in the management of COPD that are not addressed by the PICO questions in this guideline document. We have therefore provided a commentary of selected topics in this discussion. A full review of these clinical issues may be undertaken in subsequent guideline development.
# Choice of inhaler device
The choice of the inhaler device and/or the decision to use single or multiple devices for combination therapy remains a subject of clinical interest and controversy. Very few studies have compared combination products in the same device compared to separate devices. In the only randomized clinical trial examining this issue, a single-inhaler LAMA/ LABA/ICS was compared to an ICS/LABA and LAMA in separate devices; this study demonstrated non-inferiority between the two treatment strategies. 191 There is no study that has been performed in COPD comparing LABA or combined LAMA/LABA with ICS in single and separate devices. Although the use of single or multiple devices for combination therapy is a clinical reality, properly designed trials or real-life data are lacking in COPD.
# Choice of bronchodilator combination
Another topic is the question clinicians may have with respect to the equivalence or superiority of the various combined long-acting bronchodilators (LAMA/LABA). Few comparative efficacy trials compared combination long-acting bronchodilator therapy; those that did showed between-treatment differences in FEV 1 that were small and of uncertain clinical significance. 192,193 Interval for changing inhaler therapy
The decision to change a therapy should always occur after a complete evaluation of the patient and the potential benefit of a change in therapy; as well as an assessment of any adverse effects of the therapy, and with a review of patient adherence, inhaler technique and preferences. Although there is no absolute interval time at which the evaluation should be performed following a change in therapy, 6 months after initiating a long acting bronchodilator and 12 months after initiating a combination regimen with an ICS are suggested timeframes.
# Peripheral blood eosinophils in COPD
While peripheral blood eosinophil counts have demonstrated reasonable repeatability over a year in a population-based cohort of COPD patients in primary care, 194 practical uncertainty remains regarding the exact cut-off level of sputum or blood eosinophils for predicting therapeutic response in COPD. Despite this uncertainty, peripheral blood eosinophil counts may play a role in certain clinical settings. New information is incorporated into this update with respect to blood eosinophils as a potential biomarker for use in COPD patients known to have exacerbations to prevent future exacerbations. A consistent pattern of results from randomized clinical trials conducted in COPD patients at risk of exacerbations has emerged. Lower eosinophil counts (<100 eosinophils/mL) predict a lower or no response to ICS containing regimens in terms of preventing exacerbation. ICS containing regimens will benefit in reducing the likelihood of exacerbations in the magnitude of effect being greater at higher eosinophil counts, particularly !300 eosinophils/lL. 156 This provides a measure of probability of response to ICS containing regimen in patients who had previous exacerbations, aligning with a more personalized approach.
# Mortality
Reducing mortality has been a long-standing goal of therapy in COPD. Older studies have revealed mortality-reducing trends with inhaled therapy 127,195 but statistical significance was not achieved. Although there is still no definitive answer, more recent evidence from a large randomized controlled trial study demonstrated significant relative reduction in all-cause mortality during treatment with regimens that included inhaled ICS/LABA or triple therapy (LAMA/ LABA/ICS) compared to LAMA/LABA for COPD patients with high risk of exacerbations. Despite a higher incidence of study-reported pneumonia in the ICS-containing treatment regimens, mortality was reduced by 42% in favor of LAMA/LABA/ICS vs. LAMA/LABA (unadjusted p ¼ 0.01), and 39% in favor of ICS/LABA vs LAMA/LABA (unadjusted p ¼ 0.02). An analysis of adjudicated cause-specific death during treatment demonstrated fewer deaths from both respiratory and cardiovascular etiologies in the ICS-containing regimens. This topic requires further attention, but mortality is an important outcome that should have our consideration in clinical decision.
# Dissemination and implementation
Our guideline will be disseminated through traditional channels including this publication, through the CTS website and social media channels, and through an accompanying slide deck that will be used to present this content to various target groups across the country. It is also anticipated that we will produce a separate implementation document that will include key indicators of appropriate care and practical guidance for healthcare system change. Our goal is to monitor the impact of these actionable recommendations through their ability to correct knowledge gaps and improve actual behaviors within the target user groups. On a population level, we also believe that monitoring the frequency of COPD ED visits, hospital admissions and re-admissions would be relevant metrics to assess the success of this guideline. For messages targeting nonexperts, we will seek to tailor messages and produce corresponding educational content, in collaboration with key stakeholders such as provincial lung associations, RESPIPLUS and RESPTREC.
# Conclusion
This update is an important step toward optimizing the pharmacologic management of COPD. Recommendations enable better-personalized therapy based on more specific individual characteristics. The update further highlights the intent and benefit of therapy in both improving symptoms and activity limitations, and reducing the risk of AECOPD. Areas of debate still require further study, including approach to treatment "step down" targeting specific group of patients, blood eosinophil use and its cut off, and use of single or multiple inhalers for combination therapy, but recent evidence has strengthened many recommendations to optimize management of COPD. In summary, pharmacological therapy plays a foundational role in therapy, but it should never be the sole treatment in managing COPD patients. Clinicians should always combine and optimize pharmacological and non-pharmacological therapies with the dual goals of reducing symptoms and preventing AECOPD. bers of the CTS CRGC for their input and guidance. We would like to acknowledge with sincere appreciation our expert reviewer, Marc Miravitlles from the Pneumonlogy Department, University Hospital Vall d'Hebron, Ciber de Enfermedales Respiratorias (CIBERES), Barcelona, Spain.
# Editorial independence
The CTS COPD guideline panel is accountable to the CTS Canadian Respiratory Guidelines Committee and the CTS Board of Directors. The CTS COPD guideline panel is functionally and editorially independent from any funding sources of the CTS and does not receive any direct funding from external sources. The CTS receives unrestricted grants that are combined into a central operating account to facilitate the knowledge translation activities of the CTS Assemblies and its guideline panels. No funders played a role in the collection, review, analysis or interpretation of the scientific literature or in any decisions regarding the key messages presented in this document.
# Disclosures
Members of the CTS COPD Guideline Panel declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy. Individual member conflict of interest statements are posted at https://cts-sct.ca/guideline-library/. Evidence for at least one critical outcome from observational studies, case series or randomized controlled trials, with serious flaws or indirect evidence.
# ORCID
Recommendation can apply to most patients in many circumstances. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect, and may well change the estimate.
Weak recommendation, high-quality evidence 2A Benefits closely balanced with risks and burden.
Consistent evidence from randomized controlled trials without important limitations, or exceptionally strong evidence from observational studies.
The best action may differ depending on circumstances or patient or societal values. Further research is unlikely to change our confidence in the estimate of effect.
Weak recommendation, moderate-quality evidence 2B Benefits closely balanced with risks and burden.
Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence from observational studies.
Best action may differ depending on circumstances or patient or societal values.
Higher-quality research may well have an important impact on our confidence in the estimate of effect, and may change the estimate.
Weak recommendation, low-or very-lowquality evidence 2C Uncertainty in the estimates of benefits, risks and burden; benefits, risk and burden may be closely balanced.
Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials, with serious flaws or indirect evidence.
Other alternatives may be equally reasonable.
Higher-quality research is likely to have an important impact on our confidence in the estimate of effect, and may well change the estimate.
# Consensus-based unchanged
# Recommendation revised
New clinical remark Rec 7 -There is insufficient or equivocal evidence in stable COPD patients to determine whether the addition of an oral therapy, such as theophyllines, phosphodiesterase-4-inhibitors, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines or phosphodiesterase-5inhibitors, confers additional benefit to inhaled LAMA or LABA monotherapy, or LAMA plus LABA dual therapy in reducing dyspnea, improving exercise tolerance and activity levels or improving health status. (Grade 2C).
There is insufficient or equivocal evidence to determine whether the addition of an oral therapy, such as theophyllines, phosphodiesterase-4inhibitors, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines or phosphodiesterase-5-inhibitors confers additional benefit to LAMA or LABA monotherapy, or LAMA/LABA dual therapy in reducing dyspnea, improving exercise tolerance and activity levels and/ or improving health status.
# GRADE 2C
unchanged Recommendation not updated (continued)
# Acknowledgments
The authors would like to thank Anne Van Dam from CTS and Samir Gupta and Christopher Licskai, Executive mem-
# Appendix 1
A) Search strategy PICO 1: How does a clinician choose appropriate maintenance pharmacotherapies in patients with stable COPD to reduce symptom burden (notably dyspnea and exercise intolerance), increase physical activity and improve health status?
# PICO elements Population
Intervention (s)
Comparator Outcomes
Adults with stable COPD Ã , chronic bronchitis, emphysema Maintenance inhaled therapy, alone or in combination:
short-acting anticholinergic, short-acting betaagonists, long-acting bronchodilators, long-acting beta-agonists, long-acting anticholinergic, long-acting muscarinic antagonists, inhaled corticosteroids, dual long-acting bronchodilators, combination ICS/LABA, triple therapy; oral therapy, alone or in combination(s): methylxanthines, theophylline, antibiotics, nacetylcysteine, PDE-4 inhibitors, Roflumilast.
Placebo, combination therapies compared to single modality, head-to-head comparison Dyspnea, exercise, exercise tolerance, exercise capacity, health-related quality of life
# Search Terms
Inclusion/Exclusion Criteria acute exacerbations, COPD, chronic obstructive lung disease, emphysema, chronic bronchitis, lung diseases (obstructive), chronic disease management, prevention, inhaled therapy, long acting beta agonists, long acting anticholinergics, short-acting anticholinergics, inhaled corticosteroids English language studies, studies will be included based on population, intervention, comparison and outcome defined above. Include studies with follow-up duration of 3 months or greater and studies with follow-up duration of 6 months or greater. Primary and secondary outcomes will be included. If studies are included that examined an outcome of interest as a secondary outcome, the assessment of the secondary outcomes will be carefully examined and the body of evidence will be downgraded for risk of bias, if deemed necessary. We recommend either LAMA or LABA monotherapy over a SABD prn.
# Abbreviations
Clinical remark: This is applicable to a patient at low risk of AECOPD.
# GRADE 1A
From 1B (for LABA only) Recommendation not updated Rec 2 -We recommend the use of an inhaled LAMA as a preferred choice compared with an inhaled LABA to prevent AECOPD (Grade 1B).
We recommend LAMA monotherapy over LABA monotherapy.
Clinical remark: This is applicable to a patient at low risk of AECOPD.
# GRADE 1A
From 1B Recommendation not updated Rec 3 -We recommend an inhaled LAMA (Grade 1A) or suggest an inhaled LABA (Grade 2C) compared with an inhaled short-acting muscarinic antagonist to prevent AECOPD.
We recommend LAMA monotherapy over SAMA. AND We suggest LABA monotherapy over a SAMA.
Clinical remark: This is applicable to a patient at low risk of AECOPD.
# GRADE 1A
From 1C Recommendation updated Rec 8 -We recommend the use of oral Roflumilast to prevent AECOPD for patients with chronic bronchitis and a history of at least one exacerbation in the previous year despite long-acting inhaled therapy (Grade 1B). We recommend oral Roflumilast for patients with chronic bronchitis and a high risk of AECOPD despite optimal long-acting inhaled therapy.
# GRADE 1A
From 1B Recommendation not updated Rec 9 -We suggest treatment with oral N-acetylcysteine (600 mg po BID) to prevent AECOPD for patients with chronic bronchitis, a history of at least one exacerbation in the previous year, and on long-acting inhaled therapy (Grade 2B). We recommend oral N-acetylcysteine (600 mg po BID) for patients with chronic bronchitis and a high risk of AECOPD despite optimal longacting inhaled therapy.
# GRADE 1B
From 2B Recommendation updated Rec 10 -We suggest a macrolide as maintenance therapy to prevent AECOPD for patients with a history of recurrent moderate or severe COPD exacerbations in the previous year despite long-acting inhaled therapy (Grade 2A). We suggest macrolide maintenance therapy for patients with a high risk of AECOPD despite optimal long-acting inhaled therapy.
Clinical remark: Weigh the benefits against the risks of potential microbial resistance, hearing impairment and QT-prolonging drug interactions.
# GRADE 2A
unchanged Recommendation not updated New clinical remark Rec 11 -We suggest treatment with oral slow-release theophylline to prevent AECOPD for patients on long-acting inhaled therapy (Grade 2B). We suggest that oral slow-release theophylline should not be used, as it does not prevent AECOPD in patients on optimal long-acting inhaled therapy.
# GRADE 2B unchanged Recommendation updated
Abbreviations: PICO, Patient/population -Intervention or interventions -Comparison groups -Outcome or outcomes of interest; COPD, chronic obstructive pulmonary disease; ICS/LABA, inhaled corticosteroid/long-acting beta agonists; AECOPD, acute exacerbation of COPD; LAMA, long-acting muscarinic antagonists; SABD, SABD prn, short-acting bronchodilator as needed; SAMA, short-acting muscarinic antagonists; BID, bis in die (twice a day).
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Background Previous versions of the guideline from the Program in Evidence-Based Care (pebc) at Ontario Health (Cancer Care Ontario) recommended that the use of high-dose interferon alfa 2b therapy be discussed and offered to patients with resected cutaneous melanoma with a high risk of recurrence. Subsequently, several clinical trials in patients with resected or metastatic melanoma found that immune checkpoint inhibitors and targeted therapies have a benefit greater than that with interferon. It was therefore considered timely for an update to the guideline about adjuvant systemic therapy in melanoma.The present guideline was developed by the pebc and the Melanoma Disease Site Group (dsg). Based on a systematic review from a literature search conducted using medline, embase, and the Evidence Based Medicine Reviews databases for the period 1996 to 28 May 2019, the Working Group drafted recommendations. The systematic review and recommendations were then circulated to the Melanoma dsg and the pebc Report Approval Panel for internal review; the revised document underwent external review. Recommendations For patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence, the recommended adjuvant therapies are nivolumab, pembrolizumab, or dabrafenib-trametinib for patients with BRAF V600E or V600K mutations; nivolumab or pembrolizumab are recommend for patients with BRAF wildtype disease. Use of ipilimumab is not recommended. Molecular testing should be conducted to help guide treatment decisions. Interferon alfa, chemotherapy regimens, vaccines, levamisole, bevacizumab, bacillus Calmette-Guérin, and isolated limb perfusion are not recommended for adjuvant treatment of cutaneous melanoma except as part of a clinical trial.# INTRODUCTION
Melanoma is the 8th most common cancer in Canada, and the 15th in mortality 1 . Cutaneous melanoma predominates, and most clinical trials have been conducted in patients with cutaneous melanoma. Data used in developing the 8th edition of the American Joint Committee on Cancer (ajcc) cancer staging manual indicate, for cutaneous melanoma, 5-year melanoma-specific survival rates of 98% for stage i, 90% for stage ii, and 77% for stage iii disease, with rates as low as 32% for the stage iiid subgroup 2 . Given the poor survival for more advanced but resectable disease, many clinical trials have investigated the use of adjuvant systemic therapy.
Mucosal melanoma is a rare disease: it accounts for approximately 0.03% of all cancers diagnosed 3 and 1.4% of all melanomas in the United States 4 . The most common sites are the head and neck, the anorectal area, and the vulvovaginal region. Ultraviolet radiation exposure has not been associated with development of mucosal melanoma 5 , and rates are relatively consistent in various populations. Because of lower rates of cutaneous cancer in patients of Hispanic or African background 4 and in Asian populations 6,7 , mucosal melanoma constitutes a higher proportion of melanomas in those groups. Characteristics of mucosal melanoma, including causative mutations, differ from those of cutaneous melanoma, and the absolute level of response to treatment can vary. Uveal and other ocular melanomas are outside the scope of the present guideline.
For many years, interferon (ifn) was considered the only effective adjuvant treatment, and previous versions of this guideline recommended that the use of high-dose ifn alfa 2b (hd-ifn-α2b) therapy be discussed and offered to patients at high risk of recurrence 8,9 . Several trials found that ifn was associated with a recurrence-free survival (rfs) benefit, but a marginal or absent benefit for overall survival (os). That small benefit was confirmed in meta-analyses of trials, but was offset by significant adverse effects affecting quality of life. Trials in the metastatic setting found a much greater benefit to be associated with immune checkpoint inhibitors and targeted therapy, and recent trials have confirmed the benefit of some of those agents in the adjuvant setting.
Given the emergence of those new agents, an updated guideline about the adjuvant treatment of melanoma, based on a systematic review of the current evidence, was determined to be required.
# METHODS
# Guideline Developers
This guideline was developed by the Systemic Adjuvant Therapy for Adult Patients at High Risk for Recurrent Melanoma Guideline Development Group, which was convened at the request of the Melanoma Disease Site Group (dsg) of Ontario Health (Cancer Care Ontario) . The project was led by a small Working Group that was responsible for reviewing the evidence base, drafting the guideline recommendations, and responding to comments received during the document review process. The Working Group had expertise in medical oncology and health research methodology. Other members of the guideline development group served as the Expert Panel and were responsible for review and approval of the draft document. Conf lict of interest declarations were collected for all participants and were managed in accordance with the Program in Evidence-Based Care (pebc) conflict of interest policy. The director of the pebc waived the requirement that the lead author and 50% of members of the Working Group have no declared interests, with the provision that co-chairs be appointed.
# Guideline Development
The pebc produces evidence-based and evidence-informed guidance documents using the methods of the practice guidelines development cycle 10,11 . The process includes a systematic review, interpretation of the evidence, and drafting of recommendations by the Working Group, internal review by content and methodology experts, and external review by clinicians. The pebc's guideline development methods are described in more detail in the PEBC Handbook and the PEBC Methods Handbook. The present publication focuses on the guideline recommendations, with a brief summary of the methods used; the full 5-part document, including the systematic review, can be found on the oh(cco) Web site 12 .
# Guideline Objective
This guideline makes recommendations about the use of adjuvant systemic therapy in adult patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence.
# Research Questions
n What systemic therapy should clinicians recommend to adult patients who have been rendered disease-free after resection of cutaneous melanomas (including all sites of metastases, if present) and who are at high risk for subsequent recurrence? n What systemic therapy should clinicians recommend to adult patients who have been rendered disease-free after the resection of mucosal melanomas?
# Target Population
The target population is adult patients with cutaneous or mucosal melanoma with high risk of recurrence who have been rendered disease-free after resection (including resection of all locoregional or distant metastases, if present).
Patients with unresected primary disease or metastases fell outside the scope. In determining risk of recurrence, disease with any of the following characteristics was considered high risk:
n Primary melanoma with a tumour thickness greater than 4.0 mm (T4 in ajcc 6th, 7th, or 8th editions)
n If node-negative, these tumours fall into ajcc stage iib (no ulceration) or iic (ulceration). n Primary melanoma with a tumour thickness greater than 2.0-4.0 mm, with ulceration (T3b, stage iib if node-negative) n Primary melanoma with one or more of n positive sentinel lymph nodes (micrometastasis); n clinically detected positive regional lymph nodes (macrometastasis); or n in-transit, satellite, or microsatellite metastases (node-positive and stages iii a-iiic in the ajcc 6th or 7th editions, or stages iiia-iiid in the ajcc 8th edition) n Distant metastasis (stage iv) n Recurrence of melanoma that was previously completely resected
It should be noted that ajcc staging categories are for cutaneous melanoma; staging for mucosal melanoma varies depending on the primary site, and the ajcc staging designations might not apply.
# Literature Search
The literature search included clinical practice guidelines, systematic reviews, and randomized controlled trials (rcts). Details for the review, including the research questions, population of interest, interventions and comparators, outcomes, inclusion and exclusion criteria, and databases to search were determined before the literature review and were documented in the project plan. Reviews conducted before 2013 were excluded.
The literature search was conducted in embase, medline, and the Evidence Based Medicine Reviews database (Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews) for 1996 to 11 June 2018 and was subsequently updated to 28 May 2019. Complete details, including the search strategy and the inclusion and exclusion criteria are reported in the full systematic review 12 . The search strategy combined terms for melanoma plus terms for chemotherapy, immunotherapy, vaccines, or systemic therapy (including specific agents), plus terms for clinical practice guidelines, systematic reviews, or rcts. Abstracts of selected recent conferences and the ClinicalTrials.gov Web site were also reviewed. Web sites of major cancer guideline developers and practice guideline databases were reviewed for recent clinical practice guidelines.
To be included, studies had to be randomized trials of adjuvant systemic therapy in adult patients with melanoma with high risk of recurrence (see the Target Population subsection). Data extraction for the present review was conducted by a health research methodologist (GGF). Because this guideline is an update, some of the data were reproduced from a previous version 9 and were then verified in a consultation of the primary literature.
# Development of Recommendations
The Working Group drafted recommendations based on the systematic review. Where rct evidence was limited, recommendations were based on the professional experience of the authors, together with consideration of current practice. Such limitations are clearly indicated in the key evidence and qualif ying statements that follow each recommendation.
# Internal and External Review Process
Before submission of the draft report for external review, the systematic review and practice guideline were reviewed by the members of the Melanoma dsg and the pebc Report Approval Panel. The Report Approval Panel consists of the pebc Scientific Director and two other members with expertise in clinical and methodology issues. The dsg and Report Approval Panel members reviewed the draft systematic review and practice guideline and provided feedback, which was incorporated into the guideline.
Participating as Consultation Group members for the project, 4 cancer patients or survivors reviewed the draft document distributed for internal review and provided feedback on its comprehensibility, appropriateness, and feasibility. The revised draft document was then distributed for external review.
External review included both a targeted peer review that is intended to obtain direct feedback from a small number of content experts, and a professional consultation that is intended to facilitate dissemination of the guideline to Ontario practitioners and to provide opportunity for additional feedback. Results of the feedback can be found in the full guideline report on the oh(cco) Web site 12 .
# RESULTS
# Search for Guidelines
Only the guidelines by the Cancer Council Australia 13 and the Society for Immunotherapy of Cancer 14 included recent trials and recommendations about the use of immune checkpoint inhibitors and targeted therapies. The Working Group members decided that those guidelines had several limitations, including a narrower focus, and could not replace development of the present guideline. During the literature update search (May 2019), it was noted that the French Society of Dermatology had a new guideline 15,16 concerning stage iii melanoma (and stage iv, if completely resected), partially replacing their previous guideline on stages i-iii disease 17 . The 2019 National Comprehensive Cancer Network (nccn) guideline concerning melanoma represents a significant revision of previous versions and now includes immune checkpoint inhibitors and BRAFtargeted therapies 18,19 . Recommendations in both guidelines are similar to those in the present work. The nccn guideline includes diagnosis and treatment of stages 0-iv unresectable melanoma, and therefore the section concerning adjuvant systemic therapy is more limited than that in the present work; in contrast, the nccn guideline has more details on topics such as principles of molecular testing and management of adverse events (aes) associated with targeted therapy.
# Search for Systematic Reviews and Primary Literature
The literature search identified 15 systematic reviews and 63 trials (135 publications) that met the inclusion criteria. Most of the trials of ifn compared with observation, and some comparing 2 doses or durations of ifn, were covered in the meta-analysis by the International Melanoma Meta-Analysis Collaborative Group 20 that used individual patient data (ipd) for adjuvant ifn-α and in the Cochrane systematic review and meta-analysis by Mocellin et al. 21 for adjuvant ifn-α. Both reviews found small but statistically significant improvements in disease-free survival (dfs) or rfs and in os. Benefits did not vary with dose, age, sex, site of primary tumour, disease stage (i/ii or iii/iv), Breslow thickness, or presence of clinically involved nodes. Only patients with ulcerated tumours appeared to receive a benefit. The ongoing European Organisation for Research and Treatment of Cancer (eortc) 18081 trial (see NCT01502696 at /) being conducted in patients with ulcerated melanoma could potentially confirm that finding. Other ifn trials explored dose, duration, or formulation, but were generally inconclusive. Trials of vaccines and chemotherapy were also negative or inconclusive.
Several recent trials evaluated immune checkpoint inhibitors or targeted therapies and reported greater benefit than had been found in the ifn trials. Immune-related aes are significant and have to be considered. The eortc 18071 trial compared ipilimumab with placebo , the Eastern Cooperative Oncology Group E1609 trial compared ipilimumab with ifn 25,26 , CheckMate 238 compared nivolumab w it h ipilimumab 27,28 , and k e y not e-054 (eortc 1325) compared pembrolizumab with placebo 29 . Conference abst racts have repor ted a n i nd i rect compa r ison of nivolumab with placebo 30,31 . Adverse effects were greater with ipilimumab than with nivolumab or pembrolizumab. For br af-targeted therapies, vemurafenib is being compared with placebo in the brim8 trial 32 and combination dabrafenib-trametinib is being compared with placebo in the combi-ad trial 33,34 . Some of the foregoing trials included patients with mucosal melanoma, but the numbers of those patients are too small to reach conclusions specifically for mucosal melanoma. An abstract publication of an ongoing trial suggests that temozolomide-cisplatin might provide some benefit 35 .
# RECOMMENDATIONS Cutaneous Melanoma
# Recommendation 1
Nivolumab or pembrolizumab is recommended as adjuvant therapy for patients with completely resected cutaneous melanoma w it hout BR AF V600E or V600K mutations and with high risk of recurrence .
Nivolumab, pembrolizumab, or dabrafenib-trametinib is recommended as adjuvant therapy for patients with completely resected cutaneous melanoma with BRAF V600E or V600K mutations and with a high risk of recurrence .
Molecular testing of patients with high-risk melanoma to characterize mutations should be conducted to help guide appropriate treatment decisions.
Qualifying Statements: Nivolumab, pembrolizumab, and combination dabrafenib-trametinib (for BRAF V600E or V600K mutated melanoma) are all appropriate treatments; evidence to suggest which is more effective is currently insufficient. These agents were evaluated in different trials 27,29,33 and have not been directly compared in the adjuvant setting. For nivolumab and pembrolizumab, treatment-related aes, which occurred in 85% and 78% of patients respectively, tended to be mild and manageable, with the most common being fatigue, skin reactions (rash, pruritus), diarrhea, nausea, and endocrine disorders. Similar rates of grade 3 or greater treatment-related aes (14.4% and 14.7%) resulting in treatment discontinuation (9.7% and 13.8%) were reported. Combination dabrafenibtrametinib resulted in a higher rate of serious aes (36%), including pyrexia, hypertension, and hepatic effects, and a higher rate of discontinuation attributable to aes (25%). The spectrum of aes and the contraindications for immunotherapy with nivolumab or pembrolizumab compared with those for dabrafenib-trametinib should be discussed with the patient when adjuvant treatment is being decided.
The foregoing treatments were evaluated in trials requiring patients to have undergone complete regional lymphadenectomy. The Multicenter Selective Lymphadenectomy Trial-II (mslt-ii) 36 and the Dermatologic Cooperative Oncology Group slt trial 37,38 found that, in patients with clinically localized cutaneous melanoma (no satellite, in-transit, regional, or distant metastases) and positive sentinel lymph nodes, immediate completion lymph node dissection (compared with nodal observation with ultrasonography and completion lymphadenectomy only upon recurrence) did not improve melanoma-specific survival, but led to higher morbidity (lymphedema). Based on those results, routine immediate completion lymphadenectomy is no longer standard practice for patients with node-positive disease by pathology upon sentinel lymph node biopsy . In the absence of complete lymphadenectomy, some patients with positive sentinel lymph nodes assigned as stage iiia or iiib might be understaged. The trials and recommendations relating to axillary resection do not apply to patients with clinically positive lymph nodes (by palpation or radiologic investigation), and the standard of care is dissection of lymph nodes in that area (axillary, groin, or head and neck) before adjuvant therapy or adjuvant radiotherapy. In the case of unresectable disease, systemic therapy should be considered upfront.
Patient inclusion in the trials was based on the ajcc 7th edition, which subdivides stage iii into iiia, iiib, and iiic groups. The ajcc 8th edition (now in effect) has an additional iiid category. With revised criteria for the stage iii substages, stage migration is to be expected. For example, using data from the combi-a d trial 34 , 38% of patients with stage iii disease were reclassified into a different subgroup.
Patients with completely resected stage iv disease were included only in the Eastern Cooperative Oncology Group E1609 trial (abstract only, not reported separately) 25 and the CheckMate 238 trial (see the Key Evidence subsection) 27,28 . Data are therefore more limited for that population.
Patients with high-risk stage ii disease were not included in the key trials, and some trials excluded all (Check-Mate 238) or a portion (keynote-054, combi-ad) of patients with stage iiia disease. For stage iiia disease, keynote-054 excluded N1a melanomas with nodal metastases smaller than 1 mm, and the combi-a d trial excluded any nodal metastases smaller than 1 mm. The absolute benefit in patients with stage ii or iiia tumours with nodal disease smaller than 1 mm is unknown. The patient and physician should discuss the benefits and risks (aes), and such patients should be enrolled onto a clinical trial when possible. Such clinical trials are currently ongoing.
The role of radiotherapy was outside the scope of the literature review; adjuvant radiotherapy is the subject of a separate guideline 41 . Patients who received adjuvant radiotherapy were excluded from the trials of immune checkpoint inhibitors and targeted therapy, except for the E1609 trial comparing ipilimumab doses 25 .
The recommendations from the immunotherapy trials are based on interim results for dfs; most os results are not yet available, but will be forthcoming. A recent review by Suciu et al. 42 supports the view that rfs is a suitable surrogate for os. Recommendations should be re-evaluated once final results from the relevant studies are reported.
Data concerning targeted therapy for BRAF mutations other than V600E or V600K are not available, and therefore adjuvant therapy with nivolumab or pembrolizumab should be considered.
# Key Evidence:
The CheckMate 238 trial 27,28 reported a 2-year rfs of 62.6% for nivolumab (3 mg/kg) and 50.2% for ipilimumab (10 mg/kg) . It is the only trial with data for stage iv patients. For that subgroup, the 2-year rfs rates were 58.0% and 44.3% respectively. Fewer aes were observed with nivolumab: grade 3 or greater aes occurred in 14.4% and 45.9% of patients, and deaths occurred in 0% and 0.4% (n = 2) of the patients.
A combined indirect analysis of patients staged iiib and iiic from CheckMate 238 and eortc 18071 (abstract only 30 ) reported an 18-month rfs of 70.7% for nivolumab, 54.1% for ipilimumab, and 41.8% for placebo. The keynote-054 trial 29 reported an 18-month rfs of 71.4% for pembrolizumab compared with 53.2% for placebo. Grade 3 or greater aes occurred in 14.7% compared with 3.4% of patients; 1 death occurred in the pembrolizumab arm.
T he c om bi-a d t r ia l 33,34 fou nd t hat combi nat ion dabrafenib-trametinib in patients with BRAF V600E or V600K mutations was associated with improved rfs at all time points, the 4-year rfs being 54% compared with 38% (placebo). Benefit was found for all subgroups 43 . The trial included some stage iiia patients (those with nodal metastases larger than 1 mm); for that group, the 4-year dfs was 69% compared with 62% (hr: 0.58; 95% ci: 0.32 to 1.06). At 3 years, os was also better (86% vs. 77%), although not statistically significant because of the interim boundaries set in the protocol.
Vemurafenib is being evaluated in the brim8 trial 32 , which, to date, found a 2-year dfs benefit in patients staged iic-iiib (cohort 1), but not iiic (cohort 2). The study design was such that results for cohort 1 could not be considered significant unless results for cohort 2 found a significant dfs benefit. Interim (immature) os data found no benefit in patients staged iiic, but a trend toward benefit (p = 0.1) was seen for cohort 1. Because of the study design, the apparently conflicting results according to stage, and the preliminary nature of the data, vemurafenib cannot be recommended at this time.
# Interpretation of the Evidence:
The trials noted in the key evidence suggest that nivolumab, pembrolizumab, and (for BRAF V600E or V600K mutated disease) dabrafenibtrametinib are all effective in reducing recurrence, and current evidence does not suggest that one agent is better than the other. Long-term data and results from other ongoing trials might clarify which, if any, is better overall or for certain subgroups. Although direct evidence is available only for stages iiib, iiic, and iv for nivolumab and for a subset of stages iiia, iiib, and iiic for pembrolizumab (using the ajcc 7th edition), it is the opinion of the authors that the overall body of evidence suggests that those agents should offer similar efficacy in patients with a high risk of recurrence regardless of stage iii subgroup. Evidence from the metastatic setting suggests that nivolumab and pembrolizumab are equivalent in efficacy and toxicity profile.
# Recommendation 2
Ipilimumab is not recommended as adjuvant therapy for patients with completely resected cutaneous melanoma with a high risk of recurrence.
Qualifying Statements: Although ipilimumab might be effective in reducing the risk of melanoma recurrence, it has lesser efficacy and higher rates of serious aes than are seen with nivolumab, and it is not recommended.
# Key Evidence :
A lthough the eortc 18071 tria l 23,24,44 reported that, compared with placebo, ipilimumab (10 mg/ kg) was associated with improved rfs and os, a high rate of aes was observed. The rate of grades 3-4 aes was 54.1% for ipilimumab compared with 26.2% for placebo. Grades 3-4 immune-related aes were especially prevalent (41.6% vs. 2.7%), with deaths occurring in 5 patients (1.1% vs. 0%). Discontinuation of treatment because of drug-related aes occurred in 53% of patients.
The CheckMate 238 trial 27,28 reported a 2-year rfs of 62.6% for nivolumab (3 mg/kg) compared with 50.2% for ipilimumab (10 mg/kg) (hr: 0.66; p < 0.0001). Also, fewer aes occurred with nivolumab: the rate of grade 3 or greater aes was 14.4% compared with 45.9%, and the rate of deaths was 0% compared with 0.4% (2 patients).
A combined indirect analysis of the foregoing two trials (abstract only 30 ) reported an 18-month rfs of 70.7% for nivolumab, 54.1% for ipilimumab, and 41.8% for placebo.
The E1609 trial 25,26 (abstracts only) compared ipilimumab at 3 mg/kg and at 10 mg/kg w ith h d-i f n-α 2b. Preliminary results suggested equal efficacy for ipilimumab at 3 mg/kg and 10 mg/kg (3-year rfs: 56% vs. 54%). Results at approximately 4.5 years after accrual of the last patient have been reported. The os was significantly better for 3 mg/ kg ipilimumab compared with hd-ifn-α2b (hr: 0.78; 95.6% ci: 0.61 to 1.00; p = 0.044), and a trend toward a benefit in rfs was observed (hr: 0.0.85; 99.4% ci: 0.66 to 1.09; p = 0.065). A trend toward a benefit was also observed for 10 mg/kg ipilimumab compared with hd-ifn-α2b in os (hr: 0.88; 95.6% ci: 0.69 to 1.12) and rfs (hr: 0.84; 99.4% ci: 0.65 to 1.09). Grade 3 or greater aes (mostly immune-related) were experienced by 37% of patients receiving 3 mg/kg ipilimumab, in 58% of those receiving 10 mg/kg ipilimumab, and in 79% of those receiving hd-ifn-α2b, leading to treatment discontinuation in 35%, 54%, and 20% of patients. Grade 5 aes possibly related to treatment occurred in 3, 8, and 2 patients (0.6% vs. 1.6% vs. 0.3%).
# Interpretation of the Evidence:
Because the trials found nivolumab to be more effective than ipilimumab and to be associated with fewer a es, use of ipilimumab is not supported. That conclusion might have to be re-evaluated when the final trial results, including os, are reported, together with results from the ongoing CheckMate 915 and swog 1404 trials.
# Recommendation 3
Use of ifn-α for adjuvant treatment of cutaneous melanoma is no longer recommended outside of a clinical trial.
# Qualif ying Statements :
The e ortc 18081 tria l (see NCT01502696 at /) comparing pegylated ifn-α2b for 2 years with observation in ulcerated stage ii melanoma had an estimated completion date in April 2019. That trial might confirm the results of the International Melanoma Meta-Analysis Collaborative Group ipd meta-analysis 20 , which suggested that ifn-α is of benefit in ulcerated melanoma.
Interferon might have a limited role in high-risk patients not eligible for other treatments.
# Key Evidence:
The Cochrane meta-analysis 21 included 18 rcts involving 10,499 patients and compared hd-ifn-α with observation or any other treatment in patients with regional lymph node metastasis (and undergoing radical lymph node dissection) or with a tumour thickness greater than 1 mm. Adjuvant hd-ifn-α was associated with an improved dfs (hr: 0.83; 95% ci: 0.78 to 0.87; p < 0.00001) and os (hr: 0.91; 95% ci: 0.85 to 0.97; p = 0.003), representing an absolute improvement of about 6% in 5-year dfs and 3% in os.
The International Melanoma Meta-Analysis Collaborative Group 20 conducted an ipd meta-analysis comparing ifn-α with no ifn-α (observation only) in high-risk melanoma. It included fifteen ifn-α trials involving 7744 patients. Individual patient data were available from eleven of those trials (5861 patients), and summary data from the remaining trials were used. Administration of ifn-α was associated with a significant improvement in event-free survival and os (hr: 0.90; 95% ci: 0.85 to 0.97; p = 0.003). For trials providing ipd, the 5-year os was 49.1% with ifn-α compared with 46.1% without; the 10-year os was 39.9% compared with 37.1%; the 5-year efs was 37.8% compared with 34.3%; and the 10-year efs was 31.2% compared with 28.5% . Although statistically significant, the absolute differences are small.
The benefit with ifn did not vary with the dose or duration of treatment (≤6, 12-18, or ≥24 months). Results suggest that low-, intermediate-, and high-dose ifn-α regimens are associated with similar benefit; data for very-low-dose ifn (eortc 18871 and dbg 80-1 trials) are unclear. For os, the effect is weaker and statistically significant only for the low-dose group (hr: 0.86; 95% ci: 0.77 to 0.96; p = 0.007).
The meta-analysis also did not find a differential ifn benefit by age, sex, site of primary tumour, disease stage (i/ii vs. iii/iv), Breslow thickness, or presence of clinical nodes. For patients with ulcerated tumours, efs was improved (5-year efs: 32.9% vs. 26.9%; 10-year efs: 27.3% vs. 20.4%; hr: 0.79; 99% ci: 0.66 to 0.94; p = 0.0006), as was os (5-year os: 46.0% vs. 38.1%; 10-year os: 38.5% vs. 28.0%; hr: 0.77; 99% ci: 0.64 to 0.92; p = 0.0002). The efs and os benefits were approximately 6% and 8% at 5 years, and slightly higher at 10 years. No significant benefit was observed in patients with non-ulcerated tumours.
Adverse effects of hd-ifn-α and their managementbased primarily on the E1684, E1690, and 1694 trials-have been reviewed by others 45,46 . Dose reduction or delay was required in 28% -44% of patients during the induction phase and in 36% -52% during the maintenance phase in those trials. Treatment was discontinued because of aes in 10% -26% of patients. Most patients experienced acute flu-like symptoms (fever, chills, headache, myalgia, nausea, and vomiting) with grade 3 or greater aes in 4% -18% of patients. Fatigue, which has been reported in 70% -100% of patients (18% grade 3 or greater), and neuropsychiatric symptoms increase in severity over time. Other aes are anorexia, cardiotoxicity, hepatotoxicity, autoimmunity, ocular toxicity, and altered laboratory findings. Although generally manageable with careful monitoring, supportive care, and dose modifications, those a es often have a profound negative effect on quality of life and can be life-threatening.
# Interpretation of the Evidence:
The meta-analyses indicate that ifn-α is associated with a small but statistically significant improvement in os and dfs. For most patients, the aes are judged to outweigh the possible small benefit. The ipd meta-analysis suggests that the ifn-α benefit applies only to ulcerated tumours, a finding that must be confirmed in a trial designed to test efficacy specifically in ulcerated melanoma. The benefits of nivolumab, pembrolizumab, and (for BRAF-mutant melanoma) dabrafenibtrametinib exceed those of ifn-α, and therefore ifn-α is not recommended.
# Recommendation 4
Chemotherapy regimens, vaccines, levamisole, bevacizumab, bacillus Calmette-Guérin, and isolated limb perfusion are not recommended for the adjuvant treatment of cutaneous melanoma, except as part of a clinical trial.
# Key Evidence:
Most completed trials found no survival benefit. A few trials suggested a possible benefit for some of the agents, but they were either too small or were discontinued early because of more promising results with ifn-α and are therefore inconclusive. Some trials are ongoing.
# Mucosal Melanoma
# Recommendation 5
Immune checkpoint inhibitors (nivolumab or pembrolizumab) or targeted therapy (in patients with identified mutations) are recommended for adjuvant therapy of mucosal melanoma with high risk of recurrence.
Qualifying Statements: Mutation characterization is required before targeted agents are considered. Compared with cutaneous melanoma, mucosal melanoma has a different origin and spectrum of mutations. BRAF mutations are less common than they are in cutaneous melanoma, and therefore inhibitors are of little value in unselected patients. KIT mutations are more prevalent in mucosal melanoma, and inhibitors such as imatinib appear to be of value in advanced melanoma with KIT mutation 47 ; however, no trials of the adjuvant use of k it inhibitors were found.
The trials forming the key evidence for cutaneous melanoma (see recommendations 1 and 2) excluded mucosal melanoma, with the exception of the CheckMate 238 trial, which included 29 patients (3.2% of the total). That small number is insufficient to allow for any conclusions to be drawn specifically for that subgroup.
There might be a role for chemotherapy, but evidence is not sufficient to make a recommendation at this time. Adjuvant treatment of mucosal melanoma with hd-ifn-α2b compared with temozolomide-cisplatin was studied in a phase ii trial 48 in patients with stages ii and iii mucosal melanoma and in a subsequent phase i i i t r ia l942qin patients with stages i-ii7i mucosal melanoma, reported only in abstract form 35 . The phase ii study found that temozolomide-cisplatin resulted in a better os and dfs than did hd-ifn-α2b or placebo. A follow-up phase iii study confirmed the benefit of temozolomide-cisplatin compared with hd-ifn-α2b. The available evidence is limited because of a lack of full publication and inconsistency with studies in metastatic melanoma 49 . Key Evidence: Targeted agents and immune checkpoint inhibitors have not been evaluated specifically as adjuvant therapy in mucosal melanoma. Key evidence is considered to be the trials supporting their use in cutaneous melanoma 33,34 (see the earlier recommendations) and the data from trials in advanced or metastatic melanoma in which those agents were shown to be effective. D'Angelo et al. 50 conducted a pooled analysis of nivolumab alone or combined with ipilimumab in unresectable stage iii or iv mucosal melanoma, finding that nivolumab-ipilimumab had greater efficacy than either nivolumab monotherapy or ipilimumab monotherapy (objective response rate: 37.1% vs. 23.3% vs. 8.3%), but with a much greater rate of grades 3-4 aes (40% vs. 8% vs. not stated). Compared with ipilimumab alone, pfs was better with nivolumab-ipilimumab (hr: 0.35; 95% ci: 0.19 to 0.64) and with nivolumab alone (hr: 0.62; 95% ci: 0.39 to 0.98). A post hoc analysis of patients with advanced mucosal melanoma in the key note-001, -002, and -006 trials reported that pembrolizumab provided a durable tumour response 51 .
# Interpretation of the Evidence:
Recommendations for the use of immune checkpoint inhibitors in mucosal melanoma are based on extrapolation of results from cutaneous melanoma (see recommendations 1 and 2) and from trials in nonresectable mucosal melanoma.
For targeted therapy, the authors believe that cutaneous and mucosal melanoma with the same mutations would benefit from the same targeted therapies. Adjuvant therapy with dabrafenib-trametinib can therefore be considered in mucosal melanoma in which BRAF V600E or V600K is the primary mutation.
Further Qualif ying Statements : The recommended adjuvant therapies have potential for aes (see the earlier Key Evidence and Qualifying Statements subsections). Although usually manageable and reversible, those aes can be severe. It was outside the scope of the accompanying systematic review to deal with management of those aes. The reader can refer to other guidelines such as those from the Multinational Association of Supportive Care in Cancer 52 , the Eastern Cooperative Oncology Group 53 , the American Society of Clinical Oncology and the nccn 54,55 , oh(cco) 56 , and others 57,58 .
Several trials are ongoing, and the foregoing recommendations might have to be revisited upon completion of those trials.
# Implementation Considerations
Most trials of the adjuvant use of immune checkpoint inhibitors and targeted agents in melanoma are ongoing, with promising preliminary results. As a result, indications and approvals are changing rapidly. Nivolumab, pembrolizumab, and combination dabrafenib-trametinib were approved by Health Canada in early 2019 for adjuvant use in melanoma. At the time of the present review, immune checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab) and targeted therapies were being evaluated for approval and funding in Ontario. Funding might be interim pending final results of the trials mentioned in the various Key Evidence subsections of this review. Doses for administration of immune checkpoint inhibitors and targeted therapies have not been standardized and should conform with the approved indications.
# REVIEW AND UPDATE
The currency of each pebc document is ensured by periodic review and evaluation of the scientific literature and, where appropriate, the addition of newer literature to the original evidence base. That process is described in the PEBC Document Assessment and Review Protocol.
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Background Previous versions of the guideline from the Program in Evidence-Based Care (pebc) at Ontario Health (Cancer Care Ontario) recommended that the use of high-dose interferon alfa 2b therapy be discussed and offered to patients with resected cutaneous melanoma with a high risk of recurrence. Subsequently, several clinical trials in patients with resected or metastatic melanoma found that immune checkpoint inhibitors and targeted therapies have a benefit greater than that with interferon. It was therefore considered timely for an update to the guideline about adjuvant systemic therapy in melanoma.The present guideline was developed by the pebc and the Melanoma Disease Site Group (dsg). Based on a systematic review from a literature search conducted using medline, embase, and the Evidence Based Medicine Reviews databases for the period 1996 to 28 May 2019, the Working Group drafted recommendations. The systematic review and recommendations were then circulated to the Melanoma dsg and the pebc Report Approval Panel for internal review; the revised document underwent external review. Recommendations For patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence, the recommended adjuvant therapies are nivolumab, pembrolizumab, or dabrafenib-trametinib for patients with BRAF V600E or V600K mutations; nivolumab or pembrolizumab are recommend for patients with BRAF wildtype disease. Use of ipilimumab is not recommended. Molecular testing should be conducted to help guide treatment decisions. Interferon alfa, chemotherapy regimens, vaccines, levamisole, bevacizumab, bacillus Calmette-Guérin, and isolated limb perfusion are not recommended for adjuvant treatment of cutaneous melanoma except as part of a clinical trial.# INTRODUCTION
Melanoma is the 8th most common cancer in Canada, and the 15th in mortality 1 . Cutaneous melanoma predominates, and most clinical trials have been conducted in patients with cutaneous melanoma. Data used in developing the 8th edition of the American Joint Committee on Cancer (ajcc) cancer staging manual indicate, for cutaneous melanoma, 5-year melanoma-specific survival rates of 98% for stage i, 90% for stage ii, and 77% for stage iii disease, with rates as low as 32% for the stage iiid subgroup 2 . Given the poor survival for more advanced but resectable disease, many clinical trials have investigated the use of adjuvant systemic therapy.
Mucosal melanoma is a rare disease: it accounts for approximately 0.03% of all cancers diagnosed 3 and 1.4% of all melanomas in the United States 4 . The most common sites are the head and neck, the anorectal area, and the vulvovaginal region. Ultraviolet radiation exposure has not been associated with development of mucosal melanoma 5 , and rates are relatively consistent in various populations. Because of lower rates of cutaneous cancer in patients of Hispanic or African background 4 and in Asian populations 6,7 , mucosal melanoma constitutes a higher proportion of melanomas in those groups. Characteristics of mucosal melanoma, including causative mutations, differ from those of cutaneous melanoma, and the absolute level of response to treatment can vary. Uveal and other ocular melanomas are outside the scope of the present guideline.
For many years, interferon (ifn) was considered the only effective adjuvant treatment, and previous versions of this guideline recommended that the use of high-dose ifn alfa 2b (hd-ifn-α2b) therapy be discussed and offered to patients at high risk of recurrence 8,9 . Several trials found that ifn was associated with a recurrence-free survival (rfs) benefit, but a marginal or absent benefit for overall survival (os). That small benefit was confirmed in meta-analyses of trials, but was offset by significant adverse effects affecting quality of life. Trials in the metastatic setting found a much greater benefit to be associated with immune checkpoint inhibitors and targeted therapy, and recent trials have confirmed the benefit of some of those agents in the adjuvant setting.
Given the emergence of those new agents, an updated guideline about the adjuvant treatment of melanoma, based on a systematic review of the current evidence, was determined to be required.
# METHODS
# Guideline Developers
This guideline was developed by the Systemic Adjuvant Therapy for Adult Patients at High Risk for Recurrent Melanoma Guideline Development Group, which was convened at the request of the Melanoma Disease Site Group (dsg) of Ontario Health (Cancer Care Ontario) [oh(cco)]. The project was led by a small Working Group that was responsible for reviewing the evidence base, drafting the guideline recommendations, and responding to comments received during the document review process. The Working Group had expertise in medical oncology and health research methodology. Other members of the guideline development group served as the Expert Panel and were responsible for review and approval of the draft document. Conf lict of interest declarations were collected for all participants and were managed in accordance with the Program in Evidence-Based Care (pebc) conflict of interest policy. The director of the pebc waived the requirement that the lead author and 50% of members of the Working Group have no declared interests, with the provision that co-chairs be appointed.
# Guideline Development
The pebc produces evidence-based and evidence-informed guidance documents using the methods of the practice guidelines development cycle 10,11 . The process includes a systematic review, interpretation of the evidence, and drafting of recommendations by the Working Group, internal review by content and methodology experts, and external review by clinicians. The pebc's guideline development methods are described in more detail in the PEBC Handbook and the PEBC Methods Handbook. The present publication focuses on the guideline recommendations, with a brief summary of the methods used; the full 5-part document, including the systematic review, can be found on the oh(cco) Web site 12 .
# Guideline Objective
This guideline makes recommendations about the use of adjuvant systemic therapy in adult patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence.
# Research Questions
n What systemic therapy should clinicians recommend to adult patients who have been rendered disease-free after resection of cutaneous melanomas (including all sites of metastases, if present) and who are at high risk for subsequent recurrence? n What systemic therapy should clinicians recommend to adult patients who have been rendered disease-free after the resection of mucosal melanomas?
# Target Population
The target population is adult patients with cutaneous or mucosal melanoma with high risk of recurrence who have been rendered disease-free after resection (including resection of all locoregional or distant metastases, if present).
Patients with unresected primary disease or metastases fell outside the scope. In determining risk of recurrence, disease with any of the following characteristics was considered high risk:
n Primary melanoma with a tumour thickness greater than 4.0 mm (T4 in ajcc 6th, 7th, or 8th editions)
n If node-negative, these tumours fall into ajcc stage iib (no ulceration) or iic (ulceration). n Primary melanoma with a tumour thickness greater than 2.0-4.0 mm, with ulceration (T3b, stage iib if node-negative) n Primary melanoma with one or more of n positive sentinel lymph nodes (micrometastasis); n clinically detected positive regional lymph nodes (macrometastasis); or n in-transit, satellite, or microsatellite metastases (node-positive and stages iii a-iiic in the ajcc 6th or 7th editions, or stages iiia-iiid in the ajcc 8th edition) n Distant metastasis (stage iv) n Recurrence of melanoma that was previously completely resected
It should be noted that ajcc staging categories are for cutaneous melanoma; staging for mucosal melanoma varies depending on the primary site, and the ajcc staging designations might not apply.
# Literature Search
The literature search included clinical practice guidelines, systematic reviews, and randomized controlled trials (rcts). Details for the review, including the research questions, population of interest, interventions and comparators, outcomes, inclusion and exclusion criteria, and databases to search were determined before the literature review and were documented in the project plan. Reviews conducted before 2013 [the search date for version 4 of the pebc and oh(cco) guideline] were excluded.
The literature search was conducted in embase, medline, and the Evidence Based Medicine Reviews database (Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews) for 1996 to 11 June 2018 and was subsequently updated to 28 May 2019. Complete details, including the search strategy and the inclusion and exclusion criteria are reported in the full systematic review 12 . The search strategy combined terms for melanoma plus terms for chemotherapy, immunotherapy, vaccines, or systemic therapy (including specific agents), plus terms for clinical practice guidelines, systematic reviews, or rcts. Abstracts of selected recent conferences and the ClinicalTrials.gov Web site were also reviewed. Web sites of major cancer guideline developers and practice guideline databases were reviewed for recent clinical practice guidelines.
To be included, studies had to be randomized trials of adjuvant systemic therapy in adult patients with melanoma with high risk of recurrence (see the Target Population subsection). Data extraction for the present review was conducted by a health research methodologist (GGF). Because this guideline is an update, some of the data were reproduced from a previous version 9 and were then verified in a consultation of the primary literature.
# Development of Recommendations
The Working Group drafted recommendations based on the systematic review. Where rct evidence was limited, recommendations were based on the professional experience of the authors, together with consideration of current practice. Such limitations are clearly indicated in the key evidence and qualif ying statements that follow each recommendation.
# Internal and External Review Process
Before submission of the draft report for external review, the systematic review and practice guideline were reviewed by the members of the Melanoma dsg and the pebc Report Approval Panel. The Report Approval Panel consists of the pebc Scientific Director and two other members with expertise in clinical and methodology issues. The dsg and Report Approval Panel members reviewed the draft systematic review and practice guideline and provided feedback, which was incorporated into the guideline.
Participating as Consultation Group members for the project, 4 cancer patients or survivors reviewed the draft document distributed for internal review and provided feedback on its comprehensibility, appropriateness, and feasibility. The revised draft document was then distributed for external review.
External review included both a targeted peer review that is intended to obtain direct feedback from a small number of content experts, and a professional consultation that is intended to facilitate dissemination of the guideline to Ontario practitioners and to provide opportunity for additional feedback. Results of the feedback can be found in the full guideline report on the oh(cco) Web site 12 .
# RESULTS
# Search for Guidelines
Only the guidelines by the Cancer Council Australia 13 and the Society for Immunotherapy of Cancer 14 included recent trials and recommendations about the use of immune checkpoint inhibitors and targeted therapies. The Working Group members decided that those guidelines had several limitations, including a narrower focus, and could not replace development of the present guideline. During the literature update search (May 2019), it was noted that the French Society of Dermatology had a new guideline 15,16 concerning stage iii melanoma (and stage iv, if completely resected), partially replacing their previous guideline on stages i-iii disease 17 . The 2019 National Comprehensive Cancer Network (nccn) guideline concerning melanoma represents a significant revision of previous versions and now includes immune checkpoint inhibitors and BRAFtargeted therapies 18,19 . Recommendations in both guidelines are similar to those in the present work. The nccn guideline includes diagnosis and treatment of stages 0-iv unresectable melanoma, and therefore the section concerning adjuvant systemic therapy is more limited than that in the present work; in contrast, the nccn guideline has more details on topics such as principles of molecular testing and management of adverse events (aes) associated with targeted therapy.
# Search for Systematic Reviews and Primary Literature
The literature search identified 15 systematic reviews and 63 trials (135 publications) that met the inclusion criteria. Most of the trials of ifn compared with observation, and some comparing 2 doses or durations of ifn, were covered in the meta-analysis by the International Melanoma Meta-Analysis Collaborative Group 20 that used individual patient data (ipd) for adjuvant ifn-α and in the Cochrane systematic review and meta-analysis by Mocellin et al. 21 for adjuvant ifn-α. Both reviews found small but statistically significant improvements in disease-free survival (dfs) or rfs and in os. Benefits did not vary with dose, age, sex, site of primary tumour, disease stage (i/ii or iii/iv), Breslow thickness, or presence of clinically involved nodes. Only patients with ulcerated tumours appeared to receive a benefit. The ongoing European Organisation for Research and Treatment of Cancer (eortc) 18081 trial (see NCT01502696 at https://ClinicalTrials.gov/) being conducted in patients with ulcerated melanoma could potentially confirm that finding. Other ifn trials explored dose, duration, or formulation, but were generally inconclusive. Trials of vaccines and chemotherapy were also negative or inconclusive.
Several recent trials evaluated immune checkpoint inhibitors or targeted therapies and reported greater benefit than had been found in the ifn trials. Immune-related aes are significant and have to be considered. The eortc 18071 trial compared ipilimumab with placebo [22][23][24] , the Eastern Cooperative Oncology Group E1609 trial compared ipilimumab with ifn 25,26 , CheckMate 238 compared nivolumab w it h ipilimumab 27,28 , and k e y not e-054 (eortc 1325) compared pembrolizumab with placebo 29 . Conference abst racts have repor ted a n i nd i rect compa r ison of nivolumab with placebo 30,31 . Adverse effects were greater with ipilimumab than with nivolumab or pembrolizumab. For br af-targeted therapies, vemurafenib is being compared with placebo in the brim8 trial 32 and combination dabrafenib-trametinib is being compared with placebo in the combi-ad trial 33,34 . Some of the foregoing trials included patients with mucosal melanoma, but the numbers of those patients are too small to reach conclusions specifically for mucosal melanoma. An abstract publication of an ongoing trial suggests that temozolomide-cisplatin might provide some benefit 35 .
# RECOMMENDATIONS Cutaneous Melanoma
# Recommendation 1
Nivolumab or pembrolizumab is recommended as adjuvant therapy for patients with completely resected cutaneous melanoma w it hout BR AF V600E or V600K mutations and with high risk of recurrence [stage iiia (>1 mm nodal metastasis) to iiid, iv].
Nivolumab, pembrolizumab, or dabrafenib-trametinib is recommended as adjuvant therapy for patients with completely resected cutaneous melanoma with BRAF V600E or V600K mutations and with a high risk of recurrence [stage iiia (>1 mm nodal metastasis) to iiid, iv].
Molecular testing of patients with high-risk melanoma to characterize mutations should be conducted to help guide appropriate treatment decisions.
Qualifying Statements: Nivolumab, pembrolizumab, and combination dabrafenib-trametinib (for BRAF V600E or V600K mutated melanoma) are all appropriate treatments; evidence to suggest which is more effective is currently insufficient. These agents were evaluated in different trials 27,29,33 and have not been directly compared in the adjuvant setting. For nivolumab and pembrolizumab, treatment-related aes, which occurred in 85% and 78% of patients respectively, tended to be mild and manageable, with the most common being fatigue, skin reactions (rash, pruritus), diarrhea, nausea, and endocrine disorders. Similar rates of grade 3 or greater treatment-related aes (14.4% and 14.7%) resulting in treatment discontinuation (9.7% and 13.8%) were reported. Combination dabrafenibtrametinib resulted in a higher rate of serious aes (36%), including pyrexia, hypertension, and hepatic effects, and a higher rate of discontinuation attributable to aes (25%). The spectrum of aes and the contraindications for immunotherapy with nivolumab or pembrolizumab compared with those for dabrafenib-trametinib should be discussed with the patient when adjuvant treatment is being decided.
The foregoing treatments were evaluated in trials requiring patients to have undergone complete regional lymphadenectomy. The Multicenter Selective Lymphadenectomy Trial-II (mslt-ii) 36 and the Dermatologic Cooperative Oncology Group slt trial 37,38 found that, in patients with clinically localized cutaneous melanoma (no satellite, in-transit, regional, or distant metastases) and positive sentinel lymph nodes, immediate completion lymph node dissection (compared with nodal observation with ultrasonography and completion lymphadenectomy only upon recurrence) did not improve melanoma-specific survival, but led to higher morbidity (lymphedema). Based on those results, routine immediate completion lymphadenectomy is no longer standard practice for patients with node-positive disease by pathology upon sentinel lymph node biopsy [see guidelines by the pebc and oh(cco) 39 and the American Society of Clinical Oncology and the Society of Surgical Oncology 40 ]. In the absence of complete lymphadenectomy, some patients with positive sentinel lymph nodes assigned as stage iiia or iiib might be understaged. The trials and recommendations relating to axillary resection do not apply to patients with clinically positive lymph nodes (by palpation or radiologic investigation), and the standard of care is dissection of lymph nodes in that area (axillary, groin, or head and neck) before adjuvant therapy or adjuvant radiotherapy. In the case of unresectable disease, systemic therapy should be considered upfront.
Patient inclusion in the trials was based on the ajcc 7th edition, which subdivides stage iii into iiia, iiib, and iiic groups. The ajcc 8th edition (now in effect) has an additional iiid category. With revised criteria for the stage iii substages, stage migration is to be expected. For example, using data from the combi-a d trial 34 , 38% of patients with stage iii disease were reclassified into a different subgroup.
Patients with completely resected stage iv disease were included only in the Eastern Cooperative Oncology Group E1609 trial (abstract only, not reported separately) 25 and the CheckMate 238 trial (see the Key Evidence subsection) 27,28 . Data are therefore more limited for that population.
Patients with high-risk stage ii disease were not included in the key trials, and some trials excluded all (Check-Mate 238) or a portion (keynote-054, combi-ad) of patients with stage iiia disease. For stage iiia disease, keynote-054 excluded N1a melanomas with nodal metastases smaller than 1 mm, and the combi-a d trial excluded any nodal metastases smaller than 1 mm. The absolute benefit in patients with stage ii or iiia tumours with nodal disease smaller than 1 mm is unknown. The patient and physician should discuss the benefits and risks (aes), and such patients should be enrolled onto a clinical trial when possible. Such clinical trials are currently ongoing.
The role of radiotherapy was outside the scope of the literature review; adjuvant radiotherapy is the subject of a separate guideline 41 . Patients who received adjuvant radiotherapy were excluded from the trials of immune checkpoint inhibitors and targeted therapy, except for the E1609 trial comparing ipilimumab doses 25 .
The recommendations from the immunotherapy trials are based on interim results for dfs; most os results are not yet available, but will be forthcoming. A recent review by Suciu et al. 42 supports the view that rfs is a suitable surrogate for os. Recommendations should be re-evaluated once final results from the relevant studies are reported.
Data concerning targeted therapy for BRAF mutations other than V600E or V600K are not available, and therefore adjuvant therapy with nivolumab or pembrolizumab should be considered.
# Key Evidence:
The CheckMate 238 trial 27,28 reported a 2-year rfs of 62.6% for nivolumab (3 mg/kg) and 50.2% for ipilimumab (10 mg/kg) [hazard ratio (hr): 0.66; p < 0.0001]. It is the only trial with data for stage iv patients. For that subgroup, the 2-year rfs rates were 58.0% and 44.3% respectively. Fewer aes were observed with nivolumab: grade 3 or greater aes occurred in 14.4% and 45.9% of patients, and deaths occurred in 0% and 0.4% (n = 2) of the patients.
A combined indirect analysis of patients staged iiib and iiic from CheckMate 238 and eortc 18071 (abstract only 30 ) reported an 18-month rfs of 70.7% for nivolumab, 54.1% for ipilimumab, and 41.8% for placebo. The keynote-054 trial 29 reported an 18-month rfs of 71.4% for pembrolizumab compared with 53.2% for placebo. Grade 3 or greater aes occurred in 14.7% compared with 3.4% of patients; 1 death occurred in the pembrolizumab arm.
T he c om bi-a d t r ia l 33,34 fou nd t hat combi nat ion dabrafenib-trametinib in patients with BRAF V600E or V600K mutations was associated with improved rfs at all time points, the 4-year rfs being 54% compared with 38% (placebo). Benefit was found for all subgroups 43 . The trial included some stage iiia patients (those with nodal metastases larger than 1 mm); for that group, the 4-year dfs was 69% compared with 62% (hr: 0.58; 95% ci: 0.32 to 1.06). At 3 years, os was also better (86% vs. 77%), although not statistically significant because of the interim boundaries set in the protocol.
Vemurafenib is being evaluated in the brim8 trial 32 , which, to date, found a 2-year dfs benefit in patients staged iic-iiib (cohort 1), but not iiic (cohort 2). The study design was such that results for cohort 1 could not be considered significant unless results for cohort 2 found a significant dfs benefit. Interim (immature) os data found no benefit in patients staged iiic, but a trend toward benefit (p = 0.1) was seen for cohort 1. Because of the study design, the apparently conflicting results according to stage, and the preliminary nature of the data, vemurafenib cannot be recommended at this time.
# Interpretation of the Evidence:
The trials noted in the key evidence suggest that nivolumab, pembrolizumab, and (for BRAF V600E or V600K mutated disease) dabrafenibtrametinib are all effective in reducing recurrence, and current evidence does not suggest that one agent is better than the other. Long-term data and results from other ongoing trials might clarify which, if any, is better overall or for certain subgroups. Although direct evidence is available only for stages iiib, iiic, and iv for nivolumab and for a subset of stages iiia, iiib, and iiic for pembrolizumab (using the ajcc 7th edition), it is the opinion of the authors that the overall body of evidence suggests that those agents should offer similar efficacy in patients with a high risk of recurrence regardless of stage iii subgroup. Evidence from the metastatic setting suggests that nivolumab and pembrolizumab are equivalent in efficacy and toxicity profile.
# Recommendation 2
Ipilimumab is not recommended as adjuvant therapy for patients with completely resected cutaneous melanoma with a high risk of recurrence.
Qualifying Statements: Although ipilimumab might be effective in reducing the risk of melanoma recurrence, it has lesser efficacy and higher rates of serious aes than are seen with nivolumab, and it is not recommended.
# Key Evidence :
A lthough the eortc 18071 tria l 23,24,44 reported that, compared with placebo, ipilimumab (10 mg/ kg) was associated with improved rfs and os, a high rate of aes was observed. The rate of grades 3-4 aes was 54.1% for ipilimumab compared with 26.2% for placebo. Grades 3-4 immune-related aes were especially prevalent (41.6% vs. 2.7%), with deaths occurring in 5 patients (1.1% vs. 0%). Discontinuation of treatment because of drug-related aes occurred in 53% of patients.
The CheckMate 238 trial 27,28 reported a 2-year rfs of 62.6% for nivolumab (3 mg/kg) compared with 50.2% for ipilimumab (10 mg/kg) (hr: 0.66; p < 0.0001). Also, fewer aes occurred with nivolumab: the rate of grade 3 or greater aes was 14.4% compared with 45.9%, and the rate of deaths was 0% compared with 0.4% (2 patients).
A combined indirect analysis of the foregoing two trials (abstract only 30 ) reported an 18-month rfs of 70.7% for nivolumab, 54.1% for ipilimumab, and 41.8% for placebo.
The E1609 trial 25,26 (abstracts only) compared ipilimumab at 3 mg/kg and at 10 mg/kg w ith h d-i f n-α 2b. Preliminary results suggested equal efficacy for ipilimumab at 3 mg/kg and 10 mg/kg (3-year rfs: 56% vs. 54%). Results at approximately 4.5 years after accrual of the last patient have been reported. The os was significantly better for 3 mg/ kg ipilimumab compared with hd-ifn-α2b (hr: 0.78; 95.6% ci: 0.61 to 1.00; p = 0.044), and a trend toward a benefit in rfs was observed (hr: 0.0.85; 99.4% ci: 0.66 to 1.09; p = 0.065). A trend toward a benefit was also observed for 10 mg/kg ipilimumab compared with hd-ifn-α2b in os (hr: 0.88; 95.6% ci: 0.69 to 1.12) and rfs (hr: 0.84; 99.4% ci: 0.65 to 1.09). Grade 3 or greater aes (mostly immune-related) were experienced by 37% of patients receiving 3 mg/kg ipilimumab, in 58% of those receiving 10 mg/kg ipilimumab, and in 79% of those receiving hd-ifn-α2b, leading to treatment discontinuation in 35%, 54%, and 20% of patients. Grade 5 aes possibly related to treatment occurred in 3, 8, and 2 patients (0.6% vs. 1.6% vs. 0.3%).
# Interpretation of the Evidence:
Because the trials found nivolumab to be more effective than ipilimumab and to be associated with fewer a es, use of ipilimumab is not supported. That conclusion might have to be re-evaluated when the final trial results, including os, are reported, together with results from the ongoing CheckMate 915 and swog 1404 trials.
# Recommendation 3
Use of ifn-α for adjuvant treatment of cutaneous melanoma is no longer recommended outside of a clinical trial.
# Qualif ying Statements :
The e ortc 18081 tria l (see NCT01502696 at https://ClinicalTrials.gov/) comparing pegylated ifn-α2b for 2 years with observation in ulcerated stage ii melanoma had an estimated completion date in April 2019. That trial might confirm the results of the International Melanoma Meta-Analysis Collaborative Group ipd meta-analysis 20 , which suggested that ifn-α is of benefit in ulcerated melanoma.
Interferon might have a limited role in high-risk patients not eligible for other treatments.
# Key Evidence:
The Cochrane meta-analysis 21 included 18 rcts involving 10,499 patients and compared hd-ifn-α with observation or any other treatment in patients with regional lymph node metastasis (and undergoing radical lymph node dissection) or with a tumour thickness greater than 1 mm. Adjuvant hd-ifn-α was associated with an improved dfs (hr: 0.83; 95% ci: 0.78 to 0.87; p < 0.00001) and os (hr: 0.91; 95% ci: 0.85 to 0.97; p = 0.003), representing an absolute improvement of about 6% in 5-year dfs and 3% in os.
The International Melanoma Meta-Analysis Collaborative Group 20 conducted an ipd meta-analysis comparing ifn-α with no ifn-α (observation only) in high-risk melanoma. It included fifteen ifn-α trials involving 7744 patients. Individual patient data were available from eleven of those trials (5861 patients), and summary data from the remaining trials were used. Administration of ifn-α was associated with a significant improvement in event-free survival [efs (hr: 0.86; 95% ci: 0.81 to 0.91; p < 0.00001)] and os (hr: 0.90; 95% ci: 0.85 to 0.97; p = 0.003). For trials providing ipd, the 5-year os was 49.1% with ifn-α compared with 46.1% without; the 10-year os was 39.9% compared with 37.1%; the 5-year efs was 37.8% compared with 34.3%; and the 10-year efs was 31.2% compared with 28.5% . Although statistically significant, the absolute differences are small.
The benefit with ifn did not vary with the dose [no significant trend in effect for the high-(20 MU/m 2 ), intermediate-(5-10 MU/m 2 ), low-(3 MU/m 2 ), or very-low-dose (1 MU/m 2 ) regimens] or duration of treatment (≤6, 12-18, or ≥24 months). Results suggest that low-, intermediate-, and high-dose ifn-α regimens are associated with similar benefit; data for very-low-dose ifn (eortc 18871 and dbg 80-1 trials) are unclear. For os, the effect is weaker and statistically significant only for the low-dose group (hr: 0.86; 95% ci: 0.77 to 0.96; p = 0.007).
The meta-analysis also did not find a differential ifn benefit by age, sex, site of primary tumour, disease stage (i/ii vs. iii/iv), Breslow thickness, or presence of clinical nodes. For patients with ulcerated tumours, efs was improved (5-year efs: 32.9% vs. 26.9%; 10-year efs: 27.3% vs. 20.4%; hr: 0.79; 99% ci: 0.66 to 0.94; p = 0.0006), as was os (5-year os: 46.0% vs. 38.1%; 10-year os: 38.5% vs. 28.0%; hr: 0.77; 99% ci: 0.64 to 0.92; p = 0.0002). The efs and os benefits were approximately 6% and 8% at 5 years, and slightly higher at 10 years. No significant benefit was observed in patients with non-ulcerated tumours.
Adverse effects of hd-ifn-α and their managementbased primarily on the E1684, E1690, and 1694 trials-have been reviewed by others 45,46 . Dose reduction or delay was required in 28% -44% of patients during the induction phase and in 36% -52% during the maintenance phase in those trials. Treatment was discontinued because of aes in 10% -26% of patients. Most patients experienced acute flu-like symptoms (fever, chills, headache, myalgia, nausea, and vomiting) with grade 3 or greater aes in 4% -18% of patients. Fatigue, which has been reported in 70% -100% of patients (18% grade 3 or greater), and neuropsychiatric symptoms increase in severity over time. Other aes are anorexia, cardiotoxicity, hepatotoxicity, autoimmunity, ocular toxicity, and altered laboratory findings. Although generally manageable with careful monitoring, supportive care, and dose modifications, those a es often have a profound negative effect on quality of life and can be life-threatening.
# Interpretation of the Evidence:
The meta-analyses indicate that ifn-α is associated with a small but statistically significant improvement in os and dfs. For most patients, the aes are judged to outweigh the possible small benefit. The ipd meta-analysis suggests that the ifn-α benefit applies only to ulcerated tumours, a finding that must be confirmed in a trial designed to test efficacy specifically in ulcerated melanoma. The benefits of nivolumab, pembrolizumab, and (for BRAF-mutant melanoma) dabrafenibtrametinib exceed those of ifn-α, and therefore ifn-α is not recommended.
# Recommendation 4
Chemotherapy regimens, vaccines, levamisole, bevacizumab, bacillus Calmette-Guérin, and isolated limb perfusion are not recommended for the adjuvant treatment of cutaneous melanoma, except as part of a clinical trial.
# Key Evidence:
Most completed trials found no survival benefit. A few trials suggested a possible benefit for some of the agents, but they were either too small or were discontinued early because of more promising results with ifn-α and are therefore inconclusive. Some trials are ongoing.
# Mucosal Melanoma
# Recommendation 5
Immune checkpoint inhibitors (nivolumab or pembrolizumab) or targeted therapy (in patients with identified mutations) are recommended for adjuvant therapy of mucosal melanoma with high risk of recurrence.
Qualifying Statements: Mutation characterization is required before targeted agents are considered. Compared with cutaneous melanoma, mucosal melanoma has a different origin and spectrum of mutations. BRAF mutations are less common than they are in cutaneous melanoma, and therefore inhibitors are of little value in unselected patients. KIT mutations are more prevalent in mucosal melanoma, and inhibitors such as imatinib appear to be of value in advanced melanoma with KIT mutation 47 ; however, no trials of the adjuvant use of k it inhibitors were found.
The trials forming the key evidence for cutaneous melanoma (see recommendations 1 and 2) excluded mucosal melanoma, with the exception of the CheckMate 238 trial, which included 29 patients (3.2% of the total). That small number is insufficient to allow for any conclusions to be drawn specifically for that subgroup.
There might be a role for chemotherapy, but evidence is not sufficient to make a recommendation at this time. Adjuvant treatment of mucosal melanoma with hd-ifn-α2b compared with temozolomide-cisplatin was studied in a phase ii trial 48 in patients with stages ii and iii mucosal melanoma and in a subsequent phase i i i t r ia l942qin patients with stages i-ii7i mucosal melanoma, reported only in abstract form 35 . The phase ii study found that temozolomide-cisplatin resulted in a better os and dfs than did hd-ifn-α2b or placebo. A follow-up phase iii study confirmed the benefit of temozolomide-cisplatin compared with hd-ifn-α2b. The available evidence is limited because of a lack of full publication and inconsistency with studies in metastatic melanoma 49 . Key Evidence: Targeted agents and immune checkpoint inhibitors have not been evaluated specifically as adjuvant therapy in mucosal melanoma. Key evidence is considered to be the trials supporting their use in cutaneous melanoma [27][28][29][30]33,34 (see the earlier recommendations) and the data from trials in advanced or metastatic melanoma in which those agents were shown to be effective. D'Angelo et al. 50 conducted a pooled analysis of nivolumab alone or combined with ipilimumab in unresectable stage iii or iv mucosal melanoma, finding that nivolumab-ipilimumab had greater efficacy than either nivolumab monotherapy or ipilimumab monotherapy (objective response rate: 37.1% vs. 23.3% vs. 8.3%), but with a much greater rate of grades 3-4 aes (40% vs. 8% vs. not stated). Compared with ipilimumab alone, pfs was better with nivolumab-ipilimumab (hr: 0.35; 95% ci: 0.19 to 0.64) and with nivolumab alone (hr: 0.62; 95% ci: 0.39 to 0.98). A post hoc analysis of patients with advanced mucosal melanoma in the key note-001, -002, and -006 trials reported that pembrolizumab provided a durable tumour response 51 .
# Interpretation of the Evidence:
Recommendations for the use of immune checkpoint inhibitors in mucosal melanoma are based on extrapolation of results from cutaneous melanoma (see recommendations 1 and 2) and from trials in nonresectable mucosal melanoma.
For targeted therapy, the authors believe that cutaneous and mucosal melanoma with the same mutations would benefit from the same targeted therapies. Adjuvant therapy with dabrafenib-trametinib can therefore be considered in mucosal melanoma in which BRAF V600E or V600K is the primary mutation.
Further Qualif ying Statements : The recommended adjuvant therapies have potential for aes (see the earlier Key Evidence and Qualifying Statements subsections). Although usually manageable and reversible, those aes can be severe. It was outside the scope of the accompanying systematic review to deal with management of those aes. The reader can refer to other guidelines such as those from the Multinational Association of Supportive Care in Cancer 52 , the Eastern Cooperative Oncology Group 53 , the American Society of Clinical Oncology and the nccn 54,55 , oh(cco) 56 , and others 57,58 .
Several trials are ongoing, and the foregoing recommendations might have to be revisited upon completion of those trials.
# Implementation Considerations
Most trials of the adjuvant use of immune checkpoint inhibitors and targeted agents in melanoma are ongoing, with promising preliminary results. As a result, indications and approvals are changing rapidly. Nivolumab, pembrolizumab, and combination dabrafenib-trametinib were approved by Health Canada in early 2019 for adjuvant use in melanoma. At the time of the present review, immune checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab) and targeted therapies were being evaluated for approval and funding in Ontario. Funding might be interim pending final results of the trials mentioned in the various Key Evidence subsections of this review. Doses for administration of immune checkpoint inhibitors and targeted therapies have not been standardized and should conform with the approved indications.
# REVIEW AND UPDATE
The currency of each pebc document is ensured by periodic review and evaluation of the scientific literature and, where appropriate, the addition of newer literature to the original evidence base. That process is described in the PEBC Document Assessment and Review Protocol.
# ACKNOWLEDGMENTS
The Systemic Adjuvant Therapy for Adult Patients at High Risk for Recurrent Melanoma Guideline Development Group thanks Melissa Brouwers, Lise Craig, Donna Maziak, Sheila McNair, Wilson Miller, Marissa Myers, Kerry Savage, Patricia Sevean, Jonathan Sussman, Emily Vella, Cindy Walker-Dilks, Laurel Warr, Caroline Zwaal, and members of the oh(cco) Melanoma dsg for providing feedback on draft versions. They also thank Frances Wright, who served as a member of the Working Group in early stages of the project, and Megan Smy th and Jilian Sing for conducting a data audit.
The pebc is a provincial initiative of oh(cco), supported by the Ontario Ministry of Health (moh). All work produced by the pebc is editorially independent from the moh.
The complete version of this guideline and accompanying systematic review can be found at the oh(cco) Web site: https:// w w w.cancercareontario.ca/en/guidelines-advice/types-ofcancer/1161.
# CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncology's policy on disclosing conflicts of interest, and we declare the following interests: TMP reports grants from Roche, Novartis, Merck, and personal fees from Novartis, Merck, Bristol-Myers Squibb, and emd Serono, outside the submitted work. GGF reports grants to the pebc at McMaster University from oh(cco) or the moh during the conduct of the literature review and guideline development. GK reports personal fees from Bristol-Myers Squibb, Merck, Roche, and Sanofi, outside the submitted work. EM reports ser v ing on advisory boards for Novartis, Merck, Bristol-Myers Squibb, and Roche, outside the submitted work, and work as a local principal investigator on the combi-ad, comi-a Plus, and mec.5 trials. XS
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# Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC re lating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# Background
On April 5, 2022, NACI published initial guidance on a second booster dose of COVID-19 vaccines in Canada. The Statement mentioned the potential need for subsequent boosters in broader populations based on the evolution of the COVID-19 pandemic. On April 12, 2022, NACI also published updated guidance on a first booster dose of COVID-19 vaccines in Canada. Since that time:
- The epidemiology of COVID-19 continues to change and there is still considerable uncertainty with regard to the likelihood, timing, and severity of any potential future COVID-19 wave. It is possible that, consistent with other respiratory viruses, incidence of COVID-19 may increase in the later fall and winter seasons and that new variants of concern (VOC) may emerge. The current Omicron COVID-19 wave is declining nationally in Canada, with decreasing rates of hospitalizations and deaths. Nationally, the predominant Omicron sub -lineages continue to change, with BA.2 and BA.2.3 declining while the proportions of BA.2 .12.1, BA.4, and BA.5 continue to grow (1) . As of May 22, 2022, 86% of the population aged 5 years and older was vaccinated with a primary series. While the proportion of Canadians vaccinated with a primary series is high, the proportion who have received at least one additional dose has plateaued at a lower level, especially in the younger age groups. Vaccine coverage (particularly for the additional doses) increases with increasing age. Hybrid immunity (i.e., protection due to vaccination and infection) has increased as many
Canadians have now been infected with SARS-CoV-2. A national seroprevalence study of Canadian Blood Services donors (17 years of age and older) suggests that about 37% of individuals have infection-acquired antibodies (2) . Preliminary unpublished data show that about 50% of Canadian children aged less than 5 years have been infected with SARS-CoV-2, a seroprevalence rate similar or higher than older age groups (3) . When considering history of prior infection and/or vaccination, important differences by age group are observed. In general, while older adults are more likely to have been vaccinated, they are the least likely to have evidence of both vaccination and infection (i.e., hybrid immunity) among individuals 5 years of age and older (2,4) . Although the Omicron variant is associated with less severe illness compared to previous strains, it is partially evasive of immunity conferred by ancestral COVID-19 vaccines or by a previous infection with a SARS-CoV-2 variant prior to Omicron. Preliminary evidence suggests infection-and/or vaccine-acquired immunity wanes over time, which supports administration of subsequent vaccine doses (especially in populations at high risk of severe disease and/or at high risk of poor immune responses to vaccination) to improve protection in case of increasing COVID-19 indicators (e.g., case incidence, test positivity, outbreaks, wastewater signals). Some international jurisdictions have released interim guidance on forthcoming COVID -19 vaccination programs.
NACI continues to strongly recommend a primary series with an authorized mRNA vaccine in all authorized age groups. NACI also strongly recommends a booster dose for all adults, and for adolescents who are considered to be at high risk for severe disease. Immunization of those who are eligible for vaccination but have not yet received their recommended doses (primary or booster) remains a top priority in Canada. As with previous COVID-19 booster programs, a fall booster dose in advance of a potential future wave of COVID-19 will be most important for older adults and other populations at increased risk of severe COVID-19 disease, regardless of the number of booster doses previously received. Evidence to date suggests that while protection against symptomatic disease wanes over time, protection against severe disease is better maintained.
NACI continues to monitor the rapidly evolving scientific data while recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed.
NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were updated on February 14, 2022:
- To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic To transition away from the crisis phase towards a more sustainable approach to l ong term management of COVID-19 Methods NACI's recommendations on booster doses are based on the decision-making framework outlined in the published statement entitled Interim guidance on booster COVID-19 vaccine doses in Canada. This framework has been updated with evolving evidence (e.g., including consideration of population level cumulative immunity and vaccine coverage) as outlined in Table 1.
Recommendations are based on evidence of the need for (e.g., increased risk of severe illness from COVID-19 and/or increased risk of decreased protection, and waning protection due to increased time since last dose or infection) and benefit of (e.g., safety and effectiveness) booster doses in the Canadian context.
NACI also reviewed its original framework entitled Guidance on the prioritizing of key populations for COVID-19 immunization with a primary series when making these recommendations. NACI's original prioritization framework was based on evidence of increased risk of severe illness and death from COVID-19 as well as increased risk of exposure to SARS-CoV-2 in the context of constrained vaccine supply. With the evolution of the pandemic, COVID-19 vaccination, and evidence since this original framework, NACI's current recommendations for an additional booster dose focus on key populations at increased risk of severe illness and death from COVID -19.
On May 24, 2022, and June 7, 2022, NACI reviewed data on the current epidemiology of COVID-19, the level and duration of protection conferred by vaccine-induced immunity, SARS-CoV-2 infection-induced immunity and hybrid immunity (i.e., induced by vaccination and infection); as well as considered future multivalent COVID-19 vaccines.
NACI approved the following recommendations on June 22, 2022.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG)
Further information on NACI's process and procedures is available elsewhere (5,6) .
# Table 1. Underlying factors- for consideration to determine the need for and benefit of a booster dose of COVID-19 vaccine in various populations
# Underlying factors- for consideration
Evidence reviewed to determine the need for and benefit of a booster dose of COVID-19 vaccine
# Recommendations
NACI continues to strongly recommend that individuals in the authorized age groups should be immunized with a primary series of an authorized mRNA vaccine. NACI also continues to recommend a first and a second booster in some populations. NACI reiterates its recommendation on concurrent administration of COVID-19 vaccines with other vaccines. For further information on previous guidance, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
The likelihood, timing, and severity of a future wave of COVID-19 is uncertain; however, the later fall and winter months are expected to be associated with a resurgence of SARS-CoV-2 community transmission due to indoor and seasonal gatherings. Late r fall and winter is also a time when the incidence rates of other respiratory diseases are elevated, which leads to increased pressure on health systems. NACI will continue to monitor the evidence (including SARS-CoV-2 epidemiology and available vaccine options) in the coming months to provide recommendations on the type and timing of vaccines for subsequent booster doses, as well as any updates to the following interim recommendations which are provided to assist with operational planning. At this time:
In addition to offering a primary series with a COVID-19 vaccine to individuals in all authorized age groups and booster dose(s) in eligible populations previously recommended by NACI, jurisdictions should plan for the following in advance of a possible future wave of COVID-19 in Canada:
- NACI recommends that individuals who are at increased risk of severe illness from COVID-19 should be offered a fall COVID-19 vaccine booster dose- regardless of the number of booster doses previously received, including: If adults (≥18 years) or high risk adolescents (12-17 years) have not yet received a first booster dose by the fall of 2022, NACI continues to strongly recommend that a first booster dose be offered. For all currently vaccine eligible individuals (i.e., aged 5 years and older), concurrent administration of other vaccines (e.g., seasonal inactivated influenza vaccine) and any dose of a COVID-19 vaccine is acceptable and may increase program efficiency. Although Omicron is the variant predominantly circulating in Canada at the time of writing, the timing of a potential new variant or wave of COVID-19, and its characteristics (e.g., transmission, virulence, vaccine escape) cannot be reliably predicted. Given the uncertainties, the planning of a forthcoming COVID-19 booster program should include sufficient resilience and flexibility (e.g., emerging epidemiological trends may alter the timing of an upcoming booster program, triggering an earlier or later roll-out than currently anticipated). Timely, close and ongoing monitoring and assessment of national and international data will be required to ensure adaptability of response. There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions. Underlying factors to consider are listed in Table 1.
# Summary of evidence
Evolving epidemiology and vaccine coverage Cases of COVID-19, including associated hospitalizations and deaths, are currently declining in Canada. However, the likelihood, timing, and severity of a future wave of COVID-19 is uncertain. It is possible that consistent with other respiratory viruses, incidence of COVID-19 will increase in the later fall and winter seasons thus posing a risk for individuals/communities and increasing pressure on health systems. Data from Canadian Blood Services (donors aged 17 years and older) suggest that about 37% of Canadians were infected with SARS-CoV-2 by the end of April 2022 with variation by jurisdiction and higher infection rates among children, young adults, racialized communities and those residing in lower-income neighborhoods (7) . Preliminary unpublished data suggest that seroprevalence in individuals less than 17 years of age is higher compared to older age groups (3,8) . The evolution of seroprevalence rates over time suggests that the majority of infected individuals were infected by the Omicron variant. Regardless of vaccination status, age remains the greatest risk factor for severe outcomes of COVID-19. As of May 22, 2022, 86% of the population aged 5 years and older had been vaccinated with a primary series, 59% of the population aged 18 years and older had received an additional dose or booster, and 40% of the population aged 80 years and older had received two additional doses (9) . While the proportion of Canadians vaccinated with a primary series was high, the proportion who had received at least one booster had plateaued at a relatively lower level. Vaccine coverage (especially for additional doses) increased with increasing age.
# Hybrid immunity
- Available evidence shows that hybrid immunity is more robust than immunity due to infection or vaccination alone. The duration of protection from hybrid immunity has not yet been fully characterized, and it is unclear whether hybrid immunity will continue to provide strong protection against some Omicron sub-lineages (e.g. BA.4, BA.5) or potential new variants (2,(10)(11)(12)(13)(14)(15)(16) . Hybrid immunity resulting from three or more exposures to the virus antigen (i.e., ≥1 exposure from vaccination and ≥1 exposure from SARS-CoV-2 infection before or after vaccination) may provide superior protection (as measured by neutralization capacity) against VOCs, including Omicron, compared with primary vaccination only, or previous SARS-CoV-2 infection without vaccination (16) . Preliminary unpublished data from Quebec healthcare workers (mostly aged 60 years and younger) indicate that protection against Omicron BA.2 conferred by prior infection (with or without vaccination) is higher following prior infection with Omicron BA.1 compared to prior infection with pre-Omicron strains (12) . The protection against Omicron BA.2 conferred by a prior SARS-CoV-2 infection was increased by vaccination with 1 and 2 doses but did not seem to increase with a third dose. At about 4 months (132 days) of follow up, protection against Omicron BA.2 reinfection was 72% in individuals with prior BA.1 infection without vaccination and 96-97% among those with Omicron BA.1 infection and vaccination with 2 or 3 doses. Emerging Canadian evidence suggests that the proportion of the Canadian population that are infected and/or vaccinated varies by age. A large proportion of elderly adults are protected by vaccination but not by hybrid immunity. On the other hand, a large proportion of infants and young adults have been infected but not vaccinated. About 50% of children aged less than 5 years have been infected but not vaccinated as no vaccine has been authorized in this age group to date; this proportion may vary by jurisdiction. Adolescents and young adults have the highest proportion of individuals that have been both vaccinated and infected with SARS-CoV-2. However data have yet to be published and should be considered preliminary at this time (3) . It is expected that individuals who have been infected with SARS-CoV-2 may optimize their benefit from future vaccine doses by timing them according to the time since infection, using similar immunological principles to those informing intervals between vaccine doses. Emerging evidence indicates that a longer interval between SARS-CoV-2 infection and vaccination is associated with improved immune responses to COVID-19 vaccines.
Vaccine effectiveness (VE) and duration of protection following a first or second booster dose Current data suggest that COVID-19 vaccines offer higher protection against hospitalization and severe disease than against infection, and they offer reduced protection against Omicron compared to ancestral strain and previous VOCs. VE against severe disease with Omicron infection is approximately 90% shortly after a first booster dose and remains above 75% in most studies, up to 20 weeks from the first booster (17)(18)(19)(20) . VE against Omicron infection and/or symptomatic disease from a first booster of mRNA vaccine is approximately 60% shortly after the dose and decreases over time since vaccination in most studies (17)(18)(19)(20)(21)(22)(23)(24) . Evidence on second booster VE is limited and has mainly been assessed as a relative benefit compared to the first booster (25)(26)(27)(28)(29) . Preliminary data indicates that a second booster dose provides additional protection compared to a first booster, including against severe disease. The duration of protection is currently unknown (28) . Longer intervals between doses have been shown to result in a stronger and more durable immune response (30,31) and somewhat better VE than shorter intervals (30,32,33) . A longer interval between doses provides the opportunity for antibody levels to wane, which may result in a more robust immune memory response after the next dose, as it allows time for the immune response to mature in both breadth and strength. The absolute benefit of a booster will depend on the residual protection from previous vaccine doses/infection and on the level of circulating disease in the community .
# Safety
- Overall, from both Canadian and International safety surveillance data, mRNA COVID-19 vaccine reactogenicity for first and second booster doses is comparable to the reactogenicity of the primary series (25,(34)(35)(36)(37)(38)(39)(40)(41)(42) . Booster doses were well tolerated and no new safety signal was identified. However, second booster doses have generally been administered in specific populations (e.g., LTC residents, older adults) or in small groups, therefore evidence of their safety is currently limited. The risk of myocarditis and/or pericarditis following the first booster dose was lower compared to dose 2 of the primary series, which is consistent with lower risk due to extended intervals between doses (39,40,43) . The risk of myocarditis and/or pericarditis associated with additional doses is currently unknown. Evidence monitoring is ongoing on the safety of additional doses of mRNA COVID-19 vaccines.
Ethics, equity, feasibility, and acceptability (EEFA) In the face of uncertainty about how the pandemic will evolve, NACI based its recommendations on an evidence-informed framework and recommends booster doses to those at greatest risk of serious harms to avoid preventable morbidity and mortality. Planning vaccination ahead of a future wave of COVID-19 could facilitate access to vaccines, reduce inequities, and decrease the burden on healthcare systems. Intentions to accept COVID- 19 (45) . The mRNA-1273.214 (50mcg) booster dose was generally well-tolerated and its safety and reactogenicity profile was similar to the mRNA-1273 (50 mcg) dose when administered as a second booster dose. Maximizing the benefit of protection of a booster dose may be affected by the interval between doses. Longer time between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength. A longer interval may, however, also increase the chance of a period with waning (lower) protection while awaiting a next dose. As protection against infection and severe disease is highest soon after vaccine administration, vaccination at a time of low disease incidence may have limited benefit, particularly if there is an extended period of time before the next wave of COVID-19.
# RESEARCH PRIORITIES
- Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of the COVID-19 vaccines, including booster doses, through clinical trials and studies in real-world settings, including the degree and duration of protection conferred by each booster dose against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as MIS-C, post-COVID-19 condition (long COVID), or infectioninduced myocarditis or pericarditis in adult, adolescent, and pediatric populations. 2. Further evaluations of the optimal interval between booster dose administration, as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and vaccine dose administration.
- Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and pericarditis, in order to accurately inform potential risks associated with a future booster. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of additional booster doses of COVID-19 vaccine. 4. Continuous monitoring of COVID-19 epidemiology and VE in special populations at high risk of severe outcomes or long-term consequences of COVID-19 disease. 5. Further evaluation on the optimal timing and trigger for the initiation of potential future booster dose recommendations, as well as evaluation of potential risks associated with providing booster doses earlier than necessary. 6. Continuous monitoring of vaccine uptake in the Canadian population, particularly in the context of subsequent booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake.
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
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# Preamble
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC re lating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# Background
On April 5, 2022, NACI published initial guidance on a second booster dose of COVID-19 vaccines in Canada. The Statement mentioned the potential need for subsequent boosters in broader populations based on the evolution of the COVID-19 pandemic. On April 12, 2022, NACI also published updated guidance on a first booster dose of COVID-19 vaccines in Canada. Since that time:
The epidemiology of COVID-19 continues to change and there is still considerable uncertainty with regard to the likelihood, timing, and severity of any potential future COVID-19 wave. It is possible that, consistent with other respiratory viruses, incidence of COVID-19 may increase in the later fall and winter seasons and that new variants of concern (VOC) may emerge. The current Omicron COVID-19 wave is declining nationally in Canada, with decreasing rates of hospitalizations and deaths. Nationally, the predominant Omicron sub -lineages continue to change, with BA.2 and BA.2.3 declining while the proportions of BA.2 .12.1, BA.4, and BA.5 continue to grow (1) . As of May 22, 2022, 86% of the population aged 5 years and older was vaccinated with a primary series. While the proportion of Canadians vaccinated with a primary series is high, the proportion who have received at least one additional dose has plateaued at a lower level, especially in the younger age groups. Vaccine coverage (particularly for the additional doses) increases with increasing age. Hybrid immunity (i.e., protection due to vaccination and infection) has increased as many
Canadians have now been infected with SARS-CoV-2. A national seroprevalence study of Canadian Blood Services donors (17 years of age and older) suggests that about 37% of individuals have infection-acquired antibodies (2) . Preliminary unpublished data show that about 50% of Canadian children aged less than 5 years have been infected with SARS-CoV-2, a seroprevalence rate similar or higher than older age groups (3) . When considering history of prior infection and/or vaccination, important differences by age group are observed. In general, while older adults are more likely to have been vaccinated, they are the least likely to have evidence of both vaccination and infection (i.e., hybrid immunity) among individuals 5 years of age and older (2,4) . Although the Omicron variant is associated with less severe illness compared to previous strains, it is partially evasive of immunity conferred by ancestral COVID-19 vaccines or by a previous infection with a SARS-CoV-2 variant prior to Omicron. Preliminary evidence suggests infection-and/or vaccine-acquired immunity wanes over time, which supports administration of subsequent vaccine doses (especially in populations at high risk of severe disease and/or at high risk of poor immune responses to vaccination) to improve protection in case of increasing COVID-19 indicators (e.g., case incidence, test positivity, outbreaks, wastewater signals). Some international jurisdictions have released interim guidance on forthcoming COVID -19 vaccination programs.
NACI continues to strongly recommend a primary series with an authorized mRNA vaccine in all authorized age groups. NACI also strongly recommends a booster dose for all adults, and for adolescents who are considered to be at high risk for severe disease. Immunization of those who are eligible for vaccination but have not yet received their recommended doses (primary or booster) remains a top priority in Canada. As with previous COVID-19 booster programs, a fall booster dose in advance of a potential future wave of COVID-19 will be most important for older adults and other populations at increased risk of severe COVID-19 disease, regardless of the number of booster doses previously received. Evidence to date suggests that while protection against symptomatic disease wanes over time, protection against severe disease is better maintained.
NACI continues to monitor the rapidly evolving scientific data while recognizing that the trajectory of the COVID-19 pandemic remains unclear. Updated recommendations will be made as needed.
NACI's recommendations remain aligned with the goals of the Canadian COVID-19 Pandemic Response that were updated on February 14, 2022:
To minimize serious illness and death while minimizing societal disruption as a result of the COVID-19 pandemic To transition away from the crisis phase towards a more sustainable approach to l ong term management of COVID-19 Methods NACI's recommendations on booster doses are based on the decision-making framework outlined in the published statement entitled Interim guidance on booster COVID-19 vaccine doses in Canada. This framework has been updated with evolving evidence (e.g., including consideration of population level cumulative immunity and vaccine coverage) as outlined in Table 1.
Recommendations are based on evidence of the need for (e.g., increased risk of severe illness from COVID-19 and/or increased risk of decreased protection, and waning protection due to increased time since last dose or infection) and benefit of (e.g., safety and effectiveness) booster doses in the Canadian context.
NACI also reviewed its original framework entitled Guidance on the prioritizing of key populations for COVID-19 immunization with a primary series when making these recommendations. NACI's original prioritization framework was based on evidence of increased risk of severe illness and death from COVID-19 as well as increased risk of exposure to SARS-CoV-2 in the context of constrained vaccine supply. With the evolution of the pandemic, COVID-19 vaccination, and evidence since this original framework, NACI's current recommendations for an additional booster dose focus on key populations at increased risk of severe illness and death from COVID -19.
On May 24, 2022, and June 7, 2022, NACI reviewed data on the current epidemiology of COVID-19, the level and duration of protection conferred by vaccine-induced immunity, SARS-CoV-2 infection-induced immunity and hybrid immunity (i.e., induced by vaccination and infection); as well as considered future multivalent COVID-19 vaccines.
NACI approved the following recommendations on June 22, 2022.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to National Advisory Committee on Immunization (NACI): Statements and publications and the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG)
Further information on NACI's process and procedures is available elsewhere (5,6) .
# Table 1. Underlying factors* for consideration to determine the need for and benefit of a booster dose of COVID-19 vaccine in various populations
# Underlying factors* for consideration
Evidence reviewed to determine the need for and benefit of a booster dose of COVID-19 vaccine
# Recommendations
NACI continues to strongly recommend that individuals in the authorized age groups should be immunized with a primary series of an authorized mRNA vaccine. NACI also continues to recommend a first and a second booster in some populations. NACI reiterates its recommendation on concurrent administration of COVID-19 vaccines with other vaccines. For further information on previous guidance, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
The likelihood, timing, and severity of a future wave of COVID-19 is uncertain; however, the later fall and winter months are expected to be associated with a resurgence of SARS-CoV-2 community transmission due to indoor and seasonal gatherings. Late r fall and winter is also a time when the incidence rates of other respiratory diseases are elevated, which leads to increased pressure on health systems. NACI will continue to monitor the evidence (including SARS-CoV-2 epidemiology and available vaccine options) in the coming months to provide recommendations on the type and timing of vaccines for subsequent booster doses, as well as any updates to the following interim recommendations which are provided to assist with operational planning. At this time:
In addition to offering a primary series with a COVID-19 vaccine to individuals in all authorized age groups and booster dose(s) in eligible populations previously recommended by NACI, jurisdictions should plan for the following in advance of a possible future wave of COVID-19 in Canada:
1. NACI recommends that individuals who are at increased risk of severe illness from COVID-19 should be offered a fall COVID-19 vaccine booster dose* regardless of the number of booster doses previously received, including: If adults (≥18 years) or high risk adolescents (12-17 years) have not yet received a first booster dose by the fall of 2022, NACI continues to strongly recommend that a first booster dose be offered. For all currently vaccine eligible individuals (i.e., aged 5 years and older), concurrent administration of other vaccines (e.g., seasonal inactivated influenza vaccine) and any dose of a COVID-19 vaccine is acceptable and may increase program efficiency. Although Omicron is the variant predominantly circulating in Canada at the time of writing, the timing of a potential new variant or wave of COVID-19, and its characteristics (e.g., transmission, virulence, vaccine escape) cannot be reliably predicted. Given the uncertainties, the planning of a forthcoming COVID-19 booster program should include sufficient resilience and flexibility (e.g., emerging epidemiological trends may alter the timing of an upcoming booster program, triggering an earlier or later roll-out than currently anticipated). Timely, close and ongoing monitoring and assessment of national and international data will be required to ensure adaptability of response. There may be variability in how each province, territory and community assesses risk and responds to the needs of their respective jurisdictions. Underlying factors to consider are listed in Table 1.
# Summary of evidence
Evolving epidemiology and vaccine coverage Cases of COVID-19, including associated hospitalizations and deaths, are currently declining in Canada. However, the likelihood, timing, and severity of a future wave of COVID-19 is uncertain. It is possible that consistent with other respiratory viruses, incidence of COVID-19 will increase in the later fall and winter seasons thus posing a risk for individuals/communities and increasing pressure on health systems. Data from Canadian Blood Services (donors aged 17 years and older) suggest that about 37% of Canadians were infected with SARS-CoV-2 by the end of April 2022 with variation by jurisdiction and higher infection rates among children, young adults, racialized communities and those residing in lower-income neighborhoods (7) . Preliminary unpublished data suggest that seroprevalence in individuals less than 17 years of age is higher compared to older age groups (3,8) . The evolution of seroprevalence rates over time suggests that the majority of infected individuals were infected by the Omicron variant. Regardless of vaccination status, age remains the greatest risk factor for severe outcomes of COVID-19. As of May 22, 2022, 86% of the population aged 5 years and older had been vaccinated with a primary series, 59% of the population aged 18 years and older had received an additional dose or booster, and 40% of the population aged 80 years and older had received two additional doses (9) . While the proportion of Canadians vaccinated with a primary series was high, the proportion who had received at least one booster had plateaued at a relatively lower level. Vaccine coverage (especially for additional doses) increased with increasing age.
# Hybrid immunity
Available evidence shows that hybrid immunity is more robust than immunity due to infection or vaccination alone. The duration of protection from hybrid immunity has not yet been fully characterized, and it is unclear whether hybrid immunity will continue to provide strong protection against some Omicron sub-lineages (e.g. BA.4, BA.5) or potential new variants (2,(10)(11)(12)(13)(14)(15)(16) . Hybrid immunity resulting from three or more exposures to the virus antigen (i.e., ≥1 exposure[s] from vaccination and ≥1 exposure[s] from SARS-CoV-2 infection before or after vaccination) may provide superior protection (as measured by neutralization capacity) against VOCs, including Omicron, compared with primary vaccination only, or previous SARS-CoV-2 infection without vaccination (16) . Preliminary unpublished data from Quebec healthcare workers (mostly aged 60 years and younger) indicate that protection against Omicron BA.2 conferred by prior infection (with or without vaccination) is higher following prior infection with Omicron BA.1 compared to prior infection with pre-Omicron strains (12) . The protection against Omicron BA.2 conferred by a prior SARS-CoV-2 infection was increased by vaccination with 1 and 2 doses but did not seem to increase with a third dose. At about 4 months (132 days) of follow up, protection against Omicron BA.2 reinfection was 72% in individuals with prior BA.1 infection without vaccination and 96-97% among those with Omicron BA.1 infection and vaccination with 2 or 3 doses. Emerging Canadian evidence suggests that the proportion of the Canadian population that are infected and/or vaccinated varies by age. A large proportion of elderly adults are protected by vaccination but not by hybrid immunity. On the other hand, a large proportion of infants and young adults have been infected but not vaccinated. About 50% of children aged less than 5 years have been infected but not vaccinated as no vaccine has been authorized in this age group to date; this proportion may vary by jurisdiction. Adolescents and young adults have the highest proportion of individuals that have been both vaccinated and infected with SARS-CoV-2. However data have yet to be published and should be considered preliminary at this time (3) . It is expected that individuals who have been infected with SARS-CoV-2 may optimize their benefit from future vaccine doses by timing them according to the time since infection, using similar immunological principles to those informing intervals between vaccine doses. Emerging evidence indicates that a longer interval between SARS-CoV-2 infection and vaccination is associated with improved immune responses to COVID-19 vaccines.
Vaccine effectiveness (VE) and duration of protection following a first or second booster dose Current data suggest that COVID-19 vaccines offer higher protection against hospitalization and severe disease than against infection, and they offer reduced protection against Omicron compared to ancestral strain and previous VOCs. VE against severe disease with Omicron infection is approximately 90% shortly after a first booster dose and remains above 75% in most studies, up to 20 weeks from the first booster (17)(18)(19)(20) . VE against Omicron infection and/or symptomatic disease from a first booster of mRNA vaccine is approximately 60% shortly after the dose and decreases over time since vaccination in most studies (17)(18)(19)(20)(21)(22)(23)(24) . Evidence on second booster VE is limited and has mainly been assessed as a relative benefit compared to the first booster (25)(26)(27)(28)(29) . Preliminary data indicates that a second booster dose provides additional protection compared to a first booster, including against severe disease. The duration of protection is currently unknown (28) . Longer intervals between doses have been shown to result in a stronger and more durable immune response (30,31) and somewhat better VE than shorter intervals (30,32,33) . A longer interval between doses provides the opportunity for antibody levels to wane, which may result in a more robust immune memory response after the next dose, as it allows time for the immune response to mature in both breadth and strength. The absolute benefit of a booster will depend on the residual protection from previous vaccine doses/infection and on the level of circulating disease in the community .
# Safety
Overall, from both Canadian and International safety surveillance data, mRNA COVID-19 vaccine reactogenicity for first and second booster doses is comparable to the reactogenicity of the primary series (25,(34)(35)(36)(37)(38)(39)(40)(41)(42) . Booster doses were well tolerated and no new safety signal was identified. However, second booster doses have generally been administered in specific populations (e.g., LTC residents, older adults) or in small groups, therefore evidence of their safety is currently limited. The risk of myocarditis and/or pericarditis following the first booster dose was lower compared to dose 2 of the primary series, which is consistent with lower risk due to extended intervals between doses (39,40,43) . The risk of myocarditis and/or pericarditis associated with additional doses is currently unknown. Evidence monitoring is ongoing on the safety of additional doses of mRNA COVID-19 vaccines.
Ethics, equity, feasibility, and acceptability (EEFA) In the face of uncertainty about how the pandemic will evolve, NACI based its recommendations on an evidence-informed framework and recommends booster doses to those at greatest risk of serious harms to avoid preventable morbidity and mortality. Planning vaccination ahead of a future wave of COVID-19 could facilitate access to vaccines, reduce inequities, and decrease the burden on healthcare systems. Intentions to accept COVID- 19 (45) . The mRNA-1273.214 (50mcg) booster dose was generally well-tolerated and its safety and reactogenicity profile was similar to the mRNA-1273 (50 mcg) dose when administered as a second booster dose. Maximizing the benefit of protection of a booster dose may be affected by the interval between doses. Longer time between doses may result in a better response after any subsequent dose, as this allows time for the immune response to mature in breadth and strength. A longer interval may, however, also increase the chance of a period with waning (lower) protection while awaiting a next dose. As protection against infection and severe disease is highest soon after vaccine administration, vaccination at a time of low disease incidence may have limited benefit, particularly if there is an extended period of time before the next wave of COVID-19.
# RESEARCH PRIORITIES
1. Continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of the COVID-19 vaccines, including booster doses, through clinical trials and studies in real-world settings, including the degree and duration of protection conferred by each booster dose against circulating variants. The research should also consider the clinical implications of previous SARS-CoV-2 infection; repeated immunization; and outcomes after any infection such as MIS-C, post-COVID-19 condition (long COVID), or infectioninduced myocarditis or pericarditis in adult, adolescent, and pediatric populations. 2. Further evaluations of the optimal interval between booster dose administration, as well as further evaluations of the optimal interval between previous SARS-CoV-2 infection and vaccine dose administration.
3. Vigilant monitoring and reporting of adverse events of special interest, including myocarditis and pericarditis, in order to accurately inform potential risks associated with a future booster. Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of additional booster doses of COVID-19 vaccine. 4. Continuous monitoring of COVID-19 epidemiology and VE in special populations at high risk of severe outcomes or long-term consequences of COVID-19 disease. 5. Further evaluation on the optimal timing and trigger for the initiation of potential future booster dose recommendations, as well as evaluation of potential risks associated with providing booster doses earlier than necessary. 6. Continuous monitoring of vaccine uptake in the Canadian population, particularly in the context of subsequent booster doses and including consideration of measures that may reduce the risk of disparities in vaccine confidence and uptake.
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
# ACKNOWLEDGMENTS
This statement was prepared by: J Zafack, SJ Ismail, A Nunn, H Birdi, R Krishnan, N Forbes, MC Tunis, M Salvadori, R Harrison, and S Deeks, on behalf of NACI.
NACI gratefully acknowledges the contribution of: K Ramotar, N St-Pierre, and E Tarrataca.
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People who have received an organ transplant may require specific advice and counseling prior to COVID-19 immunization. There may be questions about the efficacy of vaccines in people who are immunosuppressed, and care considerations about the timing of immunization relative to treatment. 1,2 Is COVID-19 immunization recommended for solid organ transplant recipients? COVID-19 vaccines should be encouraged for people with solid organ transplants and are not contraindicated, including those who have had a COVID-19 infection. This recommendation is based on the following review: - Canadian Society of Transplantation recommend that vaccine may be given to the pre-and post-transplant patient population when it is available to them, and they may receive any of the Health Canada approved vaccines that are available to them, if age requirements are met. 3 - National Advisory Committee on Immunization recommends that immunosuppressed individuals be offered the vaccine. 4,5 - Clinically worse outcomes from COVID-19 infection: COVID-19 outcomes in organ transplant recipients have ranged from mild disease to the need for intensive care unit care and death. 6,7 Whether COVID-19 is more severe due to immunosuppression or due to underlying disease or comorbid conditions associated with high COVID-19 risk (such as advanced age, chronic kidney disease, diabetes, and heart/lung disease) is unclear. Lung transplant patients also seem to be at particularly high risk of severe disease. 6 While data specific to the safety and efficacy of COVID-19 vaccines in solid organ transplant recipients is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy 8 and it is reasonable to anticipate that vaccination will offer some benefit. Thus, the authors of this guidance agree that the benefits of increased vaccineinduced immunity against COVID-19 for this population outweigh any theoretical risks of immunization. Is COVID-19 immunization efficacious and safe for solid organ transplant recipients? Both adults and children who have had a solid organ transplant and people who are immunosuppressed in general were excluded from the clinical trials of the COVID-19 vaccines. COVID-19 Vaccines for Solid Organ Transplant Recipients#
Safety data for people with solid organ transplants are available in observational studies. The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that of nonimmunosuppressed individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available.
As with most vaccines, there is a potential for blunted immune response in individuals who are immunocompromised due to their disease or treatment. 1,2 Recently, multiple studies have been published examining the response to SARS-CoV2 mRNA-based vaccines in solid organ transplant (SOT) recipients. Overall, these studies have shown a lower antibody response to vaccine among SOT recipients when compared to the general population. Emerging studies have shown a detectable SARS-CoV-2 specific T-cells response in some patients, despite a lack of antibody response. Therefore, SOT recipients might derive clinical benefit from the vaccine despite an absent antibody response. Studies to assess vaccine effectiveness, particularly for protection against severe COVID-19 as a clinical end-point in SOT, are still needed. 21 Studies evaluating immune response in pediatric and adolescent solid organ transplant recipients are ongoing. Early data suggests adolescent transplant recipients may have better antibody response compared to adult recipients. 22 There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 23 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose.
Transplant recipients who are immunosuppressed from treatment should be informed that they may have a reduced immune response to any authorized COVID-19 vaccine series. 4 However, they should also be reassured that expert consensus is that benefits of immunization outweigh the risks. 4,6,7,14 There is a theoretical vaccine side effect that COVID-19 immunization could cause graft rejection. There is one study that found minimal evidence of donor-directed immunologic activity post-vaccination, and all immunologic changes did not correlate to graft dysfunction. The researchers suggest that COVID-19 vaccination is immunologically safe and should continue for transplant recipients. 24 Are there any specific contraindications or exceptions for solid organ transplant recipients?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 25 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylaxis without known or obvious cause, and those with suspected hypersensitivity or nonanaphylactic allergy to COVID-19 vaccine components, are advised to consult with an allergist prior to immunization. Health-care providers with patients with a history of severe allergic reactions should refer to the product monographs to COVID-19 Vaccines for Solid Organ Transplant Recipients Updated: April 18, 2023 review the full ingredient list. Potential allergens that are known to cause type 1 hypersensitivities in the mRNA vaccines include polyethylene glycol (PEG), and Polysorbate 80 in the VAXZEVRIA (AstraZeneca): viral vector vaccine.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine including the seasonal influenza vaccine. Patients should delay vaccination within the first month post-transplant, during acute rejection treatment (e.g., high dose steroids) or antibody mediated rejection protocols with rituximab -see below. 3 Are there specific recommendations or considerations for safe and/or most effective administration?
For the vast majority of solid organ transplant recipients, there are no specific recommendations that need to be considered for COVID-19 vaccine administration. A small subset of adult patients with specific timing considerations (those on the active transplant wait list, have recently had a solid organ transplant, or are undergoing acute rejection therapy) should be contacted directly by their transplant care teams to help with immunization timing. Pediatric transplant patients ages 5 and older are encouraged to be vaccinated. Pediatric patients who had solid organ transplant in the last month; have been treated for acute rejection therapy in the last month; or received rituximab in the last 3 months should contact their transplant care teams to help with immunization timing.
As part of vaccine surveillance for safety and efficacy, solid organ transplant patients should be encouraged to report any significant adverse event to their transplant clinics.
A very small group of pediatric and adult patients who are waiting to receive a solid organ transplant, have recently had a solid organ transplant, or are undergoing acute rejection therapy, will need to be specifically counselled by their posttransplant care teams on the appropriate timing of the COVID-19 vaccines. For these patients, it is recommended: 3 o Ideally, immunization should occur two weeks prior to transplant to allow for an immune response. If transplant happens before the second dose (for 2 dose vaccines), resume vaccination at least one month post-transplant. o Wait at least one month after transplant to receive the COVID-19 vaccine regardless of induction therapy (basiliximab, anti-thymocyte globulin) o Wait at least one month after active treatment for acute organ rejection (including steroid pulse even if no other drugs given) o Wait at least three months after rituximab therapy (e.g. antibody-mediated rejection protocols) Antibody testing is not recommended after vaccination. The levels of protective antibody and association with vaccine effectiveness are not known. 21 COVID-19 Vaccines for Solid Organ Transplant Recipients Updated: April 18, 2023 As all solid organ transplant recipients are immunosuppressed to varying degrees, vaccine efficacy is expected to be lower than for those who are not immunosuppressed. It is strongly recommended that patients (and their immediate household) continue to practice infection control measures while COVID-19 is circulating in the community. Household contacts and caregivers of the transplant recipient should also be immunized when possible. 3 Regardless of vaccination status, transplant recipients should follow any measures recommended by public health.
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People who have received an organ transplant may require specific advice and counseling prior to COVID-19 immunization. There may be questions about the efficacy of vaccines in people who are immunosuppressed, and care considerations about the timing of immunization relative to treatment. 1,2 Is COVID-19 immunization recommended for solid organ transplant recipients? COVID-19 vaccines should be encouraged for people with solid organ transplants and are not contraindicated, including those who have had a COVID-19 infection. This recommendation is based on the following review: • Canadian Society of Transplantation recommend that vaccine may be given to the pre-and post-transplant patient population when it is available to them, and they may receive any of the Health Canada approved vaccines that are available to them, if age requirements are met. 3 • National Advisory Committee on Immunization recommends that immunosuppressed individuals be offered the vaccine. 4,5 • Clinically worse outcomes from COVID-19 infection: COVID-19 outcomes in organ transplant recipients have ranged from mild disease to the need for intensive care unit care and death. 6,7 Whether COVID-19 is more severe due to immunosuppression or due to underlying disease or comorbid conditions associated with high COVID-19 risk (such as advanced age, chronic kidney disease, diabetes, and heart/lung disease) is unclear. Lung transplant patients also seem to be at particularly high risk of severe disease. 6 While data specific to the safety and efficacy of COVID-19 vaccines in solid organ transplant recipients is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy 8 and it is reasonable to anticipate that vaccination will offer some benefit. Thus, the authors of this guidance agree that the benefits of increased vaccineinduced immunity against COVID-19 for this population outweigh any theoretical risks of immunization. Is COVID-19 immunization efficacious and safe for solid organ transplant recipients? Both adults and children who have had a solid organ transplant and people who are immunosuppressed in general were excluded from the clinical trials of the COVID-19 vaccines. [9][10][11][12][13] COVID-19 Vaccines for Solid Organ Transplant Recipients#
Safety data for people with solid organ transplants are available in observational studies. The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that of nonimmunosuppressed individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available.
As with most vaccines, there is a potential for blunted immune response in individuals who are immunocompromised due to their disease or treatment. 1,2 Recently, multiple studies have been published examining the response to SARS-CoV2 mRNA-based vaccines in solid organ transplant (SOT) recipients. [14][15][16][17][18][19][20] Overall, these studies have shown a lower antibody response to vaccine among SOT recipients when compared to the general population. Emerging studies have shown a detectable SARS-CoV-2 specific T-cells response in some patients, despite a lack of antibody response. Therefore, SOT recipients might derive clinical benefit from the vaccine despite an absent antibody response. Studies to assess vaccine effectiveness, particularly for protection against severe COVID-19 as a clinical end-point in SOT, are still needed. 21 Studies evaluating immune response in pediatric and adolescent solid organ transplant recipients are ongoing. Early data suggests adolescent transplant recipients may have better antibody response compared to adult recipients. 22 There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 23 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose.
Transplant recipients who are immunosuppressed from treatment should be informed that they may have a reduced immune response to any authorized COVID-19 vaccine series. 4 However, they should also be reassured that expert consensus is that benefits of immunization outweigh the risks. 4,6,7,14 There is a theoretical vaccine side effect that COVID-19 immunization could cause graft rejection. There is one study that found minimal evidence of donor-directed immunologic activity post-vaccination, and all immunologic changes did not correlate to graft dysfunction. The researchers suggest that COVID-19 vaccination is immunologically safe and should continue for transplant recipients. 24 Are there any specific contraindications or exceptions for solid organ transplant recipients?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 25 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylaxis without known or obvious cause, and those with suspected hypersensitivity or nonanaphylactic allergy to COVID-19 vaccine components, are advised to consult with an allergist prior to immunization. Health-care providers with patients with a history of severe allergic reactions should refer to the product monographs to COVID-19 Vaccines for Solid Organ Transplant Recipients Updated: April 18, 2023 review the full ingredient list. [9][10][11][12][13] Potential allergens that are known to cause type 1 hypersensitivities in the mRNA vaccines include polyethylene glycol (PEG), and Polysorbate 80 in the VAXZEVRIA (AstraZeneca): viral vector vaccine.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine including the seasonal influenza vaccine. [26][27][28][29] Patients should delay vaccination within the first month post-transplant, during acute rejection treatment (e.g., high dose steroids) or antibody mediated rejection protocols with rituximab -see below. 3 Are there specific recommendations or considerations for safe and/or most effective administration?
For the vast majority of solid organ transplant recipients, there are no specific recommendations that need to be considered for COVID-19 vaccine administration. A small subset of adult patients with specific timing considerations (those on the active transplant wait list, have recently had a solid organ transplant, or are undergoing acute rejection therapy) should be contacted directly by their transplant care teams to help with immunization timing. Pediatric transplant patients ages 5 and older are encouraged to be vaccinated. Pediatric patients who had solid organ transplant in the last month; have been treated for acute rejection therapy in the last month; or received rituximab in the last 3 months should contact their transplant care teams to help with immunization timing.
As part of vaccine surveillance for safety and efficacy, solid organ transplant patients should be encouraged to report any significant adverse event to their transplant clinics.
A very small group of pediatric and adult patients who are waiting to receive a solid organ transplant, have recently had a solid organ transplant, or are undergoing acute rejection therapy, will need to be specifically counselled by their posttransplant care teams on the appropriate timing of the COVID-19 vaccines. For these patients, it is recommended: 3 o Ideally, immunization should occur two weeks prior to transplant to allow for an immune response. If transplant happens before the second dose (for 2 dose vaccines), resume vaccination at least one month post-transplant. o Wait at least one month after transplant to receive the COVID-19 vaccine regardless of induction therapy (basiliximab, anti-thymocyte globulin) o Wait at least one month after active treatment for acute organ rejection (including steroid pulse even if no other drugs given) o Wait at least three months after rituximab therapy (e.g. antibody-mediated rejection protocols) Antibody testing is not recommended after vaccination. The levels of protective antibody and association with vaccine effectiveness are not known. 21 COVID-19 Vaccines for Solid Organ Transplant Recipients Updated: April 18, 2023 As all solid organ transplant recipients are immunosuppressed to varying degrees, vaccine efficacy is expected to be lower than for those who are not immunosuppressed. It is strongly recommended that patients (and their immediate household) continue to practice infection control measures while COVID-19 is circulating in the community. Household contacts and caregivers of the transplant recipient should also be immunized when possible. 3 Regardless of vaccination status, transplant recipients should follow any measures recommended by public health.
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# CUA GUIDELINE
Prior to original Publication (March 2017), this guideline underwent review by the cua guidelines coMMittee, cua MeMbers at large, and the cua executive board. the 2023 uPdates were aPProved by the cua guidelines coMMittee and cua executive board.
# SUMMARY OF CHANGES
The current guideline summarizes the state-of-the-art knowledge on the management of cystic renal lesions by updating the 2017 Canadian Urological Association (CUA) guideline on the topic. To do so, we updated our search strategy on June 18, 2022, and have identified 38 relevant articles, which led to a revision of the content of the original publication.
The panel formulated several recommendations using the GRADE evidence to decision framework -a methodological improvement compared to the previous iteration.
Three key recommendation changes were made compared to the previous iteration:
- Patients with a renal cyst should be classified as per the v2019 Bosniak classification.
- For Bosniak III or IV cyst measuring ≤2 cm, active surveillance is now suggested as the preferred strategy. 3. For Bosniak III or IV cyst measuring 2-4 cm, active surveillance or surgery are suggested as equal options. The panel made these changes in an attempt to decrease the burden of care for patients, but also acknowledges the low-quality evidence supporting these changes. Consequently, we emphasize the need for shared decision-making. Patients opting for nonsurgical strategies should be made aware of the higher uncertainty surrounding the data supporting their treatment of choice.
# INTRODUCTION
Cystic renal lesions are usually diagnosed incidentally on routine imaging. With the increasing use of abdominal imaging, there is a growing number of individuals being diagnosed with renal cystic disease. 1 It is estimated that up to one-third of individuals over 60 years of age will be diagnosed with at least one simple renal cyst following abdominal imaging. 2 Therefore, patients are often referred to urologists for guidance and management of these lesions. Physicians need to distinguish cystic lesions from solid renal masses with necrotic components, which behave more aggressively. 3 Hence, the characterization of these cystic renal masses is crucial to determine the best clinical approach. We reviewed the literature and updated the previous iteration of the CUA guideline with the aim of offering guidance to physicians managing cystic renal lesions and to standardize their management across Canada. 4
# METHODS
A comprehensive search of the literature was carried out on June 30, 2016, in MEDLINE and PubMed, which identified 77 relevant studies to inform the development of the 2017 CUA guideline on the management SUMMARY OF RECOMMENDATIONS 1. For patients first identified with a complex cyst on ultrasound, contrast-enhanced crosssectional imaging is recommended to better characterize the cyst (Strong recommendation, moderate certainty in evidence of effects).
- Patients identified with a renal cyst should be classified according to the v2019 Bosniak classification (Expert opinion).
- For patients where disagreement or doubt exists regarding the classification of a complex renal cyst, it is the panel's opinion that such cases should be presented at a multidisciplinary meeting if it has the potential to alter management (Expert opinion). of cystic renal masses (Supplementary Figure 1; available at cuaj.ca). An updated search of the literature was completed on June 18, 2022, using the same search terms, and identified an additional 38 relevant articles, which led to a revision of the content of the original publication (Supplementary Figure 2; available at cuaj. ca). 4 The search terms used were: Bosniak, Bosniak classification, renal cysts, renal cell carcinomas, renal and kidney cancers. Prospective or retrospective studies, as well as review studies providing data on the classification, management, and outcomes of complex cystic renal masses were included. Reports limited to children or animal and basic science studies were excluded. Similarly, reports limited to congenital or acquired renal cystic diseases and case reports of five or fewer cases were also excluded.
For each recommendation, the panel considered, when available, the 11 domains of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence-to-decision framework: 1) problem; 2) desirable effects; 3) undesirable effects; 4) certainty of evidence; 5) values; 6) balance of effects; 7) resource required; 8) certainty of evidence of required resources; 9) cost-effectiveness; 10) equity; and 11) acceptability. The strength of each recommendation was rated as strong or conditional (weak).
Strong recommendations were made when the desirable benefits of treatment outweighed the undesirable consequences (harms) and are worded as recommends. Conditional recommendations were made when the benefits of treatment probably outweighed the harms and are worded as suggests. When insufficient evidence was available for a recommendation, the panel reported additional information as clinical principle or as expert opinion. Importantly, all recommendations are based on expert review of the literature and represent the consensus of all co-authors of this guideline.
The objectives of this guideline were to perform a comprehensive review of the literature and to make recommendations on the characterization, management, and followup of incidentally discovered cystic lesions. The panel proceeded with full awareness of the limitations of the cystic renal lesions literature. The low-quality evidence made it difficult to make strong recommendations for the optimal treatment and followup of cystic renal lesions. Furthermore, as the majority of Bosniak category II and IIF cystic lesions are managed conservatively, the literature tends to overestimate the true malignancy risk of these lesions, as only the most complex ones undergo surgery. Nevertheless, while taking these limitations into account, the panel did its best to summarize the current literature and provide some guidance on the management of cystic lesions.
# EVIDENCE SYNTHESIS
# Bosniak classification -Introduction
█ RECOMMENDATION 1 For patients first identified with a complex cyst on ultrasound, contrast-enhanced, cross-sectional imaging is recommended to better characterize the cyst (Strong recommendation, moderate certainty in evidence of effects).
█ RECOMMENDATION 2 Patients identified with a renal cyst should be classified according to the v2019 Bosniak classification (Expert opinion).
█ RECOMMENDATION 3 For patients where disagreement or doubt exists regarding the classification of a complex renal cyst, it is the panel's opinion that such cases should be presented at a multidisciplinary meeting if it has the potential to alter management (Expert opinion).
Renal cysts can be easily identified using standard medical imaging and, in most cases, a histological diagnosis is not required; however, lesions that are more complex may require more detailed characterization to inform the differential diagnoses and guide subsequent management. It is especially important for physicians managing the more complex cystic lesions to differentiate them from solid renal masses with necrotic components, which behave more aggressively. 3 The Bosniak renal cyst classification was initially described in 1986 5 and was later updated to add a new category called category IIF. 6 It was originally described using computed tomography (CT) imaging but other modalities, such as magnetic resonance imaging (MRI), ultrasound (US), or contrast-enhancement ultrasound (CEUS), are now being used to help better delineate these lesions. For patients first identified with a complex cyst (Bosniak classification >2) on US, contrastenhanced, cross-sectional imaging is recommended to better characterize the cyst.
Although the Bosniak classification remains the most commonly used classification to characterize renal cysts, it has traditionally been subject to poor interobserver agreement. 4,6,10, Most of the observed variation was seen among cysts categorized as Bosniak II, IIF, and III. In an attempt to diminish the shortcomings of the traditional Bosniak classification, namely the inter-reader variability, Silverman et al have proposed a revision of the classification (Bosniak v2019 classification). 24,25 A detailed description and rationale for the proposed revision may be found in the original publication. 25 Although its clinical impact and benefit of the inter-rater variability remain to be well-studied, the panel members believe that the v2019 classification is currently the preferred Bosniak classification. Importantly, if there is disagreement or doubt regarding the classification of a complex renal cyst, it is the panel's opinion that such cases should be presented at a multidisciplinary meeting if this has the potential to alter management.
# Description of Bosniak classification
By means of the Bosniak classification, renal cystic lesions can be categorized in increasing order according to risk of malignancy. Table 1 details the traditional Bosniak classification and the proposed update (v2019).
# Bosniak category i
Lesions classified as category I are simple renal cysts and represent the majority of renal lesions detected by abdominal imaging. 2 These lesions are characterized by their regular contour and a clear interface with the renal parenchyma. They do not contain any septa or calcifications, nor do they demonstrate enhancement following intravenous contrast agent injection. They are homogeneous, with fluid attenuation varying from 0-20 HU on CT scan. These lesions are also easily identifiable by US and appear as thin-walled, anechoic lesions with posterior enhancement and sharply marginated smooth walls. 6,9 The v2019 classification has slightly refined the criteria for this category by limiting the thickness of the cyst wall to ≤2 mm and enhancement of the cyst wall may be observed. 25 Bosniak category ii These cysts are slightly more complex than category I cysts. 6 The v2019 Bosniak classification has described six different types of Bosniak II cysts on CT scans, while three are described on MRIs. 31 The v2019 classification describes category II cysts as thin wall cysts (≤2 mm) that may contain thin (≤2 mm) and few septa (≤3) that may or may not enhance and/or calcifications of any type. Other types of Bosniak II cysts are detailed in Table 1. Importantly, homogeneous, non-enhancing, hyperdense cysts (≥20 HU), regardless of size, are also categorized as Bosniak II cysts based on the v2019 classification. The traditional Bosniak classification categorized these cysts as Bosniak IIF if >3 cm.
Regardless of the Bosniak classification version being used, the overwhelming majority of Bosniak category II cysts are considered benign. Although review of the literature has demonstrated that approximately 10% of the operated category II cysts are malignant, this is an overestimation of the true malignancy risk, as a significant proportion of these studies were published before the addition of the Bosniak IIF category and many of these cysts were managed conservatively without pathological confirmation (Table 2). If we exclude the earlier studies and believe that most of the conservatively managed cysts were benign, the risk of malignancy for these lesions would be <5%. This rate is still believed to be a gross overestimation of the true risk, as most of the malignant category II lesions had features that made them too complex to be considered a true category II cyst.
# Bosniak category iiF
This category represents moderately complex cystic lesions. Any lesions not fulfilling the criteria for category II but not as complex as category III should be classified in this category. These cysts were traditionally described as cysts containing an increased number of thin septa or slightly thickened but smooth septa. They may also contain thick or nodular calcification but without contrast-enhancing features. Large, hyperdense cysts (≥3 cm and >20 HU) were also traditionally classified as Bosniak IIF cysts, but this is no longer the case with the v2019 classification. In an attempt to diminish inter-reader variability, the v2019 classification has further defined what was meant by an increased number of septa or a slightly thickened septum. Thus, v.2019 Bosniak IIF cysts are described as: 1) cysts with smooth minimally thickened (3 mm) enhancing wall; 2) cysts with ≥1 thickened enhancing septa (3 mm); or 3) cysts with many (≥4) smooth, thin (≤2 mm), enhancing septa.
The review of the literature revealed that approximately 28% of surgically treated Bosniak IIF lesions were malignant; however, as previously reported, this is likely an overestimation of the true malignancy risk. 4 If all conservatively managed Bosniak IIF cysts were benign, the risk of malignancy would approach 7% (Table 2). Similar findings were reported by two separately conducted systematic reviews. 22,35 Consequently, although helpful, the addition of the Bosniak IIF category did result in a substantial number of patients being followed for a benign cyst. Interestingly, Couture et al have examined the impact of the v2019 classification on cysts classified as IIF based on the traditional classification. 36 The authors found that 76% (138/181) of Bosniak IIF cysts would have initially been diagnosed as Bosniak II according to the revised classification. The v2019 classification misidentified one cyst that eventually progressed to Bosniak IV, but the authors reported that the patient was managed by active surveillance with no signs of metastases >6 years after progressing to Bosniak IV. Thus, the authors concluded that the v2019 revision may help minimize the overdiagnosis and followup of such cysts, avoiding important costs and harm to patients. 37,38 Bosniak category iii This category encompasses a variety of cystic lesions whose differentiation between malignant and benign cannot be reliably made by imaging. 6 According to the traditional Bosniak classification, these cysts present with wall irregularity and thickening, as well as wall nodularity. They may also demonstrate contrast-enhanced septa (usually multiple) that are usually irregular, thickened, and/or calcified. A significant proportion of these cysts are thought to be malignant (mean of 58%) (Table 2) 4,7,18-21,32-34,39-63 with larger lesions or cysts containing septal nodule being more likely to be malignant than smaller ones 4,22,64 or than septated cysts without nodularity. 64 In an attempt to decrease the number of benign cysts classified as a Bosniak III, the v2019 has attempted to better define the characteristics of this category and has removed the requirement that all cystic masses with 'measurable enhancement' be included as either a Bosniak III or IV. 25 Consequently, the v2019 classification now defines Bosniak III cysts as: 1) cysts with one or more enhancing thickened septa/wall (≥4 mm width); and/or 2) cysts with one or more irregular wall or septa (displaying ≤3 mm obtusely margined convex protrusion -perpendicular axis). 25,65,66 The clinical impact of these modifications remains to be properly evaluated. According to a report for Tse et al, the prevalence of malignancy for v2019 Bosniak III cysts was 60%. 67 The prevalence varied according to subclasses. For examples, thick wall/septa Bosniak III cysts had a malignancy rate of 49%, while the rate was 76% for Bosniak III cysts displaying nodule(s) with obtuse margin of protrusion.
# Bosniak category iV
According to the original classification, category IV cysts may have similar characteristics to those classified as category III. They usually demonstrate wall thickening and/or gross and nodular thickened septa, but a solid contrast-enhancing component is also observed adjacent to the cyst wall or septa. 6,20,34, The v2019 classification has only made small modifications to this category, as it defines Bosniak IV cysts as cysts with a nodular component of any size if the margins of protrusion are acute, or a nodular component ≥4 mm if the margins of protrusion are obtuse (perpendicular axis).
Lesions in this category should be considered malignant until proven otherwise, with a mean malignancy rate of 89% (Table 2). 6,34,71 Here again, the clinical impact of the v2019 classification remains to be properly studied, but Tse et al have reported a slightly higher rate of malignancy among cysts categorized as a IV due to a nodule with acute margins of protrusion compared to Bosniak IV cysts displaying nodule with obtuse ones (87 vs. 76%). 67
# Intervention and followup
█ RECOMMENDATON 4 For patients with a Bosniak I or II cyst, followup imaging is not recommended (Strong recommendation, moderate certainty in evidence of effects).
# █ RECOMMENDATON 5
For patients with a Bosniak I or II cyst, intervention is only warranted if the cyst becomes symptomatic (Clinical principle).
# Bosniak category i
This category is composed of simple cysts that are considered benign. One should remember that the natural history of these cysts is that the majority will grow over time and thus, growth should not necessarily be considered a sign of malignancy. 72,73 Transformation into a more complex cyst is rare and has been reported in only a handful of cases. Therefore, as this is a rare occurrence, followup imaging is not recommended and intervention is only warranted if the cyst becomes symptomatic (i.e., bleeding, recurrent infection, or pain). Treatment options include percutaneous management (aspiration ± sclerotherapy) or surgery. 78 Percutaneous cyst decompression may also be considered prior to offering definitive treatment as a means to confirm that the source of symptoms are cyst-related.
# Bosniak category ii
These minimally complex cysts are also generally considered benign, but there are reports in the literature of category II lesions being malignant (Table 2); 4,18,19,21,47,49,50,55,56,58,59,71,79) however, the literature is thought to overestimate the true risk of malignancy among category II cysts, as the majority were managed conservatively or had features that made them too complex to be categorized as a Bosniak II cyst. 7,19,42,45,47,48,51,54,79 Importantly, even if malignant, most behave in a relatively benign fashion. Thus, for patients diagnosed with a properly classified Bosniak II cyst, followup is not suggested. Similar to Bosniak I cysts, intervention is only warranted if the cyst becomes symptomatic. When there is doubt as to their categorization based on imaging characteristics, these lesions should be considered as being Bosniak category IIF lesions and followed accordingly.
# Bosniak category iiF █ RECOMMENDATON 6
For patients with a Bosniak IIF cyst, a followup every 6-12 months is suggested for the first year, and then yearly if the cyst is stable (Expert opinion).
# █ RECOMMENDATON 7
For patients with a Bosniak IIF cyst that do not demonstrate progression on imaging, a followup of five years is suggested (Conditional recommendation, very low certainty in evidence of effects).
The risk of malignancy among these cysts is low (Table 2) but not trivial, and as the "F" in category IIF stipulates, a followup of these cysts is suggested. Although the traditional belief was that approximately 15% of category IIF cysts will progress in complexity over time (to Bosniak category III or IV), more recent reports have suggested that the rate was closer to 5%. 8,20,32,33,52 Progression is more likely to occur within the first two years and rarely occurs after three years. 36,52,80 Unfortunately, a clear progression pattern is yet to be identified and as a result, there is no evidence-based time limit for followup imaging.
Bosniak IIF cysts have a low malignancy rate and if malignant, a low metastatic potential. Thus, it seems reasonable to follow these lesions with imaging every 6-12 months for the first year, and then yearly thereafter if the cyst is stable. Closer monitoring may be performed but may potentially reduce the detection of a progression if the changes in the cysts from imaging to imaging are very small. CEUS may also be used to better delineate the septa number, septa and/or wall thickness, solid component, and the enhancement. Ultrasound in combination with contrast-enhanced CT or MRI may be used if the lesion is stable on followup. A followup of five years is suggested for cysts that do not demonstrate progression on imaging.
# Bosniak categories iii and iV
█ RECOMMENDATON 8 For patients with a Bosniak III or IV complex renal cyst measuring ≤2 cm in size, active surveillance is suggested as the preferred strategy (Conditional recommendation, low certainty in evidence of effects).
# █ RECOMMENDATON 9
For patients with a Bosniak III or IV complex renal cyst measuring 2-4 cm in diameter, active surveillance or surgery are suggested as the preferred management options (Conditional recommendation, very low certainty in evidence of effects).
# █ RECOMMENDATON 10
For patients with a Bosniak III or IV cyst measuring >4 cm, surgical excision is suggested as the preferred strategy (Conditional recommendation, low certainty in evidence of effects).
# █ RECOMMENDATON 11
For patients with a Bosniak III or IV complex renal cyst and significant comorbidities and/or limited life expectancy, observation (or watchful waiting) is suggested as the preferred strategy (Conditional recommendation, low certainty in evidence of effects).
# █ RECOMMENDATON 12
For patients with a Bosniak III or IV cyst undergoing surgery, partial nephrectomy is suggested over radical nephrectomy when technically and oncologically feasible, especially for small complex cysts (Conditional recommendation, moderate certainty in evidence of effects).
█ RECOMMENDATON 13 Patients with a Bosniak III or IV cyst under active surveillance should be offered definitive treatment when the oncological risk increases or when the patient wishes to undergo treatment for personal reasons. Patients should be transitioned to watchful waiting when the competing risks outweigh the benefits of treatment (Clinical principle).
Studies of resected Bosniak III and IV lesions have found that 50-60% and 80-90% of these cysts, respectively, are malignant (Table 2). The vast majority of malignant cystic renal masses are multilocular cystic renal cell carcinomas (mcRCC) 81 but all RCC subtypes may present in a predominantly cystic form. 83 There is increasing evidence that cystic RCCs have relatively low metastatic potential and carry an excellent prognosis. To reflect this indolent behavior, the International Society of Urological Pathology (ISUP) has modified its terminology and now recommends calling these lesions multilocular cystic renal neoplasm with low malignant potential. 81 Although the traditional treatment dogma was to surgically excise all Bosniak III and IV cysts, recent direct and indirect evidence suggest that this may lead to significant overtreatment. Firstly, they have a relatively high rate of benign histology. Secondly, several studies have compared the prognosis of mcRCCs to that of solid RCCs. mcRCCs have consistently fared better than their counterparts on both cancer-specific and overall survival. 40,85,86, One potential explanation for this better prognosis is that the majority of mcRCCs tumor volume is fluid and thus, the actual tumor burden is much lower when compared to similar-sized solid tumors. 86 As the outcomes of these tumors do not seem to be influenced by the overall lesion size, some experts have even suggested abandoning the current pathological T staging for mcRCC and to reassign them a new stage called pT1c (c for cystic). 86 Given the relatively high rate of benign histology and relatively indolent nature even if malignant, there is emerging evidence suggesting that these Bosniak III and IV cysts, like small renal masses, can be safely managed by active surveillance. 7,19,20,45,47,48,51,54,57,65,79,86 A small number of retrospective studies has supported this claim and one prospective Canadian study on the topic is currently ongoing (NCT04558593). 67, Given their low risk of kidney cancer-related mortality, observation (or watchful waiting) is suggested as the preferred strategy for patients with significant comorbidities and/or limited life expectancy, regardless of the cyst size. Extrapolating mainly from the small renal mass literature and similar to the recommendations from CUA guideline on the management of small renal mass, 99 active surveillance is suggested as the preferred management strategy for patients with a Bosniak III or IV cyst measuring ≤2 cm. Immediate definitive treatment (i.e., surgery or thermal ablationits role is further discussed below) remains an option and should be discussed with patients to ensure they are fully informed.
Given the absence of clear evidence, the panel was unable to achieve a consensus as to the preferred strategy for patients with a Bosniak III or IV cyst measuring 2-4 cm. Consequently, active surveillance or surgery are suggested as the preferred management options. Ideal candidates for active surveillance were felt to be: well-informed patients, patients at lower risk for malignancy (e.g., Bosniak III cyst with no wall/septa irregularity, Bosniak III or IV cysts with small nodular component), or patients at high surgical risk due to comorbidities or limited life expectancy. Thermal ablation therapies also remain an option in well-informed patients (further discussed below).
For patients with a Bosniak III or IV cyst measuring >4 cm, surgical excision is suggested as the preferred strategy. Partial nephrectomy is suggested as the surgery of choice when technically and oncologically feasible, although radical nephrectomy should still be discussed as an option. 99 Given the low metastatic potential of RCC, the panel members believe that close surgical margins can be safely performed with low risk of tumor recurrence. Although, surgical excision is the preferred strategy for these patients, active surveillance may still be considered in select cases, notably for Bosniak III patients with no wall/septa irregularity or for patients at high surgical risk due to comorbidities.
Patients managed with active surveillance should be made aware of the higher uncertainty surrounding the data and of the lack of clear intervention criteria specific to this population. In the absence of specific criteria, it is the panel members' opinion that the same criteria as the ones used to define progression in the small renal mass population should be applied (i.e., growth of tumor to >4 cm, consecutive growth rate >0.5 cm/ year, progression to metastases, and patient's choice). 99 Patients under active surveillance should be transitioned to watchful waiting when the competing risks outweigh the benefits of treatment. Likewise, there is currently no evidence to dictate any specific followup scheme. As such, it is the panel members' opinion that the same followup scheme as the one proposed for the small renal mass population should be observed (i.e., abdominal imaging every 3-6 months for the first year, and then once every 6-12 months, if the cyst remains stable). 99 Thermal ablation therapies █ RECOMMENDATON 14 Patients diagnosed with a ≤3 cm Bosniak III or IV cyst considering treatment with thermal ablation should be informed of the higher uncertainty surrounding the data on the efficacy and harms of percutaneous thermal ablation treatment compared to surgery (Expert opinion).
Extrapolating mainly from the small renal mass literature, thermal ablation therapies may be considered an alternative in select cases. 99 There is also some evidence from small case series supporting radiofrequency ablation (RFA) as a treatment alternative for this population. 23, Overall, given the limited data, RFA should be reserved to patients with small (generally ≤3 cm) Bosniak category III and IV cysts who are poor operative candidates and in whom active surveillance is not being considered. To the best of our knowledge, the role of cryotherapy in the management of Bosniak III or IV cysts is not well-defined, with only a handful of cases reported to have been treated by the approach in the literature. 52 Patients opting for the treatment alternative should be made aware of the sparse literature on the management of cystic renal lesions using these approaches.
# Role of renal tumor biopsy in the management of cystic lesions █ RECOMMENDATON 15
Patients diagnosed with a Bosniak IV cyst may be considered for biopsy if there is a significant solid component amenable to biopsy and if the result may alter management. Renal masses without a solid component should not be biopsied due to low diagnostic yield (Adopted from Kidney Cancer Research Network of Canada consensus statement on the role of renal mass biopsy in the management of kidney cancer; expert opinion).
There is now substantial evidence supporting the role of renal tumor biopsy (RTB) for the pretreatment identification of the histology of solid renal masses. 104,105 RTB is safe, accurate, and reliable. Additionally, needle core biopsy has been shown to decrease overtreat-ment rates when used in the management of solid small renal masses; 105,106 however, its role in the management of cystic renal masses is not clearly defined.
There is evidence that RTBs are significantly less informative for the diagnosis of cystic lesions than for solid ones. 104, Therefore, the utility of RTB in cystic lesions is less than that observed with solid renal masses. Nevertheless, there is literature supporting the role of RTB for histological identification of complex cysts. 44,100,101,107 It is generally felt that RTB is not diagnostic for most Bosniak III cysts, as there is minimal targetable solid component and therefore should be avoided. For Bosniak IV cysts, a biopsy of the solid component may be considered to confirm the presence of a malignant tumor and to help with decision-making if the result has the potential to alter management or if a treatment by thermal ablation is planned. 6,44,100,101,107,108 Of interest, some reports have suggested that the combination of fine needle aspiration (FNA) and core biopsy may lead to a slightly higher diagnostic yield than core biopsy alone. 110 Nevertheless, in most centers of experience, RTB are performed using core biopsy alone, as the combination is thought to add minimal value. Experts have also reported a higher diagnostic rate in Bosniak IV cyst when the solid component was >1 cm. 108
# CONCLUSIONS
The evidence for optimal management of cystic RCC, including followup, is of low quality and based on case series and indirectly from the management of solid small renal masses. Nevertheless, this guideline provides some guidance to urologists on how to best manage and follow these cystic lesions.
In summary, Bosniak category I and II cysts do not routinely require followup, whereas Bosniak category IIF cysts should be followed with routine imaging. Extrapolating from the small renal mass literature, active surveillance is now suggested as the management of choice for patients with a Bosniak category III or IV cyst measuring ≤2 cm. For patients with a Bosniak III or IV complex renal cyst measuring 2-4 cm in diameter, active surveillance or surgery are both suggested as the preferred management options. For patients with a Bosniak category III or IV cyst measuring >4 cm, surgical excision remains the mainstay treatment. Patients opting for non-surgical strategies should be aware of higher uncertainty surrounding the data supporting their treatment of choice.
The panel members recognize that there is a dire need for further studies that will offer guidance to physicians as to the optimal selection criteria for active surveillance and to define what criteria should be used as indications for intervention for patients who selected active surveillance as their initial management strategy.
COMPETING INTERESTS: Dr. Richard has been an advisory board member for Bayer, Janssen, and Sanofi; and a speakers' bureau member for Abbvie, Amgen, Astellas, Ferring, and Janssen. Dr. Bhindi has been an advisory board member for Bayer and Janssen; and has received speaker honoraria from Merck. Dr. Breau has been an advisory board member for Ferring (bladder cancer). Dr. Jewett has been an advisory board member for and received payment from Sesen Bio and Theralase Technologies Ltd. Dr. Kapoor held consultant or advisory roles with Amgen, Bristol-Myers Squibb, Eisai, Ipsen, Janssen Oncology, Merck, Novartis, and Pfizer; and received institutional research funding from Bristol-Myers Squibb. Dr. Pouliot has been an advisory board member for and received payment or grants from Amgen, Astellas, Astra Zeneca, Bayer, Janssen, Merck, Novartis, TerSera, and Tolmar; holds investments in Allogene Therapeutics; and has participated in clinical trials supported by CUOG and Kidney Cancer Canada. Dr. Leveridge has participated in advisory board meetings for Bayer and Pfizer; and has received honoraria from Bayer, Janssen, and Pfizer. Dr. So has been an advisory board member for Abbvie, Amgen, Bayer, Ferring, Janssen, Merck, and TerSera. Dr. Rendon has been an advisory board and speakers' bureau member for and has received honoraria from Abbvie, Amgen, Astellas, Astra Zeneca, Bayer, Ferring, Jansen, Pfizer, Roche, Sanofi, and Tolmar; has received honoraria/grants from Abbvie, Astellas, Bayer, Ferring, Janssen, Sanofi, TerSera, and Tolmar; holds investments in Myovant; and has participated in clinical trials supported by Abbvie, Astellas, Bavarian Nordic, Bayer, Ferring, Janssen, Myovant, and Sanofi. Dr. Tanguay has received honoraria from Pfizer, Roche Canada, and Sanofi; and has held consulting or advisory roles with BMS, Merck, Pfizer, Roche Canada, and Sanofi. The remaining authors do not report any competing personal or financial interests related to this work.
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# CUA GUIDELINE
Prior to original Publication (March 2017), this guideline underwent review by the cua guidelines coMMittee, cua MeMbers at large, and the cua executive board. the 2023 uPdates were aPProved by the cua guidelines coMMittee and cua executive board.
# SUMMARY OF CHANGES
The current guideline summarizes the state-of-the-art knowledge on the management of cystic renal lesions by updating the 2017 Canadian Urological Association (CUA) guideline on the topic. To do so, we updated our search strategy on June 18, 2022, and have identified 38 relevant articles, which led to a revision of the content of the original publication.
The panel formulated several recommendations using the GRADE evidence to decision framework -a methodological improvement compared to the previous iteration.
Three key recommendation changes were made compared to the previous iteration:
1. Patients with a renal cyst should be classified as per the v2019 Bosniak classification.
2. For Bosniak III or IV cyst measuring ≤2 cm, active surveillance is now suggested as the preferred strategy. 3. For Bosniak III or IV cyst measuring 2-4 cm, active surveillance or surgery are suggested as equal options. The panel made these changes in an attempt to decrease the burden of care for patients, but also acknowledges the low-quality evidence supporting these changes. Consequently, we emphasize the need for shared decision-making. Patients opting for nonsurgical strategies should be made aware of the higher uncertainty surrounding the data supporting their treatment of choice.
# INTRODUCTION
Cystic renal lesions are usually diagnosed incidentally on routine imaging. With the increasing use of abdominal imaging, there is a growing number of individuals being diagnosed with renal cystic disease. 1 It is estimated that up to one-third of individuals over 60 years of age will be diagnosed with at least one simple renal cyst following abdominal imaging. 2 Therefore, patients are often referred to urologists for guidance and management of these lesions. Physicians need to distinguish cystic lesions from solid renal masses with necrotic components, which behave more aggressively. 3 Hence, the characterization of these cystic renal masses is crucial to determine the best clinical approach. We reviewed the literature and updated the previous iteration of the CUA guideline with the aim of offering guidance to physicians managing cystic renal lesions and to standardize their management across Canada. 4
# METHODS
A comprehensive search of the literature was carried out on June 30, 2016, in MEDLINE and PubMed, which identified 77 relevant studies to inform the development of the 2017 CUA guideline on the management SUMMARY OF RECOMMENDATIONS 1. For patients first identified with a complex cyst on ultrasound, contrast-enhanced crosssectional imaging is recommended to better characterize the cyst (Strong recommendation, moderate certainty in evidence of effects).
2. Patients identified with a renal cyst should be classified according to the v2019 Bosniak classification (Expert opinion).
3. For patients where disagreement or doubt exists regarding the classification of a complex renal cyst, it is the panel's opinion that such cases should be presented at a multidisciplinary meeting if it has the potential to alter management (Expert opinion). of cystic renal masses (Supplementary Figure 1; available at cuaj.ca). An updated search of the literature was completed on June 18, 2022, using the same search terms, and identified an additional 38 relevant articles, which led to a revision of the content of the original publication (Supplementary Figure 2; available at cuaj. ca). 4 The search terms used were: Bosniak, Bosniak classification, renal cysts, renal cell carcinomas, renal and kidney cancers. Prospective or retrospective studies, as well as review studies providing data on the classification, management, and outcomes of complex cystic renal masses were included. Reports limited to children or animal and basic science studies were excluded. Similarly, reports limited to congenital or acquired renal cystic diseases and case reports of five or fewer cases were also excluded.
For each recommendation, the panel considered, when available, the 11 domains of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence-to-decision framework: 1) problem; 2) desirable effects; 3) undesirable effects; 4) certainty of evidence; 5) values; 6) balance of effects; 7) resource required; 8) certainty of evidence of required resources; 9) cost-effectiveness; 10) equity; and 11) acceptability. The strength of each recommendation was rated as strong or conditional (weak).
Strong recommendations were made when the desirable benefits of treatment outweighed the undesirable consequences (harms) and are worded as recommends. Conditional recommendations were made when the benefits of treatment probably outweighed the harms and are worded as suggests. When insufficient evidence was available for a recommendation, the panel reported additional information as clinical principle or as expert opinion. Importantly, all recommendations are based on expert review of the literature and represent the consensus of all co-authors of this guideline.
The objectives of this guideline were to perform a comprehensive review of the literature and to make recommendations on the characterization, management, and followup of incidentally discovered cystic lesions. The panel proceeded with full awareness of the limitations of the cystic renal lesions literature. The low-quality evidence made it difficult to make strong recommendations for the optimal treatment and followup of cystic renal lesions. Furthermore, as the majority of Bosniak category II and IIF cystic lesions are managed conservatively, the literature tends to overestimate the true malignancy risk of these lesions, as only the most complex ones undergo surgery. Nevertheless, while taking these limitations into account, the panel did its best to summarize the current literature and provide some guidance on the management of cystic lesions.
# EVIDENCE SYNTHESIS
# Bosniak classification -Introduction
█ RECOMMENDATION 1 For patients first identified with a complex cyst on ultrasound, contrast-enhanced, cross-sectional imaging is recommended to better characterize the cyst (Strong recommendation, moderate certainty in evidence of effects).
█ RECOMMENDATION 2 Patients identified with a renal cyst should be classified according to the v2019 Bosniak classification (Expert opinion).
█ RECOMMENDATION 3 For patients where disagreement or doubt exists regarding the classification of a complex renal cyst, it is the panel's opinion that such cases should be presented at a multidisciplinary meeting if it has the potential to alter management (Expert opinion).
Renal cysts can be easily identified using standard medical imaging and, in most cases, a histological diagnosis is not required; however, lesions that are more complex may require more detailed characterization to inform the differential diagnoses and guide subsequent management. It is especially important for physicians managing the more complex cystic lesions to differentiate them from solid renal masses with necrotic components, which behave more aggressively. 3 The Bosniak renal cyst classification was initially described in 1986 5 and was later updated to add a new category called category IIF. 6 It was originally described using computed tomography (CT) imaging but other modalities, such as magnetic resonance imaging (MRI), ultrasound (US), or contrast-enhancement ultrasound (CEUS), are now being used to help better delineate these lesions. [7][8][9][10][11][12][13][14][15][16][17] For patients first identified with a complex cyst (Bosniak classification >2) on US, contrastenhanced, cross-sectional imaging is recommended to better characterize the cyst.
Although the Bosniak classification remains the most commonly used classification to characterize renal cysts, it has traditionally been subject to poor interobserver agreement. 4,6,10,[18][19][20][21][22][23] Most of the observed variation was seen among cysts categorized as Bosniak II, IIF, and III. In an attempt to diminish the shortcomings of the traditional Bosniak classification, namely the inter-reader variability, Silverman et al have proposed a revision of the classification (Bosniak v2019 classification). 24,25 A detailed description and rationale for the proposed revision may be found in the original publication. 25 Although its clinical impact and benefit of the inter-rater variability remain to be well-studied, the panel members believe that the v2019 classification is currently the preferred Bosniak classification. [26][27][28][29][30] Importantly, if there is disagreement or doubt regarding the classification of a complex renal cyst, it is the panel's opinion that such cases should be presented at a multidisciplinary meeting if this has the potential to alter management.
# Description of Bosniak classification
By means of the Bosniak classification, renal cystic lesions can be categorized in increasing order according to risk of malignancy. Table 1 details the traditional Bosniak classification and the proposed update (v2019).
# Bosniak category i
Lesions classified as category I are simple renal cysts and represent the majority of renal lesions detected by abdominal imaging. 2 These lesions are characterized by their regular contour and a clear interface with the renal parenchyma. They do not contain any septa or calcifications, nor do they demonstrate enhancement following intravenous contrast agent injection. They are homogeneous, with fluid attenuation varying from 0-20 HU on CT scan. These lesions are also easily identifiable by US and appear as thin-walled, anechoic lesions with posterior enhancement and sharply marginated smooth walls. 6,9 The v2019 classification has slightly refined the criteria for this category by limiting the thickness of the cyst wall to ≤2 mm and enhancement of the cyst wall may be observed. 25 Bosniak category ii These cysts are slightly more complex than category I cysts. 6 The v2019 Bosniak classification has described six different types of Bosniak II cysts on CT scans, while three are described on MRIs. 31 The v2019 classification describes category II cysts as thin wall cysts (≤2 mm) that may contain thin (≤2 mm) and few septa (≤3) that may or may not enhance and/or calcifications of any type. Other types of Bosniak II cysts are detailed in Table 1. Importantly, homogeneous, non-enhancing, hyperdense cysts (≥20 HU), regardless of size, are also categorized as Bosniak II cysts based on the v2019 classification. The traditional Bosniak classification categorized these cysts as Bosniak IIF if >3 cm.
Regardless of the Bosniak classification version being used, the overwhelming majority of Bosniak category II cysts are considered benign. Although review of the literature has demonstrated that approximately 10% of the operated category II cysts are malignant, this is an overestimation of the true malignancy risk, as a significant proportion of these studies were published before the addition of the Bosniak IIF category and many of these cysts were managed conservatively without pathological confirmation (Table 2). If we exclude the earlier studies and believe that most of the conservatively managed cysts were benign, the risk of malignancy for these lesions would be <5%. This rate is still believed to be a gross overestimation of the true risk, as most of the malignant category II lesions had features that made them too complex to be considered a true category II cyst.
# Bosniak category iiF
This category represents moderately complex cystic lesions. Any lesions not fulfilling the criteria for category II but not as complex as category III should be classified in this category. These cysts were traditionally described as cysts containing an increased number of thin septa or slightly thickened but smooth septa. They may also contain thick or nodular calcification but without contrast-enhancing features. Large, hyperdense cysts (≥3 cm and >20 HU) were also traditionally classified as Bosniak IIF cysts, but this is no longer the case with the v2019 classification. [32][33][34] In an attempt to diminish inter-reader variability, the v2019 classification has further defined what was meant by an increased number of septa or a slightly thickened septum. Thus, v.2019 Bosniak IIF cysts are described as: 1) cysts with smooth minimally thickened (3 mm) enhancing wall; 2) cysts with ≥1 thickened enhancing septa (3 mm); or 3) cysts with many (≥4) smooth, thin (≤2 mm), enhancing septa.
The review of the literature revealed that approximately 28% of surgically treated Bosniak IIF lesions were malignant; however, as previously reported, this is likely an overestimation of the true malignancy risk. 4 If all conservatively managed Bosniak IIF cysts were benign, the risk of malignancy would approach 7% (Table 2). Similar findings were reported by two separately conducted systematic reviews. 22,35 Consequently, although helpful, the addition of the Bosniak IIF category did result in a substantial number of patients being followed for a benign cyst. Interestingly, Couture et al have examined the impact of the v2019 classification on cysts classified as IIF based on the traditional classification. 36 The authors found that 76% (138/181) of Bosniak IIF cysts would have initially been diagnosed as Bosniak II according to the revised classification. The v2019 classification misidentified one cyst that eventually progressed to Bosniak IV, but the authors reported that the patient was managed by active surveillance with no signs of metastases >6 years after progressing to Bosniak IV. Thus, the authors concluded that the v2019 revision may help minimize the overdiagnosis and followup of such cysts, avoiding important costs and harm to patients. 37,38 Bosniak category iii This category encompasses a variety of cystic lesions whose differentiation between malignant and benign cannot be reliably made by imaging. 6 According to the traditional Bosniak classification, these cysts present with wall irregularity and thickening, as well as wall nodularity. They may also demonstrate contrast-enhanced septa (usually multiple) that are usually irregular, thickened, and/or calcified. A significant proportion of these cysts are thought to be malignant (mean of 58%) (Table 2) 4,7,18-21,32-34,39-63 with larger lesions or cysts containing septal nodule being more likely to be malignant than smaller ones 4,22,64 or than septated cysts without nodularity. 64 In an attempt to decrease the number of benign cysts classified as a Bosniak III, the v2019 has attempted to better define the characteristics of this category and has removed the requirement that all cystic masses with 'measurable enhancement' be included as either a Bosniak III or IV. 25 Consequently, the v2019 classification now defines Bosniak III cysts as: 1) cysts with one or more enhancing thickened septa/wall (≥4 mm width); and/or 2) cysts with one or more irregular wall or septa (displaying ≤3 mm obtusely margined convex protrusion -perpendicular axis). 25,65,66 The clinical impact of these modifications remains to be properly evaluated. According to a report for Tse et al, the prevalence of malignancy for v2019 Bosniak III cysts was 60%. 67 The prevalence varied according to subclasses. For examples, thick wall/septa Bosniak III cysts had a malignancy rate of 49%, while the rate was 76% for Bosniak III cysts displaying nodule(s) with obtuse margin of protrusion.
# Bosniak category iV
According to the original classification, category IV cysts may have similar characteristics to those classified as category III. They usually demonstrate wall thickening and/or gross and nodular thickened septa, but a solid contrast-enhancing component is also observed adjacent to the cyst wall or septa. 6,20,34,[68][69][70] The v2019 classification has only made small modifications to this category, as it defines Bosniak IV cysts as cysts with a nodular component of any size if the margins of protrusion are acute, or a nodular component ≥4 mm if the margins of protrusion are obtuse (perpendicular axis).
Lesions in this category should be considered malignant until proven otherwise, with a mean malignancy rate of 89% (Table 2). 6,34,71 Here again, the clinical impact of the v2019 classification remains to be properly studied, but Tse et al have reported a slightly higher rate of malignancy among cysts categorized as a IV due to a nodule with acute margins of protrusion compared to Bosniak IV cysts displaying nodule with obtuse ones (87 vs. 76%). 67
# Intervention and followup
█ RECOMMENDATON 4 For patients with a Bosniak I or II cyst, followup imaging is not recommended (Strong recommendation, moderate certainty in evidence of effects).
# █ RECOMMENDATON 5
For patients with a Bosniak I or II cyst, intervention is only warranted if the cyst becomes symptomatic (Clinical principle).
# Bosniak category i
This category is composed of simple cysts that are considered benign. One should remember that the natural history of these cysts is that the majority will grow over time and thus, growth should not necessarily be considered a sign of malignancy. 72,73 Transformation into a more complex cyst is rare and has been reported in only a handful of cases. [72][73][74][75][76][77] Therefore, as this is a rare occurrence, followup imaging is not recommended and intervention is only warranted if the cyst becomes symptomatic (i.e., bleeding, recurrent infection, or pain). Treatment options include percutaneous management (aspiration ± sclerotherapy) or surgery. 78 Percutaneous cyst decompression may also be considered prior to offering definitive treatment as a means to confirm that the source of symptoms are cyst-related.
# Bosniak category ii
These minimally complex cysts are also generally considered benign, but there are reports in the literature of category II lesions being malignant (Table 2); 4,18,19,21,[39][40][41][42][43]47,49,50,55,56,58,59,71,79) however, the literature is thought to overestimate the true risk of malignancy among category II cysts, as the majority were managed conservatively or had features that made them too complex to be categorized as a Bosniak II cyst. 7,19,42,45,47,48,51,54,79 Importantly, even if malignant, most behave in a relatively benign fashion. Thus, for patients diagnosed with a properly classified Bosniak II cyst, followup is not suggested. Similar to Bosniak I cysts, intervention is only warranted if the cyst becomes symptomatic. When there is doubt as to their categorization based on imaging characteristics, these lesions should be considered as being Bosniak category IIF lesions and followed accordingly.
# Bosniak category iiF █ RECOMMENDATON 6
For patients with a Bosniak IIF cyst, a followup every 6-12 months is suggested for the first year, and then yearly if the cyst is stable (Expert opinion).
# █ RECOMMENDATON 7
For patients with a Bosniak IIF cyst that do not demonstrate progression on imaging, a followup of five years is suggested (Conditional recommendation, very low certainty in evidence of effects).
The risk of malignancy among these cysts is low (Table 2) but not trivial, and as the "F" in category IIF stipulates, a followup of these cysts is suggested. Although the traditional belief was that approximately 15% of category IIF cysts will progress in complexity over time (to Bosniak category III or IV), more recent reports have suggested that the rate was closer to 5%. 8,20,32,33,52 Progression is more likely to occur within the first two years and rarely occurs after three years. 36,52,80 Unfortunately, a clear progression pattern is yet to be identified and as a result, there is no evidence-based time limit for followup imaging.
Bosniak IIF cysts have a low malignancy rate and if malignant, a low metastatic potential. Thus, it seems reasonable to follow these lesions with imaging every 6-12 months for the first year, and then yearly thereafter if the cyst is stable. Closer monitoring may be performed but may potentially reduce the detection of a progression if the changes in the cysts from imaging to imaging are very small. CEUS may also be used to better delineate the septa number, septa and/or wall thickness, solid component, and the enhancement. [7][8][9][10][11][12][13][14][15][16][17] Ultrasound in combination with contrast-enhanced CT or MRI may be used if the lesion is stable on followup. A followup of five years is suggested for cysts that do not demonstrate progression on imaging.
# Bosniak categories iii and iV
█ RECOMMENDATON 8 For patients with a Bosniak III or IV complex renal cyst measuring ≤2 cm in size, active surveillance is suggested as the preferred strategy (Conditional recommendation, low certainty in evidence of effects).
# █ RECOMMENDATON 9
For patients with a Bosniak III or IV complex renal cyst measuring 2-4 cm in diameter, active surveillance or surgery are suggested as the preferred management options (Conditional recommendation, very low certainty in evidence of effects).
# █ RECOMMENDATON 10
For patients with a Bosniak III or IV cyst measuring >4 cm, surgical excision is suggested as the preferred strategy (Conditional recommendation, low certainty in evidence of effects).
# █ RECOMMENDATON 11
For patients with a Bosniak III or IV complex renal cyst and significant comorbidities and/or limited life expectancy, observation (or watchful waiting) is suggested as the preferred strategy (Conditional recommendation, low certainty in evidence of effects).
# █ RECOMMENDATON 12
For patients with a Bosniak III or IV cyst undergoing surgery, partial nephrectomy is suggested over radical nephrectomy when technically and oncologically feasible, especially for small complex cysts (Conditional recommendation, moderate certainty in evidence of effects).
█ RECOMMENDATON 13 Patients with a Bosniak III or IV cyst under active surveillance should be offered definitive treatment when the oncological risk increases or when the patient wishes to undergo treatment for personal reasons. Patients should be transitioned to watchful waiting when the competing risks outweigh the benefits of treatment (Clinical principle).
Studies of resected Bosniak III and IV lesions have found that 50-60% and 80-90% of these cysts, respectively, are malignant (Table 2). The vast majority of malignant cystic renal masses are multilocular cystic renal cell carcinomas (mcRCC) 81 but all RCC subtypes may present in a predominantly cystic form. 83 There is increasing evidence that cystic RCCs have relatively low metastatic potential and carry an excellent prognosis. [82][83][84][85][86][87] To reflect this indolent behavior, the International Society of Urological Pathology (ISUP) has modified its terminology and now recommends calling these lesions multilocular cystic renal neoplasm with low malignant potential. 81 Although the traditional treatment dogma was to surgically excise all Bosniak III and IV cysts, recent direct and indirect evidence suggest that this may lead to significant overtreatment. Firstly, they have a relatively high rate of benign histology. Secondly, several studies have compared the prognosis of mcRCCs to that of solid RCCs. mcRCCs have consistently fared better than their counterparts on both cancer-specific and overall survival. 40,85,86,[88][89][90][91][92][93] One potential explanation for this better prognosis is that the majority of mcRCCs tumor volume is fluid and thus, the actual tumor burden is much lower when compared to similar-sized solid tumors. 86 As the outcomes of these tumors do not seem to be influenced by the overall lesion size, some experts have even suggested abandoning the current pathological T staging for mcRCC and to reassign them a new stage called pT1c (c for cystic). 86 Given the relatively high rate of benign histology and relatively indolent nature even if malignant, there is emerging evidence suggesting that these Bosniak III and IV cysts, like small renal masses, can be safely managed by active surveillance. 7,19,20,45,47,48,51,54,57,65,79,86 A small number of retrospective studies has supported this claim and one prospective Canadian study on the topic is currently ongoing (NCT04558593). 67,[94][95][96][97][98] Given their low risk of kidney cancer-related mortality, observation (or watchful waiting) is suggested as the preferred strategy for patients with significant comorbidities and/or limited life expectancy, regardless of the cyst size. Extrapolating mainly from the small renal mass literature and similar to the recommendations from CUA guideline on the management of small renal mass, 99 active surveillance is suggested as the preferred management strategy for patients with a Bosniak III or IV cyst measuring ≤2 cm. Immediate definitive treatment (i.e., surgery or thermal ablationits role is further discussed below) remains an option and should be discussed with patients to ensure they are fully informed.
Given the absence of clear evidence, the panel was unable to achieve a consensus as to the preferred strategy for patients with a Bosniak III or IV cyst measuring 2-4 cm. Consequently, active surveillance or surgery are suggested as the preferred management options. Ideal candidates for active surveillance were felt to be: well-informed patients, patients at lower risk for malignancy (e.g., Bosniak III cyst with no wall/septa irregularity, Bosniak III or IV cysts with small nodular component), or patients at high surgical risk due to comorbidities or limited life expectancy. Thermal ablation therapies also remain an option in well-informed patients (further discussed below).
For patients with a Bosniak III or IV cyst measuring >4 cm, surgical excision is suggested as the preferred strategy. Partial nephrectomy is suggested as the surgery of choice when technically and oncologically feasible, although radical nephrectomy should still be discussed as an option. 99 Given the low metastatic potential of RCC, the panel members believe that close surgical margins can be safely performed with low risk of tumor recurrence. Although, surgical excision is the preferred strategy for these patients, active surveillance may still be considered in select cases, notably for Bosniak III patients with no wall/septa irregularity or for patients at high surgical risk due to comorbidities.
Patients managed with active surveillance should be made aware of the higher uncertainty surrounding the data and of the lack of clear intervention criteria specific to this population. In the absence of specific criteria, it is the panel members' opinion that the same criteria as the ones used to define progression in the small renal mass population should be applied (i.e., growth of tumor to >4 cm, consecutive growth rate >0.5 cm/ year, progression to metastases, and patient's choice). 99 Patients under active surveillance should be transitioned to watchful waiting when the competing risks outweigh the benefits of treatment. Likewise, there is currently no evidence to dictate any specific followup scheme. As such, it is the panel members' opinion that the same followup scheme as the one proposed for the small renal mass population should be observed (i.e., abdominal imaging every 3-6 months for the first year, and then once every 6-12 months, if the cyst remains stable). 99 Thermal ablation therapies █ RECOMMENDATON 14 Patients diagnosed with a ≤3 cm Bosniak III or IV cyst considering treatment with thermal ablation should be informed of the higher uncertainty surrounding the data on the efficacy and harms of percutaneous thermal ablation treatment compared to surgery (Expert opinion).
Extrapolating mainly from the small renal mass literature, thermal ablation therapies may be considered an alternative in select cases. 99 There is also some evidence from small case series supporting radiofrequency ablation (RFA) as a treatment alternative for this population. 23,[100][101][102][103] Overall, given the limited data, RFA should be reserved to patients with small (generally ≤3 cm) Bosniak category III and IV cysts who are poor operative candidates and in whom active surveillance is not being considered. To the best of our knowledge, the role of cryotherapy in the management of Bosniak III or IV cysts is not well-defined, with only a handful of cases reported to have been treated by the approach in the literature. 52 Patients opting for the treatment alternative should be made aware of the sparse literature on the management of cystic renal lesions using these approaches.
# Role of renal tumor biopsy in the management of cystic lesions █ RECOMMENDATON 15
Patients diagnosed with a Bosniak IV cyst may be considered for biopsy if there is a significant solid component amenable to biopsy and if the result may alter management. Renal masses without a solid component should not be biopsied due to low diagnostic yield (Adopted from Kidney Cancer Research Network of Canada [KCRNC] consensus statement on the role of renal mass biopsy in the management of kidney cancer; expert opinion).
There is now substantial evidence supporting the role of renal tumor biopsy (RTB) for the pretreatment identification of the histology of solid renal masses. 104,105 RTB is safe, accurate, and reliable. Additionally, needle core biopsy has been shown to decrease overtreat-ment rates when used in the management of solid small renal masses; 105,106 however, its role in the management of cystic renal masses is not clearly defined.
There is evidence that RTBs are significantly less informative for the diagnosis of cystic lesions than for solid ones. 104,[106][107][108][109] Therefore, the utility of RTB in cystic lesions is less than that observed with solid renal masses. Nevertheless, there is literature supporting the role of RTB for histological identification of complex cysts. 44,100,101,107 It is generally felt that RTB is not diagnostic for most Bosniak III cysts, as there is minimal targetable solid component and therefore should be avoided. For Bosniak IV cysts, a biopsy of the solid component may be considered to confirm the presence of a malignant tumor and to help with decision-making if the result has the potential to alter management or if a treatment by thermal ablation is planned. 6,44,100,101,107,108 Of interest, some reports have suggested that the combination of fine needle aspiration (FNA) and core biopsy may lead to a slightly higher diagnostic yield than core biopsy alone. 110 Nevertheless, in most centers of experience, RTB are performed using core biopsy alone, as the combination is thought to add minimal value. Experts have also reported a higher diagnostic rate in Bosniak IV cyst when the solid component was >1 cm. 108
# CONCLUSIONS
The evidence for optimal management of cystic RCC, including followup, is of low quality and based on case series and indirectly from the management of solid small renal masses. Nevertheless, this guideline provides some guidance to urologists on how to best manage and follow these cystic lesions.
In summary, Bosniak category I and II cysts do not routinely require followup, whereas Bosniak category IIF cysts should be followed with routine imaging. Extrapolating from the small renal mass literature, active surveillance is now suggested as the management of choice for patients with a Bosniak category III or IV cyst measuring ≤2 cm. For patients with a Bosniak III or IV complex renal cyst measuring 2-4 cm in diameter, active surveillance or surgery are both suggested as the preferred management options. For patients with a Bosniak category III or IV cyst measuring >4 cm, surgical excision remains the mainstay treatment. Patients opting for non-surgical strategies should be aware of higher uncertainty surrounding the data supporting their treatment of choice.
The panel members recognize that there is a dire need for further studies that will offer guidance to physicians as to the optimal selection criteria for active surveillance and to define what criteria should be used as indications for intervention for patients who selected active surveillance as their initial management strategy.
#
COMPETING INTERESTS: Dr. Richard has been an advisory board member for Bayer, Janssen, and Sanofi; and a speakers' bureau member for Abbvie, Amgen, Astellas, Ferring, and Janssen. Dr. Bhindi has been an advisory board member for Bayer and Janssen; and has received speaker honoraria from Merck. Dr. Breau has been an advisory board member for Ferring (bladder cancer). Dr. Jewett has been an advisory board member for and received payment from Sesen Bio and Theralase Technologies Ltd. Dr. Kapoor held consultant or advisory roles with Amgen, Bristol-Myers Squibb, Eisai, Ipsen, Janssen Oncology, Merck, Novartis, and Pfizer; and received institutional research funding from Bristol-Myers Squibb. Dr. Pouliot has been an advisory board member for and received payment or grants from Amgen, Astellas, Astra Zeneca, Bayer, Janssen, Merck, Novartis, TerSera, and Tolmar; holds investments in Allogene Therapeutics; and has participated in clinical trials supported by CUOG and Kidney Cancer Canada. Dr. Leveridge has participated in advisory board meetings for Bayer and Pfizer; and has received honoraria from Bayer, Janssen, and Pfizer. Dr. So has been an advisory board member for Abbvie, Amgen, Bayer, Ferring, Janssen, Merck, and TerSera. Dr. Rendon has been an advisory board and speakers' bureau member for and has received honoraria from Abbvie, Amgen, Astellas, Astra Zeneca, Bayer, Ferring, Jansen, Pfizer, Roche, Sanofi, and Tolmar; has received honoraria/grants from Abbvie, Astellas, Bayer, Ferring, Janssen, Sanofi, TerSera, and Tolmar; holds investments in Myovant; and has participated in clinical trials supported by Abbvie, Astellas, Bavarian Nordic, Bayer, Ferring, Janssen, Myovant, and Sanofi. Dr. Tanguay has received honoraria from Pfizer, Roche Canada, and Sanofi; and has held consulting or advisory roles with BMS, Merck, Pfizer, Roche Canada, and Sanofi. The remaining authors do not report any competing personal or financial interests related to this work.
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Page 3The National Advisory Committee on Blood and Blood Products (NAC) is an interprovincial medical and technical advisory body to the provincial and territorial health ministries and Canadian Blood Services (CBS). The NAC mandate is to: - Provide advice on matters pertaining to blood supply, including those directly affecting the practice of transfusion medicine in hospitals;#
- Share information about blood and blood product utilization and utilization management efforts, and play a supportive role in the development of guidelines and recommendations for product use;
- Identify opportunities to optimize transfusion medicine practices; and
- On a jurisdictional level, provide leadership in the identification, design and implementation of blood utilization management initiatives for the optimization of patient care.
The CBS Provincial Territorial Blood Liaison Committee (CBS PT BLC) requested that NAC develop recommendations and guidelines for the use of irradiated blood components for Canadian patients. NAC assembled an Irradiation Working Group to review current standards, published guidelines, and recent literature on the indications for irradiated components and the quality of irradiated red blood cell (RBC) components to facilitate recommendations for best practices. This group worked collaboratively with representatives of Quebec's National Advisory Committee on Transfusion Medicine (CCNMT) who joined the recommendation development process -thus forming the NAC-CCNMT Irradiation Working Group. Consultation with Canadian experts in transfusion medicine was included as a part of this recommendation development process. In addition, draft recommendations were circulated to a number of clinical stakeholder organizations for feedback prior to finalization.
This work was informed by the published guidelines on the use of irradiated blood components by the British Committee for Standards in Hematology (BCSH, 2010) and the guidelines for prevention of transfusion-associated graft-versus-host disease by the Australian and New Zealand Society of Blood Transfusion (ANZSBT, 2011). Published Transfusion Medicine practice standards including the Canadian Standards Association (CSA) Z902-15 standards (2015), Canadian Society for Transfusion Medicine (CSTM) standards (version 4, 2017), and Council of Europe (COE) standards (version 17, 2013); and recent publications on the quality of stored red cells post irradiation and practices involving irradiation of autologous blood collected by intraoperative cell salvage were consulted.
# Rationale for the Use of Irradiated Blood
Irradiation of cellular blood components is a well-established intervention for the prevention of transfusion-associated graft-versus-host disease (TA-GVHD). There is a system cost of providing irradiated blood components to patients that includes higher production costs, regulatory compliance and supply logistics. Recent publications have also emphasized the negative impact of irradiation on the RBC, and the importance of considering RBC age at the time of irradiation and the length of storage post-irradiation. The Working Group has therefore emphasized the need for conscientious management of hospital inventories to limit the provision of irradiated RBCs to those patients who have specific clinical indications to receive irradiated RBC units. Adherence to this practice would thereby minimize exposure of the general patient population to irradiated RBCs.
Data provided by CBS demonstrates some trends in irradiation practice in Canada over the past ten years. There has been a national increase in the percentage of irradiated RBCs from 4.5% (2004)(2005) to 6.7% (2015)(2016). There is considerable regional variation. The percentage irradiated RBC units issued by CBS ranges from 2-18%, depending on the province. The percentage of irradiated RBC units issued by Héma-Québec, in 2015-2016, was 6.0%.
TA-GVHD is a rare, usually fatal complication of transfusion resulting from the engraftment of transfused, immunocompetent donor lymphocytes and subsequent damage to recipient tissues which are perceived as foreign by the engrafted lymphocytes. Patients at most risk include those who are severely immunocompromised and those who fail to recognize the transfused donor lymphocytes as foreign if human leukocyte antigen (HLA) alleles are haploidentical.
Defining immunocompromised patient groups who should receive irradiated blood has been largely based on observational evidence, case reports, reviews and attempts to predict the degree of immunosuppression. As such, there is a lack of consistency in text books, publications and guidelines as to which patients must receive irradiated blood. Many authors address the lack of clarity by including a category of indications where there is uncertainty regarding the need for irradiated blood.
In view of growing evidence demonstrating the poor quality of post-irradiation stored RBCs, there is a need to be thoughtful about the clinical indications for irradiated blood transfusion and avoid over stocking irradiated RBC units. Without an on-site irradiator, finding a balance of stocking sufficient (but not excess) supply for patient's in-need of irradiated blood may be challenging. Concerns regarding post-irradiation component quality and storage do not apply to platelets or granulocyte concentrates due to the short shelf life of these components.
In addition to irradiation as a TA-GVHD mitigation strategy, recent observational evidence suggests that the pre-storage leukoreduction and length of time since donation may modify recipient TA-GVHD risk. To date, both pre-storage leukoreduction and increased RBC storage time have not been shown to have an equivalent efficacy for eliminating TA-GVHD risk, however.
In a recent systematic review of 348 reported TA-GVHD cases, the authors reported that greater than 94% of cases of TA-GVHD occur when the blood is less than 10 days old, with none of the TA-GVHD cases associated with components older than 14 days from collection (Kopolovic et al, 2015). A review of 290 cases referred to the Japanese Red Cross (JRC) from 1992-1999 identified 66 cases of definite TA-GVHD by microsatellite DNA analysis. The oldest blood transfused in this series was 10 days for whole blood, 11 days for RBCs without an additive solution, and 14 days for RBCs with added mannitol, adenine and phosphate (Uchida et al, 2013). In another report from the JRC, 96% of 51 cases received blood less than 96 hours old (Jawa et al, 2015). Thus, transfusion of blood stored for more than 14 days represents a potential risk mitigation strategy for patients in whom there is uncertainty regarding the degree of immune compromise.
The potential risk mitigation afforded by leukoreduction is supported by data from the Serious Hazards of Transfusion (SHOT) surveillance system in the United Kingdom. A total of 14 cases of TA-GVHD have been reported to SHOT since 1996, which include only 3 cases since the introduction of universal leukoreduction in 1999. Two of these patients were confirmed to have received leukoreduced components. The first case involved a patient with multiple myeloma, reported in 1999. The second case occurred in 2001, and involved a 14-year-old patient with relapsed acute lymphoblastic leukemia. Donors from potentially implicated units were not recalled for HLA typing. The most recent case, reported in 2012, followed an emergency intrauterine transfusion of non-irradiated, non-leukoreduced maternal red cells. The mother was subsequently found have a homozygous HLA haplotype (Bolton-Maggs, 2012). There have been no further TA-GVHD cases reported to SHOT since 2012(Bolton-Maggs, 2016.
Further observational evidence of the risk reduction associated with leukoreduction can be found in the aforementioned systematic review of 348 TA-GVHD cases. Of these, only 23 were in patients who had received leukocyte reduced components, 2 of which were pre-storage, 10 bedside and 11 unspecified (Kopolovic et al, 2015). Together with SHOT surveillance, these findings suggest that leukoreduction reduces, but does not eliminate, the risk of TA-GVHD.
It should be noted that following the 2001 terrorist attacks in New York, a decision was made in the UK to increase blood stocks. As a result, the mean age of blood issued to hospitals after 2002 went from 8 days to 12-14 days and may have also contributed to reducing TA-GVHD risk (Williamson et al, 2007).
# Document Scope and Guide
Upon review of the best-available information, the NAC-CCNMT Irradiation Working Group has compiled this recommendations document to help Canadian clinicians determine which patients should receive irradiated components, and define the age of RBCs at the time of irradiation and the length of storage post-irradiation.
Special annotations following each recommendation have been included to inform the reader of the recommendation reference:
- An asterisk (*), to indicate a verbatim statement from the referenced guideline. o A level of evidence description for the recommendation may be included from the original guideline document, if available. Recommendation statements without a reference are considered best practice statements by NAC and the Working Group, based upon published guidelines or literature.
Recommendations pertaining to the RBC age and the length of storage post-irradiation are consistent with the COE standards (17 th edition) and the newest version of the CSTM standards (version 4, 2017), but are more restrictive than current AABB (29 th ed, 2014) and CSA standards (CSA Z902-15, 2015).
In defining patients who should receive irradiated cellular components, the Working Group supports the majority of published BCSH 2010 and ANZSBT 2011 guidelines. A cautious approach for small volume (top-up) transfusions in very low birth weight neonates is maintained, given that there is variation in expert opinion in the published literature. Recommendations for neonatal transfusion include consideration of the 2016 Canadian neonatal transfusion practice survey results (see Supplement). Unless otherwise specified, recommendations made within this document may be assumed to apply to both adult and pediatric populations.
# GENERAL RECOMMENDATIONS
The NAC-CCNMT Working Group supports the following general recommendations pertaining to the type of blood component that requires irradiation, information sharing and communications of a patient's requirement for irradiated blood components. In addition, the Working Group recommends voluntary alignment with the COE standards (17 th edition) for the age of the units and post-irradiation storage conditions.
- Blood components that should be irradiated A. Recommendation: For at-risk patients, all red cell, platelet and granulocyte concentrates should be irradiated, except cryopreserved red cells after deglycerolization. It is not necessary to irradiate fresh frozen plasma, cryoprecipitate or fractionated plasma products. (BCSH 2010, Grade 1 recommendation; level B evidence)- B. Recommendation: All transfusions from first-or second-degree relatives must be irradiated, even if the patient is immunocompetent.
C. Recommendation: All HLA-selected platelets must be irradiated, even if the patient is immunocompetent.
D. Recommendation: All granulocyte components must be irradiated before issue.
# Age of cellular blood components and post-irradiation storage timelines
Recent evidence has shown that the age of RBCs at the time of irradiation is important and that prolonged storage of pre-irradiated units is associated with high potassium levels, in vitro hemolysis, and decreased post-transfusion recovery (Serrano et al, 2014). This has implications for patient safety as well as hospital inventory management practices.
The current North American standards (AABB, 29 th ed, 2014 and CSA Z902-15, 2015) specify that RBCs shall have a maximum expiration time of 28 days after irradiation or shall retain the original outdate, whichever is shorter, and do not limit the age of RBC at the time of irradiation. The NAC-CCNMT Working Group is recommending voluntary alignment with the COE Standards (17 th edition) to reduce the age of units selected for irradiation and timeline of post-irradiation storage. This more restrictive timeline is endorsed in the newest version of the CSTM Standards (version 4, 2017).
A. Recommendation: Red cell components may be irradiated up to 28 days after collection. Irradiated cells must be transfused as soon as possible, but no later than 14 days after irradiation, and in any case, no later than 28 days after collection. (Council of Europe Standards, 17 th edition, 2013)- B. Recommendation: Platelets can be irradiated at any stage during storage and can thereafter be stored up to their normal shelf life after collection. (BCSH 2010, Grade 1 recommendation; level A evidence)*
# Patient awareness
A. Recommendation: Patients at risk of TA-GVHD should be made aware of their need for irradiated blood components. It is the responsibility of the most responsible health care practitioner to inform patients at risk of TA-GVHD of their need for irradiated blood components.
# Communication
A. Recommendation: To ensure consistency of patient care across jurisdictions, particularly between hospital facilities that participate in the shared care of patients, a communications process between clinicians and the transfusion medicine laboratory facilitating sharing details of special transfusion requirements should be implemented and maintained as a best practice policy. In an ideal setting, an electronic automatic notification identifying pharmaceutical history or indication for irradiated blood to the transfusion medicine laboratory would be in place.
# INVENTORY MANAGEMENT RECOMMENDATIONS
As stated, prolonged storage of pre-irradiated units is associated with high potassium levels, in vitro hemolysis and decreased post-transfusion recovery (Serrano et al, 2014). Maintaining large inventories of irradiated red cells results in potentially harmful transfusion of irradiated red cells to patients who do not require irradiated cellular blood components.
Proactive inventory management must take into consideration the perceived risk of TA-GVHD in the local patient population, the risks of transfusing irradiated red cells to patients who do not require irradiated cellular components and the logistics of providing irradiated components for elective transfusions. Irradiation of RBCs should therefore occur as near-to as possible to the time of transfusion.
# Irradiated blood component availability
A. Recommendation: For elective transfusions reliance on a regional hub site for ondemand irradiation or limited pre-irradiated stock is recommended.
B. Recommendation: Overstocking of pre-irradiated units for emergency transfusion is not recommended. If storage of pre-irradiated inventory is absolutely necessary, then red cells that have been irradiated within 14 days of collection should be obtained, if possible.
As described above, observational evidence from UK SHOT data (Williamson et al, 2007), a recent systematic review of 348 cases of TA-GVHD (Kopolovic et al, 2015) and three reviews of Japanese Red Cross data has provided some evidence for the risk mitigating effect of universal pre-storage leukoreduction and the transfusion of older RBCs with reduced lymphocyte viability (>14 days post donation) (Uchida et al, 2013;Jawa et al, 2015).
C. Recommendation: In the event of emergency transfusion in the absence of on-site irradiation or pre-storage irradiated inventory, pre-storage leukoreduced red cells that have been stored for more than 14 days should be provided to patients with an indication for irradiated blood transfusion.
D. Recommendation: Where there is concern about the immunosuppressive potency of new drugs and uncertainty about the risk of TA-GVHD, in the absence of on-site irradiation or pre-storage irradiated inventory, pre-storage leukoreduced red cells that have been stored for more than 14 days should be provided.
E. Recommendation: Pathogen inactivation or reduction technologies cannot yet be considered an alternative or equivalent to irradiation as TA-GVHD mitigation strategies, though data in this area continues to evolve.
# CLINICAL RECOMMENDATIONS
To arrive at the following clinical recommendations NAC-CCNMT Working Group has drawn primarily upon the BCSH 2010 and ANZSBT 2011 guidelines. In addition, the 2016 survey of current practices at Canadian hospitals with Level 3 neonatal intensive care units informed neonatal transfusion recommendations (see Supplement).
For clinical conditions listed, the patient medication history must be taken into consideration by the most responsible healthcare practitioner requesting blood transfusion, as a treatment received may necessitate irradiated cellular component use. Local practices may be dictated by the ability of hospital transfusion medicine services to obtain the patient's medication history.
Appendix A provides a quick-reference of the clinical indications for transfusion of irradiated blood components, Appendix B lists immunosuppressive medications, and the Supplement summarizes results of the 2016 Canadian National Survey of Irradiation Practices in Neonatal Transfusion.
# Acute leukemia
There is no definitive evidence to support the need for irradiated blood transfusion to patients with a diagnosis of acute leukemia (any type) in adult and pediatric patients, in the absence of identified TA-GVHD risk factors. Chemotherapy regimens for acute leukemia typically do not include pharmacotherapeutic agents known to be risk factors for TA-GVHD development.
However, individual treatment protocols should be reviewed to ensure that there is no indication for irradiated blood transfusion (see Section 15 or Appendix B below).
A. Recommendation: It is not necessary to irradiate red cells or platelets for adults or children with acute leukemia, except for HLA-selected platelets or donations from first-or second-degree relatives.
(BCSH 2010, Grade 1 recommendation; level B evidence)*
# Allogeneic bone marrow or peripheral blood stem cell transplantation
Published clinical practice guidelines are in agreement with the provision of irradiated blood components to allogeneic bone marrow transplant recipients from the time conditioning chemotherapy is initiated. However, there is less certainty as to the definition of when transfusion of irradiated blood components can stop post-transplant. Some experts have suggested that if transplant recipients have completed GVHD prophylaxis immunosuppression and a threshold lymphocyte count of at least 1 x 10 9 /L has been achieved (approximately 6-12 months posttransplant), then the indication for irradiated blood component transfusion may be removed.
Due to the paucity of evidence, the decision to discontinue transfusion of irradiated blood components should remain at the discretion of the transplant physician team.
A. Recommendation: All recipients of allogeneic hematopoietic stem cell transplantation (HSCT) must receive irradiated blood components from the time of initiation of conditioning chemoradiotherapy.
(BCSH 2010, Grade 1 recommendation; level B evidence)- B. Recommendation: Irradiated blood components should be continued while the patient continues to receive graft-versus-host disease (GVHD) prophylaxis. The indication for ongoing transfusion of irradiated blood components should be reviewed at least yearly. If chronic GVHD is present or if continued immunosuppressive treatment is required, irradiated blood components should be given indefinitely.
C. Recommendation: Allogeneic blood transfused to bone marrow and peripheral blood stem cell donors 7 days prior to or during the harvest should also be irradiated.
(BCSH, Grade 2 recommendation; level C evidence)*
# Aplastic anemia
A. Recommendation: We recommend use of irradiated blood components for severe aplastic anemia patients receiving immunosuppressive therapy with ATG and/or alemtuzumab.
B. Recommendation: We cannot make a firm recommendation as to how long irradiated blood components should continue to be used after ATG administration. (BCSH 2010)- C. Recommendation: In the absence of indications necessitating irradiated component transfusion, patients with aplastic anemia do not otherwise require transfusion of irradiated red cells and platelets.
# Autologous bone marrow or peripheral blood hematopoietic stem cell transplantation
A. Recommendation: Patients undergoing bone marrow or peripheral blood stem cell 'harvesting' for future autologous re-infusion should receive irradiated cellular blood components during and for 7 days before the bone marrow/stem cell harvest to prevent the collection of viable allogeneic T lymphocytes, which can potentially withstand cryopreservation.
# Lymphoma
There is overarching consensus in published guidelines based on the literature that the risk of TA-GVHD in Hodgkin lymphoma is greater than in those with non-Hodgkin lymphoma, and appears to be unrelated to disease stage or treatment modality. Although a diagnosis of non-Hodgkin lymphoma is not in itself an absolute indication for transfusion of irradiated blood components, pharmacotherapeutics used in treatment protocols may necessitate transfusion of irradiated components to mitigate TA-GVHD risk (see Section 15 or Appendix B below). However, there is a lack of evidence and therefore controversy surrounding the time-span following which irradiated blood component transfusion is required after patients complete their treatment course with an at-risk medication.
A. Recommendation: All adults and children with Hodgkin lymphoma at any stage of the disease should have irradiated red cells and platelets for life.
(BCSH 2010, Grade 1 recommendation; level B evidence)- B. Recommendation: All patients with non-Hodgkin lymphoma receiving purine analogues and related drugs should receive irradiated cellular blood components from the time of therapy initiation. Due to the paucity of evidence, we cannot make a firm recommendation regarding the time at which irradiated component provision may be discontinued.
# Neonatal Transfusions
A survey was completed to better understand current practices in Canada regarding the use of irradiated blood components specifically for neonatal populations to inform these recommendations. The survey focused on three clinical scenarios: intrauterine transfusions, neonatal top-up (small volume) transfusions, and neonatal exchange. The survey was sent to the medical directors of transfusion medicine in Level 3 neonatal intensive care nurseries (defined according to the Neonatal Classification Tool developed in British Columbia). The Supplement to this recommendations document contains a copy of the survey distributed and collated results.
The NAC-CCNMT Working Group recommendations for neonatal transfusions are as follows:
Intra-Uterine Transfusions (IUT) and Neonatal Exchange Transfusion:
A. Recommendation: All components for IUT must be irradiated. To minimize the effect of potassium load, red cells for IUT must be as fresh as possible, and must be transfused within 24 hours of irradiation.
B. Recommendation: Irradiated cellular components are recommended for neonates who have received an IUT, in which case irradiated components should be administered until 6 months after the expected delivery date (40 weeks gestation).
C. Recommendation: It is essential to irradiate blood for neonatal exchange transfusion if there has been a previous IUT or if the donation comes from a first-or second-degree relative.
(BCSH 2010, Grade 1 recommendation; level B evidence)- D. Recommendation: For other neonatal exchange transfusion cases, irradiation is recommended provided this does not unduly delay transfusion.
(BCSH 2010, Grade 1 recommendation; level C evidence)- E. Recommendation: Red cells for neonatal exchange transfusion should be as fresh as possible, and must be transfused within 24 hours of irradiation.
Neonatal Small-volume (Top-up) Transfusions:
For small volume transfusions in neonates, the NAC-CCNMT Working Group recognizes that there is insufficient data to firmly guide transfusion practice. The BCSH 2010 guidelines do not recommend transfusion of irradiated RBC for small-volume transfusion, while the ANZSBT 2011 guidelines recommend transfusion of irradiated RBC in very low birth weight infants of less than 1300 grams. Many neonatal studies have defined very low birth weight as 1200 to 1300 grams to assess outcomes and interventions, though the World Health Organization defines very low birthweight as less than 1500g. The NAC-CCNMT Working Group leaves the decision of a very low birthweight cut-off to the discretion of local neonatology experts at hospital-based services.
F. Recommendation: Irradiated cellular components are recommended for small-volume transfusions given to neonates born with a very low birthweight, up to 4 months of age.
G. Recommendation: Where the patient is at particular risk of hyperkalemia, it is recommended that red cells be transfused within 24 hours of irradiation. Red cells stored for greater than 24 hours from irradiation must at least undergo centrifugation and supernatant plasma removal prior to transfusion.
The practice of sterile docking and splitting an adult RBC unit for sequential neonatal transfusion evolved during an era of greater risk for transfusion transmitted infection. Limiting donor exposure in neonates continues to be a priority. However, the enhanced safety of the blood system through improved donor screening, nucleic acid testing, and access to public health surveillance allows for greater emphasis to now be placed on blood component quality. This represents a shift in the risk paradigm from donor exposure towards component quality and supports the practice of sharing split portions of a single donor adult RBC unit amongst several neonates. Not only does this facilitate preservation of limited group O RBC inventory, (which is likely to be further stressed by shorter outdating with the COE standards), but it also provides an option for facilities without irradiators, as described below.
Ideally, facilities with Level 3 neonatal intensive care units should have an on-site irradiator to facilitate irradiation of RBC aliquots at the time of issue.
For hospitals without an on-site irradiator, it may be necessary to maintain a small stock of RBC units irradiated by the supplier or a regional hub hospital. In this setting, the practice of sharing a unit amongst more than one neonate should be considered as a mechanism of optimally utilizing a freshly irradiated RBC unit and minimizing the length of storage post irradiation. For a neonate requiring repeat RBC transfusion, this practice may increase donor exposure, but should facilitate a regular inventory rotation (e.g. weekly) of a shared pre-storage irradiated RBC unit, and thereby mitigate the risks associated with component quality. It remains the prerogative of the transfusion medicine medical director or attending physician to request a single donor unit for neonates who are likely to require multiple transfusions.
In all cases of neonatal small volume transfusion, aliquots must be less than 14 days postirradiation and no more than 28 days since donation. (Council of Europe Standards, 17 th edition, 2013). Aliquots more than 24 hours from irradiation must have at least undergone centrifugation and supernatant plasma removal. A recent study has demonstrated that supernatant reduction by centrifugation is preferable to gravity settling. (Serrano et al, 2017). The final hematocrit should not exceed 0.80 L/L (CSA Z902-15 Standards, 2015). All manipulation should be performed as near-to as possible to the time of RBC release for transfusion.
Emergency Transfusions:
H. Recommendation: For emergency transfusions of unmatched group O, D-negative red cells for neonatal resuscitation due to obstetrical complications and/or accidents, irradiated cellular components are NOT required.
Congenital Cardiac Abnormalities:
The presence of a congenital cardiac abnormality identified in a neonate or infant may raise the suspicion of chromosome 22q11 deletion syndrome, commonly associated with a congenital T cell immunodeficiency. Cardiac abnormalities most frequently associated with chromosome 22q11 deletions include: Tetralogy of Fallot, ventricular septal defect, interrupted aortic arch, combined pulmonary atresia and ventricular septal defect, and truncus arteriosus. (Ryan et al, 1997) I. Recommendation: There is no need to irradiate red cells or platelets for infants undergoing cardiac surgery unless clinical or laboratory features suggest a coexisting T lymphocyte immunodeficiency syndrome. (BCSH 2010, Grade 2 recommendation; level B evidence)- J. Recommendation: All neonates with complex cardiac abnormalities should receive irradiated cellular components until a congenital immune deficiency disorder is excluded by diagnostic testing for 22q11.2 deletion associated with immunodeficiency states, which include DiGeorge Syndrome. If a congenital immune deficiency disorder is confirmed, irradiated cellular components should be provided for life.
# Pharmacotherapeutics: Purine analogue drugs and other potent immunosuppressive drugs
It is difficult to provide a clear recommendation for or against the use of irradiated blood in the context of all available immunosuppressive and biologic therapies in the absence of published evidence for specific agents in specific clinical contexts. This is particularly the case for new pharmacotherapeutic agents, such as tumor necrosis alpha (TNF-α) inhibitors and interleukin inhibitors. The decision to provide irradiated blood for patients on specific immunosuppressive agents should be made in consultation with the patient's most responsible physician, with consideration given to the perceived benefits and risks of irradiated blood transfusion and availability of irradiated blood. Where there is uncertainty or concern regarding the immunosuppressive potency of a particular agent, discussion with a Transfusion Medicine expert is encouraged.
Appendix B includes a comprehensive list of potent immunosuppressive medications cited to increase TA-GVHD risk, and for which irradiated component transfusion should be considered.
A. Recommendation: Patients treated with purine analogue drugs (fludarabine, cladribine and deoxycoformicin) should receive irradiated blood components indefinitely.
(BCSH 2010, Grade 1 recommendation; level B evidence)- Irradiated blood transfusion is not required for patients treated with the purine analogues 6mercaptopurine (6-MP) and azathioprine. These medications are not considered to have the same immunosuppressive potency as the above-listed chemotherapeutic agents, and based on available literature, have not been identified to be associated with an increased TA-GVHD risk.
B. Recommendation: The situation with other purine antagonists and new or related agents, such as bendamustine and clofarabine, is unclear, but use of irradiated blood components is recommended as these agents have a similar mode of action. Irradiated blood components should be used after alemtuzumab (anti-CD52) therapy. Their use after rituximab (anti-CD20) is not recommended at this time. As new potent immunosuppressive drugs and biological agents are introduced into practice there is a need for regular review of these recommendations. (BCSH 2010, Grade 2 recommendation; level C evidence)- C. Recommendation: Due to the lack of high-quality data to firmly define a period of time following which irradiated blood components must be used in patients following treatment with purine analogues and new or related agents, consideration may be given to discontinuation of their use after at least 1 year.
Anti-thymocyte globulin (ATG) is a potent immunosuppressive agent which is available as a derivative of both horse and rabbit sources, and used in a number of clinical contexts. There is expert consensus that irradiated blood components should be provided to patients with severe aplastic anemia who receive ATG (see Section 8 above). There is no evidence of increased TA-GVHD risk in solid organ transplant recipients conditioned with ATG, and as a result, current guidelines for solid organ transplantation do not cite a specific requirement for transfusion of irradiated blood in this population (KDGIO Transplant Work Group, 2009). The risk of TA-GVHD in patients undergoing reduced-intensity conditioning with ATG alone for allogeneic bone marrow transplantation is unknown.
- Routine surgery, solid tumors, solid organ transplantation, autoimmune disorders, acquired immunodeficiency A. Recommendation: It is not necessary to irradiate blood components for patients undergoing routine surgery, those with solid tumours, HIV infection, autoimmune diseases or after solid organ transplantation (unless alemtuzumab (anti-CD52) has been used in the conditioning regimen). The effects of new regimens of chemo-and immunotherapy entering clinical practice must continue to be monitored. (BCSH 2010, Grade 2 recommendation; level C evidence)*
Intraoperative autologous red blood cell salvage techniques are important to reduce the rate of and associated risks of allogeneic blood transfusion during major surgery. In patients with cancer, the use of intraoperative cell salvage (ICS) has been controversial due to the theoretical risk of metastasis propagation from reinfusion of autologous blood contaminated with metastatic cells. However, a recent meta-analysis of 10 studies showed no significant difference in cancer recurrence rates between patients who received ICS compared to those who did not during their surgeries (Waters et al, 2012). A systematic review evaluating the use of ICS in metastatic spine tumor surgery (Kumar et al, 2014) also did not identify a greater risk of tumor dissemination or metastasis in patients who received reinfusion of autologous ICS blood, though a caution was noted in situations of tumor rupture.
The use of either gamma irradiation or a small-pore microfiber leukocyte reduction filter have been identified to be effective strategies to reduce the risk of metastatic cell transmission from ICS blood in patients with malignancy undergoing surgery (Trudeau et al, 2012). Leukoreduction filters are more accessible than on-site hospital irradiators and do not impose damage to the RBC membrane, making their use a much more common in practice. The risks and benefits of intraoperative cell salvage in the setting of surgery in patients with suspected or known malignancy must be weighed by the perioperative team, and discussed together with the patient prior to use.
# B. Recommendation:
In patients with malignancy undergoing surgery, it is not necessary to irradiate autologous blood collected by intraoperative cell salvage if a small-pore microfiber leukocyte reduction filter is used prior to blood reinfusion.
# APPENDIX A: Quick reference of clinical indications for irradiated blood component transfusion
# Patient Category Condition
# General Transfusion Practice
Directed donation (blood from first-and second-degree relatives)
HLA-selected/matched platelets Allogeneic haematopoietic stem cell or bone marrow transplant recipients,
- from the time of initiation of conditioning chemotherapy
- while the patient continues to receive GVHD prophylaxis - indefinitely if chronic GVHD is present or if continued immunosuppressive therapy is required Allogeneic blood transfused to stem cell or bone marrow transplant donors for 7 days prior to and during the stem cell harvest
# Autologous Bone Marrow Transplant
Autologous stem cell or bone marrow transplant recipients from the initiation of conditioning chemo/radiation therapy to 3 months post-transplant (6 months if total body irradiation was used in conditioning)
Patients undergoing harvesting for future autologous reinfusion, during and for 7 days before the bone marrow/stem cell harvest
# Solid Organ Transplant
Recipients of alemtuzemab conditioning therapy only
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Page 3The National Advisory Committee on Blood and Blood Products (NAC) is an interprovincial medical and technical advisory body to the provincial and territorial health ministries and Canadian Blood Services (CBS). The NAC mandate is to: • Provide advice on matters pertaining to blood supply, including those directly affecting the practice of transfusion medicine in hospitals;#
• Share information about blood and blood product utilization and utilization management efforts, and play a supportive role in the development of guidelines and recommendations for product use;
• Identify opportunities to optimize transfusion medicine practices; and
• On a jurisdictional level, provide leadership in the identification, design and implementation of blood utilization management initiatives for the optimization of patient care.
The CBS Provincial Territorial Blood Liaison Committee (CBS PT BLC) requested that NAC develop recommendations and guidelines for the use of irradiated blood components for Canadian patients. NAC assembled an Irradiation Working Group to review current standards, published guidelines, and recent literature on the indications for irradiated components and the quality of irradiated red blood cell (RBC) components to facilitate recommendations for best practices. This group worked collaboratively with representatives of Quebec's National Advisory Committee on Transfusion Medicine (CCNMT) who joined the recommendation development process -thus forming the NAC-CCNMT Irradiation Working Group. Consultation with Canadian experts in transfusion medicine was included as a part of this recommendation development process. In addition, draft recommendations were circulated to a number of clinical stakeholder organizations for feedback prior to finalization.
This work was informed by the published guidelines on the use of irradiated blood components by the British Committee for Standards in Hematology (BCSH, 2010) and the guidelines for prevention of transfusion-associated graft-versus-host disease by the Australian and New Zealand Society of Blood Transfusion (ANZSBT, 2011). Published Transfusion Medicine practice standards including the Canadian Standards Association (CSA) Z902-15 standards (2015), Canadian Society for Transfusion Medicine (CSTM) standards (version 4, 2017), and Council of Europe (COE) standards (version 17, 2013); and recent publications on the quality of stored red cells post irradiation and practices involving irradiation of autologous blood collected by intraoperative cell salvage were consulted.
# Rationale for the Use of Irradiated Blood
Irradiation of cellular blood components is a well-established intervention for the prevention of transfusion-associated graft-versus-host disease (TA-GVHD). There is a system cost of providing irradiated blood components to patients that includes higher production costs, regulatory compliance and supply logistics. Recent publications have also emphasized the negative impact of irradiation on the RBC, and the importance of considering RBC age at the time of irradiation and the length of storage post-irradiation. The Working Group has therefore emphasized the need for conscientious management of hospital inventories to limit the provision of irradiated RBCs to those patients who have specific clinical indications to receive irradiated RBC units. Adherence to this practice would thereby minimize exposure of the general patient population to irradiated RBCs.
Data provided by CBS demonstrates some trends in irradiation practice in Canada over the past ten years. There has been a national increase in the percentage of irradiated RBCs from 4.5% (2004)(2005) to 6.7% (2015)(2016). There is considerable regional variation. The percentage irradiated RBC units issued by CBS ranges from 2-18%, depending on the province. The percentage of irradiated RBC units issued by Héma-Québec, in 2015-2016, was 6.0%.
TA-GVHD is a rare, usually fatal complication of transfusion resulting from the engraftment of transfused, immunocompetent donor lymphocytes and subsequent damage to recipient tissues which are perceived as foreign by the engrafted lymphocytes. Patients at most risk include those who are severely immunocompromised and those who fail to recognize the transfused donor lymphocytes as foreign if human leukocyte antigen (HLA) alleles are haploidentical.
Defining immunocompromised patient groups who should receive irradiated blood has been largely based on observational evidence, case reports, reviews and attempts to predict the degree of immunosuppression. As such, there is a lack of consistency in text books, publications and guidelines as to which patients must receive irradiated blood. Many authors address the lack of clarity by including a category of indications where there is uncertainty regarding the need for irradiated blood.
In view of growing evidence demonstrating the poor quality of post-irradiation stored RBCs, there is a need to be thoughtful about the clinical indications for irradiated blood transfusion and avoid over stocking irradiated RBC units. Without an on-site irradiator, finding a balance of stocking sufficient (but not excess) supply for patient's in-need of irradiated blood may be challenging. Concerns regarding post-irradiation component quality and storage do not apply to platelets or granulocyte concentrates due to the short shelf life of these components.
In addition to irradiation as a TA-GVHD mitigation strategy, recent observational evidence suggests that the pre-storage leukoreduction and length of time since donation may modify recipient TA-GVHD risk. To date, both pre-storage leukoreduction and increased RBC storage time have not been shown to have an equivalent efficacy for eliminating TA-GVHD risk, however.
In a recent systematic review of 348 reported TA-GVHD cases, the authors reported that greater than 94% of cases of TA-GVHD occur when the blood is less than 10 days old, with none of the TA-GVHD cases associated with components older than 14 days from collection (Kopolovic et al, 2015). A review of 290 cases referred to the Japanese Red Cross (JRC) from 1992-1999 identified 66 cases of definite TA-GVHD by microsatellite DNA analysis. The oldest blood transfused in this series was 10 days for whole blood, 11 days for RBCs without an additive solution, and 14 days for RBCs with added mannitol, adenine and phosphate (Uchida et al, 2013). In another report from the JRC, 96% of 51 cases received blood less than 96 hours old (Jawa et al, 2015). Thus, transfusion of blood stored for more than 14 days represents a potential risk mitigation strategy for patients in whom there is uncertainty regarding the degree of immune compromise.
The potential risk mitigation afforded by leukoreduction is supported by data from the Serious Hazards of Transfusion (SHOT) surveillance system in the United Kingdom. A total of 14 cases of TA-GVHD have been reported to SHOT since 1996, which include only 3 cases since the introduction of universal leukoreduction in 1999. Two of these patients were confirmed to have received leukoreduced components. The first case involved a patient with multiple myeloma, reported in 1999. The second case occurred in 2001, and involved a 14-year-old patient with relapsed acute lymphoblastic leukemia. Donors from potentially implicated units were not recalled for HLA typing. The most recent case, reported in 2012, followed an emergency intrauterine transfusion of non-irradiated, non-leukoreduced maternal red cells. The mother was subsequently found have a homozygous HLA haplotype (Bolton-Maggs, 2012). There have been no further TA-GVHD cases reported to SHOT since 2012(Bolton-Maggs, 2016.
Further observational evidence of the risk reduction associated with leukoreduction can be found in the aforementioned systematic review of 348 TA-GVHD cases. Of these, only 23 were in patients who had received leukocyte reduced components, 2 of which were pre-storage, 10 bedside and 11 unspecified (Kopolovic et al, 2015). Together with SHOT surveillance, these findings suggest that leukoreduction reduces, but does not eliminate, the risk of TA-GVHD.
It should be noted that following the 2001 terrorist attacks in New York, a decision was made in the UK to increase blood stocks. As a result, the mean age of blood issued to hospitals after 2002 went from 8 days to 12-14 days and may have also contributed to reducing TA-GVHD risk (Williamson et al, 2007).
# Document Scope and Guide
Upon review of the best-available information, the NAC-CCNMT Irradiation Working Group has compiled this recommendations document to help Canadian clinicians determine which patients should receive irradiated components, and define the age of RBCs at the time of irradiation and the length of storage post-irradiation.
Special annotations following each recommendation have been included to inform the reader of the recommendation reference:
An asterisk (*), to indicate a verbatim statement from the referenced guideline. o A level of evidence description for the recommendation may be included from the original guideline document, if available. Recommendation statements without a reference are considered best practice statements by NAC and the Working Group, based upon published guidelines or literature.
Recommendations pertaining to the RBC age and the length of storage post-irradiation are consistent with the COE standards (17 th edition) and the newest version of the CSTM standards (version 4, 2017), but are more restrictive than current AABB (29 th ed, 2014) and CSA standards (CSA Z902-15, 2015).
In defining patients who should receive irradiated cellular components, the Working Group supports the majority of published BCSH 2010 and ANZSBT 2011 guidelines. A cautious approach for small volume (top-up) transfusions in very low birth weight neonates is maintained, given that there is variation in expert opinion in the published literature. Recommendations for neonatal transfusion include consideration of the 2016 Canadian neonatal transfusion practice survey results (see Supplement). Unless otherwise specified, recommendations made within this document may be assumed to apply to both adult and pediatric populations.
# GENERAL RECOMMENDATIONS
The NAC-CCNMT Working Group supports the following general recommendations pertaining to the type of blood component that requires irradiation, information sharing and communications of a patient's requirement for irradiated blood components. In addition, the Working Group recommends voluntary alignment with the COE standards (17 th edition) for the age of the units and post-irradiation storage conditions.
1. Blood components that should be irradiated A. Recommendation: For at-risk patients, all red cell, platelet and granulocyte concentrates should be irradiated, except cryopreserved red cells after deglycerolization. It is not necessary to irradiate fresh frozen plasma, cryoprecipitate or fractionated plasma products. (BCSH 2010, Grade 1 recommendation; level B evidence)* B. Recommendation: All transfusions from first-or second-degree relatives must be irradiated, even if the patient is immunocompetent.
C. Recommendation: All HLA-selected platelets must be irradiated, even if the patient is immunocompetent.
D. Recommendation: All granulocyte components must be irradiated before issue.
# Age of cellular blood components and post-irradiation storage timelines
Recent evidence has shown that the age of RBCs at the time of irradiation is important and that prolonged storage of pre-irradiated units is associated with high potassium levels, in vitro hemolysis, and decreased post-transfusion recovery (Serrano et al, 2014). This has implications for patient safety as well as hospital inventory management practices.
The current North American standards (AABB, 29 th ed, 2014 and CSA Z902-15, 2015) specify that RBCs shall have a maximum expiration time of 28 days after irradiation or shall retain the original outdate, whichever is shorter, and do not limit the age of RBC at the time of irradiation. The NAC-CCNMT Working Group is recommending voluntary alignment with the COE Standards (17 th edition) to reduce the age of units selected for irradiation and timeline of post-irradiation storage. This more restrictive timeline is endorsed in the newest version of the CSTM Standards (version 4, 2017).
A. Recommendation: Red cell components may be irradiated up to 28 days after collection. Irradiated cells must be transfused as soon as possible, but no later than 14 days after irradiation, and in any case, no later than 28 days after collection. (Council of Europe Standards, 17 th edition, 2013)* B. Recommendation: Platelets can be irradiated at any stage during storage and can thereafter be stored up to their normal shelf life after collection. (BCSH 2010, Grade 1 recommendation; level A evidence)*
# Patient awareness
A. Recommendation: Patients at risk of TA-GVHD should be made aware of their need for irradiated blood components. It is the responsibility of the most responsible health care practitioner to inform patients at risk of TA-GVHD of their need for irradiated blood components.
# Communication
A. Recommendation: To ensure consistency of patient care across jurisdictions, particularly between hospital facilities that participate in the shared care of patients, a communications process between clinicians and the transfusion medicine laboratory facilitating sharing details of special transfusion requirements should be implemented and maintained as a best practice policy. In an ideal setting, an electronic automatic notification identifying pharmaceutical history or indication for irradiated blood to the transfusion medicine laboratory would be in place.
# INVENTORY MANAGEMENT RECOMMENDATIONS
As stated, prolonged storage of pre-irradiated units is associated with high potassium levels, in vitro hemolysis and decreased post-transfusion recovery (Serrano et al, 2014). Maintaining large inventories of irradiated red cells results in potentially harmful transfusion of irradiated red cells to patients who do not require irradiated cellular blood components.
Proactive inventory management must take into consideration the perceived risk of TA-GVHD in the local patient population, the risks of transfusing irradiated red cells to patients who do not require irradiated cellular components and the logistics of providing irradiated components for elective transfusions. Irradiation of RBCs should therefore occur as near-to as possible to the time of transfusion.
# Irradiated blood component availability
A. Recommendation: For elective transfusions reliance on a regional hub site for ondemand irradiation or limited pre-irradiated stock is recommended.
B. Recommendation: Overstocking of pre-irradiated units for emergency transfusion is not recommended. If storage of pre-irradiated inventory is absolutely necessary, then red cells that have been irradiated within 14 days of collection should be obtained, if possible.
As described above, observational evidence from UK SHOT data (Williamson et al, 2007), a recent systematic review of 348 cases of TA-GVHD (Kopolovic et al, 2015) and three reviews of Japanese Red Cross data has provided some evidence for the risk mitigating effect of universal pre-storage leukoreduction and the transfusion of older RBCs with reduced lymphocyte viability (>14 days post donation) (Uchida et al, 2013;Jawa et al, 2015).
C. Recommendation: In the event of emergency transfusion in the absence of on-site irradiation or pre-storage irradiated inventory, pre-storage leukoreduced red cells that have been stored for more than 14 days should be provided to patients with an indication for irradiated blood transfusion.
D. Recommendation: Where there is concern about the immunosuppressive potency of new drugs and uncertainty about the risk of TA-GVHD, in the absence of on-site irradiation or pre-storage irradiated inventory, pre-storage leukoreduced red cells that have been stored for more than 14 days should be provided.
E. Recommendation: Pathogen inactivation or reduction technologies cannot yet be considered an alternative or equivalent to irradiation as TA-GVHD mitigation strategies, though data in this area continues to evolve.
# CLINICAL RECOMMENDATIONS
To arrive at the following clinical recommendations NAC-CCNMT Working Group has drawn primarily upon the BCSH 2010 and ANZSBT 2011 guidelines. In addition, the 2016 survey of current practices at Canadian hospitals with Level 3 neonatal intensive care units informed neonatal transfusion recommendations (see Supplement).
For clinical conditions listed, the patient medication history must be taken into consideration by the most responsible healthcare practitioner requesting blood transfusion, as a treatment received may necessitate irradiated cellular component use. Local practices may be dictated by the ability of hospital transfusion medicine services to obtain the patient's medication history.
Appendix A provides a quick-reference of the clinical indications for transfusion of irradiated blood components, Appendix B lists immunosuppressive medications, and the Supplement summarizes results of the 2016 Canadian National Survey of Irradiation Practices in Neonatal Transfusion.
# Acute leukemia
There is no definitive evidence to support the need for irradiated blood transfusion to patients with a diagnosis of acute leukemia (any type) in adult and pediatric patients, in the absence of identified TA-GVHD risk factors. Chemotherapy regimens for acute leukemia typically do not include pharmacotherapeutic agents known to be risk factors for TA-GVHD development.
However, individual treatment protocols should be reviewed to ensure that there is no indication for irradiated blood transfusion (see Section 15 or Appendix B below).
A. Recommendation: It is not necessary to irradiate red cells or platelets for adults or children with acute leukemia, except for HLA-selected platelets or donations from first-or second-degree relatives.
(BCSH 2010, Grade 1 recommendation; level B evidence)*
# Allogeneic bone marrow or peripheral blood stem cell transplantation
Published clinical practice guidelines are in agreement with the provision of irradiated blood components to allogeneic bone marrow transplant recipients from the time conditioning chemotherapy is initiated. However, there is less certainty as to the definition of when transfusion of irradiated blood components can stop post-transplant. Some experts have suggested that if transplant recipients have completed GVHD prophylaxis immunosuppression and a threshold lymphocyte count of at least 1 x 10 9 /L has been achieved (approximately 6-12 months posttransplant), then the indication for irradiated blood component transfusion may be removed.
Due to the paucity of evidence, the decision to discontinue transfusion of irradiated blood components should remain at the discretion of the transplant physician team.
A. Recommendation: All recipients of allogeneic hematopoietic stem cell transplantation (HSCT) must receive irradiated blood components from the time of initiation of conditioning chemoradiotherapy.
(BCSH 2010, Grade 1 recommendation; level B evidence)* B. Recommendation: Irradiated blood components should be continued while the patient continues to receive graft-versus-host disease (GVHD) prophylaxis. The indication for ongoing transfusion of irradiated blood components should be reviewed at least yearly. If chronic GVHD is present or if continued immunosuppressive treatment is required, irradiated blood components should be given indefinitely.
C. Recommendation: Allogeneic blood transfused to bone marrow and peripheral blood stem cell donors 7 days prior to or during the harvest should also be irradiated.
(BCSH, Grade 2 recommendation; level C evidence)*
# Aplastic anemia
A. Recommendation: We recommend use of irradiated blood components for severe aplastic anemia patients receiving immunosuppressive therapy with ATG and/or alemtuzumab.
B. Recommendation: We cannot make a firm recommendation as to how long irradiated blood components should continue to be used after ATG administration. (BCSH 2010)* C. Recommendation: In the absence of indications necessitating irradiated component transfusion, patients with aplastic anemia do not otherwise require transfusion of irradiated red cells and platelets.
# Autologous bone marrow or peripheral blood hematopoietic stem cell transplantation
A. Recommendation: Patients undergoing bone marrow or peripheral blood stem cell 'harvesting' for future autologous re-infusion should receive irradiated cellular blood components during and for 7 days before the bone marrow/stem cell harvest to prevent the collection of viable allogeneic T lymphocytes, which can potentially withstand cryopreservation.
# Lymphoma
There is overarching consensus in published guidelines based on the literature that the risk of TA-GVHD in Hodgkin lymphoma is greater than in those with non-Hodgkin lymphoma, and appears to be unrelated to disease stage or treatment modality. Although a diagnosis of non-Hodgkin lymphoma is not in itself an absolute indication for transfusion of irradiated blood components, pharmacotherapeutics used in treatment protocols may necessitate transfusion of irradiated components to mitigate TA-GVHD risk (see Section 15 or Appendix B below). However, there is a lack of evidence and therefore controversy surrounding the time-span following which irradiated blood component transfusion is required after patients complete their treatment course with an at-risk medication.
A. Recommendation: All adults and children with Hodgkin lymphoma at any stage of the disease should have irradiated red cells and platelets for life.
(BCSH 2010, Grade 1 recommendation; level B evidence)* B. Recommendation: All patients with non-Hodgkin lymphoma receiving purine analogues and related drugs should receive irradiated cellular blood components from the time of therapy initiation. Due to the paucity of evidence, we cannot make a firm recommendation regarding the time at which irradiated component provision may be discontinued.
# Neonatal Transfusions
A survey was completed to better understand current practices in Canada regarding the use of irradiated blood components specifically for neonatal populations to inform these recommendations. The survey focused on three clinical scenarios: intrauterine transfusions, neonatal top-up (small volume) transfusions, and neonatal exchange. The survey was sent to the medical directors of transfusion medicine in Level 3 neonatal intensive care nurseries (defined according to the Neonatal Classification Tool developed in British Columbia). The Supplement to this recommendations document contains a copy of the survey distributed and collated results.
The NAC-CCNMT Working Group recommendations for neonatal transfusions are as follows:
Intra-Uterine Transfusions (IUT) and Neonatal Exchange Transfusion:
A. Recommendation: All components for IUT must be irradiated. To minimize the effect of potassium load, red cells for IUT must be as fresh as possible, and must be transfused within 24 hours of irradiation.
B. Recommendation: Irradiated cellular components are recommended for neonates who have received an IUT, in which case irradiated components should be administered until 6 months after the expected delivery date (40 weeks gestation).
C. Recommendation: It is essential to irradiate blood for neonatal exchange transfusion if there has been a previous IUT or if the donation comes from a first-or second-degree relative.
(BCSH 2010, Grade 1 recommendation; level B evidence)* D. Recommendation: For other neonatal exchange transfusion cases, irradiation is recommended provided this does not unduly delay transfusion.
(BCSH 2010, Grade 1 recommendation; level C evidence)* E. Recommendation: Red cells for neonatal exchange transfusion should be as fresh as possible, and must be transfused within 24 hours of irradiation.
Neonatal Small-volume (Top-up) Transfusions:
For small volume transfusions in neonates, the NAC-CCNMT Working Group recognizes that there is insufficient data to firmly guide transfusion practice. The BCSH 2010 guidelines do not recommend transfusion of irradiated RBC for small-volume transfusion, while the ANZSBT 2011 guidelines recommend transfusion of irradiated RBC in very low birth weight infants of less than 1300 grams. Many neonatal studies have defined very low birth weight as 1200 to 1300 grams to assess outcomes and interventions, though the World Health Organization defines very low birthweight as less than 1500g. The NAC-CCNMT Working Group leaves the decision of a very low birthweight cut-off to the discretion of local neonatology experts at hospital-based services.
F. Recommendation: Irradiated cellular components are recommended for small-volume transfusions given to neonates born with a very low birthweight, up to 4 months of age.
G. Recommendation: Where the patient is at particular risk of hyperkalemia, it is recommended that red cells be transfused within 24 hours of irradiation. Red cells stored for greater than 24 hours from irradiation must at least undergo centrifugation and supernatant plasma removal prior to transfusion.
The practice of sterile docking and splitting an adult RBC unit for sequential neonatal transfusion evolved during an era of greater risk for transfusion transmitted infection. Limiting donor exposure in neonates continues to be a priority. However, the enhanced safety of the blood system through improved donor screening, nucleic acid testing, and access to public health surveillance allows for greater emphasis to now be placed on blood component quality. This represents a shift in the risk paradigm from donor exposure towards component quality and supports the practice of sharing split portions of a single donor adult RBC unit amongst several neonates. Not only does this facilitate preservation of limited group O RBC inventory, (which is likely to be further stressed by shorter outdating with the COE standards), but it also provides an option for facilities without irradiators, as described below.
Ideally, facilities with Level 3 neonatal intensive care units should have an on-site irradiator to facilitate irradiation of RBC aliquots at the time of issue.
For hospitals without an on-site irradiator, it may be necessary to maintain a small stock of RBC units irradiated by the supplier or a regional hub hospital. In this setting, the practice of sharing a unit amongst more than one neonate should be considered as a mechanism of optimally utilizing a freshly irradiated RBC unit and minimizing the length of storage post irradiation. For a neonate requiring repeat RBC transfusion, this practice may increase donor exposure, but should facilitate a regular inventory rotation (e.g. weekly) of a shared pre-storage irradiated RBC unit, and thereby mitigate the risks associated with component quality. It remains the prerogative of the transfusion medicine medical director or attending physician to request a single donor unit for neonates who are likely to require multiple transfusions.
In all cases of neonatal small volume transfusion, aliquots must be less than 14 days postirradiation and no more than 28 days since donation. (Council of Europe Standards, 17 th edition, 2013). Aliquots more than 24 hours from irradiation must have at least undergone centrifugation and supernatant plasma removal. A recent study has demonstrated that supernatant reduction by centrifugation is preferable to gravity settling. (Serrano et al, 2017). The final hematocrit should not exceed 0.80 L/L (CSA Z902-15 Standards, 2015). All manipulation should be performed as near-to as possible to the time of RBC release for transfusion.
Emergency Transfusions:
H. Recommendation: For emergency transfusions of unmatched group O, D-negative red cells for neonatal resuscitation due to obstetrical complications and/or accidents, irradiated cellular components are NOT required.
Congenital Cardiac Abnormalities:
The presence of a congenital cardiac abnormality identified in a neonate or infant may raise the suspicion of chromosome 22q11 deletion syndrome, commonly associated with a congenital T cell immunodeficiency. Cardiac abnormalities most frequently associated with chromosome 22q11 deletions include: Tetralogy of Fallot, ventricular septal defect, interrupted aortic arch, combined pulmonary atresia and ventricular septal defect, and truncus arteriosus. (Ryan et al, 1997) I. Recommendation: There is no need to irradiate red cells or platelets for infants undergoing cardiac surgery unless clinical or laboratory features suggest a coexisting T lymphocyte immunodeficiency syndrome. (BCSH 2010, Grade 2 recommendation; level B evidence)* J. Recommendation: All neonates with complex cardiac abnormalities should receive irradiated cellular components until a congenital immune deficiency disorder is excluded by diagnostic testing for 22q11.2 deletion associated with immunodeficiency states, which include DiGeorge Syndrome. If a congenital immune deficiency disorder is confirmed, irradiated cellular components should be provided for life.
# Pharmacotherapeutics: Purine analogue drugs and other potent immunosuppressive drugs
It is difficult to provide a clear recommendation for or against the use of irradiated blood in the context of all available immunosuppressive and biologic therapies in the absence of published evidence for specific agents in specific clinical contexts. This is particularly the case for new pharmacotherapeutic agents, such as tumor necrosis alpha (TNF-α) inhibitors and interleukin inhibitors. The decision to provide irradiated blood for patients on specific immunosuppressive agents should be made in consultation with the patient's most responsible physician, with consideration given to the perceived benefits and risks of irradiated blood transfusion and availability of irradiated blood. Where there is uncertainty or concern regarding the immunosuppressive potency of a particular agent, discussion with a Transfusion Medicine expert is encouraged.
Appendix B includes a comprehensive list of potent immunosuppressive medications cited to increase TA-GVHD risk, and for which irradiated component transfusion should be considered.
A. Recommendation: Patients treated with purine analogue drugs (fludarabine, cladribine and deoxycoformicin) should receive irradiated blood components indefinitely.
(BCSH 2010, Grade 1 recommendation; level B evidence)* Irradiated blood transfusion is not required for patients treated with the purine analogues 6mercaptopurine (6-MP) and azathioprine. These medications are not considered to have the same immunosuppressive potency as the above-listed chemotherapeutic agents, and based on available literature, have not been identified to be associated with an increased TA-GVHD risk.
B. Recommendation: The situation with other purine antagonists and new or related agents, such as bendamustine and clofarabine, is unclear, but use of irradiated blood components is recommended as these agents have a similar mode of action. Irradiated blood components should be used after alemtuzumab (anti-CD52) therapy. Their use after rituximab (anti-CD20) is not recommended at this time. As new potent immunosuppressive drugs and biological agents are introduced into practice there is a need for regular review of these recommendations. (BCSH 2010, Grade 2 recommendation; level C evidence)* C. Recommendation: Due to the lack of high-quality data to firmly define a period of time following which irradiated blood components must be used in patients following treatment with purine analogues and new or related agents, consideration may be given to discontinuation of their use after at least 1 year.
Anti-thymocyte globulin (ATG) is a potent immunosuppressive agent which is available as a derivative of both horse and rabbit sources, and used in a number of clinical contexts. There is expert consensus that irradiated blood components should be provided to patients with severe aplastic anemia who receive ATG (see Section 8 above). There is no evidence of increased TA-GVHD risk in solid organ transplant recipients conditioned with ATG, and as a result, current guidelines for solid organ transplantation do not cite a specific requirement for transfusion of irradiated blood in this population (KDGIO Transplant Work Group, 2009). The risk of TA-GVHD in patients undergoing reduced-intensity conditioning with ATG alone for allogeneic bone marrow transplantation is unknown.
15. Routine surgery, solid tumors, solid organ transplantation, autoimmune disorders, acquired immunodeficiency A. Recommendation: It is not necessary to irradiate blood components for patients undergoing routine surgery, those with solid tumours, HIV infection, autoimmune diseases or after solid organ transplantation (unless alemtuzumab (anti-CD52) has been used in the conditioning regimen). The effects of new regimens of chemo-and immunotherapy entering clinical practice must continue to be monitored. (BCSH 2010, Grade 2 recommendation; level C evidence)*
Intraoperative autologous red blood cell salvage techniques are important to reduce the rate of and associated risks of allogeneic blood transfusion during major surgery. In patients with cancer, the use of intraoperative cell salvage (ICS) has been controversial due to the theoretical risk of metastasis propagation from reinfusion of autologous blood contaminated with metastatic cells. However, a recent meta-analysis of 10 studies showed no significant difference in cancer recurrence rates between patients who received ICS compared to those who did not during their surgeries (Waters et al, 2012). A systematic review evaluating the use of ICS in metastatic spine tumor surgery (Kumar et al, 2014) also did not identify a greater risk of tumor dissemination or metastasis in patients who received reinfusion of autologous ICS blood, though a caution was noted in situations of tumor rupture.
The use of either gamma irradiation or a small-pore microfiber leukocyte reduction filter have been identified to be effective strategies to reduce the risk of metastatic cell transmission from ICS blood in patients with malignancy undergoing surgery (Trudeau et al, 2012). Leukoreduction filters are more accessible than on-site hospital irradiators and do not impose damage to the RBC membrane, making their use a much more common in practice. The risks and benefits of intraoperative cell salvage in the setting of surgery in patients with suspected or known malignancy must be weighed by the perioperative team, and discussed together with the patient prior to use.
# B. Recommendation:
In patients with malignancy undergoing surgery, it is not necessary to irradiate autologous blood collected by intraoperative cell salvage if a small-pore microfiber leukocyte reduction filter is used prior to blood reinfusion.
# APPENDIX A: Quick reference of clinical indications for irradiated blood component transfusion
# Patient Category Condition
# General Transfusion Practice
Directed donation (blood from first-and second-degree relatives)
HLA-selected/matched platelets Allogeneic haematopoietic stem cell or bone marrow transplant recipients,
• from the time of initiation of conditioning chemotherapy
• while the patient continues to receive GVHD prophylaxis • indefinitely if chronic GVHD is present or if continued immunosuppressive therapy is required Allogeneic blood transfused to stem cell or bone marrow transplant donors for 7 days prior to and during the stem cell harvest
# Autologous Bone Marrow Transplant
Autologous stem cell or bone marrow transplant recipients from the initiation of conditioning chemo/radiation therapy to 3 months post-transplant (6 months if total body irradiation was used in conditioning)
Patients undergoing harvesting for future autologous reinfusion, during and for 7 days before the bone marrow/stem cell harvest
# Solid Organ Transplant
Recipients of alemtuzemab conditioning therapy only
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Update of the optimal usage guide on sexually transmitted and blood borne infections -confirmed Mycoplasma genitalium infection#
Update of the optimal usage guide on sexually transmitted and blood borne infections -confirmed Mycoplasma genitalium infection English summary
# JULY 2022
Une production de l'Institut national d'excellence en santé et en services sociaux (INESSS)
# Introduction
Mycoplasma genitalium is a sexually transmitted bacterium that exhibits a high rate of resistance to macrolides and emerging resistance to fluoroquinolones. Mycoplasma genitalium is listed on the watch list of CDC's Antibiotic Resistance Threats in the United States. However, the exact rates of resistance in Québec and in many other parts of the world are still not known at this time.
In 2021, the Institut national d'excellence en santé et en services sociaux (INESSS) published an optimal usage guide on the pharmacological treatment of confirmed Mycoplasma genitalium infections. Since then, new recommendations have been published because of this bacterium's increased resistance to commonly administered antibiotics. Updating the optimal usage guide on confirmed Mycoplasma genitalium infections therefore seemed relevant and useful for Québec's front-line clinicians.
# Methodology
For the development and partial update of the optimal usage guide on confirmed Mycoplasma genitalium infections, a systematic review of clinical practice guidelines, expert consensus statements, consensus conference reports, guidance documents, and other documents containing clinical recommendations was conducted in accordance with INESSS's standards. The 2022 update focused only on pharmacological treatment. In addition, a manual literature search was performed by consulting the websites of North American regulatory agencies, health technology assessment agencies, government agencies, and professional associations and bodies dealing with the topic of interest. The bibliographies of the selected publications were examined for other relevant items.
The data were analyzed from the perspective of contextualizing Québec practice, using mainly legislative, regulatory, and organizational contextual information specific to Québec, and the perspectives of the different stakeholders who were consulted.
# Results
Three items were selected from the 2020 literature search and two from the 2022 search that contain recommendations and that were of adequate methodological quality, based on the AGREE II instrument. In general, a few main principles guide the treatment of confirmed Mycoplasma genitalium infections. First, when the results of screening for macrolide or fluoroquinolone resistance mutations are known, antibiotic resistance should be considered when choosing a treatment for Mycoplasma genitalium. In addition, since the use of azithromycin can induce macrolide resistance, a new treatment with azithromycin on a multi-day regimen should not be prescribed to patients who did not respond to this antibiotic during the initial treatment of a syndrome consistent with a sexually transmitted and blood-borne infection. In addition, the use of moxifloxacin as first-line therapy in all cases of confirmed Mycoplasma genitalium infection is not recommended because the other treatment options are limited. Moxifloxacin is recommended in cases of prior azithromycin use during syndromic therapy, suspected, or confirmed macrolide resistance, or a complicated infection. Sequential treatment with doxycycline before azithromycin or moxifloxacin (depending on macrolide resistance) should be recommended. Doxycycline appears to reduce the Mycoplasma genitalium bacterial load, which seems to promote the action of azithromycin and moxifloxacin. Lastly, for the treatment of a confirmed Mycoplasma genitalium infection in a pregnant or breastfeeding woman, the front-line clinician should consult an experienced colleague. The same applies to a current sexual partner who is pregnant or breastfeeding (partner of a person with a confirmed Mycoplasma genitalium infection).
For an uncomplicated Mycoplasma genitalium infection (cervicitis or urethritis), the recommended treatment depends on the patient's characteristics. For a patient in whom macrolide susceptibility has been confirmed or in the absence of data on macrolide susceptibility in a patient who has not received azithromycin during syndromic therapy, the recommended treatment is doxycycline (100 mg PO BID x 7 days) followed by azithromycin (1 g PO daily x 1 day, then 500 mg PO daily x 3 days, for a total of 2.5 g). The recommended treatment for a patient with suspected or confirmed macrolide resistance or who previously received azithromycin during syndromic therapy is doxycycline (100 mg PO BID x 7 days) followed by moxifloxacin (400 mg PO daily x 7 days). It should be noted, however, that if doxycycline has been used as first-line therapy for an uncomplicated infection and the microbiology test results show the presence of Mycoplasma genitalium, azithromycin or moxifloxacin should be administered as soon as possible after doxycycline therapy. Doxycycline should not be repeated when the interval between the completion of doxycycline therapy and the initiation of azithromycin or moxifloxacin is less than 14 days. Lastly, for a patient with suspected or confirmed fluoroquinolone resistance, it is recommended that an experienced colleague be consulted.
For the treatment of a complicated Mycoplasma genitalium infection (pelvic inflammatory disease or epididymitis/orchiepididymitis), it is also recommended that an experienced colleague be consulted. However, the antibiotic combination to be used should include moxifloxacin (400 mg PO daily x 14 days). Lastly, whether they have signs or symptoms, the patient's current partners should receive the same antibiotic therapy they are, unless the resistance data call for a different approach (empirical treatment).
# Conclusion
The development and partial update of the optimal usage guide on confirmed Mycoplasma genitalium infections were based on scientific and clinical data and on clinical practice recommendations from the literature, which were enhanced with the perspectives of various clinicians and experts, and with contextual information. Evaluating the data from these different sources enabled us to develop the optimal use guide and update it considering the best available clinical practices.
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Update of the optimal usage guide on sexually transmitted and blood borne infections -confirmed Mycoplasma genitalium infection#
Update of the optimal usage guide on sexually transmitted and blood borne infections -confirmed Mycoplasma genitalium infection English summary
# JULY 2022
Une production de l'Institut national d'excellence en santé et en services sociaux (INESSS)
# Introduction
Mycoplasma genitalium is a sexually transmitted bacterium that exhibits a high rate of resistance to macrolides and emerging resistance to fluoroquinolones. Mycoplasma genitalium is listed on the watch list of CDC's Antibiotic Resistance Threats in the United States. However, the exact rates of resistance in Québec and in many other parts of the world are still not known at this time.
In 2021, the Institut national d'excellence en santé et en services sociaux (INESSS) published an optimal usage guide on the pharmacological treatment of confirmed Mycoplasma genitalium infections. Since then, new recommendations have been published because of this bacterium's increased resistance to commonly administered antibiotics. Updating the optimal usage guide on confirmed Mycoplasma genitalium infections therefore seemed relevant and useful for Québec's front-line clinicians.
# Methodology
For the development and partial update of the optimal usage guide on confirmed Mycoplasma genitalium infections, a systematic review of clinical practice guidelines, expert consensus statements, consensus conference reports, guidance documents, and other documents containing clinical recommendations was conducted in accordance with INESSS's standards. The 2022 update focused only on pharmacological treatment. In addition, a manual literature search was performed by consulting the websites of North American regulatory agencies, health technology assessment agencies, government agencies, and professional associations and bodies dealing with the topic of interest. The bibliographies of the selected publications were examined for other relevant items.
The data were analyzed from the perspective of contextualizing Québec practice, using mainly legislative, regulatory, and organizational contextual information specific to Québec, and the perspectives of the different stakeholders who were consulted.
# Results
Three items were selected from the 2020 literature search and two from the 2022 search that contain recommendations and that were of adequate methodological quality, based on the AGREE II instrument. In general, a few main principles guide the treatment of confirmed Mycoplasma genitalium infections. First, when the results of screening for macrolide or fluoroquinolone resistance mutations are known, antibiotic resistance should be considered when choosing a treatment for Mycoplasma genitalium. In addition, since the use of azithromycin can induce macrolide resistance, a new treatment with azithromycin on a multi-day regimen should not be prescribed to patients who did not respond to this antibiotic during the initial treatment of a syndrome consistent with a sexually transmitted and blood-borne infection. In addition, the use of moxifloxacin as first-line therapy in all cases of confirmed Mycoplasma genitalium infection is not recommended because the other treatment options are limited. Moxifloxacin is recommended in cases of prior azithromycin use during syndromic therapy, suspected, or confirmed macrolide resistance, or a complicated infection. Sequential treatment with doxycycline before azithromycin or moxifloxacin (depending on macrolide resistance) should be recommended. Doxycycline appears to reduce the Mycoplasma genitalium bacterial load, which seems to promote the action of azithromycin and moxifloxacin. Lastly, for the treatment of a confirmed Mycoplasma genitalium infection in a pregnant or breastfeeding woman, the front-line clinician should consult an experienced colleague. The same applies to a current sexual partner who is pregnant or breastfeeding (partner of a person with a confirmed Mycoplasma genitalium infection).
For an uncomplicated Mycoplasma genitalium infection (cervicitis or urethritis), the recommended treatment depends on the patient's characteristics. For a patient in whom macrolide susceptibility has been confirmed or in the absence of data on macrolide susceptibility in a patient who has not received azithromycin during syndromic therapy, the recommended treatment is doxycycline (100 mg PO BID x 7 days) followed by azithromycin (1 g PO daily x 1 day, then 500 mg PO daily x 3 days, for a total of 2.5 g). The recommended treatment for a patient with suspected or confirmed macrolide resistance or who previously received azithromycin during syndromic therapy is doxycycline (100 mg PO BID x 7 days) followed by moxifloxacin (400 mg PO daily x 7 days). It should be noted, however, that if doxycycline has been used as first-line therapy for an uncomplicated infection and the microbiology test results show the presence of Mycoplasma genitalium, azithromycin or moxifloxacin should be administered as soon as possible after doxycycline therapy. Doxycycline should not be repeated when the interval between the completion of doxycycline therapy and the initiation of azithromycin or moxifloxacin is less than 14 days. Lastly, for a patient with suspected or confirmed fluoroquinolone resistance, it is recommended that an experienced colleague be consulted.
For the treatment of a complicated Mycoplasma genitalium infection (pelvic inflammatory disease or epididymitis/orchiepididymitis), it is also recommended that an experienced colleague be consulted. However, the antibiotic combination to be used should include moxifloxacin (400 mg PO daily x 14 days). Lastly, whether they have signs or symptoms, the patient's current partners should receive the same antibiotic therapy they are, unless the resistance data call for a different approach (empirical treatment).
# Conclusion
The development and partial update of the optimal usage guide on confirmed Mycoplasma genitalium infections were based on scientific and clinical data and on clinical practice recommendations from the literature, which were enhanced with the perspectives of various clinicians and experts, and with contextual information. Evaluating the data from these different sources enabled us to develop the optimal use guide and update it considering the best available clinical practices.
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7ceb9a11e96e5ff31d76e8f37871a0f5a952c69c
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cma
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To provide an evidence-based approach to the secondary prevention of ischemic stroke or transient ischemic attack (TIA).Secondary prevention refers to approaches to reduce the risk of recurrent vascular events in patients who have already suffered a stroke or TIA. Secondary prevention of ischemic stroke and TIA involves control of modifiable risk factors, antithrombotic therapy, and aetiology-specific interventions. Individualized education, counselling and therapeutic interventions aligned to the patient's values and preferences together with shared decision-making optimize engagement and long-term adherence to secondary prevention.# Positive lifestyle changes
# Healthy balanced diet:
- Promote a healthy diet, which comprises plenty of fresh fruits and vegetables, whole grain foods, proteins from plant sources (e.g., nuts, legumes), low-fat milk and diary products, and other low-fat sources of proteins (e.g., fish, lean meat, poultry). Recommend reducing saturated fat, cholesterol (<200 mg daily for patients at increased vascular risk) added sugars and sodium, and processed food. Evidence suggests that the Mediterranean-type or DASH (Dietary Approach to Stop Hypertension) diet reduces the occurrence of stroke. Refer patients to Canada's Food Guide ().
# Sodium intake:
- Target a sodium intake from all sources of <2,000mg daily). Inform patients that most salt intake comes from consuming processed foods.
# Physical activity:
- Encourage medical activity in medically stable patients. Target ≥10-minute episodes of aerobic exercise over 4-7 days per week, totalizing ≥150 minutes in addition to routine activities of daily living. Fitness assessment and the involvement of healthcare professionals (e.g., kinesiologist, physiotherapist) may help determine the type of exercise and appropriate intensity, considering functional limitations and co-morbidities. Weight:
- Target a BMI of 18.5 to 24.9 kg/m 2 or a waist circumference of <102 cm for men and <88 cm for women. Other targets may apply to non-Caucasian patients.
# Alcohol:
- Limit to 10 drinks per week, 2 drinks per day, or 3 drinks on any single occasion for women, and 15 drinks per week, 3 drinks per day or 4 on any single occasion for men (excluding pregnant women where any alcohol intake is not recommended).
# Smoking cessation:
- Address smoking cessation and a smoke-free environment at every healthcare encounter for active smokers. Three classes of pharmacological agents considered to be first-line agents for smoking cessation are: nicotine replacement therapy, varenicline and bupropion. - There is a lack of evidence regarding the timing to initiate nicotine replacement therapy in patients following a stroke. Expert opinion suggests this may begin as soon as it is medically appropriate and should take into consideration the stroke type and severity, patient interest, and physician comfort level. In general, nicotine replacement therapy is safer than continuing to smoke. - E-cigarettes may help quit smoking. However, evidence base around their population-based effectiveness is not clear. Furthermore, vaping may increase blood pressure. In addition, some smokers continue to vape even after quitting cigarettes, contrasting with nicotine replacement therapy. Most commonly individuals engage in both and a vascular risk modification strategy should target cessation of both modalities.
# Oral contraceptives and hormone replacement therapy:
- Advise most women of reproductive age who are at risk of recurrent ischemic stroke to avoid systemic estrogen-containing contraceptives. Management alternatives include progesteroneonly oral contraceptives, progesterone-only or non-hormonal intra-uterine devices, and barrier contraception. Following menopause, avoid hormone replacement therapy associated with thrombosis.
# Hypertension
Monitor blood pressure (BP):
- Hypertension is the single most important modifiable risk factor for stroke.
- Ideally, all patients should have their BP measured at each healthcare encounter and no less than once annually. - Standardized measurement techniques should be used as outlined by the Hypertension Canada guidelines. These can be reviewed at: /.
# Treat hypertension to established therapeutic targets:
- The ACE inhibitor and thiazide/thiazide-like diuretic combination is recommended following ischemic stroke or TIA. The ACE inhibitor and ARB combination is not recommended.
- Randomized trials have not defined the optimal time to initiate BP lowering therapy following stroke or TIA, but it should be initiated or modified after the acute phase and before discharge from hospital. - BP should be consistently <140/90 mm Hg in most patients (including those with nondiabetic chronic kidney disease), <130/80 mm Hg in diabetic patients. Furthermore, in patients with small subcortical strokes (lacunar strokes), systolic BP <130 mm Hg is reasonable. A similar target is reasonable for maintenance in patients with a history of intracerebral hemorrhage. - Higher BP targets might be considered to avoid hemodynamic stroke in patients with recent neurological deficits secondary to critical intracranial or extracranial arterial stenosis, but the previous BP targets hold in the long term.
# Dyslipidemia
Monitor dyslipidemia:
- Measure serum lipid levels (triglycerides, LDL-cholesterol, HDL-cholesterol, non-HDLcholesterol, total-cholesterol). Non-fasting testing is generally recommended. Fasting testing is used for patients with triglycerides >4.5 mmol/L. Treat dyslipidemia to therapeutic targets: - Treat aggressively, especially in patients with evidence of atherosclerosis or small artery disease (lacunar stroke). - Promote positive lifestyle changes, including lipid-lowering dietary changes and physical activity, to improve the lipid profile. - Use statin drugs to achieve an LDL-cholesterol level ≤1.8 mmol/L. - Consider treatment intensification in patients receiving maximally tolerated statin dose, including ezetimibe or PCSK9 inhibitors or both if LDL remains >1.8 mmol/L, and icosapen ethyl 2 g BID if triglycerides are ≥1.5 mmol/L in patients with cardiovascular disease or with diabetes plus additional vascular risk factors. - For more details refer to the Canadian Cardiovascular Society Guidelines 2021 ( ).
# Diabetes
Monitor diabetes:
- Screen for diabetes wither either a fasting plasma glucose, or 2-hour postprandial plasma glucose, or glycated hemoglobin (A1C), or 75 g oral glucose tolerance test. - Measure A1C in diabetic patients with stroke as part of their comprehensive assessment.
# Treat diabetes to established therapeutic targets:
- Most patients with diabetes and prior stroke or TIA should be treated to achieve a HbA1C level ≤ 7.0%. Most patients achieve this A1C target if preprandial or fasting blood glucose levels are at 4.0-7.0 mmol/L or if postprandial levels are at 5.0-10.0 mmol/L. - Sodium glucose-linked transporter 2 (SGLT-2) inhibitors (e.g., empagliflozin, canagliflozin) and glucagon like peptide 1 (GLP1) receptor agonists (e.g., liraglutide, semaglutide) should be considered in type 2 diabetic patients not at glycemic targets despite standard oral antihyperglycemic agents (metformin). - Refer to Diabetes Canada Guidelines for further information (). - In non-diabetic patients treated with pioglitazone for insulin resistance, the reduction of cardiovascular events is offset by increased risks of bone fracture and bladder cancer.
# ANTITHROMBOTIC THERAPY
# Antiplatelet treatment
Acute ischemic stroke or TIA:
- Antiplatelet treatment should be initiated as soon as possible following ischemic stroke or TIA, once intracerebral hemorrhage has been excluded by brain imaging. Ideally within 12 hours, and within 24 hours. - In ischemic stroke patients treated by intravenous thrombolysis, antiplatelet therapy should be initiated only after exclusion of a hemorrhagic transformation on repeat brain imaging done 24 hours after thrombolysis. In select cases, earlier treatment may be indicated -expert consultation with a stroke neurologist is recommended. - Ischemic stroke patients not already on antiplatelet agents should rapidly receive a loading dose of acetylsalicylic acid (ASA) of 160 mg, followed by 80 mg daily. Patients with ischemic stroke or TIA despite antiplatelet therapy should be assessed for treatment compliance and may be treated with the same agent or switched to another. - In patients with acute minor ischemic stroke (NIHSS <4) or TIA of noncardioembolic etiology, who are not at high risk of bleeding, the combination of clopidogrel (300 or 600 mg loading dose followed by 75 mg daily) and ASA (160 mg loading dose followed by 80 mg daily) is recommended for the first 21 days post-event, followed by antiplatelet monotherapy. The combination of ticagrelor (180 mg loading dose followed by 90 mg daily) and ASA is another reasonable option for the first 30 days post-event. - Dysphagia screening should precede oral administration of medications for all acute stroke patients. For patients with dysphagia, oral antiplatelet agents should be avoided. ASA be administered by enteral tube (80 mg daily) or rectal suppository (325 mg daily). Clopidogrel may be administered by enteral tube (75 mg daily).
# Long-term prophylaxis following ischemic stroke or TIA:
- Antiplatelet therapy is recommended, unless an anticoagulant treatment is indicated.
- Antiplatelet treatment options include ASA 80 to 325 mg daily, clopidogrel 75 mg daily, and combined ASA-dipyridamole extended-release 25/200 mg BID. - For patients with symptomatic stroke or TIA due to a culprit 70-99% intracranial stenosis, and low bleeding risk, the combination of ASA and clopidogrel should be considered for the first 3 months post-ischemic stroke or TIA, followed by indefinite treatment with a single antiplatelet agent. - In patients with coronary artery disease or peripheral vascular disease, low bleeding risk, no cardioembolic source for the index stroke and no history of lacunar or hemorrhagic stroke, rivaroxaban 2,5 mg bid may be combined to ASA 80 mg daily after the first month postischemic stroke or TIA.
# Anticoagulation for atrial fibrillation
Patients with ischemic stroke or TIA due to atrial fibrillation:
- The Clinical Guide: Stroke Prevention in Atrial Fibrillation can provide additional details.
- ASA is used in the acute phase of ischemic stroke (see above).
- Following the acute phase of ischemic stroke, oral anticoagulant therapy is strongly recommended, over single or dual antiplatelet therapy. Unless medically indicated otherwise (e.g., <1 year post-PCI), antiplatelet therapy is discontinued after the acute phase of stroke, once full-dose anticoagulation is achieved. Bridging with heparin is not recommended. - The optimal time to switch from ASA to oral anticoagulant treatment after the acute phase of stroke is undetermined. In general, full-dose anticoagulation is considered to be safe 3 days post-event for minor strokes and smaller brain infarcts, 6-7 days post-event for moderate severity strokes and moderate-sized infarcts, and 12-14 days post-event for severe strokes and larger infarcts. Repeat brain imaging is recommended <24 hours before initiating anticoagulant therapy to exclude the presence of hemorrhagic transformation of the brain infarct. - For patients experiencing TIA (no residual neurological symptoms and no acute infarct and hemorrhage on neuroimaging), anticoagulation may be started in the first 24 hours post-event (no ASA-bridging). - In atrial fibrillation patients experiencing ischemic stroke or TIA despite anticoagulant treatment, assess for and address other stroke aetiologies, anticoagulant nonadherence and underdosing, drug-drug interactions, and uncontrolled vascular risk factors. Adding ASA to anticoagulant treatment specifically for stroke prevention is not recommended because of increased bleeding risk without potential benefit.
# Patients with embolic stroke of uncertain source (ESUS):
- Atrial fibrillation can be present in a subgroup of ESUS patients; therefore, a thorough cardiac evaluation should be done to rule out underlying atrial fibrillation. In older (≥ 55 years) ESUS patients who do not have atrial fibrillation on one short term electrocardiographic monitoring (24-to 48-hour Holter), prolonged cardiac monitoring for at least 2 weeks is recommended. - At present there is no evidence to support empiric use of anticoagulation in ESUS patients.
# AETIOLOGY-SPECIFIC INTERVENTIONS
# Ischemic stroke or TIA secondary to atherosclerosis
- Patients with TIA or non-disabling stroke attributed to an ipsilateral 50-99% internal carotid artery (ICA) stenosis should be evaluated without delay by a health professional with stroke expertise to determine whether carotid revascularization is indicated. - CT-angiography or contrast-enhanced MR-angiography is recommended to confirm the degree of ICA stenosis and guide surgical decisions based on the vascular anatomy from the aortic arch to the intracranial arteries. Carotid ultrasound may be required if the degree of stenosis cannot be reliably established from CT-or MR-angiography. - In men with symptomatic 50-99% ICA stenosis and women with symptomatic 70-99% ICA stenosis, carotid revascularization (by endarterectomy or stenting) should be performed as soon as possible (ideally <14 days post-event). Women with symptomatic 50-69% ICA stenosis and high risk of recurrent event may also benefit from revascularization. The choice between endarterectomy or stenting requires expert consultation with the appropriate surgical service. - It may be reasonable to delay carotid intervention by 48 hours for moderate/ severe stroke to attenuate the perioperative risks. Index stroke severity and perioperative risks should always be balanced to the risk of early stroke recurrence. - The benefit of carotid revascularization is uncertain in patients with symptomatic 50-99% stenosis who survived to a moderate to severe stroke. - For patients with symptomatic vertebral artery or intracranial artery stenosis, medical therapy is recommended over revascularization procedures.
# Ischemic stroke or TIA secondary to cervicocephalic artery dissection
- Clinical markers of cervicocephalic artery dissection include: young age, predisposing connective tissue disease (e.g., Marfan, Ehler-Danlos), and neck trauma or extreme neck movement before stroke or TIA, and head or neck pain preceding ischemic stroke or TIA. - CT-or MR-angiography is recommended when cervicocephalic artery dissection is suspected.
- There is uncertainty about the efficacy of treatment comparing antiplatelet threapy versys anticoagulation for cervicocephalic dissection; treatment with either option is reasonable.
The treatment modality (anticoagulation with heparin or warfarin or antiplatelets) should be based on the estimated risks and benefits based on information from clinical features, brain imaging (infarct size, hemorrhagic transformation), vascular imaging (dissection location and severity, intraluminal thrombus, pseudoaneurysm), and estimated bleeding risks. - The optimal duration of antithrombotic treatment is unknown. Variables such as residual vascular changes, prior or multiple dissections, predisposing conditions are typically considered on an individual basis.
# Ischemic stroke or TIA secondary to patent foramen ovale
- Patients with an ischemic stroke or TIA attributed to a patent foramen ovale (PFO) should be evaluated without delay by a health professional with stroke and cardiovascular expertise. - In patients with PFO, clinical markers of causality include: young age, Valsalva manoeuvre at onset of ischemic stroke or TIA, physiological or cardiopulmonary conditions associated with an increased right-to-left pressure gradient, suspected or documented thromboembolic events, and non-lacunar symptoms. - Echocardiographic markers of causality include: atrial septal aneurysm, large right-to-left shunt (e.g., >20 microbubbles), and large PFO diameter (≥2 mm). - Long-term antithrombotic treatment is recommended in patients with ischemic stroke attributed to PFO.
- Antiplatelet therapy and percutaneous PFO closure are recommended in patients aged 18-60 years with a recent nonlacunar ischemic stroke attributed to PFO and exclusion of other causes from a thorough aetiological investigation. - The benefit of PFO closure for patients requiring long-term anticoagulation for another indication is uncertain. - It is reasonable to not proceed with PFO closure for patients who have none of the following higher-risk anatomical features on echocardiography: (a) atrial septal aneurysm; (b) large right-to-left shunt (e.g., >20 microbubbles); and (c) large diameter PFO (e.g., ≥2 mm) (from the guidelin - In patients with stroke attributable to a PDF, who do not undergo PFO closure, and are aged 60 or younger, either antiplatelet or anticoagulation is reasonable.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Acetylsalicylic Acid (ASA)
- Cancer and thrombosis - Cerebral venous thrombosis - Clopidogrel (Plavix®)
- Rivaroxaban (Xarelto®)
- Stroke Prevention in Atrial Fibrillation - Thrombophilia: Antiphospholipid Antibody Syndrome
# Date of Version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To provide an evidence-based approach to the secondary prevention of ischemic stroke or transient ischemic attack (TIA).Secondary prevention refers to approaches to reduce the risk of recurrent vascular events in patients who have already suffered a stroke or TIA. Secondary prevention of ischemic stroke and TIA involves control of modifiable risk factors, antithrombotic therapy, and aetiology-specific interventions. Individualized education, counselling and therapeutic interventions aligned to the patient's values and preferences together with shared decision-making optimize engagement and long-term adherence to secondary prevention.# Positive lifestyle changes
# Healthy balanced diet:
• Promote a healthy diet, which comprises plenty of fresh fruits and vegetables, whole grain foods, proteins from plant sources (e.g., nuts, legumes), low-fat milk and diary products, and other low-fat sources of proteins (e.g., fish, lean meat, poultry). Recommend reducing saturated fat, cholesterol (<200 mg daily for patients at increased vascular risk) added sugars and sodium, and processed food. Evidence suggests that the Mediterranean-type or DASH (Dietary Approach to Stop Hypertension) diet reduces the occurrence of stroke. Refer patients to Canada's Food Guide (https://food-guide.canada.ca).
# Sodium intake:
• Target a sodium intake from all sources of <2,000mg daily). Inform patients that most salt intake comes from consuming processed foods.
# Physical activity:
• Encourage medical activity in medically stable patients. Target ≥10-minute episodes of aerobic exercise over 4-7 days per week, totalizing ≥150 minutes in addition to routine activities of daily living. Fitness assessment and the involvement of healthcare professionals (e.g., kinesiologist, physiotherapist) may help determine the type of exercise and appropriate intensity, considering functional limitations and co-morbidities. Weight:
• Target a BMI of 18.5 to 24.9 kg/m 2 or a waist circumference of <102 cm for men and <88 cm for women. Other targets may apply to non-Caucasian patients.
# Alcohol:
• Limit to 10 drinks per week, 2 drinks per day, or 3 drinks on any single occasion for women, and 15 drinks per week, 3 drinks per day or 4 on any single occasion for men (excluding pregnant women where any alcohol intake is not recommended).
# Smoking cessation:
• Address smoking cessation and a smoke-free environment at every healthcare encounter for active smokers. Three classes of pharmacological agents considered to be first-line agents for smoking cessation are: nicotine replacement therapy, varenicline and bupropion. • There is a lack of evidence regarding the timing to initiate nicotine replacement therapy in patients following a stroke. Expert opinion suggests this may begin as soon as it is medically appropriate and should take into consideration the stroke type and severity, patient interest, and physician comfort level. In general, nicotine replacement therapy is safer than continuing to smoke. • E-cigarettes may help quit smoking. However, evidence base around their population-based effectiveness is not clear. Furthermore, vaping may increase blood pressure. In addition, some smokers continue to vape even after quitting cigarettes, contrasting with nicotine replacement therapy. Most commonly individuals engage in both and a vascular risk modification strategy should target cessation of both modalities.
# Oral contraceptives and hormone replacement therapy:
• Advise most women of reproductive age who are at risk of recurrent ischemic stroke to avoid systemic estrogen-containing contraceptives. Management alternatives include progesteroneonly oral contraceptives, progesterone-only or non-hormonal intra-uterine devices, and barrier contraception. Following menopause, avoid hormone replacement therapy associated with thrombosis.
# Hypertension
Monitor blood pressure (BP):
• Hypertension is the single most important modifiable risk factor for stroke.
• Ideally, all patients should have their BP measured at each healthcare encounter and no less than once annually. • Standardized measurement techniques should be used as outlined by the Hypertension Canada guidelines. These can be reviewed at: http://guidelines.hypertension.ca/diagnosisassessment/measuring-blood-pressure/.
# Treat hypertension to established therapeutic targets:
• The ACE inhibitor and thiazide/thiazide-like diuretic combination is recommended following ischemic stroke or TIA. The ACE inhibitor and ARB combination is not recommended.
• Randomized trials have not defined the optimal time to initiate BP lowering therapy following stroke or TIA, but it should be initiated or modified after the acute phase and before discharge from hospital. • BP should be consistently <140/90 mm Hg in most patients (including those with nondiabetic chronic kidney disease), <130/80 mm Hg in diabetic patients. Furthermore, in patients with small subcortical strokes (lacunar strokes), systolic BP <130 mm Hg is reasonable. A similar target is reasonable for maintenance in patients with a history of intracerebral hemorrhage. • Higher BP targets might be considered to avoid hemodynamic stroke in patients with recent neurological deficits secondary to critical intracranial or extracranial arterial stenosis, but the previous BP targets hold in the long term.
# Dyslipidemia
Monitor dyslipidemia:
• Measure serum lipid levels (triglycerides, LDL-cholesterol, HDL-cholesterol, non-HDLcholesterol, total-cholesterol). Non-fasting testing is generally recommended. Fasting testing is used for patients with triglycerides >4.5 mmol/L. Treat dyslipidemia to therapeutic targets: • Treat aggressively, especially in patients with evidence of atherosclerosis or small artery disease (lacunar stroke). • Promote positive lifestyle changes, including lipid-lowering dietary changes and physical activity, to improve the lipid profile. • Use statin drugs to achieve an LDL-cholesterol level ≤1.8 mmol/L. • Consider treatment intensification in patients receiving maximally tolerated statin dose, including ezetimibe or PCSK9 inhibitors or both if LDL remains >1.8 mmol/L, and icosapen ethyl 2 g BID if triglycerides are ≥1.5 mmol/L in patients with cardiovascular disease or with diabetes plus additional vascular risk factors. • For more details refer to the Canadian Cardiovascular Society Guidelines 2021 (https://doi.org/10.1016/j.cjca.2021.03.016 ).
# Diabetes
Monitor diabetes:
• Screen for diabetes wither either a fasting plasma glucose, or 2-hour postprandial plasma glucose, or glycated hemoglobin (A1C), or 75 g oral glucose tolerance test. • Measure A1C in diabetic patients with stroke as part of their comprehensive assessment.
# Treat diabetes to established therapeutic targets:
• Most patients with diabetes and prior stroke or TIA should be treated to achieve a HbA1C level ≤ 7.0%. Most patients achieve this A1C target if preprandial or fasting blood glucose levels are at 4.0-7.0 mmol/L or if postprandial levels are at 5.0-10.0 mmol/L. • Sodium glucose-linked transporter 2 (SGLT-2) inhibitors (e.g., empagliflozin, canagliflozin) and glucagon like peptide 1 (GLP1) receptor agonists (e.g., liraglutide, semaglutide) should be considered in type 2 diabetic patients not at glycemic targets despite standard oral antihyperglycemic agents (metformin). • Refer to Diabetes Canada Guidelines for further information (http://guidelines.diabetes.ca/cpg/chapter23). • In non-diabetic patients treated with pioglitazone for insulin resistance, the reduction of cardiovascular events is offset by increased risks of bone fracture and bladder cancer.
# ANTITHROMBOTIC THERAPY
# Antiplatelet treatment
Acute ischemic stroke or TIA:
• Antiplatelet treatment should be initiated as soon as possible following ischemic stroke or TIA, once intracerebral hemorrhage has been excluded by brain imaging. Ideally within 12 hours, and within 24 hours. • In ischemic stroke patients treated by intravenous thrombolysis, antiplatelet therapy should be initiated only after exclusion of a hemorrhagic transformation on repeat brain imaging done 24 hours after thrombolysis. In select cases, earlier treatment may be indicated -expert consultation with a stroke neurologist is recommended. • Ischemic stroke patients not already on antiplatelet agents should rapidly receive a loading dose of acetylsalicylic acid (ASA) of 160 mg, followed by 80 mg daily. Patients with ischemic stroke or TIA despite antiplatelet therapy should be assessed for treatment compliance and may be treated with the same agent or switched to another. • In patients with acute minor ischemic stroke (NIHSS <4) or TIA of noncardioembolic etiology, who are not at high risk of bleeding, the combination of clopidogrel (300 or 600 mg loading dose followed by 75 mg daily) and ASA (160 mg loading dose followed by 80 mg daily) is recommended for the first 21 days post-event, followed by antiplatelet monotherapy. The combination of ticagrelor (180 mg loading dose followed by 90 mg daily) and ASA is another reasonable option for the first 30 days post-event. • Dysphagia screening should precede oral administration of medications for all acute stroke patients. For patients with dysphagia, oral antiplatelet agents should be avoided. ASA be administered by enteral tube (80 mg daily) or rectal suppository (325 mg daily). Clopidogrel may be administered by enteral tube (75 mg daily).
# Long-term prophylaxis following ischemic stroke or TIA:
• Antiplatelet therapy is recommended, unless an anticoagulant treatment is indicated.
• Antiplatelet treatment options include ASA 80 to 325 mg daily, clopidogrel 75 mg daily, and combined ASA-dipyridamole extended-release 25/200 mg BID. • For patients with symptomatic stroke or TIA due to a culprit 70-99% intracranial stenosis, and low bleeding risk, the combination of ASA and clopidogrel should be considered for the first 3 months post-ischemic stroke or TIA, followed by indefinite treatment with a single antiplatelet agent. • In patients with coronary artery disease or peripheral vascular disease, low bleeding risk, no cardioembolic source for the index stroke and no history of lacunar or hemorrhagic stroke, rivaroxaban 2,5 mg bid may be combined to ASA 80 mg daily after the first month postischemic stroke or TIA.
# Anticoagulation for atrial fibrillation
Patients with ischemic stroke or TIA due to atrial fibrillation:
• The Clinical Guide: Stroke Prevention in Atrial Fibrillation can provide additional details.
• ASA is used in the acute phase of ischemic stroke (see above).
• Following the acute phase of ischemic stroke, oral anticoagulant therapy is strongly recommended, over single or dual antiplatelet therapy. Unless medically indicated otherwise (e.g., <1 year post-PCI), antiplatelet therapy is discontinued after the acute phase of stroke, once full-dose anticoagulation is achieved. Bridging with heparin is not recommended. • The optimal time to switch from ASA to oral anticoagulant treatment after the acute phase of stroke is undetermined. In general, full-dose anticoagulation is considered to be safe 3 days post-event for minor strokes and smaller brain infarcts, 6-7 days post-event for moderate severity strokes and moderate-sized infarcts, and 12-14 days post-event for severe strokes and larger infarcts. Repeat brain imaging is recommended <24 hours before initiating anticoagulant therapy to exclude the presence of hemorrhagic transformation of the brain infarct. • For patients experiencing TIA (no residual neurological symptoms and no acute infarct and hemorrhage on neuroimaging), anticoagulation may be started in the first 24 hours post-event (no ASA-bridging). • In atrial fibrillation patients experiencing ischemic stroke or TIA despite anticoagulant treatment, assess for and address other stroke aetiologies, anticoagulant nonadherence and underdosing, drug-drug interactions, and uncontrolled vascular risk factors. Adding ASA to anticoagulant treatment specifically for stroke prevention is not recommended because of increased bleeding risk without potential benefit.
# Patients with embolic stroke of uncertain source (ESUS):
• Atrial fibrillation can be present in a subgroup of ESUS patients; therefore, a thorough cardiac evaluation should be done to rule out underlying atrial fibrillation. In older (≥ 55 years) ESUS patients who do not have atrial fibrillation on one short term electrocardiographic monitoring (24-to 48-hour Holter), prolonged cardiac monitoring for at least 2 weeks is recommended. • At present there is no evidence to support empiric use of anticoagulation in ESUS patients.
# AETIOLOGY-SPECIFIC INTERVENTIONS
# Ischemic stroke or TIA secondary to atherosclerosis
• Patients with TIA or non-disabling stroke attributed to an ipsilateral 50-99% internal carotid artery (ICA) stenosis should be evaluated without delay by a health professional with stroke expertise to determine whether carotid revascularization is indicated. • CT-angiography or contrast-enhanced MR-angiography is recommended to confirm the degree of ICA stenosis and guide surgical decisions based on the vascular anatomy from the aortic arch to the intracranial arteries. Carotid ultrasound may be required if the degree of stenosis cannot be reliably established from CT-or MR-angiography. • In men with symptomatic 50-99% ICA stenosis and women with symptomatic 70-99% ICA stenosis, carotid revascularization (by endarterectomy or stenting) should be performed as soon as possible (ideally <14 days post-event). Women with symptomatic 50-69% ICA stenosis and high risk of recurrent event may also benefit from revascularization. The choice between endarterectomy or stenting requires expert consultation with the appropriate surgical service. • It may be reasonable to delay carotid intervention by 48 hours for moderate/ severe stroke to attenuate the perioperative risks. Index stroke severity and perioperative risks should always be balanced to the risk of early stroke recurrence. • The benefit of carotid revascularization is uncertain in patients with symptomatic 50-99% stenosis who survived to a moderate to severe stroke. • For patients with symptomatic vertebral artery or intracranial artery stenosis, medical therapy is recommended over revascularization procedures.
# Ischemic stroke or TIA secondary to cervicocephalic artery dissection
• Clinical markers of cervicocephalic artery dissection include: young age, predisposing connective tissue disease (e.g., Marfan, Ehler-Danlos), and neck trauma or extreme neck movement before stroke or TIA, and head or neck pain preceding ischemic stroke or TIA. • CT-or MR-angiography is recommended when cervicocephalic artery dissection is suspected.
• There is uncertainty about the efficacy of treatment comparing antiplatelet threapy versys anticoagulation for cervicocephalic dissection; treatment with either option is reasonable.
The treatment modality (anticoagulation with heparin or warfarin or antiplatelets) should be based on the estimated risks and benefits based on information from clinical features, brain imaging (infarct size, hemorrhagic transformation), vascular imaging (dissection location and severity, intraluminal thrombus, pseudoaneurysm), and estimated bleeding risks. • The optimal duration of antithrombotic treatment is unknown. Variables such as residual vascular changes, prior or multiple dissections, predisposing conditions are typically considered on an individual basis.
# Ischemic stroke or TIA secondary to patent foramen ovale
• Patients with an ischemic stroke or TIA attributed to a patent foramen ovale (PFO) should be evaluated without delay by a health professional with stroke and cardiovascular expertise. • In patients with PFO, clinical markers of causality include: young age, Valsalva manoeuvre at onset of ischemic stroke or TIA, physiological or cardiopulmonary conditions associated with an increased right-to-left pressure gradient, suspected or documented thromboembolic events, and non-lacunar symptoms. • Echocardiographic markers of causality include: atrial septal aneurysm, large right-to-left shunt (e.g., >20 microbubbles), and large PFO diameter (≥2 mm). • Long-term antithrombotic treatment is recommended in patients with ischemic stroke attributed to PFO.
• Antiplatelet therapy and percutaneous PFO closure are recommended in patients aged 18-60 years with a recent nonlacunar ischemic stroke attributed to PFO and exclusion of other causes from a thorough aetiological investigation. • The benefit of PFO closure for patients requiring long-term anticoagulation for another indication is uncertain. • It is reasonable to not proceed with PFO closure for patients who have none of the following higher-risk anatomical features on echocardiography: (a) atrial septal aneurysm; (b) large right-to-left shunt (e.g., >20 microbubbles); and (c) large diameter PFO (e.g., ≥2 mm) (from the guidelin • In patients with stroke attributable to a PDF, who do not undergo PFO closure, and are aged 60 or younger, either antiplatelet or anticoagulation is reasonable.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Acetylsalicylic Acid (ASA)
• Cancer and thrombosis • Cerebral venous thrombosis • Clopidogrel (Plavix®)
• Rivaroxaban (Xarelto®)
• Stroke Prevention in Atrial Fibrillation • Thrombophilia: Antiphospholipid Antibody Syndrome
# Date of Version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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This article provides guidance on managing acute kidney injury (AKI) and kidney replacement therapy (KRT) in pediatrics during the COVID-19 pandemic in the Canadian context. It is adapted from recently published rapid guidelines on the management of AKI and KRT in adults, from the Canadian Society of Nephrology (CSN). The goal is to provide the best possible care for pediatric patients with kidney disease during the pandemic and ensure the health care team's safety. Information sources: The Canadian Association of Paediatric Nephrologists (CAPN) COVID-19 Rapid Response team derived these rapid guidelines from the CSN consensus recommendations for adult patients with AKI. We have also consulted specific documents from other national and international agencies focused on pediatric kidney health. We identified additional information by reviewing the published academic literature relevant to pediatric AKI and KRT, including recent journal articles and preprints related to COVID-19 in children. Finally, our group also sought expert opinions from pediatric nephrologists across Canada. Methods: The leadership of the CAPN, which is affiliated with the CSN, solicited a team of clinicians and researchers with expertise in pediatric AKI and acute KRT. The goal was to adapt the guidelines recently adopted for Canadian adult patients for pediatric-specific settings. These included specific COVID-19-related themes relevant to AKI and KRT in a Canadian setting, as determined by a group of kidney disease experts and leaders. An expert group of clinicians in pediatric AKI and acute KRT reviewed the revised pediatric guidelines. Key findings: (1) Current Canadian data do not suggest an imminent threat of an increase in acute KRT needs in children because of COVID-19; however, close coordination between nephrology programs and critical care programs is crucial as the pandemic continues to evolve. (2) Pediatric centers should prepare to reallocate resources to adult centers as needed based on broader health care needs during the COVID-19 pandemic. (3) Specific suggestions pertinent to the optimal management of AKI and KRT in COVID-19 patients are provided. These suggestions include but are not limited to aspects of fluid management, KRT vascular access, and KRT modality choice. (4) Considerations to ensure adequate provision of KRT if resources become scarce during the COVID-19 pandemic. Limitations: We did not conduct a formal systematic review or meta-analysis. We did not evaluate our specific suggestions in the clinical environment. The local context, including how the provision of care for AKI and acute KRT is organized, may impede the implementation of many suggestions. As knowledge is advancing rapidly in the area of COVID-19, suggestions may become outdated quickly. Finally, most of the literature for AKI and KRT in COVID-19 comes from adult data, and there are few pediatric-specific studies. Implications: Given that most acute KRT related to COVID-19 is likely to be required in the pediatric intensive care unit initial setting, close collaboration and planning between critical care and pediatric nephrology programs are needed. Our group will update these suggestions with a supplement if necessary as newer evidence becomes available that may change or add to the recommendations provided.# Introduction
Reports of children with symptomatic COVID-19 infections continue to grow. There are no clear data on the incidence of acute kidney injury (AKI) in children at this time because there are so few cases thus far. Below, we will present an overview of relevant pediatric data from China, Europe, and North America, a summary of similar data from adult studies, and a discussion on the evidence linking AKI with the new condition referred to as "multisystem inflammatory syndrome" (MIS). We will then introduce critical concepts for the safe management of pediatric patients diagnosed with AKI before presenting the detailed guidelines.
# COVID-19 Infection and AKI: Pediatric Data From China
Four studies from China strongly suggest that pediatric COVID-19 is rare 1,2 and rarely requires intensive care. In the largest (n = 72 314 cases), the Chinese Center for Disease Control and Prevention reported that ~2% of all cases were less than 18 years of age. 1 In a screening study of 745 children, 10 (1.3%) had confirmed AKI. Ten patients required admission to the hospital, but none required intensive care. 3 The only center allowed to treat pediatric COVID-19 in the Wuhan region found 171 confirmed cases after testing 1391 children aged less than 16 years (12.3%): Of these, 3 required intensive care (1.7% of positive cases). 4 All 3 patients had AKI based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria and, importantly, all had preexisting conditions (hydronephrosis, leukemia, and intussusception). 4 They were treated with plasma exchange and continuous kidney replacement therapy (CKRT), resulting in 1 complete recovery, 1 partial recovery, and 1 death. 5 Finally, in a study focused on 2135 cases of pediatric COVID-19 (35% confirmed), the likelihood of critical disease (defined by the presence of life-threatening organ dysfunction) was highest in children aged less than 1 year (7/376, or ~1.9%) and substantially lower for the others (~0.3%-0.5%). 6 Unfortunately, none of these studies provided data on AKI or kidney replacement therapy (KRT). One case report of a critically ill infant with COVID-19 reported mild AKI. The infant had a history of preexisting conditions (cardiac surgery and recurrent pneumonia). 7 Furthermore, of 1065 cases from 18 studies, only 1 infant presented with pneumonia, complicated by shock and kidney failure, which required dialysis. Fortunately, the infant recovered with supportive treatment. 8
# COVID-19 Infection and AKI: Pediatric Data From Europe
Emerging data from European centers paint a similar picture. For example, Spanish investigators identified pediatric COVID-19 in ~1% of all confirmed cases from Madrid (41 of 4695). Of these, 4 patients (~10%) required intensive care. 2 In Italy, ~1.2% of cases were children below 18 years of age. None of those patients died. 9 Both studies reported no fatalities but did not include data on the incidence of AKI.
# COVID-19 Infection and AKI: Pediatric Data From North America
A cross-sectional study from 46 US and Canadian pediatric intensive care units (PICUs) which focused on 1 month starting in mid-March 2020 revealed 48 cases of critical pediatric COVID-19 (none from Canada). Most of these patients (83%) had preexisting comorbidities, such as complex syndromes (46%) or requiring immunosuppression (23%). While the treating team did not use KRT (and there are no data on AKI incidence), 1 patient required extracorporeal membrane oxygenation and 2 patients (4%) died. 10 Another multicenter cross-sectional study found a high prevalence of AKI among critically ill children with COVID-19 (44%). No child received dialysis. Most children with AKI had at least 1 comorbidity (n = 28, 60%). Three in the AKI group (6%) died. 11 In New York, a 16-year-old patient with COVID-19associated rhabdomyolysis did not develop AKI, possibly because of early fluid therapy. 12 This condition has also been described in adult patients 13 of whom a subset developed AKI.
# COVID-19 Infection and AKI: Brief Overview of Adult Data
Even in adults, AKI remains poorly defined for COVID-19 due to variations in testing rates, the case fatality rate, and the risk of other outcomes. The reported incidence of AKI across available preprints and published studies ranges from 0.5% to 39% (Table 1). Studies that reported rates of COVID-19-related AKI primarily involved hospitalized patients with the majority requiring KRT. These data suggest that except for 2 studies that reported AKI stratified according to KDIGO criteria, 25,26 published studies and preprints generally have focused on severe AKI requiring KRT (AKI-KRT) only.
# Multisystem Inflammatory Syndrome and AKI
Of particular relevance to pediatrics is the emergence of the new condition associated with COVID-19, now referred to as reported MIS. In April 2020, physicians in London, England, reported a cluster of 8 children presenting with features similar to Kawasaki disease or toxic shock syndrome, 1 of whom required KRT. 31 Common clinical features included gastrointestinal symptoms, rashes, mucous membrane changes, adenopathy, myocarditis, and fever lasting more than 5 days. 31 Many of these children had exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and several tested positive for SARS-CoV-2. 31 After this initial publication, a team in Paris, France, reported the most extensive case series to date, describing 17 patients with apparent Kawasaki disease presenting over 11 days. From this group, 8 (47%) developed AKI and 14 (82%) had SARS-CoV-2 IgG antibodies. 32 A team in Italy reported a 30-fold increase in the incidence of a Kawasaki-like disease categorized as MIS during the COVID-19 pandemic. 33 Multiple subsequent case reports of patients with MIS associated with SARS-CoV-2 describe varying degrees of endorgan involvement, including AKI. The pathophysiology of this syndrome remains unclear, and details of patients' clinical and biochemical markers related to AKI are scarce. Pediatric MIS remains an emerging entity, and measurement of incidence is challenging, though estimated to be less than 1% in children with COVID-19 infection. 39 As larger cohorts are available, the true incidence of AKI in this population may become more apparent.
# Medical Management and KRT in AKI in Children With COVID-19
While acute respiratory distress syndrome (ARDS) is the predominant clinical issue for critically ill pediatric patients, it is crucial to acknowledge that the clinical presentation is variable in children with COVID-19. For those with AKI, the overarching goal is to avoid volume overload. There are no specific therapies for AKI in children with COVID-19, and traditional AKI management principles should guide clinical decision-making. Unsurprisingly, volume overload appears to be the most likely indication for initiating acute KRT in these patients. 43,45 There is insufficient evidence to recommend any particular KRT modality. As such, providers should individualize treatment options and use existing institutional protocols for KRT prescription to meet each patient's needs based on their clinical status. Given the burden of ARDS in these children, providers should anticipate difficulty with ventilation and prone positioning, limiting the feasibility of peritoneal dialysis (PD).
# Risk Reduction and Resource Management of KRT During the COVID-19 Pandemic
Every interaction between a health care worker and a patient with suspected or confirmed COVID-19 requires personal protective equipment (PPE) and, even with its careful use, carries a risk of transmission of COVID-19. Every effort to minimize these interactions is justified. Techniques that optimize physical distancing between providers and patients with COVID-19 should be balanced with providing the best quality of care to patients. This includes the use of specialized equipment such as KRT extension tubing and remote dialysis technology, if available. Also, close coordination between nephrologists and intensivists minimizes the number of providers entering a patient room for routine assessments.
While current Canadian data do not suggest an imminent risk of KRT equipment shortage in children, providers should remain informed of up-to-date data and public health officials' recommendations. Should there be a significant rise in the incidence of severe pediatric COVID-19 disease at a local or national level, consideration should be given to efficient resource allocation. These choices could include using intermittent hemodialysis (IHD) or shorter time CKRT sessions in the face of a CKRT machine shortage, redeployment of trained dialysis staff to intensive care units as needed, and consideration for the use of home dialysis machines or PD if experiencing an IHD machine shortage. At a broader health care level, should there be a rise in severe COVID-19 illness in adult patients, the treating team may have to consider reallocation of equipment, sharing of hospital space, or redeployment of staff to care for adult patients.
# Canadian Association of Paediatric Nephrologists COVID-19 Rapid Response: Guidelines for Management of AKI in Children
# Purpose
Acute kidney injury is a potential complication of COVID-19-associated critical illness in children. The burden of COVID-19-associated AKI, as well as the unique features of this condition, has implications for the delivery of acute KRT.
Nephrology programs across the country are developing policies in this rapidly changing environment. The Canadian Association of Paediatric Nephrologists (CAPN), in close collaboration with the Canadian Society of Nephrology (CSN), has synthesized guidance documents from the broader pediatric nephrology community to provide the best care to the largest number of children with kidney disease while also ensuring the safety of the health care team.
# Principles
The following principles guided our work:
- Uncertainty-an acknowledgment that clinicians and administrators are now working in a swiftly evolving environment which will require decision-making with limited resources and levels of uncertainty that are higher than usual. 2. Macroallocation-an acknowledgment that the local context and local government priorities will shape decision-making. Those previous sacrosanct standards may need to be temporarily adjusted to maximize health outcomes for the most significant number of patients. 3. Minimize net harm-limit the spread of disease and the disruption to the health care system. 4. Reciprocity-protect our health care workforce from COVID-19, and secondarily, so that staffing levels needed for the delivery of care to patients who, by definition, require physical interventions are maintained. 5. Fairness-ensure that patients with kidney disease continue to receive appropriate treatments, regardless of their COVID-19 status and avoid outcomes that disproportionately affect those most vulnerable (eg, lower socioeconomic status). 6. Proportionality-keep restrictions on staff and patients commensurate with the level of risk to public health. 7. Respect for autonomy-continue to reflect patient and family values and beliefs as much as possible, granting that choices may be limited in a pandemic. 8. Fidelity-maintain commitment to patients to provide necessary care, even through challenging times and when there is a degree of risk to providers).
# Information Sources
# Methods
The CAPN, which is affiliated with the CSN, solicited a team of clinicians and researchers with expertise in pediatric AKI and acute KRT. The goal was to adapt the recently developed Canadian adult COVID-19-related AKI guidelines 46 for pediatric-specific settings. These included specific COVID-19-related themes that are relevant to AKI and KRT in a Canadian setting, as determined by a group of pediatric nephrologists. The revised pediatric guidelines were reviewed by a group of experts in pediatric AKI and acute KRT. We then held a Webinar, hosted by CAPN to invite pediatric nephrologists and other health care workers around the country to review the guidelines and provide feedback before the document was finalized.
We reproduced the guidance of the adult AKI continuous renal replacement therapy working group verbatim, unless the pediatric group intended a change, in which case this is highlighted. The adult rationale is reproduced either verbatim or condensed. We added, where available, pediatric context and considerations, and justify our differences from the adult AKI guidance. For many questions, no pediatric-specific data were available and no specific considerations applied. We have chosen to reproduce the adult guidelines in their entirety and include the adult nephrologists who wrote them on our writing team. We chose this approach rather than writing a document about the differences. The article would be easy to read for pediatric nephrologists and would stand alone as a useful reference and resource.
# Key Issues and Suggestions/ Considerations
# Planning for Capacity to Provide Acute KRT
We suggest planning for a 25% to 30% increase in the acute pediatric KRT capacity even though the prevalence of pediatric COVID-19 is low. This would help provide flexibility to allocate resources to adult centers as needed based on how the pandemic evolves over time.
Rationale/comments. Report of children with symptomatic COVID-19 infections is growing. At this time, there are no precise data to suggest the incidence of AKI in this population. This is likely related to the low incidence and severity of this disease in children as previously discussed above.
Lipton et al from Columbia University published an editorial commentary on the role of pediatric nephrologists in managing adults with AKI due to COVID-19. The authors share their mutually beneficial experience of pediatric to adult redeployment. The capacity of the PICU was expanded by 50% (from 41 to 60 beds), and all levels of pediatric providers worked on the front line in response to the growing demand during the pandemic. This specifically helped offload the volume of adults requiring CKRT at the adult hospital. 47 At present, COVID-19 rates in Canada are increasing after a previous downtrend. Should there be a reemergence of severe COVID-19 hospitalization rates in adults requiring increased KRT needs, consideration should be given to redeploying staff and reallocating equipment from pediatric centers to support adult patients requiring KRT, provided severe pediatric COVID-19 incidence remains unchanged.
# Management of AKI and KRT
This section provides an overview of relevant considerations. We appreciate there is a wide variation in the relative responsibilities of pediatric nephrology and PICU programs in the management of KRT in children in the PICU across Canada. Local circumstances should be taken into account in applying our suggestions. Close collaboration between pediatric nephrology and PICU programs at the local level will be required to plan for the potentially increased demands as the COVID-19 pandemic continues to evolve.
# Fluid Management
# These Suggestions are Aligned With Adult AKI Guidance, Except Where the Reason for the Change Is Discussed
We suggest judicious fluid administration to target euvolemia and avoid fluid overload while factoring that insensible losses may be very high in patients with persistent or recurrent fevers Rationale (from adult AKI guidance). The predominant clinical issue for critically ill patients with COVID-19 is ARDS: We, therefore, recommend avoiding fluid overload. However, we recognize that assessing volume status may be challenging, and a dogmatic approach to keeping patients as dry as possible should be avoided. Insensible losses in those with unremitting or recurrent fevers may be significantly increased, 48 and an overly aggressive approach to diuresis or ultrafiltration with KRT could carry potential increased risks of death 49 and longer term cognitive impairment 50 as a consequence of more frequent hypotensive episodes. 50,51 Pediatric context. We did not find pediatric-specific data.
We suggest that, under most circumstances, direct examination of patients admitted to PICU with suspected or confirmed COVID-19 does not need to be routinely performed by the nephrology consultation service Rationale (from adult AKI guidance). Information on physical findings should be sought from health care workers who have other reasons to enter the room. In addition to the usual chart-based data that inform ultrafiltration prescription for KRT, close consultation with PICU colleagues and nurses will be required. Similarly, investigations that are part of the routine assessment of patients with AKI, including urinalysis and kidney ultrasonography, may be deferred unless they are thought to influence clinical management. Adopting these practices will decrease risk to health care workers, decrease the risk of nosocomial transmission, and decrease PPE use, a scarce resource.
Pediatric context. We did not find pediatric-specific data.
We recommend that starches, gelatins, and hypotonic crystalloids should not be used for resuscitation Rationale (from adult AKI guidance). Starches and gelatins should not be used for resuscitation 40,41 because they have been shown in randomized trials to cause an increased risk of death and AKI in adults 52,53 ; hypotonic solutions such as half-normal saline should not be used for resuscitation as they are less effective at increasing intravascular volume compared with isotonic solutions. 40 Pediatric context. We did not find pediatric-specific data.
# Timing of Initiation of KRT
We recommend that traditional indications for starting KRT should be used in patients with COVID- 19 Rationale (from adult AKI guidance). In recent years, several trials provided evidence regarding the optimal timing of KRT initiation for critically ill patients with AKI. For example, STARRT-AKI trial did not show any benefit of starting KRT early among critically ill adults. 57,58 A recent systematic review of nearly 2000 patients from 9 studies randomly allocated to earlier or later initiation found no benefit for earlier initiation. 59 In the context of the COVID-19 pandemic, with limited KRT resources, we recommend using traditional indications to decide on the timing of KRT initiation. We anticipate that volume overload will be the predominant trigger to start KRT in COVID-19 patients with AKI.
Pediatric context. Observational studies have yielded mixed results regarding outcomes of early compared with late initiation of KRT in critically ill children.
# Modality Choice
We suggest that, during the COVID-19 pandemic, nephrology programs should primarily continue to use acute KRT modalities with which they have the most expertise Rationale (from adult AKI guidance). Clinical trials comparing CKRT, IHD, and sustained low-efficiency dialysis (SLED) have not demonstrated improved survival with any particular modality. 64,65 A sepsis-like syndrome, characterized by profound shock, and presumably related to high levels of circulating cytokines (referred to as "cytokine storm"), has been reported as a frequent complication of COVID-19 24,66 including reports of "hyperinflammatory shock" related to multi-inflammatory syndrome in children. 67 Kidney replacement therapy modalities that include convection, such as high-volume hemofiltration, are superior at removing larger molecules, such as cytokines; however, both proinflammatory and anti-inflammatory cytokines are removed. To date, randomized trials of septic AKI patients without COVID-19 demonstrate no additional benefit with convective-based therapies. 68,69 Also, high-volume hemofiltration involves the use of very large volumes of replacement solution, which could become scarce in the context of increased KRT use during the COVID-19 pandemic.
Pediatric context. Pediatric literature does not suggest a survival benefit attributable to 1 specific CKRT modality over another in critically ill children. 70,71 During the CAPN COVID-19 Rapid Response Team Webinar, a clear consensus emerged about this issue. In the absence of evidence of benefit for any particular modality, individual centers should use KRT modalities based on local expertise.
# We suggest not using hemoperfusion for COVID-19 patients
Rationale (from adult AKI guidance). COVID-19 patients who require KRT may, in theory, benefit from hemoperfusion because it adsorbs circulating cytokines. However, no data are supporting this specific case use. A large trial (n = 450 adult patients) did not reveal any impact on 28-day mortality when hemoperfusion was prescribed to patients with septic shock and high circulating endotoxin levels). 75 Pediatric context. There are no large trials in pediatrics evaluating this modality.
# Dose of KRT
We suggest that the treating team prescribes the established minimum dose of CKRT during the COVID-19 pandemic Rationale (from adult AKI guidance). The RENAL 76 and ATN 77 trials demonstrated that higher doses of KRT do not provide incremental survival benefits for AKI patients. On that basis, we suggest that the treating team should not prescribe higher dialysis doses to patients with COVID-19-associated AKI. Instead, the target dose of CKRT should be 2000 to 2500 mL/1.73 m2/hr of clearance (dialysis fluid rate and/or replacement fluid rate). We recognize that it might be necessary to use lower doses of CKRT if dialysate and replacement solution stocks are limited (see below). To limit solution usage, the treating team should prescribe only the necessary dose of CKRT.
Pediatric context. Because of children's highly variable body weight, we recommend that the treating team should calculate the precise dialysis dose needed for each child.
# Vascular Access
We recommend favoring the internal jugular site for temporary hemodialysis catheter insertion Rationale. Given that many patients with COVID-19 will receive prone ventilation, 40,41 internal jugular (IJ) vascular access should be considered the first choice of the temporary HD catheter insertion site in most circumstances.
Pediatric context. We did not find pediatric-specific data.
We suggest that a temporary hemodialysis catheter (or trialysis catheter with a third infusion port) be inserted preemptively, at the IJ site, in patients with worsening kidney function who are thought likely to require prone ventilation, even in the absence of an acute indication for starting KRT Rationale (from adult AKI guidance). While vascular access should not usually be inserted until a decision to initiate KRT is made, in patients with COVID-19, the high level of difficulty in successfully inserting a temporary HD catheter in a prone patient is a relevant consideration. In close consultation with the PICU team, it may be advisable to insert an HD catheter at the IJ site in patients with worsening kidney function before prone ventilation is started, even in the absence of an acute indication for starting KRT. A nontunneled catheter may be used in older children, whereas for younger, smaller patients, a tunneled catheter is preferable. Similarly, in patients with high severity of illness, it may be optimal to have multiple procedures (including arterial and central venous catheter insertion) performed at the same time, immediately after intubation or PICU admission, to preserve PPE and limit the exposure of health care workers. In this circumstance, preemptive insertion of a temporary HD catheter (or of a trialysis catheter with an additional port for medications) could also be considered for patients at risk of requiring KRT, even in the absence of an acute indication for it.
Pediatric context. We did not find pediatric-specific data.
We recommend that temporary HD catheters are vigorously flushed with saline and locked with citrate or heparin immediately after placement Rationale (from adult AKI guidance). Many reports suggest that patients with COVID-19 have an exaggerated inflammatory response ("cytokine storm") 24,31,66,67 and are hypercoagulable. 78,79 There are multiple anecdotal reports of KRT access clotting in this context. Other anecdotal reports in adults indicate that some centers have experienced less catheter dysfunction in patients with COVID-19 upon switching to using a higher concentration of heparin for catheter locks than is typically used between KRT treatments (ie, 5000 U/ mL vs 1000 U/mL). Pediatric context. We did not find pediatric-specific data. However, in pediatrics, the risk of clot-related catheter dysfunction is greater due to lower blood flow rates used, and hypercoagulability may further exacerbate this risk.
# Blood Priming and Anticoagulation for KRT
In the context of the generalized hypercoagulability that has been reported in critically ill COVID-19 patients, there are multiple anecdotal reports of frequent KRT filter and catheter clotting.
# We suggest using standard institutional protocols for blood priming extracorporeal circuits for children with COVID-19 starting on IHD or CKRT (pediatric guidance only-no parallel statement in adult AKI guidance)
Pediatric rationale. There is insufficient evidence to recommend any changes to standard blood priming practices in children. After a discussion at the CAPN COVID-19 Rapid Response Team Webinar, there was consensus that the decision to use a blood prime should be made on an individualized basis based on existing protocols.
We suggest using standard institutional protocols to determine blood flow rates (Qb) for children with COVID-19 starting on IHD or CKRT (differs from adult AKI guidance, which suggests higher than standard Qb) Pediatric rationale. Higher Qb may reduce the risk of clotting 80,81 ; however, there is insufficient evidence to recommend routine use of higher Qb in patients with COVID-19. Moreover, children receiving regional citrate anticoagulation (RCA) using a higher Qb may result in more citrate accumulation and associated complications. Routine assessment of the filter and transmembrane pressure should be done to adjust Qb and anticoagulation appropriately.
# We suggest, for patients with COVID-19 without a contraindication, using full-dose anticoagulation for KRT that includes a bolus of heparin through the filter with every new circuit
Rationale (from adult AKI guidance). Initiation of KRT with full-dose anticoagulation, including a bolus of heparin, should be considered, in consultation with PICU colleagues, in the absence of overt contraindications. Anecdotal reports suggest that higher than standard boluses and infusion rates may be required to maintain circuit patency. Providers should continue to follow their existing institutional protocols.
Pediatric context. We did not find pediatric-specific data.
# We suggest, for patients with COVID-19 already on systemic anticoagulation, using a bolus of heparin through the filter when starting KRT (or a new circuit)
Rationale (from adult AKI guidance). As above.
Pediatric context. We did not find pediatric-specific data.
We suggest, for patients on CKRT with an element of hemofiltration, minimizing the postfilter component of the total effluent rate Rationale (from adult AKI guidance). Limiting hemoconcentration may reduce the risk of circuit clotting.
Pediatric context. We did not find pediatric-specific data.
We suggest that programs with experience using RCA for CKRT consider using RCA based on the clinical status of each patient with COVID-19 (differs from adult AKI guidance which suggests using citrate plus heparin when clotting prevents delivery of prescribed dialysis) Pediatric context. Anecdotal reports suggest that RCA is generally effective in preventing circuit clotting in COVID-19 patients. Citrate may also prolong circuit lifetime in pediatric patients on CKRT. 82 We suggest that programs that do not have experience using RCA protocols for CKRT not implement them immediately Rationale (from adult AKI guidance). Implementing RCA protocols is complex under normal circumstances; programs that do not already use this approach regularly should consider other anticoagulation modalities during the pandemic.
Pediatric context. We did not find pediatric-specific data.
# We suggest that low-molecular-weight heparin be considered for CKRT anticoagulation in children with COVID-19 only by providers who already have experience using it (differs from adult AKI guidance, which does not mention the need for expertise)
Rationale (from adult AKI guidance). Some centers in the United States have reported less clotting with the use of lowmolecular-weight heparin (LMWH) protocols for CKRT than they were previously experiencing using unfractionated heparin in patients with COVID-19. In similar circumstances, LMWH is already in widespread use for outpatient IHD and nocturnal dialysis in adults. There have been reports of successful use in chronic HD in children as well. 83,84 With this experience, there is a consideration that LMWH could be used for CKRT or acute IHD or SLED. This requires close collaboration with other disciplines to develop or adapt dosing protocols, recognition by the whole team that the anticoagulation effect may be prolonged beyond the end of dialysis, and recognition that quantification of its impact if needed (eg, if bleeding occurs) is by the anti-Xa level rather than by partial thromboplastin time (PTT).
# Pediatric context.
There are no studies of LMWH use in CKRT in children: Because of this, caution and close monitoring should be used. We suggest that only centers with experience using LMWH in CKRT consider its use during the COVID-19 pandemic.
# Prevention of Intradialytic Hypotension During Intermittent KRT
We suggest adjusting the intermittent KRT prescription to optimize hemodynamic tolerance of fluid removal Rationale (from adult AKI guidance). Given that the primary consideration in many cases may be fluid overload management, various measures can be considered to improve hemodynamic tolerance of fluid removal during intermittent KRT treatments. Adjustments to the IHD prescription that may be considered include use of cool dialysate (≤35.5°C), use of higher dialysate sodium concentration (eg, 145 mmol/L), increasing time on IHD, or switching from IHD to CKRT to reduce the hourly ultrafiltration rate. Overall, there is limited evidence in this area. 81 A quasi-experimental "before-after" study that included 121 critically ill patients who underwent 537 IHD sessions showed that implementation of guidelines recommending cool dialysate and higher dialysate sodium concentration was associated with less-frequent intradialytic hypotension. 81 Isolated ultrafiltration (ultrafiltration without dialysis) is a method that may promote hemodynamic stability. During hemodialysis (HD), the removal of urea in the intravascular compartment creates a reverse osmotic gradient toward the interstitium that may reduce refilling (the movement of salts and water from extracellular and intracellular compartments to the intravascular space that is critical to the maintenance of circulating volume during dialysis). This problem does not occur in isolated ultrafiltration. However, direct evidence on this question is limited to a single study of 6 stable patients treated with outpatient HD: All were men with a mean age of 59 years. 85 Fluid targets were the same in each group, so were fluid removal and postdialysis blood pressures. We are not aware of studies in critically ill patients that have directly assessed this intervention. 51 It is perhaps ill-advised to substitute ultrafiltration time for HD time because it may reduce the dialysis dose delivered. Indeed, underdialysis is associated with higher mortality risk in critically ill patients. 86,87 Adding ultrafiltration time to HD time would increase resource needs (particularly staff time) and will increase the risk of clotting the system. Pediatric context. We did not find pediatric-specific data.
# Reducing Infection Risk to Health Care Workers Involved in Providing KRT
# Whenever possible, we recommend preferentially using KRT modalities that reduce the number of health care workers exposed to patients with COVID-19, to decrease risk to health care workers, risk of nosocomial transmission, and use of PPE, provided that centers have the expertise and support to manage the chosen modality (differs from adult AKI guidance in explicit recognition of the need for expertise and resources)
Rationale (from adult AKI guidance). Preferentially using KRT modalities that reduce health care worker exposure to patients with COVID-19 has to be considered within the local context of how the provision of KRT is organized (eg, if SLED provided by PICU nurses is compared with that provided by an additional nurse from the HD unit; whether SLED can be provided to more than 1 patient at a time for cohorts of patients with a single dialysis nurse) and concerning resource availability at that time.
Pediatric context. We did not find pediatric-specific data.
# We suggest routinely using remote control features of KRT machines, where available
Rationale (from adult AKI guidance). Although few machines are equipped with this technology at present, the use of a remote control feature may reduce infection risk by allowing control of a KRT machine in an isolation room from outside the room.
Pediatric context. We did not find pediatric-specific data.
# Considerations if KRT-related Resources Become Limited During the COVID-19 Pandemic
Current Canadian data do not suggest an imminent threat of increasing acute KRT needs in children due to COVID-19. However, there is an expectation that significant additional PICU capacity might be required to care for children with COVID-19 in the current pandemic context. Planning should consider that specific KRT-related resources may become scarce in the context of the pandemic. Planning considerations vary depending on how acute KRT is provided at the level of individual programs (eg, if a program routinely uses CKRT or SLED; whether PICU nurses or HD nurses routinely provide SLED.). The following subsections outline the considerations specific to various potential KRT-related shortages.
# Delaying the Need for KRT
We recommend that preemptive KRT (ie, before an acute indication is present) should not be used Rationale (from adult AKI guidance). See the section on Timing of Initiation above.
Pediatric context. We did not find pediatric-specific data.
We suggest that, in the context of an overall shortage of KRT resources, clinicians consider using high-dose diuretics (including serial nephron blockade, the use of a loop, and a thiazide-type diuretic together) and off-label use of potassium-binding resins to delay the need for KRT, depending on the clinical context and resource availability Rationale (from adult AKI guidance). No direct data are available on the use of conventional or novel potassium binders in critically ill children and especially infants. 88,89 In outpatients, an increased risk of intestinal ischemia, thrombosis for users of sodium-polystyrene-sulfonate (Kayexalate), compared with nonusers, has been noted in observational research: The increased risk was 5.6 events per thousand patient-years in stable outpatients, but the hazard ratio was 4.9 (95% confidence intervals: 1.1-22.3). 90 The team should be alerted to the possibility that this incremental risk may be higher in patients with COVID-19 because of the higher baseline risk of thrombosis. They should also be aware that because of this tendency, the occurrence of intestinal thrombosis in a patient treated with potassium binders should not necessarily be attributed to the use of the binder. Pediatric context. We did not find pediatric-specific data.
# Shortage of CKRT Machines
We recommend, in the context of a shortage of CKRT machines, using IHD in patients in whom intradialytic hypotension is likely to be manageable with increased vasopressor dosing Rationale (from adult AKI guidance). This needs to be weighed according to the extent to which there is a shortage of HD nurses if a separate HD nurse is required for IHD in the PICU. Also, this approach involves exposing additional nursing staff to COVID-19 infection risk and increased PPE consumption.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of CKRT machines, using IHD machines to do prolonged HD section or SLED for hemodynamically unstable patients (differs from adult AKI guidance in mentioning prolonged HD as an alternative to SLED) Rationale (from adult AKI guidance). Prolonged IHD sessions or SLED would require the HD nurse to be in the PICU. This carries the potential issue of having to deploy more HD nurses to the PICU and the increased COVID-19 risk exposure and PPE use which that entails.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of CKRT machines at centers that use CKRT, prolonged HD or SLED for hemodynamically unstable patients, preferentially using prolonged HD or SLED (differs from adult AKI guidance in mentioning prolonged HD as an alternative to SLED) Rationale (from adult AKI guidance). This suggestion needs to be weighed according to the extent to which there is a shortage of HD nurses if a separate HD nurse is required for SLED in the PICU.
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of CKRT machines, using CKRT machines to provide shorter sessions of CKRT for 2 patients in 24 hours Rationale (from adult AKI guidance). This involves using 1 CKRT machine for 10 hours on 2 patients daily (or 6 hours for 3 patients), realistically estimating 2 hours to move and clean the machine between treatments. One can consider running higher-than-usual effluent rates if there is no expectation of a shortage of CKRT fluid supplies.
Pediatric context. We did not find pediatric-specific data.
# Shortage of CKRT replacement fluid or dialysate
We recommend, in the context of a shortage of CKRT solutions (fluids), having a lower threshold for using IHD in patients in whom hemodynamic instability is likely to be manageable with increased vasopressor dosing Rationale (from adult AKI guidance). As detailed in the preceding section, this suggestion needs to be weighed according to the extent to which there is a shortage of HD nurses if a separate HD nurse is required for IHD in the PICU. Also, this approach involves exposing additional nursing staff to COVID-19 infection risk and increased PPE consumption.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of CKRT solutions (fluids), using conventional HD machines to do prolonged dialysis treatment (or SLED) in hemodynamically unstable patients Rationale (from adult AKI guidance). As detailed above, this carries the potential issue of having to deploy HD nurses to the ICU and the increased COVID-19 risk exposure and PPE use which that entails. In addition, one needs to consider and account for high risks of disequilibrium, hypokalemia, and hypophosphatemia during treatment.
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of CKRT solutions (fluids), in centers that use both CKRT and prolonged HD (or SLED) for hemodynamically unstable patients, favoring the use of prolonged HD (or SLED) if adequate staffing is available Rationale (from AKI guidance). As detailed in the preceding section, this suggestion needs to be weighed according to the extent to which there is a shortage of HD nurses if a separate HD nurse is required for HD (or SLED) in the PICU. Pediatric context. We did not find pediatric-specific data.
We suggest, if there is a shortage of CKRT solutions (fluids), using a lower dose of CKRT (eg, 10-15 mL/kg/hr) once metabolic control has been achieved
Rationale (from AKI guidance). This maximizes the number of patients who can be treated but requires attention to the possibility that underdialysis (ie, failure to deliver standard targets) may lead to excess mortality, as suggested by observational data (ref).
Pediatric context. We did not find pediatric-specific data.
We suggest, if there is a shortage of CKRT solutions, that centers consider producing CKRT solutions locally Rationale (from AKI guidance). A recent publication reports 1 such strategy. 91 The successful use of IHD machines to generate CKRT solution has also previously been reported. 92 Careful attention and planning are required to address sterility, 93 endotoxin levels, 92,94 storage, and bridging incompatible tubing connections. Locally made solutions should be used as dialysate (rather than as replacement fluid) to reduce the risk of direct introduction of potentially contaminated fluids into the bloodstream. Centers considering locally made solutions should plan their preparation to ensure adequate quality control before these solutions are used.
Pediatric context. We did not find pediatric-specific data.
# Shortage of IHD/SLED Capability (Nurses and/or Machines)
We recommend, in the context of a shortage of capacity for IHD or SLED, that centers consider redeploying resources by decreasing the frequency of dialysis for selected stable outpatients treated with maintenance HD patients, as outlined in the CSN COVID-19 Rapid Response Team recommendations for outpatient HD 95 Rationale (from adult AKI guidance). Redeployment of trained dialysis staff from outpatients to critically ill patients may be required with the intention to maximize the number of surviving patients.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of capacity for IHD or SLED machines, that centers review and consider using outdated but still operable dialysis machines and portable RO units Rationale (from adult AKI guidance). Doing this early enables an accurate understanding of available resources in the event of reallocation to adult units if needed. Providers should remain up to date with their available equipment during the COVID-19 pandemic.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of staff for IHD or SLED, dialysis-trained staff to be redeployed from other areas to provide the necessary support Rationale (from adult AKI guidance). Before redeployment, an assessment of the total number of dialysis-trained staff and the machines with which they have experience working should be undertaken. If there is a shortage for children, this may require staff redeployment from other areas of the pediatric center. However, it may be more likely that a shortage occurs in adults requiring pediatric staff's redeployment to adult centers. Institutions should be prepared to provide readily available training for acute HD nursing should this need arise. Pediatric context. We did not find pediatric-specific data.
We suggest that centers consider using any available home HD machine stockpile in the context of a shortage of machines for IHD or SLED Rationale (from adult AKI guidance). While this maximizes available resources, we recognize that staff training will likely be necessary for the use of machines outside their usual setting in each program.
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of machines for IHD or SLED, that centers consider whether home HD patients who use their machines on alternate days would be willing to share a machine, allowing the return of a device to the program for acute KRT Rationale (from adult AKI guidance). This suggestion has been made in adult nephrology guidelines. This approach has potential barriers, including the near inevitability of a breach in patient confidentiality and the potential for COVID-19 transmission between patients who have agreed to share machines. As above, staff training on an unfamiliar machine will also likely be necessary. These machines may also be considered for allocation to adult patients if needed.
Pediatric context. It must be noted that home HD is less common in children than adults, and in discussion with experts during the CAPN COVID-19 Rapid Response Team Webinar, there were no providers currently caring for any patients on home HD. However, it was felt that this suggestion would still be valid for consideration in the event of a machine shortage if such an option were available.
We suggest, in the context of a shortage of capacity for IHD or SLED, shortening SLED duration to 6 hours, permitting the treatment of 3 patients daily Rationale (from adult AKI guidance). This schedule allows 2 hours to move and clean the machine between patients. Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of capacity for IHD or SLED, that centers consider whether 1 nurse can supervise 2 or more machines simultaneously for older children who are cooperative, located close together and have the same isolation status; start and stop times can be staggered (differs from an adult by the inclusion of the idea of older children who are cooperative) Rationale (from adult AKI guidance). If machines are available, but HD nurses are limited, this will maximize benefits.
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of capacity for IHD or SLED, at centers where SLED is the modality typically used for hemodynamically unstable patients, and it is usually provided by PICU nurses (which is not widely done), using SLED rather than IHD for hemodynamically stable patients Rationale (from adult AKI guidance). This can be done to reduce HD nursing needs and PPE use (if PICU resources allow).
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of capacity for IHD or SLED, that centers consider building capacity for KRT in community hospitals or other pediatric centers that have maintenance HD units but where acute KRT is not routinely provided in PICU Rationale (from adult AKI guidance). Staffing issues need to be carefully considered and the potential need for additional KRT machines and RO units.
Pediatric context. We did not find pediatric-specific data.
# Use of Acute PD to Meet AKI-KRT Needs During the Pandemic
We suggest, in the context of an acute shortage of other KRT modalities, using acute PD if necessary Rationale (from adult AKI guidance). Acute PD can successfully be used to treat critically ill patients in various settings. 96,97 PD was the modality of choice in KRT in pediatric patients until the development of CKRT machines. 98 General guidelines for the use of PD in AKI have previously been reported. 96,99 Many considerations would be involved in the decision to use acute PD, including the following:
- - Depending on the center and nephrologists, surgeons and/or interventional radiologists may perform acute PD catheter insertion. Early planning with those specialists is warranted if resources for non-PD KRT modalities are likely to become scarce during the COVID-19 pandemic. - - Nursing exposure to COVID-19 infection risk (and PPE use) would be best limited by using a cycler/ automated PD. - - Given that volume control may often be the primary concern in COVID-19 patients with AKI, higher glucose concentration solutions may be required (eg, starting with 2.5%/2.36% glucose solutions and then titrating according to achieved ultrafiltration). - - Peritoneal dialysis may be more complicated in patients who require prone ventilation, although its acute use in a predisposed patient has previously been reported to have been successful. 100 We would suggest using another dialysis modality if feasible, as PD would increase the intra-abdominal pressure which may accelerate the need for ventilation. 101 - - Lower dialysate volumes with shorter dwell times offer several potential advantages in this setting. Low volumes may enable better ventilation relative to larger volumes, limiting pericatheter leaks as catheters are used shortly after insertion.
Pediatric context. Pediatric patients tend to be high transporters allowing higher ultrafiltration. 102
# COVID-19 Drug Dosing for Patients With Kidney Dysfunction
We suggest adjusting the dose of medications used to treat COVID-19 in patients with a low glomerular filtration rate of any cause and patients treated with maintenance dialysis Rationale (from adult AKI guidance). This consideration is not specific to patients with AKI. Currently, no medications have been approved in Canada for the treatment of COVID-19. Nonetheless, many drugs are being used off-label or through clinical trials. Given that this is a rapidly changing area, we suggest referring to continuously updated online resources that detail kidney function dosing considerations for potential therapies for COVID-19 (such as the #NephJC AKI blog). 103 Pediatric context. We did not find pediatric-specific data.
# Limitations
There are many significant limitations to this work. Several important considerations were outlined in the adult AKI guidance and are reproduced here. First, because of time constraints and the rapidly evolving information in this field, systematic review or meta-analysis was not possible. Second, none of the suggestions have been specifically evaluated in the clinical environment. Third, we cannot anticipate the many ways in which the dynamic local context, including the details of the organization of care for patients with AKI and the magnitude of the clinical need, will affect the implementation of our suggestions. Fourth, we did not address any ethical issues concerning the need to triage KRT-related resources if rationing were to be required.
Further limitations apply to these pediatric AKI considerations. We have reproduced the adult guidance and rationale throughout, often verbatim, for consistency, and highlighted areas where there are specific pediatric considerations. However, there is a lack of pediatric AKI and KRT data in children with COVID-19 infections; more research is needed. Finally, knowledge is advancing rapidly in this area; our suggestions may quickly be outdated. We recognize the importance of other curated sources of evidence and advice (eg, #NephJC blog, available at / covidaki) in this rapidly changing environment.
# Implications
Best practices may not be delivered to all patients, given time constraints, resource constraints, and local health authority priorities. The priority is to maximize benefits for the greatest number of patients. Given that most acute KRT related to COVID-19 is initiated in the PICU setting, close collaboration and planning between critical care and pediatric nephrology programs at the local level are required. Suggestions included in this document may need updating as newer evidence becomes available. As part of our knowledge translation strategy, the article will be hosted on the CSN/CAPN Web site. 104,105
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This article provides guidance on managing acute kidney injury (AKI) and kidney replacement therapy (KRT) in pediatrics during the COVID-19 pandemic in the Canadian context. It is adapted from recently published rapid guidelines on the management of AKI and KRT in adults, from the Canadian Society of Nephrology (CSN). The goal is to provide the best possible care for pediatric patients with kidney disease during the pandemic and ensure the health care team's safety. Information sources: The Canadian Association of Paediatric Nephrologists (CAPN) COVID-19 Rapid Response team derived these rapid guidelines from the CSN consensus recommendations for adult patients with AKI. We have also consulted specific documents from other national and international agencies focused on pediatric kidney health. We identified additional information by reviewing the published academic literature relevant to pediatric AKI and KRT, including recent journal articles and preprints related to COVID-19 in children. Finally, our group also sought expert opinions from pediatric nephrologists across Canada. Methods: The leadership of the CAPN, which is affiliated with the CSN, solicited a team of clinicians and researchers with expertise in pediatric AKI and acute KRT. The goal was to adapt the guidelines recently adopted for Canadian adult patients for pediatric-specific settings. These included specific COVID-19-related themes relevant to AKI and KRT in a Canadian setting, as determined by a group of kidney disease experts and leaders. An expert group of clinicians in pediatric AKI and acute KRT reviewed the revised pediatric guidelines. Key findings: (1) Current Canadian data do not suggest an imminent threat of an increase in acute KRT needs in children because of COVID-19; however, close coordination between nephrology programs and critical care programs is crucial as the pandemic continues to evolve. (2) Pediatric centers should prepare to reallocate resources to adult centers as needed based on broader health care needs during the COVID-19 pandemic. (3) Specific suggestions pertinent to the optimal management of AKI and KRT in COVID-19 patients are provided. These suggestions include but are not limited to aspects of fluid management, KRT vascular access, and KRT modality choice. (4) Considerations to ensure adequate provision of KRT if resources become scarce during the COVID-19 pandemic. Limitations: We did not conduct a formal systematic review or meta-analysis. We did not evaluate our specific suggestions in the clinical environment. The local context, including how the provision of care for AKI and acute KRT is organized, may impede the implementation of many suggestions. As knowledge is advancing rapidly in the area of COVID-19, suggestions may become outdated quickly. Finally, most of the literature for AKI and KRT in COVID-19 comes from adult data, and there are few pediatric-specific studies. Implications: Given that most acute KRT related to COVID-19 is likely to be required in the pediatric intensive care unit initial setting, close collaboration and planning between critical care and pediatric nephrology programs are needed. Our group will update these suggestions with a supplement if necessary as newer evidence becomes available that may change or add to the recommendations provided.# Introduction
Reports of children with symptomatic COVID-19 infections continue to grow. There are no clear data on the incidence of acute kidney injury (AKI) in children at this time because there are so few cases thus far. Below, we will present an overview of relevant pediatric data from China, Europe, and North America, a summary of similar data from adult studies, and a discussion on the evidence linking AKI with the new condition referred to as "multisystem inflammatory syndrome" (MIS). We will then introduce critical concepts for the safe management of pediatric patients diagnosed with AKI before presenting the detailed guidelines.
# COVID-19 Infection and AKI: Pediatric Data From China
Four studies from China strongly suggest that pediatric COVID-19 is rare 1,2 and rarely requires intensive care. In the largest (n = 72 314 cases), the Chinese Center for Disease Control and Prevention reported that ~2% of all cases were less than 18 years of age. 1 In a screening study of 745 children, 10 (1.3%) had confirmed AKI. Ten patients required admission to the hospital, but none required intensive care. 3 The only center allowed to treat pediatric COVID-19 in the Wuhan region found 171 confirmed cases after testing 1391 children aged less than 16 years (12.3%): Of these, 3 required intensive care (1.7% of positive cases). 4 All 3 patients had AKI based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria and, importantly, all had preexisting conditions (hydronephrosis, leukemia, and intussusception). 4 They were treated with plasma exchange and continuous kidney replacement therapy (CKRT), resulting in 1 complete recovery, 1 partial recovery, and 1 death. 5 Finally, in a study focused on 2135 cases of pediatric COVID-19 (35% confirmed), the likelihood of critical disease (defined by the presence of life-threatening organ dysfunction) was highest in children aged less than 1 year (7/376, or ~1.9%) and substantially lower for the others (~0.3%-0.5%). 6 Unfortunately, none of these studies provided data on AKI or kidney replacement therapy (KRT). One case report of a critically ill infant with COVID-19 reported mild AKI. The infant had a history of preexisting conditions (cardiac surgery and recurrent pneumonia). 7 Furthermore, of 1065 cases from 18 studies, only 1 infant presented with pneumonia, complicated by shock and kidney failure, which required dialysis. Fortunately, the infant recovered with supportive treatment. 8
# COVID-19 Infection and AKI: Pediatric Data From Europe
Emerging data from European centers paint a similar picture. For example, Spanish investigators identified pediatric COVID-19 in ~1% of all confirmed cases from Madrid (41 of 4695). Of these, 4 patients (~10%) required intensive care. 2 In Italy, ~1.2% of cases were children below 18 years of age. None of those patients died. 9 Both studies reported no fatalities but did not include data on the incidence of AKI.
# COVID-19 Infection and AKI: Pediatric Data From North America
A cross-sectional study from 46 US and Canadian pediatric intensive care units (PICUs) which focused on 1 month starting in mid-March 2020 revealed 48 cases of critical pediatric COVID-19 (none from Canada). Most of these patients (83%) had preexisting comorbidities, such as complex syndromes (46%) or requiring immunosuppression (23%). While the treating team did not use KRT (and there are no data on AKI incidence), 1 patient required extracorporeal membrane oxygenation and 2 patients (4%) died. 10 Another multicenter cross-sectional study found a high prevalence of AKI among critically ill children with COVID-19 (44%). No child received dialysis. Most children with AKI had at least 1 comorbidity (n = 28, 60%). Three in the AKI group (6%) died. 11 In New York, a 16-year-old patient with COVID-19associated rhabdomyolysis did not develop AKI, possibly because of early fluid therapy. 12 This condition has also been described in adult patients 13 of whom a subset developed AKI. [14][15][16]
# COVID-19 Infection and AKI: Brief Overview of Adult Data
Even in adults, AKI remains poorly defined for COVID-19 due to variations in testing rates, the case fatality rate, and the risk of other outcomes. The reported incidence of AKI across available preprints and published studies ranges from 0.5% to 39% [17][18][19][20][21][22][23][24][25][26][27] (Table 1). Studies that reported rates of COVID-19-related AKI primarily involved hospitalized patients with the majority requiring KRT. These data suggest that except for 2 studies that reported AKI stratified according to KDIGO criteria, 25,26 published studies and preprints generally have focused on severe AKI requiring KRT (AKI-KRT) only.
# Multisystem Inflammatory Syndrome and AKI
Of particular relevance to pediatrics is the emergence of the new condition associated with COVID-19, now referred to as reported MIS. In April 2020, physicians in London, England, reported a cluster of 8 children presenting with features similar to Kawasaki disease or toxic shock syndrome, 1 of whom required KRT. 31 Common clinical features included gastrointestinal symptoms, rashes, mucous membrane changes, adenopathy, myocarditis, and fever lasting more than 5 days. 31 Many of these children had exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and several tested positive for SARS-CoV-2. 31 After this initial publication, a team in Paris, France, reported the most extensive case series to date, describing 17 patients with apparent Kawasaki disease presenting over 11 days. From this group, 8 (47%) developed AKI and 14 (82%) had SARS-CoV-2 IgG antibodies. 32 A team in Italy reported a 30-fold increase in the incidence of a Kawasaki-like disease categorized as MIS during the COVID-19 pandemic. 33 Multiple subsequent case reports of patients with MIS associated with SARS-CoV-2 describe varying degrees of endorgan involvement, including AKI. [34][35][36][37][38] The pathophysiology of this syndrome remains unclear, and details of patients' clinical and biochemical markers related to AKI are scarce. Pediatric MIS remains an emerging entity, and measurement of incidence is challenging, though estimated to be less than 1% in children with COVID-19 infection. 39 As larger cohorts are available, the true incidence of AKI in this population may become more apparent.
# Medical Management and KRT in AKI in Children With COVID-19
While acute respiratory distress syndrome (ARDS) is the predominant clinical issue for critically ill pediatric patients, it is crucial to acknowledge that the clinical presentation is variable in children with COVID-19. [40][41][42][43][44][45] For those with AKI, the overarching goal is to avoid volume overload. There are no specific therapies for AKI in children with COVID-19, and traditional AKI management principles should guide clinical decision-making. Unsurprisingly, volume overload appears to be the most likely indication for initiating acute KRT in these patients. 43,45 There is insufficient evidence to recommend any particular KRT modality. As such, providers should individualize treatment options and use existing institutional protocols for KRT prescription to meet each patient's needs based on their clinical status. Given the burden of ARDS in these children, providers should anticipate difficulty with ventilation and prone positioning, limiting the feasibility of peritoneal dialysis (PD).
# Risk Reduction and Resource Management of KRT During the COVID-19 Pandemic
Every interaction between a health care worker and a patient with suspected or confirmed COVID-19 requires personal protective equipment (PPE) and, even with its careful use, carries a risk of transmission of COVID-19. Every effort to minimize these interactions is justified. Techniques that optimize physical distancing between providers and patients with COVID-19 should be balanced with providing the best quality of care to patients. This includes the use of specialized equipment such as KRT extension tubing and remote dialysis technology, if available. Also, close coordination between nephrologists and intensivists minimizes the number of providers entering a patient room for routine assessments.
While current Canadian data do not suggest an imminent risk of KRT equipment shortage in children, providers should remain informed of up-to-date data and public health officials' recommendations. Should there be a significant rise in the incidence of severe pediatric COVID-19 disease at a local or national level, consideration should be given to efficient resource allocation. These choices could include using intermittent hemodialysis (IHD) or shorter time CKRT sessions in the face of a CKRT machine shortage, redeployment of trained dialysis staff to intensive care units as needed, and consideration for the use of home dialysis machines or PD if experiencing an IHD machine shortage. At a broader health care level, should there be a rise in severe COVID-19 illness in adult patients, the treating team may have to consider reallocation of equipment, sharing of hospital space, or redeployment of staff to care for adult patients.
# Canadian Association of Paediatric Nephrologists COVID-19 Rapid Response: Guidelines for Management of AKI in Children
# Purpose
Acute kidney injury is a potential complication of COVID-19-associated critical illness in children. The burden of COVID-19-associated AKI, as well as the unique features of this condition, has implications for the delivery of acute KRT.
Nephrology programs across the country are developing policies in this rapidly changing environment. The Canadian Association of Paediatric Nephrologists (CAPN), in close collaboration with the Canadian Society of Nephrology (CSN), has synthesized guidance documents from the broader pediatric nephrology community to provide the best care to the largest number of children with kidney disease while also ensuring the safety of the health care team.
# Principles
The following principles guided our work:
1. Uncertainty-an acknowledgment that clinicians and administrators are now working in a swiftly evolving environment which will require decision-making with limited resources and levels of uncertainty that are higher than usual. 2. Macroallocation-an acknowledgment that the local context and local government priorities will shape decision-making. Those previous sacrosanct standards may need to be temporarily adjusted to maximize health outcomes for the most significant number of patients. 3. Minimize net harm-limit the spread of disease and the disruption to the health care system. 4. Reciprocity-protect our health care workforce from COVID-19, and secondarily, so that staffing levels needed for the delivery of care to patients who, by definition, require physical interventions are maintained. 5. Fairness-ensure that patients with kidney disease continue to receive appropriate treatments, regardless of their COVID-19 status and avoid outcomes that disproportionately affect those most vulnerable (eg, lower socioeconomic status). 6. Proportionality-keep restrictions on staff and patients commensurate with the level of risk to public health. 7. Respect for autonomy-continue to reflect patient and family values and beliefs as much as possible, granting that choices may be limited in a pandemic. 8. Fidelity-maintain commitment to patients to provide necessary care, even through challenging times and when there is a degree of risk to providers).
# Information Sources
# Methods
The CAPN, which is affiliated with the CSN, solicited a team of clinicians and researchers with expertise in pediatric AKI and acute KRT. The goal was to adapt the recently developed Canadian adult COVID-19-related AKI guidelines 46 for pediatric-specific settings. These included specific COVID-19-related themes that are relevant to AKI and KRT in a Canadian setting, as determined by a group of pediatric nephrologists. The revised pediatric guidelines were reviewed by a group of experts in pediatric AKI and acute KRT. We then held a Webinar, hosted by CAPN to invite pediatric nephrologists and other health care workers around the country to review the guidelines and provide feedback before the document was finalized.
We reproduced the guidance of the adult AKI continuous renal replacement therapy working group verbatim, unless the pediatric group intended a change, in which case this is highlighted. The adult rationale is reproduced either verbatim or condensed. We added, where available, pediatric context and considerations, and justify our differences from the adult AKI guidance. For many questions, no pediatric-specific data were available and no specific considerations applied. We have chosen to reproduce the adult guidelines in their entirety and include the adult nephrologists who wrote them on our writing team. We chose this approach rather than writing a document about the differences. The article would be easy to read for pediatric nephrologists and would stand alone as a useful reference and resource.
# Key Issues and Suggestions/ Considerations
# Planning for Capacity to Provide Acute KRT
We suggest planning for a 25% to 30% increase in the acute pediatric KRT capacity even though the prevalence of pediatric COVID-19 is low. This would help provide flexibility to allocate resources to adult centers as needed based on how the pandemic evolves over time.
Rationale/comments. Report of children with symptomatic COVID-19 infections is growing. At this time, there are no precise data to suggest the incidence of AKI in this population. This is likely related to the low incidence and severity of this disease in children as previously discussed above.
Lipton et al from Columbia University published an editorial commentary on the role of pediatric nephrologists in managing adults with AKI due to COVID-19. The authors share their mutually beneficial experience of pediatric to adult redeployment. The capacity of the PICU was expanded by 50% (from 41 to 60 beds), and all levels of pediatric providers worked on the front line in response to the growing demand during the pandemic. This specifically helped offload the volume of adults requiring CKRT at the adult hospital. 47 At present, COVID-19 rates in Canada are increasing after a previous downtrend. Should there be a reemergence of severe COVID-19 hospitalization rates in adults requiring increased KRT needs, consideration should be given to redeploying staff and reallocating equipment from pediatric centers to support adult patients requiring KRT, provided severe pediatric COVID-19 incidence remains unchanged.
# Management of AKI and KRT
This section provides an overview of relevant considerations. We appreciate there is a wide variation in the relative responsibilities of pediatric nephrology and PICU programs in the management of KRT in children in the PICU across Canada. Local circumstances should be taken into account in applying our suggestions. Close collaboration between pediatric nephrology and PICU programs at the local level will be required to plan for the potentially increased demands as the COVID-19 pandemic continues to evolve.
# Fluid Management
# These Suggestions are Aligned With Adult AKI Guidance, Except Where the Reason for the Change Is Discussed
We suggest judicious fluid administration to target euvolemia and avoid fluid overload while factoring that insensible losses may be very high in patients with persistent or recurrent fevers Rationale (from adult AKI guidance). The predominant clinical issue for critically ill patients with COVID-19 is ARDS: We, therefore, recommend avoiding fluid overload. [40][41][42][43][44][45] However, we recognize that assessing volume status may be challenging, and a dogmatic approach to keeping patients as dry as possible should be avoided. Insensible losses in those with unremitting or recurrent fevers may be significantly increased, 48 and an overly aggressive approach to diuresis or ultrafiltration with KRT could carry potential increased risks of death 49 and longer term cognitive impairment 50 as a consequence of more frequent hypotensive episodes. 50,51 Pediatric context. We did not find pediatric-specific data.
We suggest that, under most circumstances, direct examination of patients admitted to PICU with suspected or confirmed COVID-19 does not need to be routinely performed by the nephrology consultation service Rationale (from adult AKI guidance). Information on physical findings should be sought from health care workers who have other reasons to enter the room. In addition to the usual chart-based data that inform ultrafiltration prescription for KRT, close consultation with PICU colleagues and nurses will be required. Similarly, investigations that are part of the routine assessment of patients with AKI, including urinalysis and kidney ultrasonography, may be deferred unless they are thought to influence clinical management. Adopting these practices will decrease risk to health care workers, decrease the risk of nosocomial transmission, and decrease PPE use, a scarce resource.
Pediatric context. We did not find pediatric-specific data.
We recommend that starches, gelatins, and hypotonic crystalloids should not be used for resuscitation Rationale (from adult AKI guidance). Starches and gelatins should not be used for resuscitation 40,41 because they have been shown in randomized trials to cause an increased risk of death and AKI in adults 52,53 ; hypotonic solutions such as half-normal saline should not be used for resuscitation as they are less effective at increasing intravascular volume compared with isotonic solutions. 40 Pediatric context. We did not find pediatric-specific data.
# Timing of Initiation of KRT
We recommend that traditional indications for starting KRT should be used in patients with COVID- 19 Rationale (from adult AKI guidance). In recent years, several trials provided evidence regarding the optimal timing of KRT initiation for critically ill patients with AKI. [54][55][56] For example, STARRT-AKI trial did not show any benefit of starting KRT early among critically ill adults. 57,58 A recent systematic review of nearly 2000 patients from 9 studies randomly allocated to earlier or later initiation found no benefit for earlier initiation. 59 In the context of the COVID-19 pandemic, with limited KRT resources, we recommend using traditional indications to decide on the timing of KRT initiation. We anticipate that volume overload will be the predominant trigger to start KRT in COVID-19 patients with AKI.
Pediatric context. Observational studies have yielded mixed results regarding outcomes of early compared with late initiation of KRT in critically ill children. [60][61][62][63]
# Modality Choice
We suggest that, during the COVID-19 pandemic, nephrology programs should primarily continue to use acute KRT modalities with which they have the most expertise Rationale (from adult AKI guidance). Clinical trials comparing CKRT, IHD, and sustained low-efficiency dialysis (SLED) have not demonstrated improved survival with any particular modality. 64,65 A sepsis-like syndrome, characterized by profound shock, and presumably related to high levels of circulating cytokines (referred to as "cytokine storm"), has been reported as a frequent complication of COVID-19 24,66 including reports of "hyperinflammatory shock" related to multi-inflammatory syndrome in children. [31][32][33][35][36][37]67 Kidney replacement therapy modalities that include convection, such as high-volume hemofiltration, are superior at removing larger molecules, such as cytokines; however, both proinflammatory and anti-inflammatory cytokines are removed. To date, randomized trials of septic AKI patients without COVID-19 demonstrate no additional benefit with convective-based therapies. 68,69 Also, high-volume hemofiltration involves the use of very large volumes of replacement solution, which could become scarce in the context of increased KRT use during the COVID-19 pandemic.
Pediatric context. Pediatric literature does not suggest a survival benefit attributable to 1 specific CKRT modality over another in critically ill children. 70,71 During the CAPN COVID-19 Rapid Response Team Webinar, a clear consensus emerged about this issue. In the absence of evidence of benefit for any particular modality, individual centers should use KRT modalities based on local expertise.
# We suggest not using hemoperfusion for COVID-19 patients
Rationale (from adult AKI guidance). COVID-19 patients who require KRT may, in theory, benefit from hemoperfusion because it adsorbs circulating cytokines. [72][73][74] However, no data are supporting this specific case use. A large trial (n = 450 adult patients) did not reveal any impact on 28-day mortality when hemoperfusion was prescribed to patients with septic shock and high circulating endotoxin levels). 75 Pediatric context. There are no large trials in pediatrics evaluating this modality.
# Dose of KRT
We suggest that the treating team prescribes the established minimum dose of CKRT during the COVID-19 pandemic Rationale (from adult AKI guidance). The RENAL 76 and ATN 77 trials demonstrated that higher doses of KRT do not provide incremental survival benefits for AKI patients. On that basis, we suggest that the treating team should not prescribe higher dialysis doses to patients with COVID-19-associated AKI. Instead, the target dose of CKRT should be 2000 to 2500 mL/1.73 m2/hr of clearance (dialysis fluid rate and/or replacement fluid rate). We recognize that it might be necessary to use lower doses of CKRT if dialysate and replacement solution stocks are limited (see below). To limit solution usage, the treating team should prescribe only the necessary dose of CKRT.
Pediatric context. Because of children's highly variable body weight, we recommend that the treating team should calculate the precise dialysis dose needed for each child.
# Vascular Access
We recommend favoring the internal jugular site for temporary hemodialysis catheter insertion Rationale. Given that many patients with COVID-19 will receive prone ventilation, 40,41 internal jugular (IJ) vascular access should be considered the first choice of the temporary HD catheter insertion site in most circumstances.
Pediatric context. We did not find pediatric-specific data.
We suggest that a temporary hemodialysis catheter (or trialysis catheter with a third infusion port) be inserted preemptively, at the IJ site, in patients with worsening kidney function who are thought likely to require prone ventilation, even in the absence of an acute indication for starting KRT Rationale (from adult AKI guidance). While vascular access should not usually be inserted until a decision to initiate KRT is made, in patients with COVID-19, the high level of difficulty in successfully inserting a temporary HD catheter in a prone patient is a relevant consideration. In close consultation with the PICU team, it may be advisable to insert an HD catheter at the IJ site in patients with worsening kidney function before prone ventilation is started, even in the absence of an acute indication for starting KRT. A nontunneled catheter may be used in older children, whereas for younger, smaller patients, a tunneled catheter is preferable. Similarly, in patients with high severity of illness, it may be optimal to have multiple procedures (including arterial and central venous catheter insertion) performed at the same time, immediately after intubation or PICU admission, to preserve PPE and limit the exposure of health care workers. In this circumstance, preemptive insertion of a temporary HD catheter (or of a trialysis catheter with an additional port for medications) could also be considered for patients at risk of requiring KRT, even in the absence of an acute indication for it.
Pediatric context. We did not find pediatric-specific data.
We recommend that temporary HD catheters are vigorously flushed with saline and locked with citrate or heparin immediately after placement Rationale (from adult AKI guidance). Many reports suggest that patients with COVID-19 have an exaggerated inflammatory response ("cytokine storm") 24,31,66,67 and are hypercoagulable. 78,79 There are multiple anecdotal reports of KRT access clotting in this context. Other anecdotal reports in adults indicate that some centers have experienced less catheter dysfunction in patients with COVID-19 upon switching to using a higher concentration of heparin for catheter locks than is typically used between KRT treatments (ie, 5000 U/ mL vs 1000 U/mL). Pediatric context. We did not find pediatric-specific data. However, in pediatrics, the risk of clot-related catheter dysfunction is greater due to lower blood flow rates used, and hypercoagulability may further exacerbate this risk.
# Blood Priming and Anticoagulation for KRT
In the context of the generalized hypercoagulability that has been reported in critically ill COVID-19 patients, there are multiple anecdotal reports of frequent KRT filter and catheter clotting.
# We suggest using standard institutional protocols for blood priming extracorporeal circuits for children with COVID-19 starting on IHD or CKRT (pediatric guidance only-no parallel statement in adult AKI guidance)
Pediatric rationale. There is insufficient evidence to recommend any changes to standard blood priming practices in children. After a discussion at the CAPN COVID-19 Rapid Response Team Webinar, there was consensus that the decision to use a blood prime should be made on an individualized basis based on existing protocols.
We suggest using standard institutional protocols to determine blood flow rates (Qb) for children with COVID-19 starting on IHD or CKRT (differs from adult AKI guidance, which suggests higher than standard Qb) Pediatric rationale. Higher Qb may reduce the risk of clotting 80,81 ; however, there is insufficient evidence to recommend routine use of higher Qb in patients with COVID-19. Moreover, children receiving regional citrate anticoagulation (RCA) using a higher Qb may result in more citrate accumulation and associated complications. Routine assessment of the filter and transmembrane pressure should be done to adjust Qb and anticoagulation appropriately.
# We suggest, for patients with COVID-19 without a contraindication, using full-dose anticoagulation for KRT that includes a bolus of heparin through the filter with every new circuit
Rationale (from adult AKI guidance). Initiation of KRT with full-dose anticoagulation, including a bolus of heparin, should be considered, in consultation with PICU colleagues, in the absence of overt contraindications. Anecdotal reports suggest that higher than standard boluses and infusion rates may be required to maintain circuit patency. Providers should continue to follow their existing institutional protocols.
Pediatric context. We did not find pediatric-specific data.
# We suggest, for patients with COVID-19 already on systemic anticoagulation, using a bolus of heparin through the filter when starting KRT (or a new circuit)
Rationale (from adult AKI guidance). As above.
Pediatric context. We did not find pediatric-specific data.
We suggest, for patients on CKRT with an element of hemofiltration, minimizing the postfilter component of the total effluent rate Rationale (from adult AKI guidance). Limiting hemoconcentration may reduce the risk of circuit clotting.
Pediatric context. We did not find pediatric-specific data.
We suggest that programs with experience using RCA for CKRT consider using RCA based on the clinical status of each patient with COVID-19 (differs from adult AKI guidance which suggests using citrate plus heparin when clotting prevents delivery of prescribed dialysis) Pediatric context. Anecdotal reports suggest that RCA is generally effective in preventing circuit clotting in COVID-19 patients. Citrate may also prolong circuit lifetime in pediatric patients on CKRT. 82 We suggest that programs that do not have experience using RCA protocols for CKRT not implement them immediately Rationale (from adult AKI guidance). Implementing RCA protocols is complex under normal circumstances; programs that do not already use this approach regularly should consider other anticoagulation modalities during the pandemic.
Pediatric context. We did not find pediatric-specific data.
# We suggest that low-molecular-weight heparin be considered for CKRT anticoagulation in children with COVID-19 only by providers who already have experience using it (differs from adult AKI guidance, which does not mention the need for expertise)
Rationale (from adult AKI guidance). Some centers in the United States have reported less clotting with the use of lowmolecular-weight heparin (LMWH) protocols for CKRT than they were previously experiencing using unfractionated heparin in patients with COVID-19. In similar circumstances, LMWH is already in widespread use for outpatient IHD and nocturnal dialysis in adults. There have been reports of successful use in chronic HD in children as well. 83,84 With this experience, there is a consideration that LMWH could be used for CKRT or acute IHD or SLED. This requires close collaboration with other disciplines to develop or adapt dosing protocols, recognition by the whole team that the anticoagulation effect may be prolonged beyond the end of dialysis, and recognition that quantification of its impact if needed (eg, if bleeding occurs) is by the anti-Xa level rather than by partial thromboplastin time (PTT).
# Pediatric context.
There are no studies of LMWH use in CKRT in children: Because of this, caution and close monitoring should be used. We suggest that only centers with experience using LMWH in CKRT consider its use during the COVID-19 pandemic.
# Prevention of Intradialytic Hypotension During Intermittent KRT
We suggest adjusting the intermittent KRT prescription to optimize hemodynamic tolerance of fluid removal Rationale (from adult AKI guidance). Given that the primary consideration in many cases may be fluid overload management, various measures can be considered to improve hemodynamic tolerance of fluid removal during intermittent KRT treatments. Adjustments to the IHD prescription that may be considered include use of cool dialysate (≤35.5°C), use of higher dialysate sodium concentration (eg, 145 mmol/L), increasing time on IHD, or switching from IHD to CKRT to reduce the hourly ultrafiltration rate. Overall, there is limited evidence in this area. 81 A quasi-experimental "before-after" study that included 121 critically ill patients who underwent 537 IHD sessions showed that implementation of guidelines recommending cool dialysate and higher dialysate sodium concentration was associated with less-frequent intradialytic hypotension. 81 Isolated ultrafiltration (ultrafiltration without dialysis) is a method that may promote hemodynamic stability. During hemodialysis (HD), the removal of urea in the intravascular compartment creates a reverse osmotic gradient toward the interstitium that may reduce refilling (the movement of salts and water from extracellular and intracellular compartments to the intravascular space that is critical to the maintenance of circulating volume during dialysis). This problem does not occur in isolated ultrafiltration. However, direct evidence on this question is limited to a single study of 6 stable patients treated with outpatient HD: All were men with a mean age of 59 years. 85 Fluid targets were the same in each group, so were fluid removal and postdialysis blood pressures. We are not aware of studies in critically ill patients that have directly assessed this intervention. 51 It is perhaps ill-advised to substitute ultrafiltration time for HD time because it may reduce the dialysis dose delivered. Indeed, underdialysis is associated with higher mortality risk in critically ill patients. 86,87 Adding ultrafiltration time to HD time would increase resource needs (particularly staff time) and will increase the risk of clotting the system. Pediatric context. We did not find pediatric-specific data.
# Reducing Infection Risk to Health Care Workers Involved in Providing KRT
# Whenever possible, we recommend preferentially using KRT modalities that reduce the number of health care workers exposed to patients with COVID-19, to decrease risk to health care workers, risk of nosocomial transmission, and use of PPE, provided that centers have the expertise and support to manage the chosen modality (differs from adult AKI guidance in explicit recognition of the need for expertise and resources)
Rationale (from adult AKI guidance). Preferentially using KRT modalities that reduce health care worker exposure to patients with COVID-19 has to be considered within the local context of how the provision of KRT is organized (eg, if SLED provided by PICU nurses is compared with that provided by an additional nurse from the HD unit; whether SLED can be provided to more than 1 patient at a time for cohorts of patients with a single dialysis nurse) and concerning resource availability at that time.
Pediatric context. We did not find pediatric-specific data.
# We suggest routinely using remote control features of KRT machines, where available
Rationale (from adult AKI guidance). Although few machines are equipped with this technology at present, the use of a remote control feature may reduce infection risk by allowing control of a KRT machine in an isolation room from outside the room.
Pediatric context. We did not find pediatric-specific data.
# Considerations if KRT-related Resources Become Limited During the COVID-19 Pandemic
Current Canadian data do not suggest an imminent threat of increasing acute KRT needs in children due to COVID-19. However, there is an expectation that significant additional PICU capacity might be required to care for children with COVID-19 in the current pandemic context. Planning should consider that specific KRT-related resources may become scarce in the context of the pandemic. Planning considerations vary depending on how acute KRT is provided at the level of individual programs (eg, if a program routinely uses CKRT or SLED; whether PICU nurses or HD nurses routinely provide SLED.). The following subsections outline the considerations specific to various potential KRT-related shortages.
# Delaying the Need for KRT
We recommend that preemptive KRT (ie, before an acute indication is present) should not be used Rationale (from adult AKI guidance). See the section on Timing of Initiation above.
Pediatric context. We did not find pediatric-specific data.
We suggest that, in the context of an overall shortage of KRT resources, clinicians consider using high-dose diuretics (including serial nephron blockade, the use of a loop, and a thiazide-type diuretic together) and off-label use of potassium-binding resins to delay the need for KRT, depending on the clinical context and resource availability Rationale (from adult AKI guidance). No direct data are available on the use of conventional or novel potassium binders in critically ill children and especially infants. 88,89 In outpatients, an increased risk of intestinal ischemia, thrombosis for users of sodium-polystyrene-sulfonate (Kayexalate), compared with nonusers, has been noted in observational research: The increased risk was 5.6 events per thousand patient-years in stable outpatients, but the hazard ratio was 4.9 (95% confidence intervals: 1.1-22.3). 90 The team should be alerted to the possibility that this incremental risk may be higher in patients with COVID-19 because of the higher baseline risk of thrombosis. They should also be aware that because of this tendency, the occurrence of intestinal thrombosis in a patient treated with potassium binders should not necessarily be attributed to the use of the binder. Pediatric context. We did not find pediatric-specific data.
# Shortage of CKRT Machines
We recommend, in the context of a shortage of CKRT machines, using IHD in patients in whom intradialytic hypotension is likely to be manageable with increased vasopressor dosing Rationale (from adult AKI guidance). This needs to be weighed according to the extent to which there is a shortage of HD nurses if a separate HD nurse is required for IHD in the PICU. Also, this approach involves exposing additional nursing staff to COVID-19 infection risk and increased PPE consumption.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of CKRT machines, using IHD machines to do prolonged HD section or SLED for hemodynamically unstable patients (differs from adult AKI guidance in mentioning prolonged HD as an alternative to SLED) Rationale (from adult AKI guidance). Prolonged IHD sessions or SLED would require the HD nurse to be in the PICU. This carries the potential issue of having to deploy more HD nurses to the PICU and the increased COVID-19 risk exposure and PPE use which that entails.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of CKRT machines at centers that use CKRT, prolonged HD or SLED for hemodynamically unstable patients, preferentially using prolonged HD or SLED (differs from adult AKI guidance in mentioning prolonged HD as an alternative to SLED) Rationale (from adult AKI guidance). This suggestion needs to be weighed according to the extent to which there is a shortage of HD nurses if a separate HD nurse is required for SLED in the PICU.
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of CKRT machines, using CKRT machines to provide shorter sessions of CKRT for 2 patients in 24 hours Rationale (from adult AKI guidance). This involves using 1 CKRT machine for 10 hours on 2 patients daily (or 6 hours for 3 patients), realistically estimating 2 hours to move and clean the machine between treatments. One can consider running higher-than-usual effluent rates if there is no expectation of a shortage of CKRT fluid supplies.
Pediatric context. We did not find pediatric-specific data.
# Shortage of CKRT replacement fluid or dialysate
We recommend, in the context of a shortage of CKRT solutions (fluids), having a lower threshold for using IHD in patients in whom hemodynamic instability is likely to be manageable with increased vasopressor dosing Rationale (from adult AKI guidance). As detailed in the preceding section, this suggestion needs to be weighed according to the extent to which there is a shortage of HD nurses if a separate HD nurse is required for IHD in the PICU. Also, this approach involves exposing additional nursing staff to COVID-19 infection risk and increased PPE consumption.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of CKRT solutions (fluids), using conventional HD machines to do prolonged dialysis treatment (or SLED) in hemodynamically unstable patients Rationale (from adult AKI guidance). As detailed above, this carries the potential issue of having to deploy HD nurses to the ICU and the increased COVID-19 risk exposure and PPE use which that entails. In addition, one needs to consider and account for high risks of disequilibrium, hypokalemia, and hypophosphatemia during treatment.
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of CKRT solutions (fluids), in centers that use both CKRT and prolonged HD (or SLED) for hemodynamically unstable patients, favoring the use of prolonged HD (or SLED) if adequate staffing is available Rationale (from AKI guidance). As detailed in the preceding section, this suggestion needs to be weighed according to the extent to which there is a shortage of HD nurses if a separate HD nurse is required for HD (or SLED) in the PICU. Pediatric context. We did not find pediatric-specific data.
We suggest, if there is a shortage of CKRT solutions (fluids), using a lower dose of CKRT (eg, 10-15 mL/kg/hr) once metabolic control has been achieved
Rationale (from AKI guidance). This maximizes the number of patients who can be treated but requires attention to the possibility that underdialysis (ie, failure to deliver standard targets) may lead to excess mortality, as suggested by observational data (ref).
Pediatric context. We did not find pediatric-specific data.
We suggest, if there is a shortage of CKRT solutions, that centers consider producing CKRT solutions locally Rationale (from AKI guidance). A recent publication reports 1 such strategy. 91 The successful use of IHD machines to generate CKRT solution has also previously been reported. 92 Careful attention and planning are required to address sterility, 93 endotoxin levels, 92,94 storage, and bridging incompatible tubing connections. Locally made solutions should be used as dialysate (rather than as replacement fluid) to reduce the risk of direct introduction of potentially contaminated fluids into the bloodstream. Centers considering locally made solutions should plan their preparation to ensure adequate quality control before these solutions are used.
Pediatric context. We did not find pediatric-specific data.
# Shortage of IHD/SLED Capability (Nurses and/or Machines)
We recommend, in the context of a shortage of capacity for IHD or SLED, that centers consider redeploying resources by decreasing the frequency of dialysis for selected stable outpatients treated with maintenance HD patients, as outlined in the CSN COVID-19 Rapid Response Team recommendations for outpatient HD 95 Rationale (from adult AKI guidance). Redeployment of trained dialysis staff from outpatients to critically ill patients may be required with the intention to maximize the number of surviving patients.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of capacity for IHD or SLED machines, that centers review and consider using outdated but still operable dialysis machines and portable RO units Rationale (from adult AKI guidance). Doing this early enables an accurate understanding of available resources in the event of reallocation to adult units if needed. Providers should remain up to date with their available equipment during the COVID-19 pandemic.
Pediatric context. We did not find pediatric-specific data.
We recommend, in the context of a shortage of staff for IHD or SLED, dialysis-trained staff to be redeployed from other areas to provide the necessary support Rationale (from adult AKI guidance). Before redeployment, an assessment of the total number of dialysis-trained staff and the machines with which they have experience working should be undertaken. If there is a shortage for children, this may require staff redeployment from other areas of the pediatric center. However, it may be more likely that a shortage occurs in adults requiring pediatric staff's redeployment to adult centers. Institutions should be prepared to provide readily available training for acute HD nursing should this need arise. Pediatric context. We did not find pediatric-specific data.
We suggest that centers consider using any available home HD machine stockpile in the context of a shortage of machines for IHD or SLED Rationale (from adult AKI guidance). While this maximizes available resources, we recognize that staff training will likely be necessary for the use of machines outside their usual setting in each program.
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of machines for IHD or SLED, that centers consider whether home HD patients who use their machines on alternate days would be willing to share a machine, allowing the return of a device to the program for acute KRT Rationale (from adult AKI guidance). This suggestion has been made in adult nephrology guidelines. This approach has potential barriers, including the near inevitability of a breach in patient confidentiality and the potential for COVID-19 transmission between patients who have agreed to share machines. As above, staff training on an unfamiliar machine will also likely be necessary. These machines may also be considered for allocation to adult patients if needed.
Pediatric context. It must be noted that home HD is less common in children than adults, and in discussion with experts during the CAPN COVID-19 Rapid Response Team Webinar, there were no providers currently caring for any patients on home HD. However, it was felt that this suggestion would still be valid for consideration in the event of a machine shortage if such an option were available.
We suggest, in the context of a shortage of capacity for IHD or SLED, shortening SLED duration to 6 hours, permitting the treatment of 3 patients daily Rationale (from adult AKI guidance). This schedule allows 2 hours to move and clean the machine between patients. Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of capacity for IHD or SLED, that centers consider whether 1 nurse can supervise 2 or more machines simultaneously for older children who are cooperative, located close together and have the same isolation status; start and stop times can be staggered (differs from an adult by the inclusion of the idea of older children who are cooperative) Rationale (from adult AKI guidance). If machines are available, but HD nurses are limited, this will maximize benefits.
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of capacity for IHD or SLED, at centers where SLED is the modality typically used for hemodynamically unstable patients, and it is usually provided by PICU nurses (which is not widely done), using SLED rather than IHD for hemodynamically stable patients Rationale (from adult AKI guidance). This can be done to reduce HD nursing needs and PPE use (if PICU resources allow).
Pediatric context. We did not find pediatric-specific data.
We suggest, in the context of a shortage of capacity for IHD or SLED, that centers consider building capacity for KRT in community hospitals or other pediatric centers that have maintenance HD units but where acute KRT is not routinely provided in PICU Rationale (from adult AKI guidance). Staffing issues need to be carefully considered and the potential need for additional KRT machines and RO units.
Pediatric context. We did not find pediatric-specific data.
# Use of Acute PD to Meet AKI-KRT Needs During the Pandemic
We suggest, in the context of an acute shortage of other KRT modalities, using acute PD if necessary Rationale (from adult AKI guidance). Acute PD can successfully be used to treat critically ill patients in various settings. 96,97 PD was the modality of choice in KRT in pediatric patients until the development of CKRT machines. 98 General guidelines for the use of PD in AKI have previously been reported. 96,99 Many considerations would be involved in the decision to use acute PD, including the following:
• • Depending on the center and nephrologists, surgeons and/or interventional radiologists may perform acute PD catheter insertion. Early planning with those specialists is warranted if resources for non-PD KRT modalities are likely to become scarce during the COVID-19 pandemic. • • Nursing exposure to COVID-19 infection risk (and PPE use) would be best limited by using a cycler/ automated PD. • • Given that volume control may often be the primary concern in COVID-19 patients with AKI, higher glucose concentration solutions may be required (eg, starting with 2.5%/2.36% glucose solutions and then titrating according to achieved ultrafiltration). • • Peritoneal dialysis may be more complicated in patients who require prone ventilation, although its acute use in a predisposed patient has previously been reported to have been successful. 100 We would suggest using another dialysis modality if feasible, as PD would increase the intra-abdominal pressure which may accelerate the need for ventilation. 101 • • Lower dialysate volumes with shorter dwell times offer several potential advantages in this setting. Low volumes may enable better ventilation relative to larger volumes, limiting pericatheter leaks as catheters are used shortly after insertion.
Pediatric context. Pediatric patients tend to be high transporters allowing higher ultrafiltration. 102
# COVID-19 Drug Dosing for Patients With Kidney Dysfunction
We suggest adjusting the dose of medications used to treat COVID-19 in patients with a low glomerular filtration rate of any cause and patients treated with maintenance dialysis Rationale (from adult AKI guidance). This consideration is not specific to patients with AKI. Currently, no medications have been approved in Canada for the treatment of COVID-19. Nonetheless, many drugs are being used off-label or through clinical trials. Given that this is a rapidly changing area, we suggest referring to continuously updated online resources that detail kidney function dosing considerations for potential therapies for COVID-19 (such as the #NephJC AKI blog). 103 Pediatric context. We did not find pediatric-specific data.
# Limitations
There are many significant limitations to this work. Several important considerations were outlined in the adult AKI guidance and are reproduced here. First, because of time constraints and the rapidly evolving information in this field, systematic review or meta-analysis was not possible. Second, none of the suggestions have been specifically evaluated in the clinical environment. Third, we cannot anticipate the many ways in which the dynamic local context, including the details of the organization of care for patients with AKI and the magnitude of the clinical need, will affect the implementation of our suggestions. Fourth, we did not address any ethical issues concerning the need to triage KRT-related resources if rationing were to be required.
Further limitations apply to these pediatric AKI considerations. We have reproduced the adult guidance and rationale throughout, often verbatim, for consistency, and highlighted areas where there are specific pediatric considerations. However, there is a lack of pediatric AKI and KRT data in children with COVID-19 infections; more research is needed. Finally, knowledge is advancing rapidly in this area; our suggestions may quickly be outdated. We recognize the importance of other curated sources of evidence and advice (eg, #NephJC blog, available at http://www.nephjc.com/news/ covidaki) in this rapidly changing environment.
# Implications
Best practices may not be delivered to all patients, given time constraints, resource constraints, and local health authority priorities. The priority is to maximize benefits for the greatest number of patients. Given that most acute KRT related to COVID-19 is initiated in the PICU setting, close collaboration and planning between critical care and pediatric nephrology programs at the local level are required. Suggestions included in this document may need updating as newer evidence becomes available. As part of our knowledge translation strategy, the article will be hosted on the CSN/CAPN Web site. 104,105
# Acknowledgments
We would like to acknowledge the following individuals for providing feedback on these guidelines during the Canadian Association of Paediatric Nephrologists (CAPN) COVID- 19
# Ethics Approval and Consent to Participate
Not applicable, this work did not involve human subjects.
# Consent for Publication
All authors provided consent for publication.
# Availability of Data and Materials
Not applicable, as original data was not collected for this study.
# Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
# Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
# ORCID iDs
Abdullah Alabbas https://orcid.org/0000-0003-2312-7541
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1d25c38a568e361450dea59e7a1806cf4f3641fc
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cma
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besity is a complex chronic disease in which abnormal or excess body fat (adiposity) impairs health, increases the risk of long-term medical complications and reduces lifespan. 1 Epidemiologic studies define obesity using the body mass index (BMI; weight/height 2 ), which can stratify obesity-related health risks at the population level. Obesity is operationally defined as a BMI exceeding 30 kg/m 2 and is subclassified into class 1 (30-34.9), class 2 (35-39.9) and class 3 (≥ 40). At the population level, health complications from excess body fat increase as BMI increases. 2 At the individual level, complications occur because of excess adiposity, location and distribution of adiposity and many other factors, including environmental, genetic, biologic and socioeconomic factors (Box 1). 11 Over the past 3 decades, the prevalence of obesity has steadily increased throughout the world, 12 and in Canada, it has increased threefold since 1985. 13 Importantly, severe obesity has increased more than fourfold and, in 2016, affected an estimated 1.9 million Canadian adults. 13 Obesity has become a major public health issue that increases health care costs 14,15 and negatively affects physical and psychological health. 16 People with obesity experience pervasive weight bias and stigma, which contributes (independent of weight or BMI) to increased morbidity and mortality. 17 Obesity is caused by the complex interplay of multiple genetic, metabolic, behavioural and environmental factors, with the latter thought to be the proximate cause of the substantial#
rise in the prevalence of obesity. 18,19 A better understanding of the biological underpinnings of this disease has emerged in recent years. 19 The brain plays a central role in energy homeostasis by regulating food intake and energy expenditure (Box 2). 24 Decreased food intake and increased physical activity lead to a negative energy balance and trigger a cascade of metabolic and neurohormonal adaptive mechanisms. 25,26 Therapies that target these alterations in neurohormonal mechanisms can become effective tools in the long-term management of obesity. 27 Novel approaches to diagnose and assess obesity in clinical practice have been proposed. 11,18,19,28 Although BMI is widely used to assess and classify obesity (adiposity), it is not an accurate tool for identifying adiposity-related complications. 19 Waist circumference has been independently associated with an increase in cardiovascular risk, but it is not a good predictor of visceral adipose tissue on an individual basis. 29 Integration of both BMI and waist circumference in clinical assessment may identify the higher-risk phenotype of obesity better than either BMI or waist circumference alone, particularly in those individuals with lower BMI. 30,31 In addition to BMI and waist circumference measurements, a comprehensive history to identify the root causes of obesity, appropriate physical examination and relevant laboratory investigations will help to identify those who will benefit from treatment. 32 The Edmonton obesity staging system has been proposed to guide clinical decisions from the obesity assessment and at each BMI category (Appendix 1, available at www.cmaj.ca/lookup/ suppl/doi:10.1503/cmaj.191707/-/DC2). 28 This 5-stage system of obesity classification considers metabolic, physical and psychological parameters to determine the optimal obesity treatment. In population studies, it has been shown to be a better predictor of all-cause mortality when compared with BMI or waist circumference measurements alone. 33,34 There is a recognition that obesity management should be about improved health and well-being, and not just weight loss. Because the existing literature is based mainly on weight-loss outcomes, several recommendations in this guideline are weight-loss centred. However, more research is needed to shift the focus of obesity management toward improving patient-centred health outcomes, rather than weight loss alone.
Despite growing evidence that obesity is a serious chronic disease, it is not effectively managed within our current health system. 37,38 Canadian health professionals feel ill equipped to support people living with obesity. Biased beliefs about obesity also affect the level and quality of health care that patients with obesity receive. 42 The dominant cultural narrative regarding obesity fuels assumptions about personal irresponsibility and lack of willpower and casts blame and shame upon people living with obesity. 41 Importantly, obesity stigma negatively influences the level and quality of care for people living with obesity. 42 With increased knowledge of the disease state and better approaches to assess and manage obesity, it is timely to update the 2006 Canadian clinical practice guideline. 43 The goal of this update is to disseminate to primary care practitioners evidenceinformed options for assessing and treating people living with obesity. Importantly, this guideline incorporates the perspectives of people with lived experience and of interprofessional primary care providers with those of experts on obesity management, and researchers. This article is a summary of the full guideline, which is available online (/).
# Scope
The target users for this guideline are primary health care professionals. The guideline may also be used by policy-makers and people affected by obesity and their families. The guideline is focused on obesity in adults. The recommendations are intended to serve as a guide for health care providers; clinical discretion should be used by all who adopt these recommendations. Resource limitations and individual patient preferences may make it difficult to put every recommendation into practice, but the guideline is intended to improve the standard of, and access to, care for individuals with obesity in all regions of Canada.
# Box 1: Complications of obesity
Adipose tissue not only influences the central regulation of energy homeostasis, but excessive adiposity can also become dysfunctional and predispose the individual to the development of many medical complications, such as:
- Type 2 diabetes 3 - Gallbladder disease 4 - Nonalcoholic fatty liver disease 5 - Gout 6 Excess and ectopic body fat are important sources of adipocytokines and inflammatory mediators that can alter glucose and fat metabolism, leading to increased cardiometabolic and cancer risks, and thereby reducing disease-free duration and life expectancy by 6 to 14 years. 1,7,8 It is estimated that 20% of all cancers can be attributed to obesity, independent of diet. 9 Obesity increases the risk of the following cancers: 10 - Colon (both sexes) - Kidney (both sexes) - Esophagus (both sexes) - Endometrium (women) - Postmenopausal breast (women) Box 2: Appetite regulation - The control of appetite is complex and involves the integration of the central neural circuits including the hypothalamus (homeostatic control), the mesolimbic system (hedonic control) and the frontal lobe (executive control).
- The crosstalk between homeostatic and hedonic eating is influenced by mediators from adipose tissue, the pancreas, gut and other organs.
- Cognitive functions in the prefrontal cortex exert executive control on food choices and the decision to eat. The interconnectivity of these neural networks drives eating behaviour and has been shown to be altered in obesity.
# Effects:
Weight bias thinking that people with obesity do not have enough willpower or are not cooperative
# Stigma acting on weight-biased beliefs
# Recommendations
This clinical practice guideline informs the arc of the patient journey and clinical management approach in the primary care setting. The guideline recommendations are shown in Table 1.
A complete description of the recommendations and supporting evidence are available in the 19 chapters of the full guideline (/). This synopsis outlines a discussion of the guiding principles that the executive committee determined as important for advancing clinical practice in Canada.
There are 5 steps in the patient arc to guide a health care provider in the care of people living with obesity. Each step is outlined below with highlights of the relevant recommendations and a discussion of supporting evidence. 1. Recognition of obesity as a chronic disease by health care providers, who should ask the patient permission to offer advice and help treat this disease in an unbiased manner. 2. Assessment of an individual living with obesity, using appropriate measurements, and identifying the root causes, complications and barriers to obesity treatment. 3. Discussion of the core treatment options (medical nutrition therapy and physical activity) and adjunctive therapies that may be required, including psychological, pharmacologic and surgical interventions. 4. Agreement with the person living with obesity regarding goals of therapy, focusing mainly on the value that the person derives from health-based interventions. 5. Engagement by health care providers with the person with obesity in continued follow-up and reassessments, and encouragement of advocacy to improve care for this chronic disease.
# Step 1: Recognition of obesity as a chronic disease and obtaining patient permission
Primary care providers should recognize and treat obesity as a chronic disease, caused by abnormal or excess body fat accumulation (adiposity), which impairs health, with increased risk of premature morbidity and mortality. 1,2,18, Obesity is a complex and heterogeneous chronic disease that does not present in the same way in all patients and that requires individualized treatment and long-term support like any other complex chronic disease.
Weight bias in health care settings can reduce the quality of care for patients living with obesity. 42 A key to reducing weight bias, stigma and discrimination in health care settings is for health care providers to be aware of their own attitudes and behaviours toward individuals living with obesity. 48 This can be achieved by completing a self-assessment tool, like the Implicit Association Test, for weight bias. 49 A full description and supporting evidence for weight bias recommendations are available online ( . ca/guidelines/) in the chapter titled "Reducing weight bias in obesity management, practice and policy."
Health care providers should not assume that all patients living with obesity are prepared to initiate obesity management. Health care providers should ask the patient permission to discuss obesity, and if the patient permits, then a discussion on treatment can begin. 50,51 Step 2: Assessment Primary care clinicians should promote a holistic approach to health with a focus on health behaviours in all patients and address the root causes of weight gain with care to avoid stigmatizing and overly simplistic narratives.
Direct measurement of height, weight and waist circumference and calculation of BMI should be included in routine physical examination for all adults. Although BMI has its limitations, it remains a valuable tool for screening purposes and for population health indices. 52 For persons with increased BMI (between 25 mg/m 2 and 34.9 mg/m 2 ), waist circumference should be regularly measured to identify individuals with increased visceral adiposity and adiposity-related health risks. 53 Root causes of obesity include biological factors such as genetics, epigenetics, neurohormonal mechanisms, associated chronic diseases and obesogenic medications, sociocultural practices and beliefs, social determinants of health, built en vironment, individual life experiences like adverse childhood experiences, and psychological factors such as mood, anxiety, binge-eating disorder, attention-deficit/hyperactivity disorder, self-worth and identity. 50 Working with people to understand their context and culture, and integrate their root causes, allows for the development of personalized plans. These plans can be integrated into long-term therapeutic relationships with chronic disease follow-up of obesity and related comorbidities, including addressing the root causes of obesity such as existing conditions and obesogenic medications.
We recommend obtaining a comprehensive history to identify these root causes of weight gain, as well as physical, mental and psychosocial barriers. Physical examination, laboratory, diagnostic imaging and other investigations should be carried out based on clinical judgment. We also recommend measuring blood pressure in both arms and obtaining fasting glucose or glycated hemoglobin values and a lipid panel to determine cardiometabolic risk, and when indicated, alanine aminotransferase to screen for nonalcoholic fatty liver disease.
# Step 3: Discussion of treatment options
Adults living with obesity should receive individualized care plans that address their root causes of obesity and that provide support for behavioural change (e.g., nutrition, physical activity) and adjunctive therapies, which may include psychological, pharmacologic and surgical interventions.
# Nutrition and exercise
All individuals, regardless of body size or composition, would benefit from adopting a healthy, well-balanced eating pattern and engaging in regular physical activity. Aerobic activity (30-60 min) on most days of the week can lead to a small amount of weight and fat loss, improvement in cardiometabolic parameters, and weight maintenance after weight loss. 54 Weight loss and weight-loss maintenance require a long-term reduction in caloric intake. Long-term adherence to a healthy eating pattern that is personalized to meet individual values and preferences, while fulfilling nutritional needs and treatment goals, is an important element of managing health and weight.
Medical nutrition therapy is a foundation for chronic disease management, including obesity management. 55,56 However, medical nutrition therapy should not be used in isolation in obesity management, as sustaining weight loss may be difficult long term because of compensatory mechanisms in the brain that promote positive caloric intake by increasing hunger and ultimately causing weight gain. 57,58 Instead, medical nutrition therapy, in combination with other interventions (psychological, pharmacologic, surgical), should be tailored to meet an individual's health-related or weight-related outcomes. 56,59 The weight loss achieved with health behavioural changes is usually 3%-5% of body weight, which can result in meaningful improvement in obesity-related comorbidities. 60 The amount of weight loss varies substantially among individuals, depending on biological and psychosocial factors and not simply on individual effort. The development of evidence-informed strategies at the health system and policy levels can be directed at managing obesity in adults.
Level 2b, grade B 7 Continued longitudinal national and regional surveillance of obesity that includes self-reported and measured data (i.e., height, weight, waist circumference) may be collected on a regular basis.
# Level 2b, grade B
Enabling participation in activities of daily living for people living with obesity
We recommend that health care providers ask people living with obesity if they have concerns about managing self-care activities, such as bathing, getting dressed, bowel and bladder management, skin and wound care, and foot care.
# Level 3, grade C 9
We recommend that health care providers assess fall risk in people living with obesity, as this could interfere with their ability and interest in participating in physical activity.
# Level 3, grade C
# Assessment of people living with obesity 10
We suggest that health care providers involved in screening, assessing and managing people living with obesity use the 5As framework (see Appendix 2 ‡) to initiate the discussion by asking for their permission and assessing their readiness to begin treatment.
# See recommendation 12
We suggest that a comprehensive history to identify root causes of weight gain as well as complications of obesity and potential barriers to treatment be included in the assessment.
# Level 4, grade D 13
We recommend measuring blood pressure in both arms, fasting glucose or glycated hemoglobin and lipid profile to determine cardiometabolic risk and, where appropriate, ALT to screen for nonalcoholic fatty liver disease in people living with obesity.
# Level 3, grade D 14
We suggest that health care providers consider using the Edmonton Obesity Staging System (see Appendix 1) § to determine the severity of obesity and guide clinical decision-making.
# Level 4, grade D
The role of mental health in obesity management 15 We recommend regular monitoring of weight, glucose and lipid profile in people with a mental health diagnosis and who are taking medications associated with weight gain. 19 We suggest that nutrition recommendations for adults of all body sizes be personalized to meet individual values, preferences and treatment goals to support a dietary approach that is safe, effective, nutritionally adequate, culturally acceptable and affordable for long-term adherence.
We suggest that after a patient has been discharged from the bariatric surgical centre, primary care providers conduct annual review of the following: weight, nutritional intake, activity, adherence to multivitamin and mineral supplements, assessment of comorbidities and laboratory tests to assess and treat for nutritional deficiencies as required.
Level 4, grade D (consensus) 53 We suggest that primary care providers consider referral back to the bariatric surgical centre or to a local specialist for technical or gastrointestinal symptoms, nutritional issues, pregnancy, psychological support, weight regain or other medical issues related to bariatric surgery, as described in the chapter titled "Bariatric surgery: postoperative management.
Level 4, grade D (consensus) 54 We suggest that bariatric surgical centres provide follow-up and appropriate laboratory tests at regular intervals postsurgery with access to appropriate health care professionals (dietitian, nurse, social worker, bariatric physician, surgeon, psychologist or psychiatrist) until discharge is deemed appropriate for the patient.
Level 4, grade D (consensus) 55 We recommend that primary care clinicians identify people with overweight and obesity, and initiate patient-centred, health-focused conversations with them.
Level 3, grade C
We recommend that health care providers ensure they ask people for their permission before discussing weight or taking anthropometric measurements. 74 We recommend that primary care providers discuss weight-management targets specific to the reproductive years with adult women with obesity: preconception weight loss (level 3, grade C); gestational weight gain of 5 kg to 9 kg over the entire pregnancy (level 4, grade D); postpartum weight loss of -at minimum -gestational weight gain (level 3, grade C) to reduce the risk of adverse outcomes in the current or in a future pregnancy.
# See recommendation 75
Primary care providers should offer behaviour change interventions including both nutrition and physical activity to adult women with obesity who are considering a pregnancy (level 3, grade C), who are pregnant (level 2a, grade B) and who are postpartum (level 1a, grade A) in order to achieve weight targets.
# See recommendation 76
We recommend that primary care providers encourage and support pregnant women with obesity to consume foods consistent with a healthy dietary pattern in order to meet their target gestational weight gain.
# Level 3, grade C 77
We recommend that primary care providers encourage and support pregnant women with obesity who do not have contraindications to exercise during pregnancy to engage in at least 150 minutes per week of moderate intensity physical activity, to assist in the management of gestational weight gain.
# Level 3, grade C 78
Health care providers should not prescribe metformin for gestational weight gain in pregnant women with obesity (level 1b, grade A). We suggest that weight-management medications not be used during pregnancy or breastfeeding (level 4, grade D).
# See recommendation 79
We recommend that women with obesity be offered additional breastfeeding support because of decreased rates of initiation and continuation.
Level 3, grade C
# Obesity management and Indigenous Peoples
We suggest that health care providers for Indigenous people living with obesity:
- Engage with the patient's social realities.
- Validate the patient's experiences of stress and systemic disadvantage influencing poor health and obesity, exploring elements of their environment where reduced stress could shift behaviours. - Advocate for access to obesity-management resources within publicly funded health care systems, recognizing that resources beyond may be unaffordable and unattainable for many. - Help patients recognize that good health is attainable, and they are entitled to it. - Negotiate small, attainable steps relevant to the patient's context. - Address resistance, seeming apathy and paralysis in patients and providers.
- Self-reflect on anti-Indigenous sentiment common within health care systems, exploring patient motivations and mental health (e.g., trauma, grief) as alternative understandings of causes and solutions to their health problems. Explore one's own potential for bias influenced by systemic racism. - Expect patient mistrust in health systems; reposition themselves as a helper to the patient instead of as an expert, which may stir resistance and be a barrier to patients' wellness. - When resistance, seeming apathy and paralysis are encountered, explore patient mental and emotional health needs, which have unique drivers and presentations in many Indigenous contexts. - Build complex knowledge by healing relationships.
- Build patient knowledge and capacity for obesity self-management through longitudinal explorations of cooccurring health, social, environmental and cultural factors. Strive to build relationships that incorporate healing from multigenerational trauma that, owing to residential schools and child welfare system involvement, may more frequently include sexual abuse. - Build their own knowledge regarding the health legacy of colonization -including ongoing experiences of anti-Indigenous discrimination within systems and wider society -to facilitate relationships built on mutual understanding. - Ensure knowledge provided is congruent with the patient's perspectives and educational level, and is learner centred, including potential for patient anticipation of racism or unequal treatment. - Connect to behaviour, the body and Indigenous ways of knowing, doing and being.
- Elicit and incorporate the patient's individual and community-based concepts of health and healthy behaviours in relation to body size, activity and food preferences (e.g., preference for or scarce access to land-based foods and activities).
# - Deeply engage in learning of common values and principles regarding communication and knowledge-sharing in
Indigenous contexts (e.g., relationalism, noninterference).
# Level 4, grade D (consensus)
Note: ALT = alanine aminotransferase, BMI = body mass index. *A complete description of the recommendations and supporting evidence is available at /. The weight at which the body stabilizes when engaging in healthy behaviours can be referred to as the "best weight"; this may not be an "ideal" weight on the BMI scale. Achieving an "ideal" BMI may be very difficult. If further weight loss is needed to improve health and well-being beyond what can be achieved with behavioural modification, then more intensive pharmacologic and surgical therapeutic options can be considered.
# Psychological and behavioural interventions
All health interventions such as healthy eating and physical activity strategies, medication adherence or surgery preparation and adjustment approaches rest on behaviour change. 61 Psychological and behavioural interventions are the "how to" of change. They empower the clinician to guide the patient toward recommended behaviours that can be sustained over time. 60 A full description of psychological and behavioural interventions and supporting evidence are available online (. ca/guidelines/) in the chapter titled "Effective psychological and behavioural interventions in obesity management."
# Pharmacotherapy
We recommend adjunctive pharmacotherapy for weight loss and weight-loss maintenance for individuals with BMI ≥ 30 kg/m 2 or BMI ≥ 27 kg/m 2 with adiposity-related complications, to support medical nutrition therapy, physical activity and psychological interventions. Options include liraglutide 3.0 mg, naltrexone-bupropion combination and orlistat. Pharmacotherapy augments the magnitude of weight loss beyond that which health behaviour changes can achieve alone and is important in the prevention of weight regain. A full description and supporting evidence are available online ( / guidelines/) in the chapter titled "Pharmacotherapy in obesity management."
# Bariatric surgery
Bariatric surgery may be considered for people with BMI ≥ 40 kg/m 2 or BMI ≥ 35 kg/m 2 with at least 1 obesity-related disease. The decision regarding the type of surgery should be made in collaboration with a multidisciplinary team, balancing the patient's expectations, medical condition, and expected benefits and risks of the surgery. A full description and supporting evidence are available online (/) in the chapters titled "Bariatric surgery: selection and preoperative workup," "Bariatric surgery: options and outcomes" and "Bariatric surgery: postoperative management."
# Step 4: Agreement regarding goals of therapy
Because obesity is a chronic disease, managing it in the long term involves patient-provider collaboration. 67 Health care providers should talk with their patients and agree on realistic expectations, person-centred treatments and sustainable goals for behaviour change and health outcomes. 68 Helpful actions in primary care consultations to mitigate antifat stigma include explicitly acknowledging the multiple determinants of weight-disrupting stereotypes of personal failure or success attached to body composition; focusing on behavioural interventions to improve overall health; and redefining success as healthy behaviour change regardless of body size or weight. 69 As this disease is chronic in nature, the treatment plan must be long term. Health care providers and patients should design and agree on a personalized action plan that is practical and sustainable and addresses the drivers of weight gain. 70 Step 5: Follow-up and advocacy
There is a need to advocate for more effective care for people living with obesity. This includes improving the education and lifelong learning of health care providers to be able to deliver effective, evidence-based obesity care. We also need to support allocation of health care resources to improve access to effective behavioural, pharmacologic and surgical therapeutic options.
There are substantial barriers affecting access to obesity care in Canada, including a profound lack of interdisciplinary obesity management programs, a lack of adequate access to health care providers with expertise in obesity, long wait times for referrals and surgery, and the high costs of some treatments. ,37,71-73 In general, health care professionals are poorly prepared to treat obesity. 74 None of the anti-obesity medications available in Canada is listed as a benefit on any provincial or territorial formulary and none is covered under any provincial public drug benefit or pharmacare program. 71 Wait times for bariatric surgery in Canada are the longest of any surgically treatable condition. 37,71 Although access to bariatric surgery has increased in some parts of Canada, it is still limited in most provinces and nonexistent in the 3 territories. 37,71,75 Patients referred to bariatric surgery can wait as long as 8 years before meeting a specialist or receiving the surgery.
The lack of access to obesity treatments is contributing to rising levels of severe obesity in Canada. 46 Canadians affected by obesity are left to navigate a complex landscape of weight-loss products and services, many of which lack a scientific rationale and openly promote unrealistic and unsustainable weight-loss goals. 76 The steering committee (n = 16) consisted of some lead authors of each chapter and a person living with obesity; this committee identified additional researchers (chapter leads and authors) to write each chapter. The executive committee and steering committee met in person in April 2017 and December 2017 and at least monthly by phone.
# Methods
# Composition of participating groups
Chapter leads and chapter authors (n = 60) were selected based on their expertise in clinical practice and research in the field of obesity medicine. The number of chapter authors per chapter ranged from 2 to 4. Some chapter leads identified additional authors to participate in writing each chapter.
We engaged people living with obesity (n = 7) through participation of the Public Engagement Committee of Obesity Canada. One member of the Public Engagement Committee (I.P.) was assigned to the steering committee for this guideline. The Public Engagement Committee met by phone once per month. We obtained contributions from committee members through online surveys, focus groups and individual conversations.
We engaged Indigenous community members through a focus group (n = 14). Additionally, we obtained the insights of health care providers working with Indigenous communities via a consensus-building process between these clinicians and chapter authors, carried out over the spring of 2019, which further grounded evidence in clinical practice. Details are available online (/) in the chapter titled "Obesity management with Indigenous Peoples."
Obesity Canada staff, consultants and volunteers (n = 15) provided administrative support and project coordination for the guideline development process. Table 2 outlines the guideline development process and the responsibilities of each group of participants.
# Selection of priority topics
The executive committee conducted a mind-mapping exercise to identify the scope of the guideline and the broad sections and chapters (April-June 2017). 79
# Literature review and quality assessment
The McMaster Evidence Review and Synthesis Team supported the guideline development through literature searches based on the PI/PECOT questions for each chapter. A health sciences librarian, based at McMaster Health Sciences Library (Hamilton, Ont.), used this information to create search strategies for the MEDLINE and Embase databases. The searches were for peer-reviewed and published literature in the English language; the search dates were January 2006 to June 2018. There were 14 searches that mapped directly to the chapters and another 7 searches that helped provide context for various chapters. Search strategies are available on the obesity guideline webpage (/). Once a search was conducted, the results were uploaded to EndNote, where the duplicates were removed and the final set of citations was uploaded to DistillerSR software for selection and review. 80 In addition to the electronic searches, the chapter authors identified additional citations and added them to the main search results.
Two reviewers completed screening of article titles and abstracts and independently selected studies for possible inclusion. Any citation that was selected for inclusion by either reviewer was moved to full-text review. One or more authors of the relevant chapter conducted reviews of full-text articles for relevancy. Selected citations were then assessed for their methodological quality using the Shekelle approach. 77,81 Each citation was categorized into prevention, treatment, evaluation of diagnostic properties or prognosis. Once that selection was made, the appropriate methods worksheet was displayed in the Distiller SR platform, from which the methodological questions were answered and a level of evidence generated based on the type and quality of the study. The levels of evidence informed the strength of the recommendations and were generated from the methods worksheets (Box 3). 77
# Development of recommendations
Recommendations were formulated by the steering committee, chapter leads and chapter authors based on the highest level of evidence available (Box 3). 77 Chapter leads and authors reviewed the type and strength of the available evidence (level) and added the study reference that provided the highest level of evidence for the specific recommendation.
Recognizing the importance of qualitative research in addressing questions pertinent to the care of people living with obesity, content experts in qualitative research (S.K., X.R.S., D.C.S., L.C., S.R.M.) were involved in the review of all materials informing these recommendations. Consensus appraisal of evidence quality by reviewers with expertise in qualitative methods informed the level of evidence in these recommendations. Some grade D recommendations were formulated based on expert committee reports, opinions or clinical experience of respected authorities, and referenced accordingly; other grade D recommendations formulated by chapter authors were noted with "Consensus" after the grade D.
Chapter authors used a standardized terminology to make the recommendation more specific. The actionable verbs used for each of the recommendations were informed by the literature (Table 3). We used an iterative process to finalize the recommendations. Methodologists from MERST provided an independent review of recommendations that had a grade between A and C, for which they examined the clarity of wording and the fidelity of the recommendations with the evidence. Two methodologists (a primary and secondary reviewer) reviewed each recommendation, using checklists as a guide for assigning levels of evidence to each citation. The methodologists met, discussed and reached consensus on grading the recommendations, and reported their suggestions regarding revisions to the wording or grading to the executive committee. Chapter leads edited the recommendations based on the MERST review process.
The executive committee voted on each recommendation, to ensure consensus. If a recommendation did not reach 100% agreement, the executive committee discussed the recommendation in depth until consensus was achieved. The chapter leads subsequently modified the wording of this recommendation, as required, and the executive committee approved the newly worded recommendation. The executive committee provided final approval of all the recommendations. All the recommendations included in this guideline achieved 100% agreement.
# External review
External reviewers (primary care health care professionals and people living with obesity ) reviewed the recommendations for relevance and feasibility. We made some modifications to reflect language and the context of the primary care setting. A separate external peer review was conducted for each chapter. The executive committee developed and managed the competing interest policy and procedures for mitigating bias. The policy and disclosures of competing interest are available on the guideline website. All participants were required to disclose potential competing interests. We maintained detailed competing interest declarations throughout the process for all members of the steering and executive committees, as well as the participating methodologists from MERST. We used the International Committee of Medical Journal Editors' disclosure form, with the addition of government funding sources.
# Management of competing interests
Individuals with relevant disclosures were not excluded from conducting the critical appraisals or voting on recommendations. However, the executive committee asked individuals with direct competing interests to abstain from voting in the areas in which they had the conflict. Any discussion regarding off-label use of drugs included the caveat that the use was off label.
As mentioned earlier, methodologists from MERST who had no competing interests reviewed and graded 78 each included study to ensure the evidence had been appropriately assessed. They also reviewed the recommendations (graded between A and C) to ensure that recommendations were aligned with the evidence. Finally, we conducted an external review process to assess the feasibility of the recommendations and evaluate for the presence of bias.
# Implementation
Obesity Canada and the Canadian Association of Bariatric Surgeons and Physicians have created a joint guideline website () that hosts the full guideline; interim updates; a quick reference guide; key messages; health care provider tools, slide kits, videos and webinars; and resources for people living with obesity and their support systems, in English and French. The guideline will be hosted on the website as a living document. Each chapter lead will monitor evidence related to this guideline and will collaborate with the executive committee to update the recommendations if new evidence becomes available that could influence the recommendations. A framework for implementation (5As Framework) is available in Appendix 2.
More than 10 years after the release of the first Canadian obes ity guideline in 2006, access to obesity care remains an issue in Canada. 37,71 Obesity is not officially recognized as a chronic disease by the federal, provincial and territorial, and municipal governments, despite declarations by the Canadian Medical Association 85 and the World Health Organization. 86 The lack of recognition of obesity as a chronic disease by public and private payers, health systems, the public and media has a trickle-down effect on access to treatment. 72 Obesity continues to be treated as a self-inflicted condition, which affects the type of interventions and approaches that are implemented by governments or covered by health benefit plans. 87 Implementation of this guideline will require targeted policy action, as well as advocacy efforts and engagement from people living with obesity, their families and health care providers. Canadian organizations have come together to change the narrative regarding obesity in Canada, to eliminate weight bias and obesity stigma, and to change the way health care systems and policies approach obesity. 88 This guideline will be used to assist in advocacy efforts to federal and provincial governments to improve the care of individuals with obesity.
# Other guidelines
In 2006, the first evidence-based Canadian clinical practice guideline on the prevention and management of obesity in adults and children was released. 43 In 2015, the Canadian Task Force on Preventive Health Care, in collaboration with scientific staff of the Public Health Agency of Canada and the McMaster Evidence Review and Synthesis Centre, released a set of recommendations for prevention of weight gain and use of behavioural and pharmacologic interventions to manage overweight and obesity in adults in primary care. 89 This guideline was not designed to "apply to people with BMI of 40 or greater, who may benefit from specialized bariatric programs" and reviewed only intervention trials conducted in settings generalizable to Canadian primary care. The guideline also did not include surgical treatments.
# Gaps in knowledge
The recommendations in this guideline are informed by the best level of evidence available in 2020. We acknowledge that ongoing research will continue to inform and advance obesity management. 90,91 Current treatment options, apart from surgical intervention, rarely yield sustained weight loss beyond 20%, and for some people living with obesity, this level of weight loss may be inadequate for the resolution or improvement of many adiposityrelated medical complications. There is a need for more treatment options to meet the needs of people with obesity. Weight regain continues to be a challenge for many patients who have received treatment. 92
# Conclusion
Obesity is a prevalent, complex chronic disease that affects a large number of adults in Canada and globally, and yet only a small fraction of people living with obesity who could benefit from treatment have access to care. This updated evidenceinformed guideline is an attempt to enhance access and care by people living with obesity through recognition among health care providers that obesity requires long-term treatment. The newer insights into appetite regulation and the pathophysiology of obesity have opened new avenues for treating this chronic disease. Reducing weight bias and stigma, understanding the root causes of obesity, and promoting and supporting patient-centred behavioural interventions and appropriate treatment by health care providers -preferably with the support of interdisciplinary care teams -will raise the standards of care and improve the well-being of people living with obesity. Dissemination and implementation of this guideline are integral components of our goals to address this prevalent chronic disease. Much more effort is needed to close the gaps in knowledge through obesity research, education, prevention and treatment.
# GUIDELINE
Competing interests: Sean Wharton reports receiving honoraria and travel expenses and has participated in academic advisory boards for Novo Nordisk, Bausch Health, Eli Lilly and Janssen. Sean Wharton is also the medical director of a medical clinic specializing in weight management and diabetes. David Lau reports receiving grants and research support from AstraZeneca, Novo Nordisk and the Canadian Institutes of Health Research (CIHR); speaker bureau fees from AstraZeneca, Bausch Health, Boehringer Ingelheim, Diabetes Canada, Eli Lilly, Merck and Novo Nordisk; and consulting fees from Amgen, AstraZeneca, Bausch Health, Boehringer Ingelheim, Gilead, HLS Therapeutics, Janssen, Eli Lilly and Novo Nordisk. Michael Contributors: All of the authors contributed to the conception and design of the work and the acquisition, analysis, and interpretation of data. All of the authors drafted the manuscript, revised it critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.
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besity is a complex chronic disease in which abnormal or excess body fat (adiposity) impairs health, increases the risk of long-term medical complications and reduces lifespan. 1 Epidemiologic studies define obesity using the body mass index (BMI; weight/height 2 ), which can stratify obesity-related health risks at the population level. Obesity is operationally defined as a BMI exceeding 30 kg/m 2 and is subclassified into class 1 (30-34.9), class 2 (35-39.9) and class 3 (≥ 40). At the population level, health complications from excess body fat increase as BMI increases. 2 At the individual level, complications occur because of excess adiposity, location and distribution of adiposity and many other factors, including environmental, genetic, biologic and socioeconomic factors (Box 1). 11 Over the past 3 decades, the prevalence of obesity has steadily increased throughout the world, 12 and in Canada, it has increased threefold since 1985. 13 Importantly, severe obesity has increased more than fourfold and, in 2016, affected an estimated 1.9 million Canadian adults. 13 Obesity has become a major public health issue that increases health care costs 14,15 and negatively affects physical and psychological health. 16 People with obesity experience pervasive weight bias and stigma, which contributes (independent of weight or BMI) to increased morbidity and mortality. 17 Obesity is caused by the complex interplay of multiple genetic, metabolic, behavioural and environmental factors, with the latter thought to be the proximate cause of the substantial#
rise in the prevalence of obesity. 18,19 A better understanding of the biological underpinnings of this disease has emerged in recent years. 19 The brain plays a central role in energy homeostasis by regulating food intake and energy expenditure (Box 2). 24 Decreased food intake and increased physical activity lead to a negative energy balance and trigger a cascade of metabolic and neurohormonal adaptive mechanisms. 25,26 Therapies that target these alterations in neurohormonal mechanisms can become effective tools in the long-term management of obesity. 27 Novel approaches to diagnose and assess obesity in clinical practice have been proposed. 11,18,19,28 Although BMI is widely used to assess and classify obesity (adiposity), it is not an accurate tool for identifying adiposity-related complications. 19 Waist circumference has been independently associated with an increase in cardiovascular risk, but it is not a good predictor of visceral adipose tissue on an individual basis. 29 Integration of both BMI and waist circumference in clinical assessment may identify the higher-risk phenotype of obesity better than either BMI or waist circumference alone, particularly in those individuals with lower BMI. 30,31 In addition to BMI and waist circumference measurements, a comprehensive history to identify the root causes of obesity, appropriate physical examination and relevant laboratory investigations will help to identify those who will benefit from treatment. 32 The Edmonton obesity staging system has been proposed to guide clinical decisions from the obesity assessment and at each BMI category (Appendix 1, available at www.cmaj.ca/lookup/ suppl/doi:10.1503/cmaj.191707/-/DC2). 28 This 5-stage system of obesity classification considers metabolic, physical and psychological parameters to determine the optimal obesity treatment. In population studies, it has been shown to be a better predictor of all-cause mortality when compared with BMI or waist circumference measurements alone. 33,34 There is a recognition that obesity management should be about improved health and well-being, and not just weight loss. [34][35][36] Because the existing literature is based mainly on weight-loss outcomes, several recommendations in this guideline are weight-loss centred. However, more research is needed to shift the focus of obesity management toward improving patient-centred health outcomes, rather than weight loss alone.
Despite growing evidence that obesity is a serious chronic disease, it is not effectively managed within our current health system. 37,38 Canadian health professionals feel ill equipped to support people living with obesity. [39][40][41] Biased beliefs about obesity also affect the level and quality of health care that patients with obesity receive. 42 The dominant cultural narrative regarding obesity fuels assumptions about personal irresponsibility and lack of willpower and casts blame and shame upon people living with obesity. 41 Importantly, obesity stigma negatively influences the level and quality of care for people living with obesity. 42 With increased knowledge of the disease state and better approaches to assess and manage obesity, it is timely to update the 2006 Canadian clinical practice guideline. 43 The goal of this update is to disseminate to primary care practitioners evidenceinformed options for assessing and treating people living with obesity. Importantly, this guideline incorporates the perspectives of people with lived experience and of interprofessional primary care providers with those of experts on obesity management, and researchers. This article is a summary of the full guideline, which is available online (http://obesitycanada.ca/guidelines/).
# Scope
The target users for this guideline are primary health care professionals. The guideline may also be used by policy-makers and people affected by obesity and their families. The guideline is focused on obesity in adults. The recommendations are intended to serve as a guide for health care providers; clinical discretion should be used by all who adopt these recommendations. Resource limitations and individual patient preferences may make it difficult to put every recommendation into practice, but the guideline is intended to improve the standard of, and access to, care for individuals with obesity in all regions of Canada.
# Box 1: Complications of obesity
Adipose tissue not only influences the central regulation of energy homeostasis, but excessive adiposity can also become dysfunctional and predispose the individual to the development of many medical complications, such as:
• Type 2 diabetes 3 • Gallbladder disease 4 • Nonalcoholic fatty liver disease 5 • Gout 6 Excess and ectopic body fat are important sources of adipocytokines and inflammatory mediators that can alter glucose and fat metabolism, leading to increased cardiometabolic and cancer risks, and thereby reducing disease-free duration and life expectancy by 6 to 14 years. 1,7,8 It is estimated that 20% of all cancers can be attributed to obesity, independent of diet. 9 Obesity increases the risk of the following cancers: 10 • Colon (both sexes) • Kidney (both sexes) • Esophagus (both sexes) • Endometrium (women) • Postmenopausal breast (women) Box 2: Appetite regulation [20][21][22][23] • The control of appetite is complex and involves the integration of the central neural circuits including the hypothalamus (homeostatic control), the mesolimbic system (hedonic control) and the frontal lobe (executive control).
• The crosstalk between homeostatic and hedonic eating is influenced by mediators from adipose tissue, the pancreas, gut and other organs.
• Cognitive functions in the prefrontal cortex exert executive control on food choices and the decision to eat. The interconnectivity of these neural networks drives eating behaviour and has been shown to be altered in obesity.
# Effects:
Weight bias thinking that people with obesity do not have enough willpower or are not cooperative
# Stigma acting on weight-biased beliefs
# Recommendations
This clinical practice guideline informs the arc of the patient journey and clinical management approach in the primary care setting. The guideline recommendations are shown in Table 1.
A complete description of the recommendations and supporting evidence are available in the 19 chapters of the full guideline (http://obesitycanada.ca/guidelines/). This synopsis outlines a discussion of the guiding principles that the executive committee determined as important for advancing clinical practice in Canada.
There are 5 steps in the patient arc to guide a health care provider in the care of people living with obesity. Each step is outlined below with highlights of the relevant recommendations and a discussion of supporting evidence. 1. Recognition of obesity as a chronic disease by health care providers, who should ask the patient permission to offer advice and help treat this disease in an unbiased manner. 2. Assessment of an individual living with obesity, using appropriate measurements, and identifying the root causes, complications and barriers to obesity treatment. 3. Discussion of the core treatment options (medical nutrition therapy and physical activity) and adjunctive therapies that may be required, including psychological, pharmacologic and surgical interventions. 4. Agreement with the person living with obesity regarding goals of therapy, focusing mainly on the value that the person derives from health-based interventions. 5. Engagement by health care providers with the person with obesity in continued follow-up and reassessments, and encouragement of advocacy to improve care for this chronic disease.
# Step 1: Recognition of obesity as a chronic disease and obtaining patient permission
Primary care providers should recognize and treat obesity as a chronic disease, caused by abnormal or excess body fat accumulation (adiposity), which impairs health, with increased risk of premature morbidity and mortality. 1,2,18,[44][45][46][47] Obesity is a complex and heterogeneous chronic disease that does not present in the same way in all patients and that requires individualized treatment and long-term support like any other complex chronic disease.
Weight bias in health care settings can reduce the quality of care for patients living with obesity. 42 A key to reducing weight bias, stigma and discrimination in health care settings is for health care providers to be aware of their own attitudes and behaviours toward individuals living with obesity. 48 This can be achieved by completing a self-assessment tool, like the Implicit Association Test, for weight bias. 49 A full description and supporting evidence for weight bias recommendations are available online (http://obesitycanada . ca/guidelines/) in the chapter titled "Reducing weight bias in obesity management, practice and policy."
Health care providers should not assume that all patients living with obesity are prepared to initiate obesity management. Health care providers should ask the patient permission to discuss obesity, and if the patient permits, then a discussion on treatment can begin. 50,51 Step 2: Assessment Primary care clinicians should promote a holistic approach to health with a focus on health behaviours in all patients and address the root causes of weight gain with care to avoid stigmatizing and overly simplistic narratives.
Direct measurement of height, weight and waist circumference and calculation of BMI should be included in routine physical examination for all adults. Although BMI has its limitations, it remains a valuable tool for screening purposes and for population health indices. 52 For persons with increased BMI (between 25 mg/m 2 and 34.9 mg/m 2 ), waist circumference should be regularly measured to identify individuals with increased visceral adiposity and adiposity-related health risks. 53 Root causes of obesity include biological factors such as genetics, epigenetics, neurohormonal mechanisms, associated chronic diseases and obesogenic medications, sociocultural practices and beliefs, social determinants of health, built en vironment, individual life experiences like adverse childhood experiences, and psychological factors such as mood, anxiety, binge-eating disorder, attention-deficit/hyperactivity disorder, self-worth and identity. 50 Working with people to understand their context and culture, and integrate their root causes, allows for the development of personalized plans. These plans can be integrated into long-term therapeutic relationships with chronic disease follow-up of obesity and related comorbidities, including addressing the root causes of obesity such as existing conditions and obesogenic medications.
We recommend obtaining a comprehensive history to identify these root causes of weight gain, as well as physical, mental and psychosocial barriers. Physical examination, laboratory, diagnostic imaging and other investigations should be carried out based on clinical judgment. We also recommend measuring blood pressure in both arms and obtaining fasting glucose or glycated hemoglobin values and a lipid panel to determine cardiometabolic risk, and when indicated, alanine aminotransferase to screen for nonalcoholic fatty liver disease.
# Step 3: Discussion of treatment options
Adults living with obesity should receive individualized care plans that address their root causes of obesity and that provide support for behavioural change (e.g., nutrition, physical activity) and adjunctive therapies, which may include psychological, pharmacologic and surgical interventions.
# Nutrition and exercise
All individuals, regardless of body size or composition, would benefit from adopting a healthy, well-balanced eating pattern and engaging in regular physical activity. Aerobic activity (30-60 min) on most days of the week can lead to a small amount of weight and fat loss, improvement in cardiometabolic parameters, and weight maintenance after weight loss. 54 Weight loss and weight-loss maintenance require a long-term reduction in caloric intake. Long-term adherence to a healthy eating pattern that is personalized to meet individual values and preferences, while fulfilling nutritional needs and treatment goals, is an important element of managing health and weight.
Medical nutrition therapy is a foundation for chronic disease management, including obesity management. 55,56 However, medical nutrition therapy should not be used in isolation in obesity management, as sustaining weight loss may be difficult long term because of compensatory mechanisms in the brain that promote positive caloric intake by increasing hunger and ultimately causing weight gain. 57,58 Instead, medical nutrition therapy, in combination with other interventions (psychological, pharmacologic, surgical), should be tailored to meet an individual's health-related or weight-related outcomes. 56,59 The weight loss achieved with health behavioural changes is usually 3%-5% of body weight, which can result in meaningful improvement in obesity-related comorbidities. 60 The amount of weight loss varies substantially among individuals, depending on biological and psychosocial factors and not simply on individual effort. The development of evidence-informed strategies at the health system and policy levels can be directed at managing obesity in adults.
Level 2b, grade B 7 Continued longitudinal national and regional surveillance of obesity that includes self-reported and measured data (i.e., height, weight, waist circumference) may be collected on a regular basis.
# Level 2b, grade B
Enabling participation in activities of daily living for people living with obesity
8
We recommend that health care providers ask people living with obesity if they have concerns about managing self-care activities, such as bathing, getting dressed, bowel and bladder management, skin and wound care, and foot care.
# Level 3, grade C 9
We recommend that health care providers assess fall risk in people living with obesity, as this could interfere with their ability and interest in participating in physical activity.
# Level 3, grade C
# Assessment of people living with obesity 10
We suggest that health care providers involved in screening, assessing and managing people living with obesity use the 5As framework (see Appendix 2 ‡) to initiate the discussion by asking for their permission and assessing their readiness to begin treatment.
# See recommendation 12
We suggest that a comprehensive history to identify root causes of weight gain as well as complications of obesity and potential barriers to treatment be included in the assessment.
# Level 4, grade D 13
We recommend measuring blood pressure in both arms, fasting glucose or glycated hemoglobin and lipid profile to determine cardiometabolic risk and, where appropriate, ALT to screen for nonalcoholic fatty liver disease in people living with obesity.
# Level 3, grade D 14
We suggest that health care providers consider using the Edmonton Obesity Staging System (see Appendix 1) § to determine the severity of obesity and guide clinical decision-making.
# Level 4, grade D
The role of mental health in obesity management 15 We recommend regular monitoring of weight, glucose and lipid profile in people with a mental health diagnosis and who are taking medications associated with weight gain. 19 We suggest that nutrition recommendations for adults of all body sizes be personalized to meet individual values, preferences and treatment goals to support a dietary approach that is safe, effective, nutritionally adequate, culturally acceptable and affordable for long-term adherence.
52
We suggest that after a patient has been discharged from the bariatric surgical centre, primary care providers conduct annual review of the following: weight, nutritional intake, activity, adherence to multivitamin and mineral supplements, assessment of comorbidities and laboratory tests to assess and treat for nutritional deficiencies as required.
Level 4, grade D (consensus) 53 We suggest that primary care providers consider referral back to the bariatric surgical centre or to a local specialist for technical or gastrointestinal symptoms, nutritional issues, pregnancy, psychological support, weight regain or other medical issues related to bariatric surgery, as described in the chapter titled "Bariatric surgery: postoperative management.
Level 4, grade D (consensus) 54 We suggest that bariatric surgical centres provide follow-up and appropriate laboratory tests at regular intervals postsurgery with access to appropriate health care professionals (dietitian, nurse, social worker, bariatric physician, surgeon, psychologist or psychiatrist) until discharge is deemed appropriate for the patient.
Level 4, grade D (consensus) 55 We recommend that primary care clinicians identify people with overweight and obesity, and initiate patient-centred, health-focused conversations with them.
Level 3, grade C
# 56
We recommend that health care providers ensure they ask people for their permission before discussing weight or taking anthropometric measurements. 74 We recommend that primary care providers discuss weight-management targets specific to the reproductive years with adult women with obesity: preconception weight loss (level 3, grade C); gestational weight gain of 5 kg to 9 kg over the entire pregnancy (level 4, grade D); postpartum weight loss of -at minimum -gestational weight gain (level 3, grade C) to reduce the risk of adverse outcomes in the current or in a future pregnancy.
# See recommendation 75
Primary care providers should offer behaviour change interventions including both nutrition and physical activity to adult women with obesity who are considering a pregnancy (level 3, grade C), who are pregnant (level 2a, grade B) and who are postpartum (level 1a, grade A) in order to achieve weight targets.
# See recommendation 76
We recommend that primary care providers encourage and support pregnant women with obesity to consume foods consistent with a healthy dietary pattern in order to meet their target gestational weight gain.
# Level 3, grade C 77
We recommend that primary care providers encourage and support pregnant women with obesity who do not have contraindications to exercise during pregnancy to engage in at least 150 minutes per week of moderate intensity physical activity, to assist in the management of gestational weight gain.
# Level 3, grade C 78
Health care providers should not prescribe metformin for gestational weight gain in pregnant women with obesity (level 1b, grade A). We suggest that weight-management medications not be used during pregnancy or breastfeeding (level 4, grade D).
# See recommendation 79
We recommend that women with obesity be offered additional breastfeeding support because of decreased rates of initiation and continuation.
Level 3, grade C
# Obesity management and Indigenous Peoples
# 80
We suggest that health care providers for Indigenous people living with obesity:
• Engage with the patient's social realities.
• Validate the patient's experiences of stress and systemic disadvantage influencing poor health and obesity, exploring elements of their environment where reduced stress could shift behaviours. • Advocate for access to obesity-management resources within publicly funded health care systems, recognizing that resources beyond may be unaffordable and unattainable for many. • Help patients recognize that good health is attainable, and they are entitled to it. • Negotiate small, attainable steps relevant to the patient's context. • Address resistance, seeming apathy and paralysis in patients and providers.
• Self-reflect on anti-Indigenous sentiment common within health care systems, exploring patient motivations and mental health (e.g., trauma, grief) as alternative understandings of causes and solutions to their health problems. Explore one's own potential for bias influenced by systemic racism. • Expect patient mistrust in health systems; reposition themselves as a helper to the patient instead of as an expert, which may stir resistance and be a barrier to patients' wellness. • When resistance, seeming apathy and paralysis are encountered, explore patient mental and emotional health needs, which have unique drivers and presentations in many Indigenous contexts. • Build complex knowledge by healing relationships.
• Build patient knowledge and capacity for obesity self-management through longitudinal explorations of cooccurring health, social, environmental and cultural factors. Strive to build relationships that incorporate healing from multigenerational trauma that, owing to residential schools and child welfare system involvement, may more frequently include sexual abuse. • Build their own knowledge regarding the health legacy of colonization -including ongoing experiences of anti-Indigenous discrimination within systems and wider society -to facilitate relationships built on mutual understanding. • Ensure knowledge provided is congruent with the patient's perspectives and educational level, and is learner centred, including potential for patient anticipation of racism or unequal treatment. • Connect to behaviour, the body and Indigenous ways of knowing, doing and being.
• Elicit and incorporate the patient's individual and community-based concepts of health and healthy behaviours in relation to body size, activity and food preferences (e.g., preference for or scarce access to land-based foods and activities).
# • Deeply engage in learning of common values and principles regarding communication and knowledge-sharing in
Indigenous contexts (e.g., relationalism, noninterference).
# Level 4, grade D (consensus)
Note: ALT = alanine aminotransferase, BMI = body mass index. *A complete description of the recommendations and supporting evidence is available at http://obesitycanada.ca/guidelines/. The weight at which the body stabilizes when engaging in healthy behaviours can be referred to as the "best weight"; this may not be an "ideal" weight on the BMI scale. Achieving an "ideal" BMI may be very difficult. If further weight loss is needed to improve health and well-being beyond what can be achieved with behavioural modification, then more intensive pharmacologic and surgical therapeutic options can be considered.
# Psychological and behavioural interventions
All health interventions such as healthy eating and physical activity strategies, medication adherence or surgery preparation and adjustment approaches rest on behaviour change. 61 Psychological and behavioural interventions are the "how to" of change. They empower the clinician to guide the patient toward recommended behaviours that can be sustained over time. 60 A full description of psychological and behavioural interventions and supporting evidence are available online (http://obesitycanada. ca/guidelines/) in the chapter titled "Effective psychological and behavioural interventions in obesity management."
# Pharmacotherapy
We recommend adjunctive pharmacotherapy for weight loss and weight-loss maintenance for individuals with BMI ≥ 30 kg/m 2 or BMI ≥ 27 kg/m 2 with adiposity-related complications, to support medical nutrition therapy, physical activity and psychological interventions. Options include liraglutide 3.0 mg, naltrexone-bupropion combination and orlistat. Pharmacotherapy augments the magnitude of weight loss beyond that which health behaviour changes can achieve alone and is important in the prevention of weight regain. [62][63][64][65][66] A full description and supporting evidence are available online (http://obesitycanada.ca / guidelines/) in the chapter titled "Pharmacotherapy in obesity management."
# Bariatric surgery
Bariatric surgery may be considered for people with BMI ≥ 40 kg/m 2 or BMI ≥ 35 kg/m 2 with at least 1 obesity-related disease. The decision regarding the type of surgery should be made in collaboration with a multidisciplinary team, balancing the patient's expectations, medical condition, and expected benefits and risks of the surgery. A full description and supporting evidence are available online (http://obesitycanada.ca/guidelines/) in the chapters titled "Bariatric surgery: selection and preoperative workup," "Bariatric surgery: options and outcomes" and "Bariatric surgery: postoperative management."
# Step 4: Agreement regarding goals of therapy
Because obesity is a chronic disease, managing it in the long term involves patient-provider collaboration. 67 Health care providers should talk with their patients and agree on realistic expectations, person-centred treatments and sustainable goals for behaviour change and health outcomes. 68 Helpful actions in primary care consultations to mitigate antifat stigma include explicitly acknowledging the multiple determinants of weight-disrupting stereotypes of personal failure or success attached to body composition; focusing on behavioural interventions to improve overall health; and redefining success as healthy behaviour change regardless of body size or weight. 69 As this disease is chronic in nature, the treatment plan must be long term. Health care providers and patients should design and agree on a personalized action plan that is practical and sustainable and addresses the drivers of weight gain. 70 Step 5: Follow-up and advocacy
There is a need to advocate for more effective care for people living with obesity. This includes improving the education and lifelong learning of health care providers to be able to deliver effective, evidence-based obesity care. We also need to support allocation of health care resources to improve access to effective behavioural, pharmacologic and surgical therapeutic options.
There are substantial barriers affecting access to obesity care in Canada, including a profound lack of interdisciplinary obesity management programs, a lack of adequate access to health care providers with expertise in obesity, long wait times for referrals and surgery, and the high costs of some treatments. ,37,71-73 In general, health care professionals are poorly prepared to treat obesity. 74 None of the anti-obesity medications available in Canada is listed as a benefit on any provincial or territorial formulary and none is covered under any provincial public drug benefit or pharmacare program. 71 Wait times for bariatric surgery in Canada are the longest of any surgically treatable condition. 37,71 Although access to bariatric surgery has increased in some parts of Canada, it is still limited in most provinces and nonexistent in the 3 territories. 37,71,75 Patients referred to bariatric surgery can wait as long as 8 years before meeting a specialist or receiving the surgery.
The lack of access to obesity treatments is contributing to rising levels of severe obesity in Canada. 46 Canadians affected by obesity are left to navigate a complex landscape of weight-loss products and services, many of which lack a scientific rationale and openly promote unrealistic and unsustainable weight-loss goals. 76 The steering committee (n = 16) consisted of some lead authors of each chapter and a person living with obesity; this committee identified additional researchers (chapter leads and authors) to write each chapter. The executive committee and steering committee met in person in April 2017 and December 2017 and at least monthly by phone.
# Methods
# Composition of participating groups
Chapter leads and chapter authors (n = 60) were selected based on their expertise in clinical practice and research in the field of obesity medicine. The number of chapter authors per chapter ranged from 2 to 4. Some chapter leads identified additional authors to participate in writing each chapter.
We engaged people living with obesity (n = 7) through participation of the Public Engagement Committee of Obesity Canada. One member of the Public Engagement Committee (I.P.) was assigned to the steering committee for this guideline. The Public Engagement Committee met by phone once per month. We obtained contributions from committee members through online surveys, focus groups and individual conversations.
We engaged Indigenous community members through a focus group (n = 14). Additionally, we obtained the insights of health care providers working with Indigenous communities via a consensus-building process between these clinicians and chapter authors, carried out over the spring of 2019, which further grounded evidence in clinical practice. Details are available online (http://obesitycanada.ca/guidelines/) in the chapter titled "Obesity management with Indigenous Peoples."
Obesity Canada staff, consultants and volunteers (n = 15) provided administrative support and project coordination for the guideline development process. Table 2 outlines the guideline development process and the responsibilities of each group of participants.
# Selection of priority topics
The executive committee conducted a mind-mapping exercise to identify the scope of the guideline and the broad sections and chapters (April-June 2017). 79
# Literature review and quality assessment
The McMaster Evidence Review and Synthesis Team supported the guideline development through literature searches based on the PI/PECOT questions for each chapter. A health sciences librarian, based at McMaster Health Sciences Library (Hamilton, Ont.), used this information to create search strategies for the MEDLINE and Embase databases. The searches were for peer-reviewed and published literature in the English language; the search dates were January 2006 to June 2018. There were 14 searches that mapped directly to the chapters and another 7 searches that helped provide context for various chapters. Search strategies are available on the obesity guideline webpage (http://obesitycanada.ca/guidelines/). Once a search was conducted, the results were uploaded to EndNote, where the duplicates were removed and the final set of citations was uploaded to DistillerSR software for selection and review. 80 In addition to the electronic searches, the chapter authors identified additional citations and added them to the main search results.
Two reviewers completed screening of article titles and abstracts and independently selected studies for possible inclusion. Any citation that was selected for inclusion by either reviewer was moved to full-text review. One or more authors of the relevant chapter conducted reviews of full-text articles for relevancy. Selected citations were then assessed for their methodological quality using the Shekelle approach. 77,81 Each citation was categorized into prevention, treatment, evaluation of diagnostic properties or prognosis. Once that selection was made, the appropriate methods worksheet was displayed in the Distiller SR platform, from which the methodological questions were answered and a level of evidence generated based on the type and quality of the study. The levels of evidence informed the strength of the recommendations and were generated from the methods worksheets (Box 3). 77
# Development of recommendations
Recommendations were formulated by the steering committee, chapter leads and chapter authors based on the highest level of evidence available (Box 3). 77 Chapter leads and authors reviewed the type and strength of the available evidence (level) and added the study reference that provided the highest level of evidence for the specific recommendation.
Recognizing the importance of qualitative research in addressing questions pertinent to the care of people living with obesity, content experts in qualitative research (S.K., X.R.S., D.C.S., L.C., S.R.M.) were involved in the review of all materials informing these recommendations. Consensus appraisal of evidence quality by reviewers with expertise in qualitative methods informed the level of evidence in these recommendations. Some grade D recommendations were formulated based on expert committee reports, opinions or clinical experience of respected authorities, and referenced accordingly; other grade D recommendations formulated by chapter authors were noted with "Consensus" after the grade D.
Chapter authors used a standardized terminology to make the recommendation more specific. The actionable verbs used for each of the recommendations were informed by the literature (Table 3). [82][83][84] We used an iterative process to finalize the recommendations. Methodologists from MERST provided an independent review of recommendations that had a grade between A and C, for which they examined the clarity of wording and the fidelity of the recommendations with the evidence. Two methodologists (a primary and secondary reviewer) reviewed each recommendation, using checklists as a guide for assigning levels of evidence to each citation. The methodologists met, discussed and reached consensus on grading the recommendations, and reported their suggestions regarding revisions to the wording or grading to the executive committee. Chapter leads edited the recommendations based on the MERST review process.
The executive committee voted on each recommendation, to ensure consensus. If a recommendation did not reach 100% agreement, the executive committee discussed the recommendation in depth until consensus was achieved. The chapter leads subsequently modified the wording of this recommendation, as required, and the executive committee approved the newly worded recommendation. The executive committee provided final approval of all the recommendations. All the recommendations included in this guideline achieved 100% agreement.
# External review
External reviewers (primary care health care professionals and people living with obesity [n = 7]) reviewed the recommendations for relevance and feasibility. We made some modifications to reflect language and the context of the primary care setting. A separate external peer review was conducted for each chapter. The executive committee developed and managed the competing interest policy and procedures for mitigating bias. The policy and disclosures of competing interest are available on the guideline website. All participants were required to disclose potential competing interests. We maintained detailed competing interest declarations throughout the process for all members of the steering and executive committees, as well as the participating methodologists from MERST. We used the International Committee of Medical Journal Editors' disclosure form, with the addition of government funding sources.
# Management of competing interests
Individuals with relevant disclosures were not excluded from conducting the critical appraisals or voting on recommendations. However, the executive committee asked individuals with direct competing interests to abstain from voting in the areas in which they had the conflict. Any discussion regarding off-label use of drugs included the caveat that the use was off label.
As mentioned earlier, methodologists from MERST who had no competing interests reviewed and graded 78 each included study to ensure the evidence had been appropriately assessed. They also reviewed the recommendations (graded between A and C) to ensure that recommendations were aligned with the evidence. Finally, we conducted an external review process to assess the feasibility of the recommendations and evaluate for the presence of bias.
# Implementation
Obesity Canada and the Canadian Association of Bariatric Surgeons and Physicians have created a joint guideline website (http://obesitycanada.ca/guidelines) that hosts the full guideline; interim updates; a quick reference guide; key messages; health care provider tools, slide kits, videos and webinars; and resources for people living with obesity and their support systems, in English and French. The guideline will be hosted on the website as a living document. Each chapter lead will monitor evidence related to this guideline and will collaborate with the executive committee to update the recommendations if new evidence becomes available that could influence the recommendations. A framework for implementation (5As Framework) is available in Appendix 2.
More than 10 years after the release of the first Canadian obes ity guideline in 2006, access to obesity care remains an issue in Canada. 37,71 Obesity is not officially recognized as a chronic disease by the federal, provincial and territorial, and municipal governments, despite declarations by the Canadian Medical Association 85 and the World Health Organization. 86 The lack of recognition of obesity as a chronic disease by public and private payers, health systems, the public and media has a trickle-down effect on access to treatment. 72 Obesity continues to be treated as a self-inflicted condition, which affects the type of interventions and approaches that are implemented by governments or covered by health benefit plans. 87 Implementation of this guideline will require targeted policy action, as well as advocacy efforts and engagement from people living with obesity, their families and health care providers. Canadian organizations have come together to change the narrative regarding obesity in Canada, to eliminate weight bias and obesity stigma, and to change the way health care systems and policies approach obesity. 88 This guideline will be used to assist in advocacy efforts to federal and provincial governments to improve the care of individuals with obesity.
# Other guidelines
In 2006, the first evidence-based Canadian clinical practice guideline on the prevention and management of obesity in adults and children was released. 43 In 2015, the Canadian Task Force on Preventive Health Care, in collaboration with scientific staff of the Public Health Agency of Canada and the McMaster Evidence Review and Synthesis Centre, released a set of recommendations for prevention of weight gain and use of behavioural and pharmacologic interventions to manage overweight and obesity in adults in primary care. 89 This guideline was not designed to "apply to people with BMI of 40 or greater, who may benefit from specialized bariatric programs" and reviewed only intervention trials conducted in settings generalizable to Canadian primary care. The guideline also did not include surgical treatments.
# Gaps in knowledge
The recommendations in this guideline are informed by the best level of evidence available in 2020. We acknowledge that ongoing research will continue to inform and advance obesity management. 90,91 Current treatment options, apart from surgical intervention, rarely yield sustained weight loss beyond 20%, and for some people living with obesity, this level of weight loss may be inadequate for the resolution or improvement of many adiposityrelated medical complications. There is a need for more treatment options to meet the needs of people with obesity. Weight regain continues to be a challenge for many patients who have received treatment. 92
# Conclusion
Obesity is a prevalent, complex chronic disease that affects a large number of adults in Canada and globally, and yet only a small fraction of people living with obesity who could benefit from treatment have access to care. This updated evidenceinformed guideline is an attempt to enhance access and care by people living with obesity through recognition among health care providers that obesity requires long-term treatment. The newer insights into appetite regulation and the pathophysiology of obesity have opened new avenues for treating this chronic disease. Reducing weight bias and stigma, understanding the root causes of obesity, and promoting and supporting patient-centred behavioural interventions and appropriate treatment by health care providers -preferably with the support of interdisciplinary care teams -will raise the standards of care and improve the well-being of people living with obesity. Dissemination and implementation of this guideline are integral components of our goals to address this prevalent chronic disease. Much more effort is needed to close the gaps in knowledge through obesity research, education, prevention and treatment.
# GUIDELINE
Competing interests: Sean Wharton reports receiving honoraria and travel expenses and has participated in academic advisory boards for Novo Nordisk, Bausch Health, Eli Lilly and Janssen. Sean Wharton is also the medical director of a medical clinic specializing in weight management and diabetes. David Lau reports receiving grants and research support from AstraZeneca, Novo Nordisk and the Canadian Institutes of Health Research (CIHR); speaker bureau fees from AstraZeneca, Bausch Health, Boehringer Ingelheim, Diabetes Canada, Eli Lilly, Merck and Novo Nordisk; and consulting fees from Amgen, AstraZeneca, Bausch Health, Boehringer Ingelheim, Gilead, HLS Therapeutics, Janssen, Eli Lilly and Novo Nordisk. Michael Contributors: All of the authors contributed to the conception and design of the work and the acquisition, analysis, and interpretation of data. All of the authors drafted the manuscript, revised it critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.
# Acknowledgements:
The authors thank Obesity Canada staff members Dawn Hatanaka, Nicole Pearce, Brad Hussey, Robert Fullerton and Patti Whitefoot-Bobier for their coordinating support as well as their contributions for the development of the Obesity Guidelines website, online resources, tables and figures. The authors also thank members of the Obesity Canada Public Engagement Committee (Lisa Schaffer, Candace Vilhan, Kelly Moen, Doug Earle, Brenndon Goodman), who contributed to the creation of the research questions and reviewed key messages for individuals living with obesity and recommendations for health care providers. The authors also thank McMaster Evidence Review and Synthesis Team (MERST) member Donna Fitzpatrick, who played a critical role in developing the methods needed for the guideline; and thank the reviewers whose comments helped to improve the chapters and this manuscript. The authors thank Barbara Kermode-Scott and Brad Hussey for editing the guidelines, Elham Kamran and Rubin Pooni for research assistance, and Jordan Tate from the Physician Learning Program at the University of Alberta for designing the 5As framework for the guideline.
Correspondence to: Sean Wharton, sean.wharton@utoronto.ca
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Recommendations were developed by the Task Group and were based on available evidence as well as collective expert opinion (where there was limited or no published evidence).- This guideline provides criteria to help determine whether or not a procedure performed by a HCW is an exposure-prone procedure. It does not provide risk categories for these procedures. Refer to the section on Exposure-prone procedures for detailed information. - This guideline provides a viral load cut-off level to inform an infected HCW's fitness for practice, thus increasing patient safety and optimizing the work force.# LIST OF FIGURES
# LIST OF TABLES
# IV EXECUTIVE SUMMARY
# Background
Healthcare workers (HCWs) have an ethical and professional duty to care for their patients in accordance with established standards of practice and care, acting in good faith, and not allowing their personal interests to conflict with their professional obligations. This responsibility includes minimizing the risk of patient exposure to bloodborne viruses (BBVs) while receiving care.
The purpose of this guideline is to provide a national framework for developing policies and procedures to prevent the transmission of bloodborne viruses (BBVs), specifically human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) from infected HCWs to patients in the healthcare setting. Failure to adhere to infection prevention and control principles identified as Routine Practices could result in transmission of BBVs. This guideline assumes that HCWs will adhere to Routine Practices when providing care to all patients at all times and in all settings. Recommendations on these practices are provided in PHAC's guideline titled Routine Practices and Additional Precautions for Preventing the Transmission of Infection in Healthcare Settings. As long as infected HCWs adhere to these practices, the risk of transmission of BBVs from infected HCWs to patients is negligible, except during exposure-prone procedures (EPPs), which may pose an increased but minimal risk. Exposure-prone procedures are invasive procedures where there is a risk that injury to the infected HCW may result in the exposure of the patient's open tissues to the blood of the HCW and depending on the nature of that exposure and host factors (e.g. immunity) transmission of the BBV may occur.
# This document, Guideline on the Prevention of Transmission of Bloodborne Viruses from
# Scope
This guideline is a key part of PHAC's work to provide evidence-based recommendations within the context of the Canadian healthcare system; thus providing national leadership as well as the underpinnings for organizational policy and a consistent pan-Canadian approach to the management of HCWs infected with a BBV.
Recommendations provided in this guideline are intended to assist those involved with the assessment and management of HCWs infected with a BBV, either individually (e.g., treating physician, members of an Expert Review Panel) or generally (e.g., regulatory authorities). This guideline applies to all HCWs with specific recommendations for HCWs infected with a BBV. Implementation of these recommendations will increase patient safety while allowing HCWs infected with a BBV to continue to work safely.
# Risk factors
Although it is well documented that the risk of a BBV transmission from patient to HCW is significantly higher than the risk of transmission from HCW to patient, the focus of this guideline is to further reduce the minimal risk to patients and to provide guidance for the consistent management of HCWs infected with BBVs. Efforts to prevent HCW-to-patient transmission of BBVs involve understanding the factors that affect the HCWs' risk of occupational acquisition of a BBV and the subsequent risk of transmission of the BBV during an EPP.
With the availability of the hepatitis B vaccine, immune HCWs are protected from occupational acquisition of HBV. Therefore, ensuring HBV immunity among HCWs as early as possible and on admission into health professional training programs is paramount. Nevertheless, multiple percutaneous injuries throughout a HCW's career may place them at risk for occupational acquisition of HIV or HCV infection. Adequate training and education on the prevention and management of occupational injuries and potential exposures are fundamental to all HCWs as part of an occupational health program. In addition, ongoing awareness of their own serologic status is essential for HCWs who perform EPPs.
In defining the risk of transmission of a BBV from an infected HCW to a patient, it is necessary to consider both the actual risk informed by available evidence and the risk perceived by the public as these both inform what is considered acceptable risk. Patient safety studies show that the most frequent types of adverse events affecting hospitalized patients are adverse drug events, wound infections, and surgical complications. Some risks, such as those known to be associated with surgical procedures, are generally accepted by patients. Although a precise assessment of the real risk of HCW-to-patient transmission of BBVs has not been determined, factors described in reports involving potential patient exposure (with or without ensuing transmission) provided some evidence for the development of this guideline.
While zero risk of transmission is unattainable, the availability of a vaccine that prevents HBV infection, effective treatment for HCV resulting in a sustained virologic response, and suppression of HIV with strict adherence to antiviral therapy, could render this risk negligible.
# Methodology
A project protocol was developed to outline the steps and methods for conducting the systematic reviews and environmental scans to inform recommendations provided in this guideline. The project protocol was circulated for comments and refinement by the Guideline Development Task Group (Task Group) and PHAC, and retained for internal reference. Systematic reviews were then conducted for Key Questions to inform the risk of transmission of HIV, HCV, and HBV from infected HCWs to patients. Additional systematic reviews were conducted to address Key Questions examining infectivity of each virus related to the source serum viral load at time of exposure. The literature informing the systematic reviews consisted primarily of lookback investigations and other descriptive studies. A published systematic review of randomized controlled trials (RCTs) was available and therefore used, along with other studies, to inform the effectiveness of double gloving in preventing HCW-to-patient transmission of a BBV. Evidence from all eligible studies was reviewed and qualitatively synthesized. Where applicable, the body of evidence was graded using PHAC's Infection Prevention and Control Guidelines: Critical Appraisal Tool Kit.
Environmental scans of relevant literature were conducted for Key Questions where the topic dealt with organizational, regulatory, and/or ethical issues not solely or directly informed by scientific research. No grade of evidence was assigned to recommendations from the environmental scans.
Summaries of published epidemiologic investigations involving HCWs infected with a BBV globally, from the late 1980s to 2018, were tabulated and are provided in the guideline appendices.
# Key stakeholder input and expert review
The process of developing this guideline involved consultation with relevant federal, provincial and territorial (FPT) partners and key stakeholder organizations which included clinicians with relevant expertise. A preliminary consultation with a targeted group of key stakeholders involved a needs assessment conducted prior to the development of the guideline to inform its scope and key issues. Existing guidelines developed for use in other countries and relevant provincial and territorial policies in Canada were reviewed for scope and content prior to the development of this guideline. Upon completion of a preliminary draft guideline, an extensive consultation with FPT partners and key stakeholders was done to obtain feedback. All feedback received from the consultation processes were reviewed and addressed as deemed appropriate by the Task Group prior to finalizing the guideline.
# Limitations
For ethical and methodological reasons, RCTs are not feasible to assess potentially harmful situations such as the transmission of BBVs. Many studies informing this guideline were weak in study design, with their overall quality ranging from mostly low and medium to a few high quality studies. In some instances, comparator interventions used in the selection criteria for the systematic reviews did not allow for substantially minimizing confounding factors. Where graded, the grade of evidence ranged from CI to BII. For items where there was a paucity of published studies, inconclusive study results, or information was obtained solely from environmental scans, expert opinion of the Task Group members informed recommendations for practice.
# New approach and additional content: how this guideline differs from Health Canada's 1998 consensus document
In the past 20 years there has been remarkable progress in the prevention, diagnosis tools, treatment regimens, and management of infections due to BBVs as well as major improvements in guideline development methodology. These advancements were considered in developing this guideline. As a result, there are key differences in the approach used for the development of this guideline and Health Canada's 1998 consensus document. Some key items include:
- The Task Group was selected by PHAC based on identified expertise needed for the guideline topic -infectious diseases, medical microbiology and virology, infection prevention and control, public health, occupational health, hepatology, dentistry, medical ethics, and obstetrics and gynecology. The Task Group reported to PHAC's National Advisory Body on Infection Prevention and Control.
- An evidence-based approach involving rigorous review and synthesis of the evidence with expert interpretation of the evidence was used in the development of this guideline.
- The evidence base reviewed for the development of this guideline included publications of epidemiologic investigations of potential and confirmed exposure incidents; similar guidance developed by other organizations and governments; relevant policy documents, and reports from government institutions or professional organizations outside of the indexed medical literature.
- Six systematic reviews, a narrative review, and three environmental scans of the most current and relevant literature were conducted to inform the guideline content.
- Where possible, evidence from eligible studies in the systematic reviews was graded.
- Key stakeholder consultation was conducted prior to writing the guideline and an extensive consultation followed the development of the first draft of the guideline.
- The guideline is a comprehensive document providing extensive background information on each section and summary tables where applicable.
- This guideline provides detailed information for establishing Expert Review Panels to assess the risk of transmission of a BBV from an infected HCW to patients. If a HCW infected with a BBV has been reviewed by an Expert Review Panel and deemed safe to practice, this negates the need for disclosure of the HCW's serologic status to patients. Refer to the section on Expert Review Panels for detailed recommendations.
- This guideline provides detailed information for conducting lookback investigations if deemed necessary following the identification of an infected HCW or a HCW-to-patient transmission of a BBV. Refer to the section on Lookback investigations related to infected healthcare workers for detailed recommendations.
- Recommendations provided in this guideline were thought to be sufficient to prevent transmission from HCWs co-infected with two or all three of these BBVs. If a HCW who performs EPPs is co-infected, the HCW should meet the defined criteria recommended for safe practice by HCWs infected with each virus.
- This guideline made every reasonable effort to further reduce the minimal risk of HCWto-patient transmission of BBVs, with recommendations striking a balance between the reasonable expectations of the public (protection from harm) and the reasonable expectations of individual HCWs (right to privacy). The major recommendations supported by relevant background information and context are summarized here. Users of this guideline should refer to the appropriate section(s) for the full recommendation and the context provided in footnotes.
# Recommendations for healthcare worker students and trainees
- Professional schools should provide counselling to students and trainees infected with a BBV on potential implications of their BBV status to their future career, in order to facilitate making an informed decision regarding their preferred stream of study.
- Professional schools should provide all students and trainees with training and/or education on Routine Practices, including hand hygiene and sharps safety.
# Recommendations for healthcare worker and patient exposures
- Every organization or jurisdiction should have a mechanism for risk assessment to determine whether a patient or HCW exposure has occurred.
- Administrative control measures should include an obligation and mechanism for reporting patient and HCW exposure incidents in every organization or jurisdiction, and a mechanism for assessing the risk of transmission.
- Healthcare organizations should have written policies and procedures for post-exposure prophylaxis and management of exposed patients and HCWs. 4. All HCWs should know that a patient's possible exposure to a HCW's blood requires further management and that such events are reported in their facility/organization/jurisdiction.
- All HCWs have an ethical and professional obligation to report and be tested (as per institutional policy) following an exposure to a patient's blood or body fluid or a patient's exposure to the HCW's blood.
Recommendations for management of healthcare workers infected with HIV 1.
All HCWs who perform EPPs have ethical and professional obligations to know their HIV status.
If negative, those performing EPPs should be tested at appropriate intervals as determined by their level of risk and whenever an exposure has occurred.
- HCWs infected with HIV should seek medical care from a physician with expertise in HIV management for optimal health maintenance and should be managed according to current recommendations with regular monitoring of HIV RNA levels. 4. HCWs infected with HIV should be restricted from performing EPPs until: a) the HCW is under the care of a physician with expertise in HIV management; and b) the HCW is either on effective combination antiretroviral therapy or has been identified as an elite controller; and c) the HCW's viral load is undetectable. 5. HCWs infected with HIV who are on effective combination antiretroviral therapy (or are elite controllers), and have an undetectable viral load, should have no restrictions on practice based on HIV status alone.
- HCWs infected with HIV who do not perform EPPs do not need any restrictions on practice based on HIV status alone. 7. If a HCW-to-patient transmission of HIV occurs, the HCW should cease clinical practice immediately until determination for fitness to return to practice is made.
# Recommendations for management of healthcare workers infected with HCV
- All HCWs who perform EPPs have ethical and professional obligations to know their HCV status. 2. If negative, those performing EPPs should be tested at appropriate intervals as determined by their level of risk and whenever an exposure has occurred. 3. Confirmation of active HCV infection should be done using HCV RNA testing. HCWs infected with HCV should seek medical care from a physician with expertise in HCV management for optimal health maintenance and should be managed according to current recommendations.
- HCWs testing positive for HCV RNA should be restricted from performing EPPs until: a) the HCW is under the care of a physician with expertise in HCV management; and b) the HCW has completed effective therapy; and c) the HCW has tested negative for HCV RNA at least 12 weeks post-treatment. Note: Expert Review Panels may individualize practice restrictions to allow a HCW to perform EPPs while on effective therapy provided the virus is undetectable; the HCW's practice should then be restricted post treatment until a sustained virologic response (SVR) is confirmed.
- HCWs testing negative for HCV RNA 12 weeks post-treatment can be considered to have SVR and should have no restrictions on practice based on HCV status alone.
- HCWs infected with HCV who do not perform EPPs do not need any restrictions on practice based on HCV status alone.
- If a HCW-to-patient transmission of HCV occurs, the HCW should cease clinical practice immediately until determination for fitness to return to practice is made.
Recommendations for HBV immunization for healthcare workers (pre-exposure prevention)
- All susceptible HCWs (including students or trainees) should be immunized with hepatitis B (HB) vaccine, unless a medical contraindication exists.
- Students should complete their vaccination series and demonstrate immunity prior to starting any clinical rotations.
- If a HCW has documentation of receiving a complete HB vaccine series but does not have documentation of anti-HBs serology following immunization, or, if a HCW reports HB immunization but has incomplete or no documentation of HB immunization, serologic testing for anti-HBs should be done and then:
- If an anti-HBs titre of at least 10 IU/L is confirmed, testing need not be repeated nor should further immunization be undertaken, with the exception of immunocompromised persons who should be tested periodically for waning immunity, and persons with chronic renal disease or on dialysis, who should be tested yearly. - If testing for anti-HBs is done 1 to 6 months after vaccination and the anti-HBs titre is less than 10 IU/L, a primary vaccine failure has occurred and the HCW should be given a second vaccine series. The HCW should be retested 1 to 6 months after completion of the second series.
- If the HCW is tested more than 6 months after the initial series and the anti-HBs titre is less than 10 IU/L, the cause may be either a primary vaccine failure or waning antibody. Evidence shows that, in immunocompetent people, immunity is long lasting although antibody may be non-detectable. The HCW should receive one booster dose and be retested one month later to document an anamnestic response. If the anti-HBs titre is still less than 10 IU/L, the HCW should be tested for HBsAg and anti-HBc to rule out pre-existing chronic HBV infection. If both tests are negative, then a second vaccine series is indicated followed by anti-HBs serology 1 to 6 months after completing the second series.
- HCWs who have documented evidence of failure to respond to two series of HB vaccine (i.e., anti-HBs titre of less than 10 IU/L) are unlikely to benefit from further immunization and will need passive immunization after potential exposure to HB. Occupational health or infectious disease specialists may be consulted regarding any new strategies that may be available such as intradermal vaccination or high potency vaccine.
- If an HB exposure occurs, and a HCW has had a documented anti-HBs titre of at least 10 IU/L, no further testing is needed unless the HCW is immunocompromised or has chronic renal disease or is on dialysis. These HCWs should be tested for anti-HBs after a potential HB exposure and given additional vaccine and HBIg if their anti-HBs titre is less than 10 IU/L.
# Recommendations for management of healthcare workers infected with HBV
- All HCWs who perform EPPs have ethical and professional obligations to know their HBV status.
- HCWs who remain susceptible to HBV should be tested at appropriate intervals as determined by their level of risk and whenever an exposure has occurred.
- HCWs born or previously residing in high HBV endemic countries should be tested for both anti-HBc and HBsAg to fully define HBV status. 4. HCWs infected with HBV should seek medical care from a physician with expertise in HBV management for optimal health maintenance and should be managed according to current recommendations with regular monitoring of HBV DNA level.
- HCWs infected with HBV should be restricted from performing EPPs until a) the HCW is under the care of a physician with expertise in HBV management; and b) the HCW's HBV DNA level is below 10 3 IU/ml (5 x 10 3 GE/ml) or equivalent and monitored regularly (every 3 to 6 months).
- HCWs infected with HBV who have HBV DNA levels less than or equal to 10 3 IU/ml (5 x 10 3 GE/ml) or equivalent should have no restrictions on practice based on HBV status alone.
- HCWs infected with HBV who do not perform EPPs do not need restrictions on practice based on HBV status alone.
- If a HCW-to-patient transmission of HBV occurs, the HCW should cease clinical practice immediately until determination for fitness to return to practice is made.
Abbreviations: anti-HBc, antibody to hepatitis B core antigen; HBcAg, Hepatitis B core antigen; HBsAg, Hepatitis B surface antigen
# Recommendations for double gloving for infected healthcare workers
There is insufficient evidence to recommend for or against double gloving to prevent HCW-topatient transmission of a BBV.
# Recommendations for healthcare workers' disclosure obligations and right to privacy
- A HCW infected with a BBV who performs EPPs does not have an obligation to routinely disclose his or her serologic status to patients to obtain their informed consent provided that the HCW's health status and practice have been assessed by an Expert Review Panel and all the panel's recommendations are followed.
- All HCWs, including those infected with a BBV, have a right to privacy and confidentiality of personal health information.
- Regulatory authorities should have policies on the management of HCWs infected with a BBV that are transparent about and detail how the right to privacy of HCWs will be upheld.
- When a patient has been exposed to the blood of a HCW, the HCW must seek follow-up through their organizational process and the patient must be promptly informed of the nature of the exposure and the appropriate post-exposure protocol. However, the identity and confidentiality of the HCW should be protected to the greatest extent possible.
# Summation
This guideline was developed with a rigorous methodology involving robust systematic reviews, a narrative review, environmental scans, summaries of published epidemiologic investigations, and grading of available evidence with consideration of collective expert opinion in the development of recommendations. Adhering to recommendations provided in this guideline will result in safer practice for HCWs infected with a bloodborne virus. As new evidence develops, it may be necessary to update the recommendations.
# FOREWORD
# Purpose of Guideline
The Public Health Agency of Canada (PHAC) develops evidence-based infection prevention and control (IPC) guidelines. These guidelines support IPC professionals, occupational health professionals, healthcare organizations, and healthcare providers in developing, implementing and evaluating IPC policies, procedures and programs that improve the quality and safety of health care and patient outcomes. Recommendations provided in these guidelines complement provincial and territorial public health efforts in monitoring, preventing, and controlling healthcare-associated infections.
# The purpose of this document, Guideline on the Prevention of Transmission of Bloodborne
Viruses from Infected Healthcare Workers in Healthcare Settings, is to provide a national framework for developing policies and procedures to prevent the transmission of three bloodborne viruses (BBVs), namely hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) from infected healthcare workers (HCWs) to patients in the healthcare setting. These three viruses account for most cases of healthcare-associated transmission of BBVs reported worldwide (1) .
This evidence-based guideline replaces PHAC's 1998 Proceedings of the Consensus Conference on Infected Health Care Workers: Risk for Transmission of Bloodborne Pathogens (2) . Recommendations provided in this guideline apply to all HCWs, including student and trainee HCWs.
Following these recommendations will result in safer practice for HCWs infected with a BBV.
The information in this guideline was current at the time of publication. Scientific knowledge and medical technology are constantly evolving. Therefore, research and revisions to keep pace with advances in the field are necessary.
Guidelines, by definition, include principles and recommendations and should not be regarded as rigid standards. This guideline may need to be adapted to meet local, provincial and territorial requirements, or particular individual circumstances.
# Target Audience
This guideline is intended to assist those involved with the assessment and management of HCWs infected with a BBV, either individually (e.g., treating physician, members of Expert Review Panels) or generally (e.g., regulatory authorities). Key stakeholders impacted by this guideline and their inter-relationship with respect to managing the risk of transmission of BBVs from infected HCWs to patients, is shown in Figure 1.
# P even on o an m on o BBV om n e ed HCW o pa en
Legend 1 Regulated HCWs employed federally must be registered with the regulatory authority in their province or territory of work. 2 In some P/T jurisdictions, students of regulated health professions are not regulated therefore responsibility for managing these HCWs lies with their educational institution.
Abbreviations: P/T, provinces and territories; HCWs, healthcare workers; BBVs, bloodborne viruses
# DESCRIPTION
The first section of this guideline describes the guideline development process. This is followed by a summary of the risk of transmission of BBVs, risk of injury to HCWs, student and trainee considerations, and definition of exposure-prone procedures (EPPs). The risk of HCW-to-patient transmission is discussed by type of virus, and recommendations to prevent transmission and to manage infected HCWs are provided. Finally, the roles and responsibilities of Expert Review Panels, considerations for conducting lookback investigations, and HCW's disclosure obligations and their right to privacy are discussed.
# 2.1Guideline Development Process and Methodology
The core methods applied to the development of this guideline included identifying and reviewing existing guidelines, conducting a needs assessment, systematically reviewing evidence, grading the body of evidence, and synthesizing the evidence. A Guideline Development Task Group (Task Group) consisting of experts from across the country, developed recommendations based on available peer-reviewed evidence and collective expert opinion (where there was an absence of evidence). A broad consultation was conducted with key stakeholders to obtain feedback on the draft guideline. Relevant expert review and feedback continued throughout the development of this guideline.
# Consultation
The Public Health Agency of Canada (PHAC) consulted with federal, provincial and territorial partners and key stakeholder organizations during the development of the guideline. This consultation consisted of two parts, a needs assessment conducted in 2011 and 2012 (prior to the development of the guideline), and a broad consultation conducted in 2017 and 2018 (upon completion of the first draft of the guideline).
The needs assessment was conducted to inform the scope and development of the guideline. Organizations with direct responsibilities for the assessment and management of HCWs infected with a BBV were invited to complete the Questionnaire on the Development of a Guidance Document for the Management of Healthcare Workers Infected with Bloodborne Pathogens.
The national organizations invited to complete or share the needs assessment questionnaire with their members were identified with the assistance of the Task Group based on the following criteria: 1) national scope; 2) health professional regulatory authorities with members who might perform EPPs; 3) health professional faculties with students and trainees who might perform EPPs; 4) organizations with subject matter experts that might participate in the expert review process of HCWs infected with a BBV; and 5) upon request of another organization. The organizations invited were: The needs assessment was conducted using an online questionnaire that could be completed by any individual from these organizations. Each organization determined their own process to complete the questionnaire therefore it was not possible to determine individual response rates for the needs assessment. In total, 120 questionnaires were returned with 82 of these completed in full and 38 partially completed. Respondents were from all provinces and territories in Canada. The data collected was exported to an Excel spreadsheet and an analysis was performed using qualitative and basic quantitative methods. A summary of issues identified from the needs assessment is presented in Figure 2.
# Figure 2: Key issues and/or controversies identified regarding the management of a healthcare worker infected with a bloodborne virus
A broad consultation with federal, provincial and territorial partners and key stakeholder organizations was conducted upon development of the draft guideline. This involved a thorough review of the draft guideline by individual(s) within a stakeholder organization with a goal to: 1) identify potential issues and/or concerns with any of the recommendations, including their feasibility and applicability; 2) correct erroneous information, if any; and 3) encourage broad support for the recommendations across the country. The organizations that were invited to provide feedback are summarized in Appendix III, Table 35. Each organization rolled up the individual feedback received into one organizational response and a completed feedback form was sent to PHAC. Each organization determined their own process to complete the feedback form therefore it was not possible to determine the response rates for the broad consultation.
The feedback received from the broad consultation primarily identified the need for:
- Clarity of terminology - Additional citations - Minor grammatical edits - Clear explanation of the guideline development methodology and consultation process - Correction of erroneous background information or provision of supplemental background information with references - Substantive edits to some technical content in the guideline - Consideration of the applicability and feasibility of some recommendations - Consideration of the potential impacts of some recommendations on existing organizational policies All feedback received was tabulated and each item reviewed by the Task Group and PHAC staff to determine the appropriate action needed. Revisions were made to the draft guideline where needed and a rationale was documented where revisions were not made because the suggested edits were considered to be unnecessary, erroneous, ambiguous or not supported by current evidence.
# Review of the Literature
A project protocol was developed to outline the steps and methods for reviewing relevant literature by conducting systematic reviews and environmental scans to inform recommendations provided in this guideline. The systematic review and environmental scan parameters, literature search strategy, and approach for evidence analysis were established prior to the initiation of the project. The project protocol was then circulated for internal comment and refinement by the Task Group and PHAC.
A series of Key Questions were needed to clearly address the identified issues from the needs assessment as well as the defined scope and objectives of the guideline. Ten Key Questions were drafted by the PHAC writing team and reviewed by the Task Group. Each question was structured to focus on a fundamental issue to be addressed in the guideline. A systematic review was conducted for questions where a clearly defined population, intervention, comparator and outcome (PICO) were identified and/or where it was considered necessary to review existing data for consideration in the development of recommendations. There were some limitations in identifying adequate comparator interventions and available data was qualitatively synthesized. Seven of the 10 questions developed were addressed using a systematic review process. A published systematic review of randomized controlled trials (RCTs) was available and therefore used, along with other studies, to inform one of the seven questions (i.e. clinical effectiveness of double gloving). Three questions were addressed by conducting environmental scans (refer to section 1.1.3).
# Systematic Reviews
Systematic reviews were conducted to summarize the evidence for the risk of transmission of HIV, HCV, and HBV from infected HCWs to patients. The literature search parameters were developed upon review of the project outline developed by the Task Group.
Prior to conducting the literature search, the Cochrane Collaboration Database of Systematic Reviews, the International Prospective Register of Systematic Reviews, the NIH Library of Systematic Review Protocols and Protocol Registries, the Database of Abstracts of Review of Effect, and the TRIP Database were searched for any previous systematic reviews that addressed this topic (3)(4)(5)(6)(7) . No published systematic review was found.
Literature search strategy concepts and keywords were selected for each topic. Four databases were reviewed: Ovid MEDLINE, EMBASE, Global Health and Scopus. Worldwide literature was searched from 1995 until the present. The literature search was conducted in 2013 and updated in 2015. Additional relevant references were obtained from supplemental sources and from manual search of reference lists of eligible studies.
The literature searches resulted in references. The references were screened for relevance and then sorted into topic-specific folders and sub-folders. All published research findings relevant to each sub-topic were reviewed. Scopus Search Alert, Global Health Search Alert, ProMED postings, Safe Injection Global Network, and the Public Health Agency of Canada Daily News were used to stay up-to-date with new studies after the formal literature searches were completed.
Relevant articles were screened for eligibility for each systematic review. For the systematic reviews informing the preventive or management measures to reduce the risk of transmission of a BBV, the criteria for selecting eligible population included infected HCWs performing or assisting with EPPs (irrespective of whether transmission occurred) and those providing direct patient care involving non-EPPs but where transmission occurred.
Critical appraisal of eligible studies was conducted using PHAC's Critical Appraisal Tool Kit (the Tool Kit) (8,9) . A grade was provided for the strength of the body of evidence informing each recommendation. This grade was based on a combination of strength of the individual study designs, quality of the individual studies, number of studies informing a recommendation, consistency of results from these studies, and directness of the body of evidence (i.e., assessing whether the evidence specifically researched the association of interest needed to inform the recommendation). The Tool Kit uses a grading scale that rates all levels of evidence from metaanalyses of randomized controlled trials to ecologic studies; and rates expert opinion lower than published scientific evidence. Within the hierarchy of scientific evidence, meta-analyses of RCTs are generally considered to be the best evidence available. For ethical and methodological reasons, RCTs are not feasible to assess potentially harmful situations such as the transmission of BBVs. In such situations, the best evidence becomes the evidence that exists at the highest level within the hierarchy of evidence. The body of evidence that exists to inform this guideline consists mostly of epidemiologic investigations of past exposure incidents. Although these studies are weak in design, they are nonetheless, the best available evidence informing this issue. As a result, the grade of evidence in this guideline falls within the range of CI to BII. Refer to Table 34, Appendix II, for further details on the criteria used for this rating. A grade of CII indicates where the evidence base consisted of low quality studies regardless of study design or existing studies reported contradictory results or there was a paucity of relevant studies thus the evidence was mostly based on expert opinion.
Evidence from eligible studies were reviewed and summarized. Companion articles providing additional information about eligible studies were identified in the systematic review literature database as well as from supplemental sources and/or manual search of reference list of eligible studies. Where relevant, the additional information reported in the companion articles was included in the tabular summary of the corresponding eligible study. A synthesis of evidence is provided along with the recommendations developed. Where there were insufficient published studies or inconclusive study results, a consensus of experts in the field provided recommendations specific to practice. In addition, current practice and complex ethical and legal issues were considered and discussed in the development of final recommendations.
# Environmental Scans
An environmental scan of relevant literature (limited to English and French) was conducted for three Key Questions where the topic dealt with organizational, regulatory, and/or ethical issues not solely or directly informed by scientific research. This included the sections on disclosure of a HCW's serologic status, establishing Expert Review Panels and conducting lookback investigations.
The core methods used for conducting the environmental scans included identification and review of relevant documents obtained from a search of grey literature including policy documents, guidance from other organizations, and reports from government institutions or professional organizations outside of the indexed medical literature. These sources were used to identify the general consensus of opinion regarding these issues (10) . These sections were written as a text and/or tabular summary of the relevant literature.
The literature searches related to the disclosure of serologic status and the expert review process were limited to English and French language articles worldwide. Information obtained facilitated the development of recommendations based on relevant national and/or international guidelines, as well as regulatory authorities' and professional associations' policy statements. Relevant national guidelines on conducting lookback investigations, publications of past investigations and expert opinion informed the section on lookback investigations, with recommendations developed to fit the Canadian context.
Recommendations not informed by a systematic review of the scientific literature or where the topic deals with organizational, regulatory, and/or ethical issues not solely or directly informed by scientific research have no grade of evidence assigned.
# Guideline Development Task Group (Task Group)
The Guideline on the Prevention of Transmission of Bloodborne Viruses from Infected Healthcare Workers in Healthcare Settings is one in a series of Infection Prevention and Control (IPC) guidelines developed by PHAC. Technical expertise for the review of the evidence and development of recommendations were provided by the Task Group. The Task Group for this guideline was composed of members with expertise in infectious diseases, medical microbiology and virology, infection prevention and control, public health, occupational health, hepatology, dentistry, medical ethics and obstetrics and gynecology. The Task Group reported to PHAC's National Advisory Committee on Infection Prevention and Control.
# List of Guideline Development Task Group Members
Participation in the Task Group does not constitute endorsement by affiliated organizations.
The following individuals formed the Task Group (affiliations were at time of development of the guideline):
# INTRODUCTION
# Background
Healthcare professionals, including physicians, dentists, nurses, physician assistants, dental hygienists and midwives, have an ethical and professional obligation to prioritize the well-being of their patients first, by providing safe, compassionate, competent and ethical care at all times (11)(12)(13)(14)(15)(16)(17)(18) .
This responsibility includes minimizing the risk of exposure to pathogens within healthcare settings (19) . Certain surgical procedures may pose a risk of healthcare worker (HCW) injury with the possibility of exposing a patient to the blood of a HCW (20)(21)(22)(23)(24) . In 1998, Health Canada released recommendations from a consensus conference that was held to address the risk of transmission of bloodborne viruses (BBVs) from infected HCWs to patients (2) . This prompted key stakeholder organizations to develop policies on the issue. The policies of the professional regulatory authorities are direct and binding regulation on regulated HCWs infected with a BBV in Canada (25) . In addition, Medical Officers of Health, under their respective provincial or territorial Public Health Act, may issue an order to stop practice when an imminent risk to public health has been identified. This evidence-based guideline is intended to provide a framework for a pan-Canadian approach to the management of HCWs infected with a BBV.
To minimize the risk of BBV transmission from HCWs to patients, all HCWs should adhere to Routine Practices (synonymous with Standard Precautions, refer to Glossary) (19,26) , including performing hand hygiene as required, using personal protective equipment as appropriate, and taking care in the use and disposal of needles and other sharp instruments (27) . This guideline assumes that HCWs will adhere to Routine Practices when providing care to all patients at all times and in all settings (19) . As long as infected HCWs adhere to these practices, the risk of transmission of BBVs from infected HCWs to patients is negligible except during exposureprone procedures (EPPs), which may pose minimal risk (28) . Efforts to prevent BBV transmission involve understanding the factors that increase or decrease the risk of transmission during an EPP, thus providing a framework for developing recommendations for the management of HCWs infected with a BBV who perform or assist with EPPs (29) . There are published reports of HCW-to-patient BBV transmission solely due to IPC breaches, with some cases involving egregious breaches such as the illicit diversion of patient medication involving reuse of needles for self-injection by a HCW (30) . Illicit diversion of injectable patient medication by a HCW is considered malpractice and is not within the scope of this document.
A review of the literature to inform this guideline revealed primarily lookback investigations and other descriptive studies. Inherent limitations with these study designs make it difficult to conclusively discern the contribution of various risk factors to the transmission of a BBV from an infected HCW to a patient. Information relating to exposure incidents and history of injection drug use or other personal risk factors reported in lookback investigations is generally obtained from interviews. Such reports do not allow for assessing the extent of recall bias (bias due to differences in accuracy of recollection of past events), interviewer bias (bias in how information is solicited, recorded, and interpreted), or social desirability bias (providing responses that are considered to be socially or politically desirable). The retrospective nature of lookback investigations limits the information obtained from the report to the data the authors had access to or chose to report. Moreover, incidences of transmission where no EPP was involved and IPC breaches were not reported pose additional questions and thus require careful review (31,32) . It is possible that an infected HCW who has very poor IPC practices could infect patients without doing exposure-prone procedures. Therefore, the situation of every infected HCW should be reviewed. This does not necessarily require a formal review by a panel, but at least a review of what procedures the HCW performs, how they follow IPC practices, and whether they are on treatment. It is also an opportunity to reinforce appropriate IPC practices.
# Determinants of Risk of Transmission of Bloodborne Viruses
Three determinants of risk influencing the likelihood of transmission of BBVs from infected HCWs to patients during an EPP have been previously outlined (2) . These include the risk of percutaneous injury for the HCW; risk of the contaminated instrument or HCW's blood contacting the patient's open tissues; and susceptibility of the patient. Although the HCW with high levels of circulating BBV may pose some risk if their blood contacts a patient, the risk approaches zero if that HCW is treated and eradicates (HCV) or decreases (HIV and HBV) circulating virus in their blood.
For each BBV, reported exposure incidents, regardless of whether transmission occurred, have been assessed to provide a comprehensive context for the development of this guideline. The extent of reporting bias for HCWs infected with a BBV and not implicated in transmission to patients via EPPs or non-EPPs is unknown. As a result, the risk of transmission of BBVs from HCWs to patients may be overestimated in the literature. A series of BBV transmission incidents have involved a chain of patient-to-HCW-to-patient transmissions (33) . The risk of transmission of BBVs from patients to HCWs during clinical activities is influenced by the prevalence of BBVs in the population, frequency of contact with infected patients, communicability of the BBV, immunologic status of the HCW, and years of experience with tasks that include blood exposure risk (34)(35)(36)(37) . An increased prevalence of BBVs in a population served by HCWs who perform EPPs increases the risk of occupational exposure of HCWs to BBVs (38) . One urban academic hospital in the US reported that up to 38% of all surgical procedures conducted there involved exposure to HBV, HCV, and HIV (39) .
Despite the perceived risk, a 2007 systematic review investigating a total of 6,956 HCW injuries with HCV-contaminated needles, found no cases of HCV seroconversion (40) . In one study, a total of 99 injuries occurred during 1,382 (7.1%) surgical procedures with 89% of these sustained by residents or attending surgeons. In 29 of the 99 injuries (32%) sustained by surgeons, the sharp instrument that caused the HCW injury contacted the patient after it had penetrated the HCW's skin (21) . Another study estimated that patients may be exposed to the blood of at least one HCW in as many as one in six cardiothoracic surgery procedures that carry a high exposure risk (41) . Many changes have occurred in the operating room environment since these studies were conducted, nonetheless, ongoing improvement to protect HCWs from sharps injuries will also protect patients from possible exposure to BBVs. Seroconversion of HCWs may not be recognized in a timely manner or prior to a patient exposure incident. In addition, published lookback investigations of patient exposure incidents show that very rarely is the exposure recognized during or immediately following the incident. If exposure is recognized, timely reporting of the exposure would allow for prompt initiation of post-exposure prophylaxis for the patient (for HIV and HBV) (42) .
From a review of cases of BBV transmission from infected HCWs to patients worldwide, the factors that influence the risk of percutaneous injury and/or the risk of transmission of BBVs given HCW injury have been identified. These factors include (29,38,(43)(44)(45)(46)(47)(48) :
- Reports of potential patient exposure to HCWs infected with a BBV have identified dermatitis on the HCW's hands as one factor that may amplify the risk of transmission (49)(50)(51) . In one of these incidents, atopic eczema lesions prevented the HCW from wearing gloves systematically (50) . Another incident reported severe dermatitis on the HCW's hand with episodes of serous or bloody drainage from nodular lesions during the exposure period (49) . Adherence to Routine Practices should prevent transmission of BBVs via dermatitis (19) .
# Perception and Comparison of Risk
Along with the actual risks of transmission of BBVs, the risk perceived by the public has to be considered in determining acceptable risk (52) . Generally, people are more fearful of things that are extremely unlikely but considered beyond their control (53) . While zero risk is unattainable, every reasonable effort should be made to reduce the risk to a minimum with recommendations striking a balance between the rights and reasonable expectations of the public (informed consent and protection from harm) and the rights and reasonable expectations of individual HCWs (privacy and freedom from discrimination) (54) .
Patient safety studies show that the most frequent types of adverse events affecting hospitalized patients are adverse drug events, wound infections, and surgical complications (55,56) . Risks associated with surgical procedures have been estimated and generally appear to have been accepted by patients (57) . Examples include the mortality risk of anesthesia for surgical inpatients, which is estimated at 0.82 in 100,000 (58) and the risk for surgical site infections, which is estimated to be between 2 to 5% (59,60) . The risk of transmission of BBVs from an infected HCW to a patient via an EPP is lower than the risk of acquiring a healthcare-associated infection while receiving health care or the risk of acquiring BBVs via other mechanisms such as sexual activity with infected partners (61,62) . In the 2004 report published by the UK Advisory Panel for Healthcare Workers Infected with Bloodborne Viruses (UKAP), the risk of HCW-to-patient transmission of a BBV was presented in comparison to the risk of patient-to-HCW transmission of a BBV based on modelling studies (refer to Table 1) (63)(64)(65) . These studies collectively show that the risk of a BBV transmission from patient to HCW is significantly higher than the risk of transmission from HCW to patient. ; if e-antigen negative, the risk is 1-6% (66,67) .
Considering HCW's access to both effective treatment for HCV and effective vaccine against HBV, and the minimal risk of HCW-to-patient transmission of HIV, it is reasonable to expect that measures taken to address the risk of a BBV transmission from HCW to patient should avoid triggering public fears, unduly restricting individual freedom, or violating human rights (68) .
It has been reported that the risk of physicians transmitting BBVs to patients will continue to fall as more effective methods of prevention and treatment are identified (69) . To date, there are no documented cases of transmission of any BBV from Canadian dentists to patients, and also no documented transmissions of either HIV or HCV from Canadian physicians to patients. There is only one report of a Canadian physician (an orthopedic surgeon) implicated in transmitting HBV to four patients; the surgeon was compliant with universal precautions (refer to Glossary) with no obvious breaks in technique (70) . This incident occurred prior to the availability of modern antiviral therapy for HBV (71) . In addition, there have been numerous investigations of infected HCWs that did not identify transmission of a BBV.
# Risk of Injury to a Healthcare Worker
With the introduction of routine hepatitis B (HB) vaccination, most HCWs are protected from infection with this BBV, virtually eliminating the risk of HCW-to-patient transmission. On the other hand, multiple percutaneous injuries throughout a HCW's career may place them at risk for occupational acquisition of HIV or HCV infection that may go unnoticed and therefore not treated. This in turn may pose minimal risk of transmission to patients in the event of a HCW injury while performing an EPP (72)(73)(74)(75)(76)(77)(78) .
Surveillance of HCW occupational exposures indicates that percutaneous injuries are the most commonly reported route of HCW exposure to blood or bodily fluid (79,80) . A modelling study conducted within the framework of the World Health Organization's Global Burden of Disease project in 2002 estimated the global burden of occupational infections with HIV, HCV and HBV attributable to sharps and injuries among HCWs (81) . Bloodborne infections and injuries occurring in the year 2000 in 14 geographical regions and four age groups were assessed.
Overall, it was estimated that 1,000 HIV, 16,000 HCV, and 66,000 HBV infections may have occurred among HCWs worldwide due to occupational exposure through percutaneous injuries (33,81) . This amounted to 4.4%, 39%, and 37% of all HCW injuries resulting in HIV, HCV, and HBV infections respectively. The true incidence of occupational exposure to BBVs due to a HCW injury is unknown but likely to be higher than currently available publications due to late reporting and unreported cases (80,82) . Of all HCWs, nurses report percutaneous injuries most often while doctors report them least often (83) .
Risk of injury, and by extrapolation risk of BBV transmission to HCWs who perform EPPs, is dependent on the types of procedures they do. Certain HCWs such as laboratory technologists, phlebotomists, and surgeons perform procedures that have an increased incidence of injury and occupational exposure. Sharps and needlestick injuries are reported to be about six times more common among surgical personnel compared with nonsurgical personnel (82,84) . The frequency of HCW injury also varies among surgical specialties. Based on reports, the most at-risk procedures for HCW injury have been identified during major vascular, intra-abdominal, gynecologic, and orthopedic surgeries (85,86) . A study investigating the numbers and circumstances of percutaneous injuries among surgical personnel found that the procedure injury rate ranged from 4% (orthopedic) to 10% (gynecologic) and was s ignificantly related to procedure duration (21) . The American College of Surgeons reported that patients' blood makes contact with the skin or mucous membranes of operating room personnel in as many as 50% of operations, with cuts or needlestick injuries occurring in up to 15% of operations (87) . Surgeons and first assistants were found to be at highest risk of injury, sustaining up to 59% of injuries in the operating room (87) . At one institution, needlestick injury prevalence increased from medical students to residents and fellows (100%) and 11% of these needlestick injuries involved patients infected with a BBV (88) . Although sharps injury rates among surgical residents have been shown to decrease with increasing surgical experience, non-compliance with sharps injury reporting protocols is most common among senior surgeons with about 50% or more of these injuries not reported (36,84,89,90) . At one institution, lack of time and fear of potential embarrassment or consequence were reported to be the two critical components of underreporting of needlestick injuries (82) .
It has been reported that most dental HCWs (dentists, hygienists, assistants and oral surgeons) experience approximately three injuries per year (91) . A survey of a random sample of 300 dentists found that all respondents had protocols in place for managing and reporting sharp injuries to dental team members but only 48% of respondents had protocols for reporting patient exposures to the blood of a member of the dental team (35) . Dental HCWs were previously reported to have a low risk for occupationally acquired HIV but a higher risk for acquiring HBV than the average citizen (92) . With the development of a vaccine against HBV, the risk for acquiring HBV has been mostly mitigated for HCWs.
Adequate training and education on the prevention and management of occupational exposures is fundamental for HCWs as part of an occupational health program for sharps safety and prevention of exposure to BBVs (19,80) . Healthcare worker injuries can be reduced by use of blunt suture needles, improved instruments, reinforced gloves, changes in surgical technique and use of less invasive procedures (29,93,94) . Safety-engineered sharp devices should be used wherever possible for the safety of patients and HCWs (19) . Further information and recommendations on sharps safety, prevention of HCW exposure to blood or body fluids, and first aid when there has been a HCW exposure can be found in PHAC's Routine Practices and Additional Precautions for Preventing the Transmission of Infection in Healthcare Settings (19) .
# HEALTHCARE WORKER STUDENT AND TRAINEE SPECIFIC ISSUES
Key issues that have been identified for the health and safety of HCW students and trainees include necessary training in IPC, reducing the risk of occupational injury, assessment of immunization status, and confirming immunity to vaccine-preventable diseases (e.g., HBV) as early as possible on admission into health professional training programs (19,(95)(96)(97)(98) .
A prospective cohort study showed that medical students had a high risk for needlestick injuries, which most commonly occurred in the operating room (99) . A more recent study reported that 28% of medical students, 83% of residents and/or fellows and 100% of faculty had been exposed to a sharp injury at some point in their career (45) . By the final year of training, 99% of surgical residents have had a needlestick injury, with 53% of these injuries involving a high risk patient (patient with a history of a BBV infection or injection drug use) (84) . Occupational injuries among HCWs in dentistry show the highest rate of exposure occurs among dental students and assistants, with needlestick injuries predominating (46,100) . Nursing students have also been reported to be at increased risk of occupational needlestick injury due to limited clinical experience (101) .
The increased risk of injury among medical, dental and nursing students and trainees, if not mitigated, could pose a concern for students, trainees and patients. Education of student and trainee HCWs on risks and precautions, immunizations, use of less invasive procedures, protection strategies to minimize risk of injuries (e.g., use of safety engineered devices), and procedures to manage exposures will improve student and trainee knowledge and reduce their exposure risk (34,36,81,90,99,102,103) .
Despite increased rates of occupational sharp injuries to students and trainees, the risk for this group of HCWs to acquire a BBV, followed by secondary transmission to patients is still considered to be minimal. Professional schools should provide education to all students and trainees regarding the implications of infection with a BBV. Medical students are very unlikely to be performing exposure-prone procedures and transmission in dental school has not been reported in the literature. Strategies to reduce student and trainee injuries are primarily for their health and safety.
# EXPOSURE-PRONE PROCEDURES
Exposure-prone procedures (EPPs) are invasive procedures where there is a risk that injury to the HCW may result in the exposure of the patient's open tissues to the blood of the HCW. For transmission of a BBV from an infected HCW to patient to occur during an EPP, three conditions are necessary (104) :
- HCW must sustain an injury or have a condition that allows for exposure 2. HCW's blood must come in contact with a patient's wound, traumatized tissue, mucous membranes, or similar portal of entry 3. HCW must be sufficiently viremic EPPs with risk of transmission include (105) :
a. Digital palpation of a needle tip in a body cavity (a hollow space within the body or one of its organs); or the simultaneous presence of the HCW's fingers and a needle or other sharp instrument or object (such as bone splinters, sternal wires etc.) in a blind or highly confined anatomic site, e.g., as may occur during major abdominal, cardiothoracic, vaginal, pelvic and/or orthopedic operations b. Repair of major traumatic injuries c. Cutting or removal of any oral or perioral tissue, during which the patient's open tissues may be exposed to the blood of an injured infected HCW.
Transmission has been documented with several surgical and dental procedures, most of which meet the above definition of an EPP. There is insufficient evidence to accurately categorize most surgical, dental and medical procedures in terms of transmission risk (106) . As a result, risk categories developed so far have been based on expert consensus on the risk of contact between the HCW's blood and that of the patient (106,107) . This guideline does not provide risk categories for EPPs. The approach taken involves providing criteria to help experts determine whether or not a procedure is an EPP. When assessing the procedures performed by an infected HCW, experts in the appropriate specialties should be engaged in determining which procedures fit the criteria for an EPP (108) .
Failure to adhere to IPC principles identified as Routine Practices could result in transmission of BBVs during a procedure. For reference purposes only, a list of procedures reported to date which involved documented transmission of a BBV, is presented in Table 2. Documented transmissions via non-EPPs have to be assessed on a case-by-case basis in order to rule out IPC breaches, illicit diversion of patient medication involving reuse of needles for self-injection by a HCW, and determine the possible mechanism(s) of transmission.
# Specialty Procedures
Cardiothoracic Valve replacement surgery (41,76,(109)(110)(111) surgery Coronary artery bypass graft surgery (41,76,(110)(111)(112)(113)(114) Pulmonary surgery (76) Other bypass surgery (110) Valve and coronary artery replacement (41) Thymectomy (111) Open-lung biopsy (111) Repair of congenital heart defects (111) Orthotopic heart transplantation (111) Orthopedic Placement of a total hip prosthesis with bone graft (72)
surgery
Thompson's hip hemiarthroplasty (115) Hip replacement (75,116) Revision of total knee replacement (70) Total knee replacement (70,116) Obstetrics and Caesarian section (117)(118)(119) gynecology Hysterectomy (120) Hysterectomy and removal of ovarian cyst (119) Uterus/adnexa extirpation (121) General Repair of inguinal hernia (121)(122)(123) surgery Cholecystectomy (119) Cholecystectomy and nephrectomy (119) Sigmoid resection (121) Ileocecal resection (121) Creation or removal of intestinal stoma (121) Transanal drainage (121) Excision of ganglion (121) Hernia repair and bladder neck resection (124) Vascular surgery
Abdominal aortic aneurysm surgery (76) Aorta bifurcation prosthesis (121) Ligation and stripping of varicose veins (121)
# Specialty
# Procedures
Dentistry and Extraction of two maxillary third molars under local anaesthesia; prophylaxis, and cosmetic oral surgery bonding (125,126) Extractions, prophylaxis, periodontal scaling and root planing, and fixed and removable prosthodontics (126) Extractions, prophylaxis, periodontal scaling and root planing, and restorative fillings (126) Examination, prophylaxis, fluoride treatment, restorative fillings and crowns, and root canal therapy under local anaesthesia (127) Examination and radiographs, prophylaxis, extraction, restorative fillings and root canal therapy (127) Root canal therapy and restorative filling under local anesthesia (127) Examinations, radiographs, prophylaxes and restorative fillings under local anaesthesia (128) Dental extraction (129) Reduction of fractured mandible (129) Enucleation of maxillary cyst (129) Root canal and cyst enucleation (129) Surgery and dental extraction (130) Crown (130) Miscellaneous Acupuncture (131) Electroencephalogram with reusable subdermal electrodes (132) Administration of intravenous antibiotics (133) Monitoring of patient and administration of two subcutaneous injections of heparin with a non-safety injection device (32) Care of an implanted venous port and administration of intravenous antibiotics (134) Venepuncture and cannulation (135) Administration of anesthesia (31,(136)(137)(138)(139) Hemodialysis (140) Abbreviations: BBV, bloodborne virus; HCW, healthcare worker A Procedures reported in the literature which involved transmission of HIV, HCV or HBV. Only procedures that are named in the investigations are included and where multiple procedures were done on a patient, it was not indicated which procedure was involved in transmission. All procedures done on a single patient are listed as a single line item. Where more than one patient had identical procedures, it was listed only once.
# Recommendations for Healthcare Worker and Patient Exposures A
Recommendations 1. Every organization or jurisdiction should have a mechanism for risk assessment to determine whether a patient or HCW exposure has occurred.
- Administrative control measures should include an obligation and mechanism for reporting patient and HCW exposure incidents in every organization or jurisdiction, and a mechanism for assessing the risk of transmission.
- Healthcare organizations should have written policies and procedures for post-exposure prophylaxis and management of exposed patients and HCWs.
- All HCWs should know that a patient's possible exposure to a HCW's blood requires further management and that such events are reported in their facility/organization/jurisdiction.
- All HCWs have an ethical and professional obligation to report and be tested (as per institutional policy) following an exposure to a patient's blood or body fluid or a patient's exposure to the HCW's blood.
A The term 'HCWs' in this document includes students and trainees.
# RISK OF TRANSMISSION OF HIV
There is a lack of consistency in the body of evidence relating to viral load units of measurement for BBVs. In this document, HIV viral load is reported as copies/mL as this is the current reporting practice for Canadian laboratories.
# Incidence and Prevalence of HIV
The prevalence of HIV infection in the general Canadian population rose steadily during the 1980s, corresponding to the initial rise of HIV incidence in the Canadian population (141) . In 2016, PHAC reported an estimated 2,165 new HIV infections in Canada (142) . Approximately 63,110 people were living with HIV (including AIDS) by the end of 2016, representing a 5% increase from the estimate at the end of 2014 (142) . The number and rate (per 100,000) of reported cases of HIV infection in Canada from 2000 to 2016 based on data from the CNDSS can be found on PHAC's Notifiable Diseases Online page here:
Although surveillance data are limited by underreporting, an increase in numbers of people living with HIV has been observed since the late 1990s. This may largely be related to the development of more effective, less toxic and better-tolerated therapies. These developments delayed the progression of HIV to acquired immune deficiency syndrome (AIDS), resulting in reduced mortality (79,143) .
In addition to the potential risk for occupational exposure, HCWs can have the same risk factors for acquiring HIV as the general population (e.g., injection drug use, sexual contact). There are currently no published HIV prevalence data among HCWs in Canada. The total number of reported AIDS cases among adults in Canada (15 or older) due to occupational exposure from 1979 to 2012 is 9, with 7 of these cases occurring before 2006 (144) . The setting for these occupational transmissions was not reported.
# Estimated Risk of HIV Transmission
Studies have estimated the risk of HIV transmission from patients to HCWs after percutaneous injury to range from about 0% to 3% (27,145,146) . Several risk factors may collectively increase seroconversion risk by as much as 50 times (145) . A case-control study of 33 HCWs who acquired HIV from occupational percutaneous exposure, compared with 665 controls who were similarly exposed to HIV-infected blood but not infected, found that the significant risk factors for seroconversion were (146) :
-deep injury, -injury with a device that was visibly contaminated with the source's blood (larger volume of blood), -exposures involving a needle placed in the source's artery or vein, -exposure to a source who died of AIDS within two months after the exposure (possibly due to higher titre of HIV in the blood), and -lack of post-exposure prophylaxis.
It is reasonable to assume that the same risk factors for seroconversion apply to transmission of HIV from HCWs to patients. There is very limited evidence of transmission of HIV from an infected HCW to a patient during an EPP. Nonetheless, the few transmission incidents reported globally confirm that the risk is not zero nor should it be considered hypothetical (refer to Table 3). The development of effective antiretroviral therapies, and their use by HCWs or patients infected with HIV will minimize the risk of transmission in the event of an exposure during an EPP (69,147) . The HIV transmission rates calculated from two of four reported incidents involving HCW-topatient transmission of HIV were 0.1% and 0.4% (refer to Table 20, Appendix I) (72,117) . Transmission rates from the other two reported incidents are not helpful in assessing risk from EPPs as one incident involved a non-EPP (32) , and another incident reported IPC breaches, although it was unclear if this was applicable to all infected patients (148) . To determine the observed rate of transmission of HIV from infected HCWs to patients in previous HIV exposure incidents, a meta-analysis of eligible exposure incidents was conducted . A total of 17 incidents were eligible for the meta-analysis including 14 with no transmission of HIV. The pooled transmission rate for HIV using the random effects DerSimonian-Laird model was 0.0056% (95% CI: 0-0.026%). This corresponds to a chance of 5.6 per 100,000 individuals (95% CI: 0 to 26.2 per 100,000 individuals) becoming infected in the absence of IPC breaches and illicit diversion of intravenous patient medication. The range of the observed transmission rate from this meta-analysis is similar to calculations from previous modelling studies (53,64) .
# Review of Patient Exposure Incidents with Transmission of HIV
In the worldwide literature search conducted for this systematic review, published investigations reported HIV transmission from five infected HCWs to patients. For four of the infected HCWs, the exposure incidents involved an EPP.
In the early 1990s, a number of publications documented epidemiologic investigations involving patients of a dentist infected with HIV in the USA (125,126,128,148) . The dentist was symptomatic in late 1986 and diagnosed in 1987. The dentist practised while symptomatic with advanced HIV infection; therefore the viral load, although not reported at time of exposure, was most likely very high. The dentist continued to practise for a period of time prior to beginning antiretroviral therapy with Zidovudine (a less effective regimen than currently available therapy); but was not adherent to treatment while practising. A lookback investigation was conducted and involved testing 43% of potentially exposed patients. Phylogenetic analysis confirmed transmission of HIV from the infected dentist to six patients. Breaches in IPC were reported but attempts to determine the mechanism of transmission were inconclusive (126) .
The second transmission event was published in 1999 with a probable transmission of HIV from an orthopedic surgeon to a patient in France (72) . About 33% of his patients were tested, and one was found to be infected with HIV. This patient was operated on three times by the infected surgeon with prolonged duration of potential exposure during one difficult procedure that lasted over 10 hours (149) .
The third HIV transmission event was published in 2002 and involved a nurse in France (32) . The nurse was co-infected with HCV and had advanced cirrhosis. The nurse monitored the patient and gave two subcutaneous injections of heparin calcium with a non-safety injection device. The nurse denied having a history of injection drug use. The mechanism of transmission, although clearly not via an EPP, remains unknown.
The fourth HIV transmission event was published in 2003 (117,150) . An obstetrician/gynecologist in Spain transmitted HIV to a patient during a caesarean section. The HCW admitted to having sustained a percutaneous injury during the procedure. The patient and family were reported to have seen the injury during the procedure although it was not promptly reported by the HCW at the time of injury (151) .
The fifth incident of HCW-to-patient transmission of HIV was published in France in 2005 (149,152) . A thoracic surgeon was identified as HIV positive during an investigation of a newly acquired HIV infection in a patient who had undergone coronary artery bypass surgery. The patient had no other recognized risk factors and no percutaneous injuries to the surgeon were reported. The surgeon had tested negative for HIV two years earlier and had a viral load of 12,000 copies/mL at time of diagnosis. Details of the investigation of this event have not been published and are therefore not included in the tables provided in this guideline.
It is possible that other HIV transmission incidents from HCW to patient have occurred but have not been published. The published lookback investigations involving patients exposed to HCWs infected with HIV with documented transmission are summarized by HCW specialty in Table 3. A total of 12,550 patients were reported to be exposed to 4 HCWs infected with HIV. Of these patients, a total of 4,261 (34%) had their HIV status examined. Transmission of HIV from HCWs to patients occurred in 9 of these patients with 6 of these transmissions possibly involving IPC breaches. A detailed summary of the individual exposure incidents is presented in Table 20, Appendix I.
# Number of patients infected
Dentistry (128,148) 1 1691 735 (43) 6 Orthopedic surgery (72) 1 3004 983 (33) 1
Nursing (32) 1 7580 2293 ( 30) 1 Obstetrics and gynecology (117) 1 275 250 ( 91 For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HIV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where HCW-to-patient transmission was reported. Epidemiologic investigations of all four published investigations were eligible for inclusion in the systematic review. Three of the four investigations involved EPPs. Findings on key preventive measures and risk factors for transmission are summarized in Table 4.
) 1 (1) 1 (0) 2 (1) 1 (0) 0 (0) 1 (0) 0 (0) 1 (1) Total No EPP (non-EPP) 2 (0) 1 (0) 1 (0) 2 (1) 2 (1) 0 (1) 0 (0) 0 (0) Total NR EPP (non-EPP) 0 (0) 1 (1) 0 (0) 0 (0) 1 (0) 2 (0) 3 (1) 2 (0)
Abbreviations: HIV, human immunodeficiency virus; EPP, exposure-prone procedure; IPC: infection prevention and control; PEP, post-exposure prophylaxis; NR, not reported; HCW, healthcare worker A N=4 for total number of infected HCWs from all reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made.
H Percutaneous injury: Percutaneous injury potentially exposing patient to HCW's blood was reported. I Patient PEP: Post-exposure prophylaxis was offered to exposed patient(s). J Diversion ruled out: Illicit diversion of patient medication by HCW was ruled out. K The HCW was on and off treatment while practising (non-adherent). L Although no percutaneous injury potentially exposing the infected patient was recorded, the HCW reported frequent injuries and noted blood under his gloves more than once a week. M The HCW was unaware of their serologic status at the time of the index patient's exposure incident but was aware after being hospitalized and diagnosed in 1996 (32,153) .
# Review of Patient Exposure Incidents with No Transmission of HIV
In 1995, a summary of all published and unpublished investigations from the CDC database showed that among 22,171 patients who were treated by 51 HCWs infected with HIV (29 dentists and dental students, 8 physicians and medical students, 13 surgeons or obstetricians, and 1 podiatrist), a total of 113 patients with HIV were reported (154) . Results from epidemiologic and laboratory testing did not indicate that a HCW was the source of any of these infections.
The only publicly available HIV lookback investigation conducted in Canada was done in 2004 and involved 2,560 patients operated on by an infected HCW at a pediatric hospital (155) . In this report, a total of 2175 patients (85%) were tested and no HIV infections were identified.
A review of all investigations of potential exposure to BBVs in healthcare settings in Ireland was conducted between 2007 and 2011 (156) . This study identified one lookback investigation that involved testing 66 potentially exposed patients for HIV; no case of transmission from the infected HCW was identified.
Published lookback investigations, from 1985 to 2014, involving 36 incidents of patients exposed to HCWs infected with HIV with no documented transmission are summarized by HCW specialty in Table 5. A total of 41,939 patients were reported to be exposed to 36 HCWs infected with HIV in a variety of healthcare settings. Of these patients, a total of 18,391 (44%) had their HIV status examined and no transmission was found. A detailed summary of the individual exposure incidents is presented in Table 21, Appendix I. For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HIV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where no transmission was reported. Of the 44 epidemiologic investigations with no documented transmission of HIV, 15 investigations (all involving EPPs) were eligible for inclusion in the systematic review. Findings on key preventive measures and risk factors for transmission are summarized in Table 6.
) 11 (0) 1 (0) 1 (0) 0 (0) 0 (0) 1 (0) Total No EPP (non-EPP) 7 (0) 1 (0) 1 (0) 4 (0) 6 (0) 6 (0) 0 (0) 0 (0) Total NR EPP (non-EPP) 5 (0) 9 (0) 3 (0) 10 (0) 8 (0) 9 (0) 15 (0) 14 (0)
Abbreviations: HIV, human immunodeficiency virus; EPP, exposure-prone procedure; IPC: infection prevention and control; PEP, post-exposure prophylaxis; NR, not reported; HCW, healthcare worker A N=15 for total number of infected HCWs from all reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made. An obvious limitation in all lookback investigations is that only a percentage of potentially exposed patients are tested. Although it is not clear what the minimal criteria are to reliably conclude that there was no evidence of transmission in an exposure episode (e.g., magnitude of the lookback investigation or minimum percentage of exposed patients that should be tested), it has been indicated that available studies collectively provide evidence that the overall risk of transmission from HCWs infected with HIV to patients is "likely to be very low" (172) . Although this risk is not zero, it can be rendered negligible if HCWs infected with HIV who perform EPPs adhere to recommendations that have addressed the identified risk factors from previous exposure incidents.
Recommendations provided for minimizing risk of HCW-to-patient transmission of HIV have taken into consideration preventive measures and risk factors reported in exposure incidents to date.
# HIV Viral Load
Deciding on a viral load cut-off level to determine an infected HCW's fitness for practice increases patient safety and optimizes the work force. High viral load is associated with both the acute phase of the infection (which may go unnoticed) and with late-stage AIDS at which time the HCW is more likely to be symptomatic (179) . Currently, there is a paucity of empirical data relating viral load and occupational transmissibility of HIV in a quantitative manner. Instances of HIV transmission during an EPP without documented IPC breaches have not provided robust data to inform a viral load cut off. This is primarily because the HCW's viral load at time of patient exposure, although expected to be high was most often not reported or unknown (72,117,150,180) .
Although viral load at the time of an exposure incident is usually not available, studies discussed thus far indicate that regardless of viral load, the risk of HIV transmission through an EPP is minimal. A 10-year lookback investigation involving 545 of 1,669 patients operated on by a cardiothoracic surgeon infected with HIV found no transmission occurred despite a viral load over 100,000 copies/mL at time of diagnosis (178) .
In conducting the systematic review to inform HIV infectivity or transmissibility related to viral load, the selection criteria allowed for inclusion of studies with blood-to-blood exposure and the reported time between potential exposure and source viral load determination. As a result, data informing this section includes data from patient-to-HCW exposure via percutaneous or other sharps injury. This allows for an analysis of HIV transmission (or absence thereof) from one person to another with different viral loads reported during exposure. Table 7 shows the relevant information from eligible studies of this systematic review. Overall, the studies did not show a consistent trend between high viral load and increased infectivity or transmissibility. In one study involving a HCW exposed to a high viral load of 5.3 x 10 7 copies/mL (via a deep needlestick injury), HIV transmission did not occur (181) . The lowest viral load at which HIV transmission occurred from one individual to another via a definite blood-to-blood exposure was 1500 copies/mL (117) .
The demand for accurate, reproducible, and cost-effective viral load assays is recognized at a global level (182) . Studies have shown that certain assays are less reliable for accurate viral load measurements. Genetic variation in HIV subtypes or extreme divergence within HIV subtypes may also significantly affect the ability to detect and quantify the viral RNA in clinical specimens (182) . Due to the different assays used for viral load measurements or incomplete information reported on the assay used, it is not possible to accurately compare the viral loads across studies presented in Table 7. Standardizing assays and units for measuring BBV viral load will allow for more accurate comparison across studies.
Most individuals initiating antiretroviral therapy (ART) experience effective and prolonged control of viral replication in the plasma (183)(184)(185)(186) . The impact of time of initiation of therapy on viral suppression and optimization of treatment outcome has been discussed in several studies (79,183,(186)(187)(188)(189) . In a study investigating HCW's exposure risk during surgical procedures on patients infected with HIV, the patients' viral load was reduced prior to surgery. This was done in an effort to ensure the safety of the operating team and best possible conditions for patients (147) . Collectively, these studies suggest that antiretroviral therapy lowers viral load thus minimizing the risk of HCW-to-patient or patient-to-HCW transmission. To date, there has not been a single reported case of HCW-to-patient transmission of HIV from an infected HCW receiving and adhering to antiretroviral therapy (71) . The reported transmission incidents involved untreated or treatment non-adherent HCWs. This suggests that recommendations to minimize risk of transmission should focus on treatment of infected HCWs as a means to maintain a low viral load. Strict adherence to therapy is essential for sustained HIV suppression, reduced risk of drug resistance, improved overall health, quality of life, and survival, as well as decreased risk of HIV transmission.
# Elite Controllers
Elite controllers are defined as individuals infected with HIV who are not receiving therapy and have maintained undetectable viral load in the blood (HIV RNA < 50 copies/mL) for at least one year, based on three separate viral load assessments (190)(191)(192)(193) . This spontaneous control of viral replication in the absence of therapy is estimated to occur in approximately 1 in 300 individuals infected with HIV (191,192) .
Although elite controllers have undetectable viremia by standard clinical assays, when using more sensitive assays for RNA detection in the plasma, studies have reported that almost all elite controllers have detectable levels of plasma viremia and viral 'blips' of > 50 copies/mL occur (192,(194)(195)(196) . This shows that virus from elite controllers is replication-competent and has no substantial genetic defect. Additional studies involving elite controllers show that despite undetectable plasma RNA levels, residual viral replication occurs in the absence of therapy and contributes to a chronic inflammation state (192,197,198) . As a result, elite controllers (including HCWs who perform EPPs) should be followed closely, as some may experience CD4 + cell decline, loss of viral control, or complications related to HIV infection. (199) Patient A Articles reporting transmission linked to sexual, blood transfusion and perinatal routes have been excluded. B Different assays may yield different values in copies/mL. C Zidovudine for 4 years before the transmission. D Initiated PEP (zidovudine 1000 mg per day) within one hour of exposure but stopped after 5 days due to side effects. E Article identified during the systematic review for risk of transmission of HIV or viral load and infectivity for HCV or HBV. F Goujon et al (2000) report that the HCW's viral load was 1,800 x 10 2 copies/mL (153) . G Source asymptomatic at time of diagnosis however, had had 'severe glandular fever' two years before (and one month after likely exposure event). H Application of topical therapy to active psoriasis lesions without gloves. I Source with HIV-HCV co-infection. J Source had measurement of two plasma VL samples while being cared for by the exposed person. The exposed person was likely infected in 1999 with possible seroconversion illness seven months prior to source's death. During the exposure period, the source was not on treatment from February to July 1999. K The source individual was on highly active antiretroviral therapy at the time of the fight. L The source patient was HIV-HCV co-infected. The exposed person received an expanded 3-drug HIV PEP. There was no HIV transmission however, HCV was transmitted. M Coma in injection drug user. N The HCW delayed in reporting the injury so commencement of PEP was delayed for 84 hours. O Patient admitted with a diagnosis of dementia.
# Recommendations for Management of Healthcare Workers Infected with HIV
Recommendations A 1.
All HCWs who perform EPPs have ethical and professional obligations to know their HIV status B .
If negative, those performing EPPs should be tested at appropriate intervals as determined by their level of risk and whenever an exposure has occurred.
# Grade of evidence: CI
A The grade of the body of evidence upon which a recommendation is based is shown here (refer to Table 34, Appendix II for the grading scale). The full critical appraisal tool informing this scale can be found in PHAC's Critical Appraisal Tool Kit (8) . B Ethical obligation may be traced to principles of non-maleficence (the duty to intentionally refrain from actions that cause harm), which includes an obligation for HCWs not to impose risks of harm to patients and creates a standard of due care (12)(13)(14)209) C There are variations in minimum detectable viral load thresholds for different assays. In addition, there may be situations where very low viral loads and/or transient blips (up to 400 copies/mL) may occur. These blips may not be clinically relevant and thus do not indicate treatment failure and will not necessarily trigger practice restrictions or lookback investigations. However, some jurisdictions may manage transient blips by maintaining stricter or more conservative thresholds (210) . D Refer to the section on Expert Review Panels.
# RISK OF TRANSMISSION OF HCV
There is a lack of consistency in the body of evidence relating to viral load units of measurement for BBVs. In this document, HCV viral load is reported as IU/mL (copies/mL) as this is the current reporting practice for Canadian laboratories and the WHO (211) .
# Incidence and Prevalence of HCV
The first Canadian study to report seroprevalence of HCV infection based on a nationally representative household sample was the Canadian Health Measures Survey (CHMS) conducted from 2007 to 2011 (212) . Estimates in this study are based on data collected from 8,434 survey respondents. Although the number of new cases of HCV in Canada has decreased in recent years, the number of prevalent cases remains high. Data from the CHMS, showed that an estimated 0.5% (95% CI: 0.3-0.9) of the population, representing a total of approximately 138,600 (95% CI: 55,800-221,300) people (aged 14-79 years) had laboratory evidence of an HCV infection as identified by HCV antibody (212) . Hepatitis C infection was more common in the 50-79 year old group compared to the 14-49 year old group and in individuals living in lower income households. A modelling study estimated that between 0.64 and 0.71% of the overall Canadian population was living with chronic HCV infection in 2011 and 44% of these individuals were undiagnosed (213) .
The number and rate (per 100,000) of reported cases of HCV infection in Canada from 1991 to 2016 based on data from the CNDSS can be found on PHAC's Notifiable Diseases Online page here:
The prevalence of anti-HCV positivity in HCWs worldwide ranges from 0% to 9.7% in different studies (48) . Several studies in western countries have concluded that the seroprevalence of HCV among HCWs is low and comparable to that of the general population (27,(214)(215)(216)(217) . On the other hand, a systematic review and meta-analysis of data from studies conducted internationally, generated different findings for the estimated prevalence of HCV among HCWs compared to the general population (218) . The study population was limited to HCWs in direct contact with patients or with blood. Results showed that the prevalence of HCV infection was significantly higher in HCWs than in the control general population. Stratification by occupational groups showed the highest prevalence was among medical and laboratory personnel, and HCWs who had a high risk of blood contact (surgeons, midwives, microbiologists, pathologists, blood bank and dialysis staff). Although a higher prevalence was also reported for dental HCWs (dentists and dental hygienists) than for the control group, the stratification for this group of HCWs was limited due to a paucity of published studies. Stratification by nursing staff did not show a significant increase in prevalence although results may have been confounded by blood exposure misclassification for this group of HCWs (218) . The study authors noted the need for prospective studies focusing on HCW-specific activity and personal risk factors for HCV infection.
In addition to the potential risk for occupational exposure, HCWs are subject to the same nonoccupational risk factors for HCV as the general population. It is not known if the prevalence of HCV among Canadian HCWs is similar to that reported for the general public. This information as well as a Canadian estimate of the rate of transmission from infected HCWs to patients is needed to determine the true risk of transmission in Canada.
# Estimated Risk of HCV Transmission
The risk of transmission of HCV through contaminated blood exposure, as estimated from modelling studies and lookback investigations has been found to be higher than that for transmission of HIV (65) .
Table 22, Appendix I, shows that the rate of transmission to patients estimated from epidemiologic lookback investigations following exposure episodes via an EPP varied, ranging from 0.04 to 3.7%. Generalizations regarding risk cannot be made from these transmission studies as the rates vary according to circumstances unique to each incident, such as viral load of infected HCW, sample size of the lookback investigation, and possible IPC breaches. As a result, mathematical modelling studies are also used to estimate the risk of transmission of HCV. One modelling study concluded that the risk of transmission of HCV from an infected surgeon to patient(s) is about 0.0062 to 0.057%, corresponding to 1 chance in 1,750 to 1 in 16,000 procedures (65) . When the surgeon's serologic status was unknown, the risk of transmission during a single operation was about 0.00008 to 0.000074%, corresponding to 1 chance in 135,000 to 1 in 1.2 million. This risk is comparable to the chance of acquiring HCV by receiving a blood transfusion from first-time donors who have previously screened negative for HCV antibodies (65) . Literature reviews show that the risk of HCW-to-patient HCV transmission (in incidents where illicit diversion of injectable patient medication by HCWs was considered unlikely) was less than 0.6% (30,33,219) .
To estimate the rate of transmission of HCV from infected HCWs to patients from reported HCV exposure incidents, a meta-analysis of eligible exposure incidents was conducted . A total of 9 incidents were eligible for the meta-analysis with 2 of them involving no transmission of HCV. The pooled transmission rate for HCV using the random effects DerSimonian-Laird model was 0.46% (95% CI: 0.07-1.17%). This corresponds to a chance of 460 per 100,000 individuals (95% CI: 70 to 1170 per 100,000 individuals) becoming infected in the absence of IPC breaches and illicit diversion of patient medication.
# Review of Patient Exposure Incidents with Transmission of HCV
There have been over 20 epidemiologic investigations of HCV transmission from infected HCWs to patients conducted between 1996 and 2016 (refer to Table 22, Appendix I). It is likely that other transmission incidents have occurred but were either not published or not reported as exposures are often unrecognized and the asymptomatic phase of HCV infection can last many years, so transmission is not easily detected. The majority of investigations were triggered by patients showing symptoms of acute hepatitis C or testing positive for HCV following surgical procedures. According to the reports from these investigations, a total of at least 13,494 patients were considered to be exposed to HCV during EPPs and in a few cases non-EPPs performed by HCWs infected with HCV. In most cases, the HCWs were either unaware of their HCV status or the study did not report on their awareness. As a result, the infected HCWs continued to perform EPPs without seeking medical attention for their infection. Of the exposed patients, a total of 8,652 (64%) were tested for HCV. Transmission of HCV from HCWs to patients occurred in 30 of these patients. Table 8 provides a breakdown of the number of patients exposed and the number of patients tested, grouped by HCW specialty. A detailed summary of the individual exposure incidents is presented in Table 22, Appendix I.
In comparison to HIV and HBV transmissions, cases of HCW-to-patient HCV transmission were disproportionately attributed to confirmed or suspected HCW illicit diversion of patient medications involving reuse of needles for self-injection by the HCW. These situations often involved infected anesthesiologists or nurse anesthetists. A recent systematic review of HCV infections from healthcare-associated outbreaks between 1999 to 2012 showed that up to 50% were attributable to HCW tampering (diversion, self-injection, and substitution) of anesthetic opioids (220) . Transmission risk from tampering was substantially higher than from surgery. Investigations reporting confirmed illicit diversion of patient medication by an infected HCW do not inform recommendations for risk of transmission during an EPP, and are therefore not included in the detailed summary of exposure investigations presented in Table 22, Appendix I (221)(222)(223) .
Some investigations revealed possible or known breaches in IPC practices as the mechanism of transmission, and therefore, may not inform recommendations for risk of transmission during an EPP (50,134,(136)(137)(138) . However, these studies may provide insight into possible mechanism(s) of HCV transmission during a non-EPP. In Canada, the only reported outbreak of HCV in a tertiary-care hospital involved IPC breaches by HCWs participating in and performing procedures on each other as part of a research study, which resulted in HCV transmission from one infected healthcare technologist to 4 other HCWs. A subsequent lookback investigation to assess for HCW-to-patient transmission did not identify any patients infected (51) .
A case report of HCV transmission from an infected anesthetist to a patient without EPPs was reported in 2005 (31) . This was the first case of transmission where the anesthetist was known to be HCV-RNA positive prior to the procedure and adhered to existing IPC protocols to minimize the risk of transmission. The anesthetist's HCV-RNA level was not available at the time of the exposure incident, but was found to be 11 million copies/mL when tested several years later. The anesthetist inserted a cuffed oral endotracheal tube and also inserted a peripheral cannula. The HCW denied any possibility of injection drug use, reported no open wounds, IPC breaches, or injuries during the procedure. The study authors postulated that transmission may have occurred by HCV shed from abrasions to the anesthetist and then inoculated to the patient via microabrasions. The study did not report on whether the anesthetist had undergone treatment for HCV infection. Another report of HCW-to-patient transmission of HCV during a non-EPP involved an infected home care nurse. This incident draws attention to the risk of transmission in home care settings and the challenges of confirming direction of transmission (134) . Identification of the mechanism and implications of transmission of HCV from an infected HCW to a patient in the absence of EPP and no reported IPC breach may require a closer review of these incidents (135) . Among patients with acute HCV infection in Italy and Spain, a documented risk factor was hospitalization without any invasive procedure in some patients (224,225) . Although it was very difficult to determine the exact mechanism of HCV transmission, the mechanisms reported included patient-to-patient transmission, an outbreak due to the use of multidose drug vials, or poor IPC practices. The prolonged viability of HCV in fomites and on hospital equipment has been hypothesized to contribute significantly to healthcare-associated transmission in the absence of invasive procedures (226) .
Several studies show that EPPs were the sole or major mechanism of transmission and are therefore the basis upon which risk of transmission of HCV from an infected HCW to a patient and recommendations for prevention are based (75,76,109,112,113,118,120,219,(227)(228)(229)(230)(231) .
The summary of epidemiologic investigations reporting HCW-to-patient transmission of HCV excludes studies that did not report the number of patients exposed and the number of patients tested (refer to Table 8). Most of the infected patients (21 out of 30) acquired their infection from either infected cardiothoracic surgeons or obstetrician/gynecologists.
A transmission incident that was recognized in 2012, involved a retired obstetrician / gynecologist who had practised for over 30 years and was unaware of an HCV infection until after retirement (78) . In an extensive lookback investigation spanning over 18 years, four out of 5500 patients (0.07%) were found to be infected (to date of writing this guideline) (78) . In another episode, an infected midwife who worked on the post-natal unit transmitted HCV to one patient (135) .
In the two transmission incidents involving anesthetists, no IPC breach was reported although drug diversion could not be ruled out in one investigation (31,137) . General surgery (231) 1 1,461 1,193 (82) 1 Orthopedics (75) 1 229 207 (90) 1 Hemodialysis (140) 1 In 2016, a lookback investigation was conducted on a HCW infected with HCV in the UK (232) . When the HCW was initially found to be seropositive, the UK Advisory Panel for Healthcare Workers Infected with Bloodborne Viruses (UKAP) advised that patients did not need to be notified as the risk of transmission was thought to be low. However, following the emergence of two infected patients, further investigations found it was "probable" the HCW transmitted the virus during a surgical procedure. In total, 8,383 patients across the UK received letters informing them of the situation and urging them to arrange a blood test.
For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HCV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where HCW-to-patient transmission was reported. Seventeen such investigations were eligible for inclusion in the systematic review. Nine of the 17 investigations involved an EPP. Findings on key preventive measures and risk factors for transmission are summarized in Table 9. 3) 7 (3) Abbreviations: HCV, hepatitis C virus; EPP, exposure-prone procedure; IPC, infection prevention and control; NR, not reported; HCW, healthcare worker A N=17 for total number of infected HCWs from all reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made. H Percutaneous injury: Percutaneous injury potentially exposing patient to HCW's blood was reported. I Diversion ruled out: Illicit diversion of patient medication by HCW was ruled out. J Several articles indicate that although a percutaneous injury during an EPP on a specific patient was not described, injuries were reported to occur during certain procedures. The HCWs could not recall ever bleeding into a patient's wound (75,109,118) . K The HCW denied drug abuse but the authors could not rule this out as an explanation for transmission (137) . L Several members of the care team were tested, including surgeons, anesthesiologists, and nurses (50) . The specialty of the infected HCW was not reported, however, as it was reported that the infected HCW did not wear gloves systematically, the data have been pooled in the non-EPP column.
# Review of Patient Exposure Incidents with No Transmission of HCV
Published epidemiologic investigations for HCV transmission from eleven infected HCWs to patients did not find any cases of transmission. Of these investigations, the nine incidents that reported the number of patients exposed and tested are summarized by HCW specialty in Table 10. Exposure incidents due to five of the infected HCWs are documented in a single report (63) . A total of 9,837 patients were reported to be exposed to the nine HCWs infected with HCV. Of these patients, a total of 5,738 (58%) had their HCV status examined and no transmission was found. A detailed summary of the 11 individual exposure incidents is presented in Table 23, Appendix I. Infection prevention and control breaches were reported in three of the investigations (173,233,234) . One investigation was conducted in Canada to determine possible HCV transmission from a general surgeon to patients who underwent high risk procedures in the three years before the surgeon was found to be seropositive (77) . Healthcare technology (51) 1 498 215 (43) Orthopedic surgery (235) 1 1,513 1,068 (71) Obstetrics and gynecology (63) B Staged lookback investigations related to the practices of 5 infected HCWs were recommended by the UKAP. These involved the last 500 patients (of each HCW) who had undergone higher risk EPPs. Upon extension of the lookback investigation related to one of the five infected HCWs, potentially exposed patients from 1987 onwards were tested for HCV and HCW-to-patient transmission was identified (234) . This information is captured in Table 22, Epidemiologic investigations reporting transmission of HCV from infected HCW to patient (Appendix I).
C Information on two additional HCWs infected with HCV is not included due to missing data on the number of potentially exposed and tested patients.
For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HCV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where no transmission was reported. Three such investigations were eligible for inclusion in the systematic review. Two of the three investigations involved an EPP. Findings on key preventive measures and risk factors for transmission are summarized in Table 11. Recommendations provided for minimizing risk of HCW-to-patient transmission of HCV have taken into consideration preventive measures and risk factors reported in exposure incidents to date.
) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0) 0 (0) Total No EPP (non-EPP) 2 (1) 1 (0) 1 (0) 1 (1) 0 (0) 0 (0) 0 (0) Total NR EPP (non-EPP) 0 (0) 1 (1) 1 (1) 1 (0) 2 (1) 1 (1) 2(
# HCV Viral Load
Acute HCV infection is often asymptomatic, therefore detection and diagnosis can be difficult. Studies show that intermittent low level HCV viremia can occur up to two months before the period of exponential increase in viral load and the high titre plateau-phase viremia that usually precede seroconversion (236) . In general, 50 to 85% of people infected with HCV develop chronic infections with some variability based on certain factors (212,237) . In the chronic phase of HCV infection, infected persons can transmit infection via blood and other infected body secretions (33) .
High viral load appears to be a major determinant influencing an infected individual's efficiency in transmitting HCV (238) . Most of the viral load testing conducted in lookback investigations of patients exposed to an infected HCW was done months after the exposure episode, perhaps making this information unreliable for determining infectivity based on viral load at the time of exposure.
Complete spontaneous or therapy-induced resolution of HCV infection can occur (239) . Spontaneous clearance of HCV is found to occur more frequently among those who experience symptomatic HCV with high viral titres, and occurs during the first 3 to 6 months of infection (240,241) . In a prospective cohort study, the spontaneous viral clearance rate after six months of infection was 18%; another study reported a 20 to 50% chance of spontaneous resolution of infection (242,243) .
Hepatitis C viremia is unusual after successful treatment, which is defined as sustained virologic response (SVR) or undetectable HCV RNA 8-12 weeks after therapy is completed (244)(245)(246)(247) . A meta-analysis reported that SVR appears durable in the majority of patients at 5 years posttreatment with a summary 5-year recurrence risk of 0.95% among HCV mono-infected "lowrisk" patients (248) . Notably, the higher pooled estimates of recurrence observed in high-risk and coinfected cohorts were driven by an increase in reinfection rather than late relapse. Sustained virologic response with undetectable HCV-RNA following completion of current HCV therapy is considered a durable and clinically significant endpoint (244,246,247,249) . Treatment for HCV continues to improve and published data shows success rates in treatment should be over 90% (212,248,(250)(251)(252)(253)(254)(255)(256)(257) .
There is not much variability reported in viral loads of HCWs infected with HCV involved in transmission incidents (between 10 5 to 10 7 IU/mL) and there is no viral load that is considered non-infective. In conducting the systematic review to inform HCV infectivity or transmissibility related to viral load, the selection criteria allowed for inclusion of studies with blood-to-blood exposure and the reported time between potential exposure and source viral load determination.
As a result, data informing this section includes data from patient-to-HCW exposure via percutaneous or other sharps injury. This allows for an analysis of HCV transmission (or absence thereof) from one person to another with different viral loads reported during exposure. Table 12 shows the relevant information from eligible studies of this systematic review.
The risk of transmission of HCV can be eliminated with treatment of the infected HCW resulting in no detectable HCV RNA in the blood. As a result, recommendations provided for managing HCWs infected with HCV are focused on treatment rather than identifying a viral load cut-off level for fitness-for-work. (134) Companion L : (263) HCW A Articles reporting transmission linked to sexual, blood transfusion, and maternal-child routes have been excluded. B Viral load as reported in study (R) or calculated using an assay-specific conversion factor (C). If the assay for quantification was not reported in the study or if unable to determine the conversion factor, 'NR' was included in the relevant cell. One copy is equal to 1 genome equivalent (266) . C Treatment failed. D The source patient underwent a colonoscopy with multiple biopsies on the same morning and prior to the two exposed patients who also underwent colonoscopies with either multiple biopsies or a polypectomy. Serious IPC breaches were identified related to the endoscope cleaning and disinfection procedures (between all patients) and for the administration of anesthesia (between the two exposed patients). E Quantiplex bDNA 2.00, Chiron Diagnostics Europe, Cergy Pontoise, France. F Quantiplex HCV RNA Assay ; Chiron Corp, Emeryville, Calif. G Amplicor HCV Monitor Test and Quanti-Path Kit, Roche Diagnostics (one IU/mL is equal to 0.9 copy/mL therefore 1 copy/mL is equivalent 1.1 IU/mL). H Versant 3.0 b-DNA Assay (one IU/mL is equal to 5.2 copies/mL). I The HCW became symptomatic 3 days after the exposed patient's procedure. J Injury with tip of needle used to monitor capillary blood glucose in spouse with diabetes and known chronic hepatitis C infection. K In-house real-time (rt)-PCR (detection limit 600 IU/mL). L Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table.
M The authors report as a possible case of HCW-to-patient transmission during home care as they were not able to determine the direction of transmission as the serologic status of the HCW was not known prior to the investigation (134) . In 2010, the authors report that an audit of the HCW's IPC practices is ongoing (263) ; in 2011, they emphasize the importance of HCWs wearing gloves if exposed to blood, in addition to other routine IPC practices (134) . N (8) .
B Ethical obligation may be traced to principles of non-maleficence (the duty to intentionally refrain from actions that cause harm), which includes an obligation for HCWs not to impose risks of harm to patients and creates a standard of due care (12)(13)(14)209) . C Due to the availability of effective therapy for HCV with sustained virologic response, this guideline does not recommend a serum HCV RNA cut off level for practice restrictions as recommended in other guidelines. D The overarching principle for management of HCWs infected with HCV who perform EPPs is to restrict practice while the virus is detectable (267) . E Refer to the section on Expert Review Panels.
# RISK OF TRANSMISSION OF HBV
There is a lack of consistency in the body of evidence relating to viral load units of measurement for BBVs. In this document, HBV viral load is reported as IU/mL (GE/mL) as this is the current reporting practice for Canadian laboratories and WHO (268) .
# Incidence and Prevalence of HBV
Approximately two billion people worldwide have serologic evidence of past or present HBV infection and approximately 350 million people are currently chronically infected (269,270) . Canada is considered a country of low HBV endemicity; however, there are substantially more reported cases within the foreign-born population, Indigenous peoples of Canada, people who inject drugs and men who have sex with men (212) . In Canada, the rates of reported acute HBV infections declined from 1.0 to 0.6 per 100,000 between 2005 and 2012 (237) . Primary HBV infection can be self-limited, with elimination of the virus from blood and subsequent lasting immunity against reinfection, or it can progress to chronic infection (270) . The risk for progression to chronic infection is inversely related to age at the time of infection (270) . Persons with chronic HBV infection are the major source of new infections (270) . Chronic HBV is likely to occur in 90% of infants infected at birth (212,237,270,271) . Reporting of chronic HBV infection was variable across provinces and territories until 2009, making interpretation of earlier trends difficult. The number and rate (per 100,000) of reported cases of HBV infection in Canada from 1969 to 2016 based on data from the CNDSS can be found on PHAC's Notifiable Diseases Online page here:
Approximately half of all HBV cases are asymptomatic and approximately half of individuals infected with HBV are unaware of their status. As a result, the true incidence of HBV infection is most likely significantly underestimated (212,269) .
The introduction of the HBV vaccine in 1982, followed by the implementation of routine childhood immunization programs in Canada in the 1990s and screening during pregnancy have all contributed to decreasing rates of HBV (95,212,237) . Results from the Canadian Health Measures Survey conducted from 2007 to 2011, showed that 72.6% (95% CI: 69.6-75.4) of children aged 14-19 years had vaccine-induced immunity, and this rate decreased with increasing age but natural immunity increased with age (212) . Overall, the incidence of hepatitis B infection has decreased in all age groups in recent years, and has virtually disappeared in the cohorts that have benefited from routine immunization programs (95) .
Several seroprevalence surveys conducted before the availability of the HBV vaccine showed that HCWs had prevalence rates of past or present HBV infection that were three to fivefold higher than the general US population (272) . Following the implementation of preventive measures including HB vaccine and universal precautions (refer to Glossary), there was a significant decline in the incidence rates among HCWs (270,273) .
In addition to potential risk of occupational exposure, HCWs who have not been vaccinated or who are nonimmune following vaccination are subject to the same risk factors for HBV infection as the general population. The rates of HBsAg and anti-HBc positivity in HCWs worldwide published in several studies over the last three decades range from 0.1% to 8.1% and 6.2% to 73.4% respectively (48) . It is not known if the seroprevalence of HBV among Canadian HCWs is similar to that reported for the general public.
# HBV Serologic Markers
HBV is a DNA virus with a core protein surrounded by a coat containing surface antigen (HBsAg). The serologic markers of chronic HBV infection are varied and complex. Antigens and antibodies associated with HBV infection include HBsAg and antibody to HBsAg (anti-HBs), antibody to HBcAg (anti-HBc), and hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe). At least one serologic marker is present during each of the different phases of HBV infection (270) . The serologic markers are briefly described in Table 26, Appendix I (62,270,(274)(275)(276) . Some individuals infected with HBV carry a viral strain with a nucleotide substitution in the precore region of the viral genome. This mutation prevents transcription of the precore region and therefore, the release of HBeAg from the hepatocyte which results in a negative serum test for HBeAg.
The serologic markers currently used to identify a person's HBV status are HBsAg, anti-HBc IgG, and anti-HBs (270) . The only way to definitively differentiate acute from chronic infection is if HBsAg persists for more than 6 months. Table 27, Appendix I describes the typical serologic patterns used to interpret HBV serologic status. HCWs infected with HBV have transmitted infection to patients while in the incubation period of infection, during acute hepatitis, a few months following acute hepatitis, and during the chronic phase of infection.
# Estimated Risk of HBV Transmission
HBV is highly infectious, can be transmitted in the absence of visible blood, and has been reported to remain infectious on environmental surfaces for at least 7 days (66,270,277,278) . Hepatitis B virus is approximately 100 times and 10 times more infectious than HIV and HCV respectively. Several instances of healthcare-associated transmission were documented in the 1980s and summarized in several articles (64,269,279) .
In a study involving 405 reported cases of acute HBV infection, 262 cases were interviewed for risk factors. A total of 1.9% reported percutaneous injury and 3.1% reported healthcareassociated risk factors (269) . In studies of HCWs who sustained injuries from needles contaminated with HBV, the risk of developing acute hepatitis if the blood was both HBsAg positive and HBeAg positive was 22-31%; and the risk for developing serologic evidence of HBV infection was 37-62%. By comparison, if the blood was HBsAg positive and HBeAg-negative, the risks decreased to 1-6% and 23-37% respectively (277) . It is reasonable to assume that the same risk for seroconversion, following patient exposure to an HBV-contaminated needle, apply to HBV transmission from HCWs to patients.
Results from prospective studies showed that the estimated risk of transmission during exposure of two groups of 1,000 patients each to HBsAg positive HCWs and to HBsAg negative HCWs were both estimated to be less than 1% (280) . Transmission rates ranging from 0.06-11.11% have been reported from retrospective lookback investigations (refer to Table 24, Appendix I). This highlights the limitation of retrospective studies (triggered by reported transmission events) in obtaining data on transmission rates. When an infected patient is the trigger for an investigation seeking to identify other potentially exposed patients, the study design will result in documented transmission (the index patient) (280) . On the other hand, if an infected HCW is the trigger for an investigation (lookback), results will indicate either transmission or no transmission to patients.
Although prospective studies provide an opportunity for appropriate controls, the infected HCWs' knowledge that they are being followed may influence them to follow more stringent precautions to prevent transmission (280) . Data informing the risk of transmission of HBV is mostly informed by published lookback investigations thus providing more incidents of transmission than no transmission of HBV.
Table 24 (Appendix I) shows the rates of transmission estimated from epidemiologic investigations following a transmission or exposure event. The risk of infection was positively associated with the invasiveness of the procedures (121,281) . Generalizations cannot be made from the transmission rates in these studies due to circumstances specific to each incident, including the viral load of the infected HCW, level of risk posed by the procedure(s) associated with transmission, sample size (which was very small in most studies), and possible IPC breaches (132,133,139,282,283) . As a result, mathematical modelling studies are also used to estimate the risk of transmission of HBV. A modelling study concluded that the risk of transmission of HBV from an infected surgeon is about 0.24-0.024%, corresponding to 1 chance in 420 to 1 in 4,200 per procedure (64) . The probability of transmission during a single procedure by an HBeAg positive surgeon is 0.24%. In one transmission incident, the risk of acquiring HBV from an infected surgeon did not significantly exceed the risk of acquiring HBV from other sources (284) .
To determine the observed rate of transmission of HBV from infected HCWs to patients in previous HBV exposure incidents, a meta-analysis of eligible exposure incidents was conducted . A total of 20 incidents were eligible for the meta-analysis including 3 with no transmission of HBV. The pooled transmission rate for HBV using the random effects DerSimonian-Laird model was 1.45% (95% CI: 0.601-2.658%). This corresponds to a chance of 1,450 per 100,000 individuals (95% CI: 601 to 2658 per 100,000 individuals) becoming infected in the absence of IPC breaches and illicit diversion of patient medication.
# Review of Patient Exposure Incidents with Transmission of HBV
Since the introduction of serologic testing in the 1970s, there have been over 45 reported incidents of HCW-to-patient transmission of HBV (273) . Published investigations (from 1986 to date) have been summarized in Table 24, Appendix I. A summary of these transmission incidents by HCW specialty is provided in Table 13. All levels of experience including trainees, clinical assistants and senior surgeons are represented; technical expertise or competence was not usually identified as a contributing factor in transmission incidents (285) . No dentist-to-patient transmission of HBV has been reported since the late 1980s. Two published incidents of HCWto-patient HBV transmission occurred in Canada. One involved transmission by an infected electroencephalogram technician due to IPC breaches during a non-EPP (132) and the other involved transmission by an infected orthopedic surgeon during an EPP (284) (refer to Table 24).
A review of reported HCW-to-patient HBV transmission incidents in medical and dental settings, suggests that HCWs infected with HBV who are not involved in EPPs do not transmit infection unless there are IPC breaches (285) .
A total of 35,665 patients were exposed to 21 HCWs infected with HBV from a variety of healthcare specialties. Out of this exposed group of patients, a total of 22,191 (62%) were tested and 216 of them were confirmed to be infected with HBV (refer to Table 13). The number of infected patients could be higher if one includes the additional 38 infected patients that were considered by the study authors to be probable or possible transmission from a HCW or were cases of undetermined origin where transmission during a procedure could not be ruled out.
# Eight of the investigation reports did not address the hepatitis B (HB) immunization status of the
HCWs who were infected. The remaining studies provided some information about whether the HCWs completed a full or partial vaccination series and whether they had documented serological confirmation of immune status as a result. Two HCWs had been vaccinated but most likely acquired their infection before vaccination. Of the incidents that reported immunization data, none of the infected HCWs implicated in transmission of HBV to their patients had completed a full HB vaccination series with documented serological confirmation of their immunity or there was inadequate investigation of nonresponder status after vaccination (116,121,123,124) . (119) . C Performed venepuncture, inserted intravenous lines and prepared and administered intravenous antibiotics. D HCW performed electroencephalograms with reusable needle electrodes.
For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HBV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where HCW-to-patient transmission was reported. Twenty-eight such investigations were eligible for inclusion in the systematic review. Twenty-three of the 28 investigations involved an EPP. Findings on key preventive measures and risk factors for transmission are summarized in Table 14. (41) EPP Yes
The Incident Investigation Teams and Others, 1997 (119) 5) 23 ( 5) Abbreviations: HBV, hepatitis B virus; EPP, exposure-prone procedure; IPC: infection prevention and control; PEP, post-exposure prophylaxis; NR, not reported; HCW, healthcare worker A N=28 for total number of infected HCWs from reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made. H HB vaccine: HCW had previous HBV vaccine. I Percutaneous injury: Percutaneous injury potentially exposing patient to HCW's blood was reported. J Patient PEP: Post-exposure prophylaxis was offered to exposed patient(s). K Diversion ruled out: Illicit diversion of patient medication by HCW was ruled out. L Response to HB vaccine not assessed post-vaccination for five HCWs (110,122,123,130,133) . M HCW was a known non-responder. Since the HCW was hepatitis B e antigen negative with hepatitis B e antibodies and there was no report of transmission, the HCW was allowed to practice as per existing guidelines (115) . N Evaluation of lack of response to vaccine not performed for four HCWs (116,121,123,124) . O One HCW was allowed to perform surgical procedures prior to confirmation of response to HB vaccine (123) . P Two incidents during a 6-month period when HCW cut hand while breaking a glass vial with frank bleeding on one occasion (133) . Q HCW was vaccinated in 1990 without prior serologic testing; testing in 1992 revealed chronic carrier status that did not require further follow up (139) . R HCW recalled several needlestick injuries but never reported them and did not recall an injury when providing care to the index case (290) .
# Review of Patient Exposure Incidents with No Transmission of HBV
There are very few reported HBV patient exposure incidents that describe a lack of transmission from the infected HCW. Three incidents reported in the literature are presented in Table 25, Appendix I. Only one study provided information on numbers of patients potentially exposed and tested related to a HCW infected with HBV (refer to Table 15). One study compared the risk factors for two infected surgeons, one who performed uncomplicated or low risk procedures and the other who performed higher risk procedures (122) . All patients who were seropositive for HBV infection were operated on by the surgeon who performed lower risk procedures, wore single gloves for operations and did not have post-exposure vaccination offered to his patients (refer to Table 16). An accelerated course of HB vaccine was offered to patients of the surgeon who performed higher risk procedures, under the premise that even if infection had already occurred, severe illness and the development of a chronic state may be prevented (refer to Table 16).
A second study was conducted prospectively to investigate possible transmission of HBV from nine infected HCWs to 246 patients (280) . Patients were exposed a total of 483 times and no transmission was documented. Two of the nine infected HCWs who were HBeAg positive and had circulating HBV DNA accounted for a total of two-thirds of patient contacts. This study reported aggregate data for number of patients exposed to all nine HCWs therefore could not be included in Table 15. (1 dental technician, 1 ICU nurse and 1 medical student) over a 30-month period. The results of the study were pooled for all patients of all HCWs (n=246) and for all exposures (n=483) with no evidence of transmission identified (280) .
For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HBV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where no transmission was reported. Three such investigations were eligible for inclusion in the systematic review, all involving an EPP. Findings on key preventive measures and risk factors for transmission are summarized in Table 16.
) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0) 0 (0) Total No EPP (non-EPP) 1 (0) 0 (0) 0 (0) 1 (0) 1 (0) 0 (0) 0 (0) 0 (0) 0 (0) Total NR EPP (non-EPP) 0 (0) 3 (0) 3 (0) 2 (0) 2 (0) 3 (0) 3 (0) 2 (0)
3 (0) Abbreviations: HBV, hepatitis B (HB) virus; EPP, exposure-prone procedure; IPC: infection prevention and control; PEP, post-exposure prophylaxis; NR, not reported; HCW, healthcare worker A N=3 for total number of infected HCWs from all reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made. H HB vaccine: HCW had previous HBV vaccine I Percutaneous injury: Percutaneous injury potentially exposing patient to HCW's blood was reported. J Patient PEP: Post-exposure prophylaxis was offered to exposed patient(s). K Diversion ruled out: Illicit diversion of patient medication by HCW was ruled out.
Recommendations provided for minimizing risk of HCW-to-patient transmission of HBV have taken into consideration preventive measures and risk factors reported in exposure incidents to date.
# HBV Viral Load
There was no clinical test for HBV viral load until the late 1990s. In general, the presence of eantigen is associated with high HBV viral load and was therefore used as a surrogate measure for infectivity in earlier recommendations (124,291) . However, a small subset of persons who are HBeAg negative may still have a high viral load (105,292) . Following reported transmission incidents from HBeAg negative HCWs (114,115,119,121,293) , and detection of HBV DNA in 64.5% of HBeAg-negative carriers (294) , the focus for assessing infectivity and risk of transmission has changed from HBeAg status to HBV DNA levels. Viral load and volume of blood determine the transmission risk of HBV and as a result, recent guidelines have indicated that viral loads are a more accurate measure on which to base recommendations for practice restrictions of HCWs infected with HBV who perform EPPs (105,190,273,295) . A comparison of various guidelines on this topic show a lack of consensus for the threshold above which practice restrictions are recommended for HCWs infected with HBV (44,105,273,(296)(297)(298) . This is likely the result of a very limited evidence base available to inform an optimal threshold (299,300) .
Several lookback investigations predate the availability of viral load testing. Information on viral load provided in some lookback investigations is limited by the inability to link HCW viral load at time of transmission with rate of transmission. The viral load is usually tested weeks or months after transmission has occurred. This has led to concerns that data on HBV DNA levels to inform a cut-off level for HCWs who perform EPPs is not sufficiently robust (47) .
There are considerable differences in results obtained from various HBV DNA quantitative assays for individual sera (301) . In addition, various publications use slightly different conversion factors for the unit(s) used to report HBV DNA, largely based on the assay used. For purposes of this guideline, HBV DNA is expressed in terms of IU/mL as recommended by the World Health Organization (WHO). The unit copies/mL is considered equivalent to genome equivalent (GE/mL) and one IU/mL is considered approximately equivalent to 5 GE/mL or copies/mL (105,266,302) .
Results from transmission incidents indicate that risk of transmission was higher with HBV DNA levels above 1.8 x 10 5 IU/mL (10 6 GE/mL) (292) . Analysis of HBV DNA levels in surgeons who transmitted HBV to their patients helped identify an HBV DNA level above which transmission of HBV during an EPP could not be excluded. The identified HBV DNA level was 6.9 x 10 3 IU/mL (4 x 10 4 GE/ml) (refer to Table 17) (294) . The study authors noted that assays for HBV DNA based on polymerase chain reaction (PCR) have a ½ log10 variance. In addition, fluctuations in HBV DNA levels up to 2 log10 have been reported in invidividuals infected with HBV who were HBeAg-negative and even higher fluctuations in individuals infected with HBV who are not on treatment. This necessitates allowing for in vitro variation in test results and in vivo fluctuations in HBV DNA levels (as demonstrated in HBeAg-negative individuals) before defining a cut-off HBV DNA level (294,303) . A review of available data showed that a minimal risk strategy would be to set a cut off level well below levels documented in transmission incidents to allow for fluctuations and a 3 log10 safety margin was considered sufficient to account for this (47) . A viral load cut-off level of 2,000 IU/mL (10 4 GE/mL) is recommended in Europe (273) , and 1,000 IU / ml (5x10 3 GE / mL) in the US (105) . The thresholds provided are thought to increase patient safety as well as optimize the workforce by preventing loss of HCWs who are safe to practice (273) .
Treatment with current antivirals reduces HBV DNA levels to undetectable or almost undetectable levels in most persons (105,268,(304)(305)(306)(307)(308) . Virtually all persons infected with HBV under treatment can expect reduction in HBV DNA viral loads within weeks or months of initiating therapy (105,306) . In a study involving 18 surgeons with chronic HBV infection monitored every three to six months for a median period of 5.6 years, antiviral therapy was offered if HBV DNA was above 10 5 copies/ml (57) . Sustained viral suppression was achieved in both HBeAg-negative and HBeAg-positive surgeons (57,300) . The provision of regular expert monitoring, including quantification of HBV DNA was considered a necessary aspect of successfully managing infected surgeons using antiviral therapy. A small proportion of untreated individuals infected with HBV who are HBeAg negative with low HBV DNA are at risk for having fluctuating HBV DNA levels. Regular monitoring of HBV DNA will assess for these fluctuations making it unnecessary to have a very high safety margin in setting a viral load cut off level for HBV infection (47) . If a HCW performing EPPs elects not to go on therapy, they would need to have their viral load checked frequently and would not be able to do EPPs if they go above the threshold. In addition, with a safety margin of 3 log10, there is no real difference between a HBV DNA cut-off level of 1000 IU/mL and 2000 IU/mL. HBV treatment is very effective at suppressing the viral load and HBV blips while on treatment would not go beyond 1000 IU/mL. The availability of safe and effective antiviral agents to treat chronic HB infection provides a greater imperative to identify persons who might benefit from medical evaluation, management, and treatment (270) . (266) . C One IU/mL is considered equivalent to 5 copies/mL (302) (therefore 1 copy/mL is equivalent to 0.2 IU/mL) except for studies described in Corden (2003) (294) where an assay-specific conversion factor of 5.82 was used as indicated by Roche. D Companion: Articles that provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table. E Semi-quantitative PCR dot-blot hybridization, with comparison serum containing 108 chimpanzee-infectious material (105) . F Liquid hybridization and enzyme-linked oligonucleotide assay (105) . G Lightcycler PCR (105) . H Semi-quantification by end-point dilution (105) . I Limited dilution PCR (105) . J Chiron Quantiplex Branched DNA assay and Roche Amplicor HBV DNA monitor (105) . K Versant HBV bDNA 3.0 assay. L Detection assay based on TaqMan technology.
# HBV Vaccination
Prior to the introduction of a vaccine in the 1980s, HBV was a major occupational risk to HCW with exposure to blood, blood products, and other body fluids. HBV infection is currently preventable by vaccination, and Canada has had high risk and universal childhood HBV immunization programs in place, in all provinces and territories, since the mid-1990s (62) . A survey conducted over a decade after the introduction of vaccines showed that 90% of dentists in Canada had completed an immunization series and an additional 3% had natural immunity (309,310) . A study to identify the proportion of transplant surgeons in the US who were adequately vaccinated against HBV was conducted in 2006 (311) . Out of 94 surgeons (27.3% of participants) who reported at least one needlestick exposure while operating on a patient infected with HBV, 14 (14.9%) were inadequately vaccinated. The authors concluded that the surgeons underestimated both the risk of percutaneous exposure while operating, and the risk of becoming infected with HBV if exposed. An inadequate vaccination series is likely to lead to antibody loss during long-term follow up of HCWs (312) .
Evidence-based strategies to improve compliance with HB immunization recommendations in the Canadian Immunization Guide have been successful (313) . Although the success of HB vaccination programs is well documented among the younger population (Figure 3), there may be many HCWs who remain at risk of acquiring HBV. The risk of HBV transmission to a HCW who has been fully immunized and has developed an immune response after vaccination is virtually zero (314,315) . Therefore, increasing the emphasis on universal HB vaccination programs among HCWs in Canada will reduce the future risk of HBV transmission from HCWs to patients and from patients to HCWs. and 2009 to 2011 Canadian Health Measures Survey (212) .)
Strategies applied by a university postgraduate medical school to improve medical trainee compliance with immunization standards led to very high compliance with statistically significant increases in compliance over a 3-year period (313) . Canada's National Advisory Committee on Immunization (NACI), recommends immunization with HB vaccine and postimmunization serologic testing within 1 to 6 months of completion of the vaccine series for people who are at increased risk of infection through occupational exposure to blood, blood products and bodily fluids that may contain HBV (95) . This group includes all HCWs exposed to blood and other body fluids. Detailed recommendations on HB vaccination can be found in the Canadian Immunization Guide (95) .
Response to HB vaccine after a 3-dose series is generally greater than 95% in young healthy people (95,316) . For cases of nonresponse, revaccination with ≥1dose of HB vaccine subsequent to the primary series increases the proportion of persons achieving vaccine-induced seroprotection and a cumulative response rates of 69% has been reported among initial nonresponders after three revaccination doses (277) . The vaccine response decreases with age and several factors have been used to predict risk of nonresponse or vaccine failure (317) . Although typical anti-HBs levels in the 100s to 1000s IU/L are achieved following vaccination, levels of anti-HBs above 10 IU/L have been documented to provide virtually complete protection against HBV (310) . HCWs who perform EPPs and do not have a protective level of antibody titre against HBsAg (anti-HBs > 10 IU/L) after vaccination require further investigation (95,116,119) . A potential cause of vaccine nonresponse is established chronic HBV infection. Other common causes include immune suppression (steroid therapy), chronic illness (hepatitis C infection, dialysis, rheumatoid inflammatory diseases), smoking and older age (318,319) .
Once there is a record of a complete vaccination series and seroconversion has been documented for a HCW, i.e., anti-HBs titre ≥ 10 IU/L, he/she can be considered immune and no further testing is required, even if an exposure occurs. HCWs who have not responded to appropriate vaccination should be counseled on their ongoing risk of infection as well as the use of measures to reduce the risk of transmission. They should also be regularly assessed for infection (e.g., annually and after exposure) (95) .
People who develop an anti-HBs titre of at least 10 IU/L (adequate anti-HBs titre) following the completion of a recommended vaccination schedule are considered protected for life (95) . Exceptions are some immunocompromised persons and people with chronic renal disease or on dialysis, who may require periodic booster doses if their anti-HBs titre falls below 10 IU/L. In immunocompetent individuals, although anti-HBs titres may become non-detectable over time, immune memory persists (95) . An assessment of evidence on long-term efficacy and effectiveness of HB vaccines in immunocompetent individuals, with particular focus on individuals immunized as infants and HCWs has been conducted (320,321) . NACI currently recommends that, following immunization of immunocompromised individuals, initial annual monitoring of HB antibody levels may be considered (322) . - If an anti-HBs titre of at least 10 IU/L is confirmed B , testing need not be repeated nor should further immunization be undertaken, with the exception of immunocompromised persons who should be tested periodically for waning immunity, and persons with chronic renal disease or on dialysis, who should be tested yearly. - If testing for anti-HBs is done 1 to 6 months after vaccination and the anti-HBs titre is less than 10 IU/L B , a primary vaccine failure has occurred and the HCW should be given a second vaccine series. The HCW should be retested 1 to 6 months after completion of the second series.
- If the HCW is tested more than 6 months after the initial series and the anti-HBs titre is less than 10 IU/L B , the cause may be either a primary vaccine failure or waning antibody. Evidence shows that, in immunocompetent people, immunity is long lasting although antibody may be non-detectable. The HCW should receive one booster dose and be retested one month later to document an anamnestic response (defined as anti-HBs titre ≥10 IU/L one to four weeks post booster vaccination). If the anti-HBs titre is still less than 10 IU/L B , the HCW should be tested for HBsAg and anti-HBc to rule out pre-existing chronic HBV infection. If both tests are negative, then a second vaccine series is indicated followed by anti-HBs serology 1 to 6 months after completing the second series B .
- HCWs who have documented evidence of failure to respond to two series of HB vaccine (i.e., anti-HBs titre of less than 10 IU/L) are unlikely to benefit from further immunization and will need passive immunization after potential exposure to HB B, C . Occupational health or infectious disease specialists may be consulted regarding any new strategies that may be available such as intradermal vaccination or high potency vaccine.
- If an HB exposure occurs, and a HCW has had a documented anti-HBs titre of at least 10 IU/L, no further testing is needed unless the HCW is immunocompromised or has chronic renal disease or is on dialysis. These HCWs should be tested for anti-HBs after a potential HB exposure and given additional vaccine and HBIg if their anti-HBs titre is less than 10 IU/L B .
Abbreviations: HB, hepatitis B; anti-HBs, antibody to surface antigen; HBIg, hepatitis B immune globulin A Recommendations 3 (adapted) and 4 are excerpted from the Canadian Immunization Guide (95) . Additional information is provided in the 1993 NACI Hepatitis B statement (323) . This statement was published prior to the development of the NACI methodology for grading of recommendations (324) . As a result, these recommendations are not graded.
B Anti-HBs titre less than 10 IU/L is the international standard utilized by most laboratories but may vary by jurisdiction. Check with your local laboratory for the standard used locally. C The HCW should be referred to a specialist in immunization. (8) . B Ethical obligation may be traced to principles of non-maleficence (the duty to intentionally refrain from actions that cause harm), which includes an obligation for HCWs not to impose risks of harm to patients and creates a standard of due care (12)(13)(14)209) C Countries or areas with moderate to high risk of HBV are identified by the World Health Organization (325) . D Refer to the Canadian Immunization Guide for immunization of persons new to Canada (95) . E HBV antiviral therapy may be required to allow HCWs infected with HBV to perform EPPs. F One IU/mL is considered equivalent to 5 copies/mL (i.e., 1 copy/mL is equivalent to 0.2 IU/mL) (302) . G Because the focus is on patient safety, HCWs who perform EPPs should be treated at this serum level regardless of recommendations in current treatment guidelines. With adherence to treatment as part of the threshold for infected HCWs to perform EPPs, HBV DNA levels are reduced to almost undetectable in most people. As a result, several known inconsistencies (e.g., differences in recommended HBV DNA threshold in various international guidelines, in-vivo fluctuations in a person's HBV DNA levels without treatment, variation in HBV DNA test results based on different assays used, or variations in results from repeated test of the same blood sample using the same assay) will likely have minimal impact on decisions regarding practice restrictions.
H Refer to the section on Expert Review Panels.
# CO-INFECTION WITH BLOODBORNE VIRUSES
Due to similar routes of infection, co-infection with any combination of HIV, HCV or HBV is not uncommon, especially among individuals with high risk of blood exposure such as hemophiliacs and people who use injection drugs (32,184,(326)(327)(328)(329) . A review of published literature on co-infection involving any two or all three of these BBVs was conducted in order to summarize considerations or challenges associated with management of HCWs with a BBV co-infection related to the risk of BBV transmission to patients.
Reports of co-infection with HIV-HBV and HBV-HCV are limited (328,330) , while reports of coinfection with HIV-HCV are more extensive (326,327,327,(331)(332)(333)(334)(335)(336)(337)(338)(339) . There is limited published data on co-infection by all three viruses (340)(341)(342)(343) .
Overall, studies on BBV co-infection focus more on disease progression and prognosis and not much is reported on the effect of co-infection on infectivity or transmissibility of these viruses. Following the review of currently available publications on BBV co-infection, recommendations provided in this guideline for the management of individual BBVs were thought to be sufficient to prevent transmission from co-infected HCWs. This is because these recommendations primarily focus on treatment for the infections and setting viral load thresholds for safely performing EPPs. The effect of co-infection on disease progression and treatment is relevant primarily for the treating physician responsible for the clinical management of the infected HCW (184,344) .
If a HCW who performs EPPs is co-infected with any combination of these BBVs, the HCW should meet the defined criteria recommended for safe practice by HCWs infected with each virus (296) .
# DOUBLE GLOVING
Several studies investigating IPC practices of surgeons implicated in transmission of a BBV to patient(s) assessed the gloving practices of the infected HCW (116,118,122,345) . Glove failure due to perforations and/or HCW injury can result in exposure to blood and body fluids and therefore increased risk of transmission of a BBV. It is unclear if glove failure carries the same risk for both HCWs and patients when either is infected. The practice of double gloving (wearing two pairs of gloves) as an effort to mitigate this risk has been well documented and is discussed below.
Studies attempting to assess potential benefits of double gloving are mainly focused on protecting HCWs as data show they have a higher risk of acquiring a BBV from patients than vice versa (63) . Some studies report that due to paucity of evidence, no conclusions can be drawn regarding the comparative effectiveness of double versus single gloving for minimizing the risk of transmission of BBVs (346) . Other studies have drawn conclusions from the limited available evidence (347)(348)(349) . The different conclusions reached in these studies likely reflect differences in interpretation of the evidence as it relates to risk of BBV transmission.
Most relevant studies on gloving practices compared glove perforation rates by assessing for body fluid contact or leaks in gloves (20,347,348,(350)(351)(352)(353)(354)(355) . Glove perforation is particularly high during certain types of procedures. Healthcare workers performing orthopedic, cardiothoracic, gynecologic and trauma surgeries are more frequently involved in procedures with higher risk of glove perforations and percutaneous injury than other HCWs (20)(21)(22)(23)(24)86,356) .
When two pairs of gloves are worn, the number of perforations to the inner glove and consequently potential HCW exposure to patient blood, is significantly reduced (70-87%) compared to when a single pair of gloves is used (87,348,(355)(356)(357) . As a result, some literature and lookback investigations postulated that there would be a similar reduction in the risk of BBV transmission from HCW to patient, with double gloving more protective than a single pair of gloves (49,350,351) .
A systematic review of RCTs investigated whether double gloving reduced the incidence of infections including surgical site infections, and bloodborne infections in surgical patients and in the surgical team (356) . The secondary study objective was to determine if additional glove protection reduced the number of perforations to the innermost pair of surgical gloves. Eligible RCTs involving two or more types of gloving including single gloving, double gloving, triple gloving, glove liners, knitted outer gloves, steel weave outer gloves, and perforation indicator systems were compared. A total of 61 RCTs informed the authors' conclusions on the various outcomes measured. A meta-analysis of 14 of these trials which included 8,885 surgeries, demonstrated that the addition of a second pair of gloves significantly reduced perforations to the innermost gloves (odds ratio 4.10, 95% confidence interval 3.30-5.09) (356) . Collectively, these studies may indicate that double gloving is indeed important for procedures with high risk of glove perforations and may therefore be a relevant preventive measure for transmission of bloodborne infections.
Deterrents against the wide adoption of double gloving by HCWs who perform EPPs include the need to change a habit, decreased manual dexterity and tactile sensation, constriction of the hands and digits leading to discomfort, paucity of evidence, and low perceived personal risk by HCWs (20,349,350,353,(358)(359)(360) . In many cases, a period of adaptation and "retraining" seems to be required before practitioners feel comfortable with double gloving (87,361) . A prospective randomized controlled trial involving 53 surgeons concluded that double gloving did not have a substantial impact on manual dexterity or tactile sensitivity when compared to single gloves or no gloves (358) . Results from a survey of 155 surgeons and residents affiliated with two Canadian universities showed that 43% of them routinely double gloved in 75% or more of procedures (361) . Some professional organizations recommend double gloving as a standard of practice for invasive procedures in order to reduce body fluid exposure caused by glove tears and sharps injuries in surgeons and scrub personnel (87,(362)(363)(364)(365) . In a Canadian survey of 170 surgeons, 87% of orthopedic surgeons double gloved while none of the urologists surveyed did (349) . In certain types of surgery (such as neurosurgery), where delicate manipulation of instruments and tissues is required, double gloving may impair the surgeon's ability to safely perform the procedures. Thus, the surgeon may decide to forego double gloving. Although it is clear that double gloving reduces the risk of exposure to blood and body fluids due to glove perforations, the evidence is insufficient to determine how it affects the risk for BBV transmission from HCW to patient and vice versa (347,356) . As a result, it is not possible to conclusively state that double gloving is a critical element for preventing transmission of BBVs between HCWs and patients.
Double gloving by HCWs, to protect themselves and their patients, may best be addressed as a matter of preference until further studies are conducted. Factors to consider in making a decision whether or not to double glove based on identified risk factors for glove perforations are summarized below (24,351,353) :
- The addition of a second pair of surgical gloves significantly reduces perforations to innermost gloves (355,356,361) . - Sensitivity and manual dexterity may be improved by choosing a suitable combination of inner-and outer-glove size (358) .
- Wearing two pairs of gloves does not substantially impact tactile sensitivity or manual dexterity to the point of resulting in more perforations (356,358) .
- Wearing one pair of orthopedic gloves (thicker than standard latex) is as effective as wearing two pairs of standard latex gloves in reducing the number of perforations to innermost gloves (366) .
- Risk of glove perforation has been reported to increase with the length and complexity of the procedure as well as HCW expertise and risk of injury associated with the procedure (24,84) . Deep procedures carry a significantly higher risk of glove failure (up to sevenfold) compared with superficial procedures (348,359) .
- The frequency of glove changes depends on length of procedure, amount of blood loss, and HCW injury (347,351,367) . - Glove perforations are significantly higher for emergency procedures than they are for scheduled procedures (24,353,367) .
- If double gloving, wearing glove perforation indicator systems results in significantly more inner glove perforations being detected during surgery than when wearing standard double latex gloves (348,368) .
- If HCWs choose to double glove, they should do so routinely and not based on the risk status of a patient. Occasional double gloving would not provide the opportunity for the HCW to adapt to it thereby potentially posing a risk to both the HCW and the patient (87) .
# Recommendation for Double Gloving for Infected Healthcare Workers
Recommendation 1. There is insufficient evidence to recommend for or against double gloving to prevent HCW-to-patient transmission of a BBV. Grade of evidence: Not applicable due to insufficient data specific to BBV transmission
# INFECTION PREVENTION AND CONTROL MANAGEMENT OF INFECTED HEALTHCARE WORKERS
# Reporting Obligations
In all provinces and territories, certain HCWs are obligated by law to report patients infected with specified communicable diseases including HIV, HBV and HCV to public health (369) . There may be additional ethical, legal or regulatory reporting requirements related to patients infected with a BBV, who are also HCWs. As a result, all treating clinicians should be familiar with the reporting obligations in effect within their province or territory of practice (369) .
# Expert Review Panels
Within the context of this guideline, Expert Review Panels (ERPs) are advisory committees to the relevant jurisdictional authority (e.g., public health, regulatory authority) whose primary role is to assess the risk of transmission of a BBV from an infected HCW to patients and assess whether practice modifications or restrictions are needed if the infected HCW performs EPPs.
A review of existing guidelines from Canada, the United States, the United Kingdom, Europe, France, Ireland, Australia, and the Netherlands shows differences in approach to convening and/or implementing an expert review process (2,44,105,190,273,298,300,370,371) . The UK has a nationallevel ERP called The UK Advisory Panel for Healthcare Workers Infected with Bloodborne Viruses (UKAP), which has been in place since 1991 (234) . In 2011, France recommended a similar approach for the creation of an ERP at a national level (44) .
# Canadian Approach
The approach taken for the establishment of ERPs in Canada varies across provinces and territories (P/Ts). Table 36 (Appendix III) describes key elements of the expert review process in two provinces that have a centralized approach for all HCWs. ERPs have been convened by P/T ministries of health or public health agencies, as well as by university faculties (e.g., medicine) or regulatory authorities for HCW professional groups (274,(372)(373)(374)(375)(376)(377)(378)(379)(380) . Health Canada's 1998 consensus document recommended the creation of an ERP (2) . At the time of developing this guideline, not all HCWs infected with a BBV in Canada had access to an ERP. Where ERPs exist, the process for implementation and monitoring for compliance with recommendations provided by the panel also varies across P/Ts. The inconsistencies in establishing an ERP and developing a framework for their decision-making have led to inconsistent practices across Canada. This could result in movement of an infected HCW between provinces and territories, a situation where an infected HCW is not being managed, or management of an infected HCW using advice that is not based on available evidence regarding risk of transmission. A consistent evidence-based approach across the country will improve patient safety and support the effective and equal treatment of HCWs infected with a BBV irrespective of where they work in Canada. This guideline is intended to support consistency in availability of ERPs and their practices nationally.
For purposes of developing this guideline, an environmental scan of relevant literature was conducted to address the key question, What issues are relevant to the expert review process in Canada for the management of HCWs infected with HIV / HCV / HBV? Characteristics of ERPs in Canada were identified through an environmental scan of publicly available documents and personal communication where necessary. Upon review of relevant documents, current practice, and stakeholder engagement, essential components were identified to inform recommendations for establishment of effective ERPs by provincial and territorial health authorities. These recommendations prioritize patient safety using a consistent and evidence-based approach to decision-making regarding the management of infected HCWs while ensuring that each HCW's right to privacy and the confidentiality of their personal medical information are maintained.
# Recommendations for Expert Review Panels
Recommendations for the governance, authority, responsibility and processes for ERPs are provided below. These issues should be clearly defined for each P/T such that all HCWs (including students) who may be affected by the policies are afforded the opportunity to receive expert guidance related to their BBV infection. o The composition of the panel and who it reports to should be publicly available. - P/Ts and regulatory authorities without the necessary resources and expertise to establish an ERP, should partner with another P/T to ensure that all HCWs infected with a BBV have access to an ERP.
- Expert Review Panels should engage relevant stakeholders such as public health, health faculties and healthcare institutions.
- Indemnification should be provided for all ERP members.
- The ERP should be adequately resourced to complete its mandate. The governing authority for an ERP is responsible for addressing the remuneration of the ERP members.
- The ERP should be convened in a timely manner when an infected HCW is identified for review.
- There should be sufficient members on the ERP to provide the breadth of expertise required to assess the risk posed by a HCW infected with a BBV, and offer recommendations to mitigate the risk. Membership on an ERP should include an infectious disease physician and a public health professional. Other members may include: a hepatologist, surgeon, medical/clinical microbiologist, infection prevention and control professional, occupational health physician, bioethicist, member of the public, and peer HCW (in the same area of practice as the HCW infected with a BBV).
# Roles and Responsibilities
- An ERP should assess the risk that the HCW may pose to patients and make recommendations on fitness for practice based on the HCWs' health status and practice. - The HCW or their delegate should have an opportunity to present information during the assessment for fitness to practice.
- The HCW or their delegate should have an opportunity to discuss the recommendations prior to implementation and have an opportunity for clarification or a re-evaluation.
- The ERP processes should be conducted in a manner that protects the HCW's privacy and maintains confidentiality.
- The ERP or regulatory authority should sign a written agreement with the HCW that identifies the recommendations and specifies any practice modifications or restrictions, with whom the agreement will be shared with (regulatory authority, program director, etc.), who will be monitoring the HCW's compliance, and who will be responsible for monitoring the HCW's health status. Ensuring that the HCW is under the care of a clinician with expertise in management of the BBV(s) is an important aspect of care for the HCW; this care provider may have an ongoing role in receiving test results and communicating status updates with the regulatory authority at defined intervals.
- Recommendations of the ERP including the signed agreement should be in the possession of the regulatory authority that is responsible for monitoring the HCW's compliance with the recommendations.
- The relevant authority should have a process in place in the event a HCW wishes to request a re-evaluation of any ERP recommendation(s). Acceptable reasons for a reevaluation should be outlined and may include concerns with the process, availability of new treatment regimens, or new information about the HCW's health status or practice.
# Referral to an ERP
There are several mechanisms for initiating a referral to an ERP. The options provided here are not exhaustive.
- All HCWs, including students and trainees, may self-refer to an ERP.
- The referral to the ERP may be initiated by the Medical Officer of Health or the regulatory authority; with appropriate information communicated in writing, in person, or by phone. If initiated by the regulatory authority, their monitoring department may send a list of HCWs infected with BBVs to an ERP for review. - The referral to the ERP may be initiated by the HCW and done via telephone contact to maintain anonymity. Alternatively, the HCW may choose to initiate the referral via an advocate, surrogate, or legal representative. Most often the advocate is the treating physician.
- In the case of students and trainees, the referral may be initiated through the undergraduate or post-graduate office of the faculty.
- If the HCW is a student or trainee, a person in charge of the program or a faculty member may provide procedural advice and assistance to the student or trainee.
# Implementation, Monitoring and Compliance with ERP Recommendations
- The ERP should provide recommendations informed by Sections 6.6, 7.6 and 8.9
Recommendations for Management of HCWs infected with HIV, HCV and HBV respectively. - The HCW and treating clinician should provide the relevant authority with the necessary information to confirm compliance with the recommendations.
- The relevant regulatory authority may remove the HCW's licence if the HCW is noncompliant with practice restrictions. - In the event that a HCW who is being monitored changes jurisdictions or institutions, the regulatory authority or faculty should inform the appropriate jurisdictional authorities subject to applicable laws.
A sample flow chart providing an overview of the interactions and responsibilities of regulated HCWs infected with a BBV, an ERP, and relevant authorities is shown in Figure 4. Although local jurisdictions can adapt the referral and implementation processes within the context of the relevant authorities and available resources, specific guidelines and recommendations are provided above for each key step. Table 37 (Appendix III) lists select regulated and unregulated HCWs in Canada by P/T.
Policies regarding the management of HCWs infected with BBVs must comply, as appropriate, with applicable jurisdictional health and privacy legislation, employment law, Human Rights codes and the Canadian Charter of Rights and Freedoms.
Abbreviations: HCW, healthcare worker; BBV, bloodborne virus; EPPs, exposure-prone procedures; IPC, infection prevention and control; ERP, Expert Review Panel; P/T, provincial and territorial Regulated HCW infected with a BBV (1) Regulated HCW infected with a BBV (1) Yes No HCW consults with relevant authority (2) HCW consults with relevant authority (2) Does the HCW perform or wish to perform EPPs (4) ?
Does the HCW perform or wish to perform EPPs (4) ?
Restrictions on practice not needed based on BBV status alone Restrictions on practice not needed based on BBV status alone HCW notifies regulatory authority (5) HCW notifies regulatory authority (5) Relevant authority ensures review of HCW's general practice (including IPC) by an individual with the appropriate expertise (3) Relevant authority ensures review of HCW's general practice (including IPC) by an individual with the appropriate expertise (3)
# E p R w P ERP
R n 11 0 PC M g m d HCW d o mm d n E HCW h h d u n u u p b A k p d o p h o h du h HCW p o m w d k p o m M mm d h h HCW m mp w h d d p d R g mm d b d w m b HCW h h d p C mm n d d w h h h R p p d qu m d p g S d po o g g u h y R gu y ho y d n E u w o HCW PC p by n nd d w h h pp op p b E o p n Ob w g m w h h HCW
x ert evie anel ( ) (6) Expert Review Panel (ERP) (6) efer to sectio . I ana e ent of Infecte s for etails n reco en atio s: Refer to section 11.0 IPC Management of Infected HCWs for details on recommendations: a.
valuates 's ealt status an c rre t or f t re ractice a. Evaluates HCW's health status and current or future practice . ssesses ris ose t atients in t e course f t e ties t e erf r s or oul li e to erf r b. Assesses risk posed to patients in the course of the duties the HCW performs or would like to perform c.
akes reco en ations t at t e ust co ly it as a con ition of continue or future ractice c. Makes recommendations that the HCW must comply with as a condition of continued or future practice . e-evaluates ori inal reco en ations ase on ne infor ation a out 's ealt status an /or current or future ractice d. Re-evaluates original recommendations based on new information about HCW's health status and/or current or future practice e. o unicates as ee e it t e source of t e referral (7) e. Communicates as needed with the source of the referral (7) f. e orts as er juris ictional re ire ents an /or ractice (8) f. Reports as per jurisdictional requirements and/or practice (8) . en s re rt t overnin a t orit (9) g. Sends report to governing authority (9) e lator aut rit consi eratio s: Regulatory authority considerations: a.
ns res revie f 's I ractices a i ivi ual it t e a r riate ex ertise (3) a. Ensures review of HCW's IPC practices by an individual with the appropriate expertise (3) . nf rces ractice restrictio s b. Enforces practice restrictions c.
tains a ritten a ree ent it t e c. Obtains a written agreement with the HCW d. Refers back to the ERP should the HCW's health status or type of procedures they want to perform changes e. Monitors HCW compliance f. Receives necessary information to confirm compliance with ERP recommendations g. Restricts or puts conditions on licence as recommended by the ERP h. Informs relevant P/T regulatory authorities if the infected HCW who is being monitored changes jurisdictions, subject to applicable laws d. Refers back to the ERP should the HCW's health status or type of procedures they want to perform changes e. Monitors HCW compliance f. Receives necessary information to confirm compliance with ERP recommendations g. Restricts or puts conditions on licence as recommended by the ERP h. Informs relevant P/T regulatory authorities if the infected HCW who is being monitored changes jurisdictions, subject to applicable laws
Has the HCW and/or treating clinician provided the necessary information demonstrating compliance with and fulfillment of all ERP recommendations (10) ?
Has the HCW and/or treating clinician provided the necessary information demonstrating compliance with and fulfillment of all ERP recommendations (10) ?
HCW can practice in compliance with recommendations from the ERP (11) HCW can practice in compliance with recommendations from the ERP (11) HCW practice restrictions continue (11) HCW practice restrictions continue (11) Yes
# No
Legend 1. This model could be adapted to align with jurisdictional requirements and for unregulated HCWs, including students in some P/Ts, to ensure that all infected HCWs have access to the appropriate expertise in a timely manner. The process includes assessment for risk of transmission of the BBV during the provision of care; the provision of recommendations to the HCW, including practice restrictions if applicable; and the monitoring of the HCW's compliance with the recommendations.
For example, regulatory authority, public health.
- An individual with the appropriate expertise may vary depending on the types of procedures performed by the infected HCW. At a minimum, the review should include all the elements of Routine Practices for the prevention of transmission of infections in healthcare settings (i.e., hand hygiene, aseptic technique, sharps safety and prevention of exposure to BBVs, etc.). If a HCW should want to start performing EPPs, they will need to notify their regulatory authority again. 4. Question to be answered by the relevant authority (e.g., regulatory authority, public health). Other reasons for referral to an ERP may include: Confirmed HCW-to-patient transmission of a BBV; and presence of extenuating circumstances that may increase risk of exposure to patients (e.g., identified IPC breaches).
The regulatory authority can be notified from other sources as well (e.g., a peer HCW, a Medical Officer of Health, a diagnosing or treating physician). 6. The Chair of the ERP may work with the regulatory authority to determine the need for practice restrictions and subsequent referral to the ERP. 7. Communication or notification beyond the source of referral should only be done with the consent of the infected HCW and subject to applicable laws. 8. May include communicating with or reporting to the faculty program director, P/T public health and/or the HCW's employer.
# DISCLOSURE OBLIGATIONS AND RIGHT TO PRIVACY
This section addresses the HCW's disclosure obligations to their patients and the HCW's right to privacy. Few Canadian guidelines and policies address the issue of disclosure obligations to patients. None of those reviewed regard routine disclosure of HCW serologic status to patients as a necessary requirement for the provision of care. When a HCW infected with a BBV has been reviewed by an ERP and deemed safe to practice, the issue of disclosure is not applicable.
# International Approach
The United States Centers for Disease Control and Prevention (CDC) previously required that HCWs infected with HBV or HIV who perform EPPs disclose their serologic status to their patients (291) . However, this is no longer a requirement in the CDC's updated recommendations for the management of HCWs infected with HBV (105) . These recommendations state that routine mandatory disclosure might be counterproductive to public health, as it might lead to avoidance of testing, vaccination, treatment and/or management, and may result in non-compliance with practice oversight from an ERP. The risk of transmission of a BBV is greater from unknown infections than from known infections. Mandatory disclosure was "accepted to be an insurmountable barrier to practice, and might limit patient and community access to quality medical care" (105) .
Internationally, none of the reviewed policy documents regard disclosure of a HCW's serologic status to patients as a necessary requirement for the provision of care (44,105,190,370,371) . The HCW right to privacy is comprehensively addressed, but the practical steps to ensure that this right is upheld are not included in most policies.
A harmonized, evidence-based approach to addressing HCW disclosure obligations and right to privacy is warranted, and stands to benefit HCWs, patients, and society. Ensuring safe medical care and protecting HCW privacy rights should be achieved in a consistent and transparent manner in all healthcare settings across Canada. An essential precursor for safe patient care is the ethical and professional obligations of the HCW performing EPPs to know their serologic status, and seek and receive necessary guidance accordingly (refer to section 11.0 Infection Prevention and Control Management of Infected Healthcare Workers) (11)(12)(13)(14)(15)(16)(17)(18) . This obligation of HCWs in Canada, whether ethical or professional, is increasingly recognized. Concurrently, policies are being developed to address issues related to HCW rights to privacy, and attenuate risks to patients in healthcare settings. This trend does not, however, extend to a disclosure obligation of serologic status from HCW to patient.
# Disclosure Obligations
Many of the current guidelines and policies that address HCWs and BBV infections do not contain explicit recommendations regarding disclosure obligations of HCWs to patients. None of the reviewed guidelines and policies recommends mandatory routine disclosure of HCW serologic status to patients, regardless of whether or not the HCW performs EPPs (13,54,71,274,377,(381)(382)(383)(384) .
Some publications suggest that mandatory disclosure of a HCW's serologic status to patients be restricted to cases arising when: (1) exposure from a HCW infected with a BBV to a patient has occurred;
(2) the HCW has been non-compliant with an ERP's recommendations or (3) viral load in the infected HCW constitutes a material risk to the patient. If the ERP has deemed the HCW safe to practice, this negates both material risk and a need for disclosure.
# Right to Privacy
The right to privacy of a HCW infected with a BBV is addressed in most relevant Canadian and international guidelines and policies. While the wording to describe this right varies, the guidelines and policies uniformly recognize the importance of maintaining HCW privacy without specifying mechanisms to achieve this.
# Ethical Aspects
There is an inherent ethical dilemma in considering disclosure. The risk of transmission of a BBV from HCW to patient is non-zero (i.e. the risk exists, even if minimal). Therefore patients have an interest in knowing about the risk, while HCWs have an interest in protecting their privacy; given the impact that disclosing to patients might have on their practice and personal lives.
Ethically, the interests of the patient and HCW must also be balanced against other competing rights and interests which, in this case, may include denying patients the services of HCWs without improving the safety of care, creating unfair hardship for HCWs, and creating an economic burden on the health system.
HCWs performing EPPs have ethical and professional obligations to know their serologic status, and to seek guidance and follow expert advice if infected (refer to section 11.0 Infection Prevention and Control Management of Infected Healthcare Workers). These obligations may be traced to principles of non-maleficence (the duty to intentionally refrain from actions that cause harm), respect for autonomy (the responsibility to obtain informed consent from patients for treatment, and provide all information material to their decision making), and the right to privacy (the obligation to minimize the extent to which HCWs may experience stigmatization, discrimination and/or reduced professional prospects as a result of disclosing their serologic status) (209) . It is expected that HCWs follow all the elements of code of practice of which informed consent and fitness to practice are included.
# Legal Context
In accordance with the Canadian legal system, policies regarding the management of HCWs infected with BBVs must comply, as appropriate, with applicable jurisdictional health and privacy legislation, employment law, Human Rights codes and the Canadian Charter of Rights and Freedoms (385) . Provincial Human Rights codes prohibit discrimination on several grounds, including "disability", a term that, under antidiscrimination law in Canada, includes infection with HBV, HIV and/or HCV.
In all provinces and territories in Canada, HIV (or AIDS), HBV and HCV are reportable diseases under public health legislation (386)(387)(388) . It has not been established, however, whether an obligation to disclose serologic status to patients exists under common law. Such an obligation would likely infringe upon the HCWs' rights to privacy and freedom from discrimination under the Charter and Human Rights codes. When such conflicts arise between the Charter, Human Rights Codes and common law, the courts recognize that rights are non-absolute and have limits, and evaluate the case on consideration of matters such as the balance between the provision of safe health care to patients and respect for the rights of HCWs (54) . Fiduciary duties may require HCWs to disclose their serologic status when performing EPPs. However, if the HCW takes reasonable steps to reduce the risk of transmission to acceptable levels, fiduciary duty obligations may be satisfied without having to disclose serologic status (54) .
A HCW infected with HBV, HCV and/or HIV could in theory face legal liability for failure to obtain informed consent if the HCW does not disclose their serologic status. To give informed consent, a patient must be provided with all information material to the proposed treatment plan, including all 'material, and special or unusual risks' (389,390) . The likelihood of risk and the consequences of the risk (impacts of the HIV, HBV or HCV infections) would be factors considered by the Courts to determine whether the HCW serologic status constitutes a material risk to be disclosed to the patient. In the context of EPPs, the risk could therefore be considered material for the purpose of informed consent. In previous cases, courts have affirmed that physicians did not have to routinely disclose their medical information to patients (391) , and that the informed consent requirement is to be judged by the "reasonable patient" standard, i.e., what a reasonable patient in that position would have expected to hear before consenting (390) . It has been suggested that the disclosure obligations may be better managed by regulatory authorities.
It is possible the courts may also take into account the public policy consequences of disclosure, and the special nature of the relationship between HCWs and patients, in determining whether and to what extent an obligation exists (392) .
The following recommendations are based on a review of existing Canadian and international guidelines and policies, taking into consideration the ethical and legal contexts.
12.6 Recommendations for HCW Disclosure Obligations and Right to Privacy Recommendations 1. A HCW infected with a BBV who performs EPPs does not have an obligation to routinely disclose his or her serologic status to patients to obtain their informed consent provided that the HCW's health status and practice have been assessed by an Expert Review Panel and all the panel's recommendations are followed.
- All HCWs, including those infected with a BBV, have a right to privacy and confidentiality of personal health information.
- Regulatory authorities should have policies on the management of HCWs infected with a BBV that are transparent about and detail how the right to privacy of HCWs will be upheld.
- When a patient has been exposed to the blood of a HCW, the HCW must seek follow-up through their organizational process and the patient must be promptly informed of the nature of the exposure and the appropriate post-exposure protocol. However, the identity and confidentiality of the HCW should be protected to the greatest extent possible.
# LOOKBACK INVESTIGATIONS RELATED TO INFECTED HEALTHCARE WORKERS
# Overview of Lookback Investigations
This section addresses the principles and considerations for lookback investigations, which may be performed following the identification of a HCW-to-patient transmission or identification of an infected HCW with no known transmission to patients.
Complete reports on lookback investigations are rarely published in peer-reviewed journals (168) .
There have been five Canadian lookback investigations involving infected HCWs published to date. These involved two HCWs infected with HBV (70,132) , two HCWs infected with HCV (51,77) , and one HCW infected with HIV (155) . Key aspects from these investigations are summarized in Table 18. Although the majority of lookback investigations are initiated as a result of transmission of a BBV infection through exposure-prone procedures (EPPs), one significant Canadian lookback investigation identified transmission during non-EPPs due to IPC breaches (132) . Detailed information on relevant lookback investigations published internationally between 1985 and 2016 can be found in summary tables for each BBV in Appendix 1: Epidemiologic investigations summary tables.
Several countries have national regulations and/or policies that frame and guide decisions and risk assessments surrounding lookback investigations (2,190,370,393,394) .
Healthcare organizations have an obligation to inform patients of an exposure incident where there is a risk of transmission of a BBV (231,233,395) . Neglecting this patient right prevents them from obtaining an early diagnosis and treatment and minimizing risk of secondary transmission (165) . In a survey of patients involved in a large lookback investigation, the majority of patients stated that they wished to know about an exposure despite the anxiety that the knowledge caused them (395) .
A HCW's right to privacy and confidentiality of his or her personal health information must be respected during a lookback investigation (165) . It is feasible to conduct the investigation and publish a report without infringing on the rights of the affected HCW (155,393) . This is important to reassure and encourage potentially infected HCWs to come forward in the future (168) . Abbreviations: LB, lookback investigation; HCW, healthcare worker; EPP, exposure-prone procedure; HBV, hepatitis B virus; NR, not reported; IPC, infection prevention and control; HCV, hepatitis C virus; HIV, human immunodeficiency virus A Articles that provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table. B In addition to patients identified prior to the lookback investigation. C The report states that approximately 40 full-time equivalent positions were required in the first week alone. In addition, external expertise was obtained from the provincial ministry of health, public health, medical regulatory authority, legal counsel, and a communications consultant. D A phased approach by greatest risk of transmission and exposure was used. The parameters for the screening period were determined based on the HCW's abnormal laboratory findings and HCV mutation over time. E As there was no transmission identified in the first phase, the investigators decided not to pursue screening of patients with a lower risk of exposure thus permitting an efficient use of public health resources.
# Key Considerations and Objectives of a Lookback Investigation
Lookback investigations require resources to identify, notify, counsel and test all the potentially exposed patients (165) . These investigations often involve collaboration between a healthcare organization or facility where an infected HCW practiced and public health authorities. Although such collaborations may potentially pose a challenge for conducting the investigation, the process is generally coordinated by an Investigation Management Team with the expertise needed to successfully and efficiently manage the investigation (122,156,171,370) .
Lookback investigations are both time consuming and costly activities requiring significant financial and human resources (115) . Direct and indirect costs are associated with salaries for personnel, honoraria for expert advice, counseling and testing of patients, courier services and support services such as information technology, telephone services, security, and media relations. These resources can come at the expense of other institutional or public health activities (114) . One report stated that the cost of a lookback investigation was equivalent to a third of the state's entire annual budget for HIV and AIDS surveillance (excluding the costs to other organizations involved in the investigation) (49) . Investigations conducted in the early 1990s cost over US $100,000 (49,159) , with the cost for lab testing alone in one investigation estimated at US $76,000 (32) . In the UK, the total cost for lookback investigations, where reported, exceeded well over £200,000 (168,172) . Canadian healthcare organizations or facilities may not have sufficient resources, either human, laboratory or financial, to conduct a lookback investigation without support from public health authorities. Poor quality patient information retention by a health organization or facility (148) , or the lack of computerized information systems to assist with information retrieval, can also hinder an investigation.
Lookback investigations related to an infected HCW may be undertaken to: a. notify patients of their potential exposure b. identify infected patients and provide appropriate advice and treatment recommendations c. prevent secondary transmission d. reassure the public e. maintain the public's trust and confidence in the healthcare system f. contribute to the evidence base on risk of transmission.
# Recommendations for Conducting Lookback Investigations
Recommendations provided in this section are expert opinion informed by published lookback investigations and existing guidelines (2,190,298,393,394,396) as well as current practice.
Prior to initiating a lookback investigation, a risk assessment is conducted by a team with the expertise needed to determine the requirement for an investigation and if applicable, define its scope. Recommendations for conducting the risk assessment are provided below including supporting tools to facilitate decision making.
# Risk assessment to determine requirement for a lookback investigation
- If a HCW who performs EPPs is found to be infected with a BBV, a team should be assembled to perform a risk assessment. Some organizations may have a standing risk assessment panel or process that could be utilized. - The HCW should cease performing EPPs immediately and be referred to an ERP for practice evaluation while the risk assessment is underway.
- Although there is a necessary link between the tasks done by both groups, the team responsible for performing the risk assessment should be different from the Expert Review Panel (ERP).
- Members of the risk assessment team should be familiar with the legal obligations in effect within their jurisdiction that may impact the decision-making process related to lookback investigations.
- The risk assessment team should include individuals with sufficient expertise to assess both the risk of potential exposure and transmission and to identify the process required to address these risks (e.g., infectious disease physician with expertise in relevant BBV, infection control professional, public health physician, peer HCW, medical microbiologist, bioethics expert, facility senior management, and legal counsel).
- Processes should be in place to ensure there is no conflict of interest or bias with regards to conducting the lookback investigation.
- For a consistent and thorough approach to risk assessment, pre-developed tools should be used to perform the assessment. Refer to the following tools below: o A checklist to record relevant information (Table 19).
- An algorithm and legend for guidance on the risk assessment (Figure 5). Data collected in Table 19 will facilitate use of the risk assessment algorithm (Figure 5). The risk assessment team will need to consider the information compiled in Table 19 as well as any additional details unique to each event in order to make a decision regarding whether or not there was a risk of patient exposure and a lookback investigation is required. 12 Has the HCW's practice ever been reviewed by an ERP? Note: If yes, identify the ERP recommendations and whether the HCW was compliant with them.
# Questions to consider related to extenuating circumstances
13 Has the HCW complied with current infection prevention and control standards (i.e., Routine Practices)?
14 Does the HCW use technique(s) (e.g., surgical) that may increase his/her risk of percutaneous injuries during procedures that can put patients at risk of exposure to the HCW's blood?
15 Has the HCW had percutaneous injuries that exposed a patient to the HCW's blood (both reported and unreported)?
16 Has the HCW ever noted blood on his/her hands after removal of surgical gloves following procedures performed on patients?
17 Has the HCW ever had evidence of a skin condition on his/her hands that potentially created an exit portal for BBVs (e.g., dermatitis)?
Abbreviations: HCW, healthcare worker; BBV, bloodborne virus; ERP, Expert Review Panel; EPP, exposure-prone procedure A Adapted from UKAP (2004) enquiry pro forma (63) . Is there HCW-to-patient transmission? (2) Are there extenuating circumstances that may have amplified the risk of transmission? (3) Perform a LB Consider performing a LB (refer to Table 19) (4) Has the HCW ever performed an EPP while potentially infectious? (5) LB is not required based on risk of transmission of BBV (6) Has the HCW's practice been assessed by an ERP?
Were modifications in HCW practice recommended? (9) LB is not required based on risk of transmission of BBV (11) Abbreviations: HCW, healthcare worker; BBV, bloodborne virus; LB, lookback investigation; EPP, exposureprone procedure; ERP, Expert Review Panel; IPC, infection prevention and control
# Yes
Has the HCW demonstrated compliance with ERP recommendations? (10) No Yes Did the HCW's viral load at the time of potential patient exposure exceed recommended levels? (7) Yes Perform a LB Yes Consider performing a LB (refer to Table 19) (4) No Need for LB determined on a case-by-case basis (refer to Table 19) (8) Unknown Legend 1. Identification of a HCW infected with a BBV may trigger a risk assessment to determine if a lookback investigation is required. In addition, the HCW should be referred to an ERP as soon as possible to have their health status and practice reviewed (if not previously done). 2. As determined by a traceback investigation. Refer to Appendix V, Glossary for a definition of traceback investigation.
Extenuating circumstances include IPC breaches by the HCW that put patients at risk of exposure during the provision of care or illicit diversion of patient medication. 4. Refer to Table 19: Checklist for risk assessment and lookback investigations related to a HCW infected with a BBV for questions to consider to assist the decision-making process. 5. Refer to section 5.0 Exposure-prone procedures. 6. A lookback investigation may not be required based solely on risk of transmission of BBV however, a risk assessment team may determine that a lookback investigation is necessary based on other considerations (e.g., contribute to evidence base, alleviate public anxiety). 7. HCW who, at the time of potential patient exposure, had: i) HBV viral load greater or equal to 10 3 IU/ml (5x10 3 GE/ml); ii) detectable HIV viremia; or iii) circulating HCV RNA. 8. The risk assessment team should determine the need for a LB on a case-by-case basis considering all relevant information. 9. Refer to relevant sections: 6.0 Risk of Transmission for HIV, 7.0 Risk of Transmission for HCV, 8.0 Risk of Transmission for HBV and 11.2 Expert Review Panels. 10. Refer to section 11.2 Expert Review Panels. 11. Although the risk of transmission is not zero, it can be rendered negligible if HCWs infected with a BBV who perform EPPs adhere to recommendations which have addressed the identified risk factors from previous exposure incidents.
# Figure 5: Risk assessment to determine requirement for a lookback investigation related to a HCW infected with a BBV
# Lookback investigation: scope, roles and functions
- A LB investigation management team with an identified lead should be assembled to coordinate the investigation. This may be the same group as the risk assessment team.
- The investigation management team should include individuals with expertise in infectious disease, infection prevention and control, public health, medical microbiology, bioethics, laboratory services, the relevant BBV and the types of procedures performed by the infected HCW. In addition, representatives from the facility's senior management, communications department, risk management, and legal counsel should be included. Members of the investigation management team should be familiar with the legal obligations in effect within their jurisdiction that may impact the decision-making process related to lookback investigations.
- Members of the investigation management team should sign a pledge of confidentiality.
- The lookback investigation should be undertaken in a reasonable amount of time.
- The lookback investigation should be a collaborative process between the healthcare organization or facility where the infected HCW practices and public health authorities.
- The healthcare settings and organizations or local public health could be the lead authority depending on: o whether the HCW has practiced in more than one healthcare organization or facility within the jurisdiction of the local public health authority o whether the HCW has practiced outside of a healthcare organization or facility (e.g., private practice) o whether the healthcare organization or facility has sufficient resources to conduct the lookback investigation. - The local public health authority may request assistance from their provincial or territorial counterparts, who may also request federal assistance if the investigation goes beyond their jurisdiction.
# Access to resources
- Lookback investigations can be resource intensive and impact on laboratory resources should be considered. The public health laboratory should be involved with the investigation, whenever possible, to ensure appropriate testing, reporting and accountability.
- Detailed molecular analysis of samples in the investigation should be done to confirm or exclude HCW-to-patient transmission.
- Members of the risk assessment and investigation management teams should have access to appropriate patient information to support the decision-making process as per relevant provincial and territorial legislation.
- Provincial or territorial public health authorities may request the assistance of their federal counterparts.
- Lookback investigations should be conducted in a manner that facilitates efficient and effective use of public health and institutional resources.
# Risk communications
- A well-developed and coordinated communication strategy should be in place prior to patient notification. o Consideration should be given to setting up a call centre with a telephone hotline for public inquiries with personnel trained to provide accurate information while managing the anxiety that may be generated. o A list of potentially exposed patients to be notified should be assembled such that all patients are notified simultaneously and prior to public announcements. o All information necessary to inform the advice and counselling provided to potentially exposed individuals and their families should be compiled prior to patient notification. o All reasonable steps should be taken to identify and contact potentially exposed patients and encourage them to be tested for their own benefit. o Communication via traditional news media (press releases and conferences) as well as use of social media should be well coordinated. o Communication strategies should consider the following stakeholders: facility or organization personnel, the media, healthcare providers in the community, political representatives of the district and the general public. - Reports on lookback investigations should be published to contribute to the evidence base on risk of transmission from HCW to patients, inform future policy development, estimate cost associated with these investigations and improve patient safety.
- A national repository to document all lookback investigations, including those where no transmission was found, should be created.
# HCW confidentiality and right to privacy A
- Every effort should be made to avoid revealing the identity or information that would allow deductive disclosure of the HCW infected with a BBV. However, there may be instances where patient safety precludes this.
- Members of the investigation management team have an obligation to keep the information they receive confidential and respect the HCW's right to privacy.
- The right to privacy still applies if the infected HCW has died, or has already been identified publicly.
- The number of individuals who know the identity of the infected HCW should be kept to a minimum at all stages. It may not be necessary for all members of the team(s) to be aware of the identity of the infected HCW. A Adapted from the UK's HIV Infected Health Care Workers: Guidance on Management and Patient Notification, 2005 (393) APPENDIX I: EPIDEMIOLOGIC INVESTIGATIONS SUMMARY TABLES F Article met the eligibility criteria for data extraction to inform the systematic review on the risk for transmission of HIV from infected HCWs to patients. G Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table.
H Total number of patients tested consisted of: 519 patients initially tested (which identified the second and third cases); plus three patients later tested (who were identified by cross-matching the patient list with the state's AIDS surveillance records, self-identification, and routine testing for application to the military); plus an additional 141 patients tested with no evidence of transmission amongst them (126,128) . I Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HIV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HIV infection. If so, a response of "Compatible with HIV" was recorded. J Indicates whether the HCW was aware of their HIV-positive serologic status at any time during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of "NR" was recorded. K Indicates whether IPC breaches were identified. A response of "Yes" indicates any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Task Group determined that by current standards, an IPC breach was present. A response of "No" indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. L The HCW was unaware of their serologic status at the time of the index patient's exposure incident but was aware after being hospitalized and diagnosed in 1996 (32,153) . (161) Companion H : (398) US (403) Companions H : (404)(405)(406) UK C Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HIV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HIV infection. If so, a response of "Compatible with HIV" was recorded. D Indicates whether the HCW was aware of their HIV-positive serologic status at any time during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of "NR" was recorded. E Indicates whether IPC breaches were identified. A response of "Yes" may also indicate any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Task Group determined that by current standards, an IPC breach was present. A response of "No" indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. F Article met the eligibility criteria for data extraction to inform the systematic review on the risk for transmission of HIV from infected HCWs to patients. G The severe dermatitis on the HCW's hands contributed to the decision to investigate potential transmission of HIV to his patients. H Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table.
I HCW with HIV-HBV co-infection. J Article reported on this HCW risk factor but did not report on the screening period. As a result, it is unclear if the HCW risk factor existed during the time span selected for screening potentially exposed patients. K Investigations providing information on HCW risk factors and/or data on number of exposed and tested patients are included in this table. In the UK, HCWs infected with HIV were restricted from performing any exposure-prone procedures until 2014 (190,393) . Public Health England reports that there were 39 investigations related to HCWs infected with HIV between 1998 and 2008 in the UK with no evidence of transmission (190) . Higher-risk exposure-prone procedures, where theatre scrub nurses infected with HIV had acted as first assistants, were a part of these investigations but were excluded from this table as no relevant information was reported (63,173,234) . L HCW with HIV-HBV co-infection identified as a result of screening. G Article met the eligibility criteria for data extraction to inform the systematic review of HCV exposure incidents with HCW to patient transmission. H Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HCV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HCV infection. If so, a response of "Compatible with HCV" was recorded. I Indicates whether the HCW was aware of their HCV-positive serologic status at any time during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of "NR" was recorded. J Indicates whether IPC breaches were identified. A response of "Yes" may also indicate any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Team and/or the Task Group determined that by current standards, an IPC breach was present. A response of "No" indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. K Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table. L Ross et al. (2000a) reported that the HCW did not wear gloves and had a weeping wound on a finger of his right hand which bled repeatedly and was not covered during the provision of care to patients (136) . M Two separate lookback investigations for the same infected HCW have been combined. The first investigation involved testing of potentially exposed patients in the 6 months before the HCW's acute illness. The HCW was not aware of their serologic status and was symptomatic during the screening period (1995). The second investigation involved testing of potentially exposed patients in the 18 months following unsuccessful treatment for hepatitis C infection (1996 to 1997). N Investigations providing information on HCW risk factors and/or data on number of exposed and/or tested patients are included in this table. In the United Kingdom, HCV RNA positive HCWs are restricted from performing EPPs unless they have been successfully treated (411) . Since 2005, if no evidence of transmission of HCV or other risk factor increasing risk of transmission from an HCV-infected HCW is present, the UKAP does not recommend that patients be notified or tested (173) . O The infected HCW's specialty is not described however it is reported that his atopic eczema prevented him from wearing gloves systematically. Based on this information, it was determined that cardiothoracic surgery was not the procedure where transmission occurred. Note that several HCWs were tested including a surgeon, 4 nurses, 2 cardiopulmonary bypass technicians, 2 surgical assistants and 4 anesthesiologists. P HCW was diagnosed as HCV positive in 2006 but had a subsequent negative PCR result. In 2010, the HCW's viral load was 2.4 x 10 6 IU/mL. Q Four of the 48 potentially exposed patients were known to be infected with HCV. (32) has also been excluded from this table as no viral sequencing and analysis of risk factors was undertaken for the 43 HCV-positive patients that were identified. B Screening period: Time span selected by the investigators to screen patients. C HCW risk factors reported to be present at any point during the screening period. D Article met the eligibility criteria for data extraction to inform the systematic review on the risk for transmission of HCV from infected HCWs to patients. E Although diagnosed in 2003, a stored sample of blood from April 1991, when the HCW was first denied for blood donation, was seropositive for HCV. F Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HCV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HCV infection. If so, a response of 'Compatible with HCV' was recorded. G Indicates whether the HCW was aware of their HCV-positive serologic status at any point during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of 'NR' was recorded.
H Indicates whether IPC breaches were identified. A response of 'Yes' may also indicate any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Team and/or the Task Group determined that by current standards, an IPC breach was present. A response of 'No' indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. I IPC breaches were reported during the research project which led to transmission however there was no report of IPC breach related to the HCW's practice during patient care. J Investigations providing information on HCW risk factors and/or data on number of exposed and/or tested patients are included in this table. In the United Kingdom, HCV RNA positive HCWs are restricted from performing exposure-prone procedures unless they have been successfully treated (411) . Since 2005, if no evidence of transmission of HCV or other risk factor increasing risk of transmission from a HCW infected with HCW is present, the UKAP does not recommend that patients be notified or tested (173) .
K Staged lookback investigations related to the practices of 5 infected HCWs were recommended by the UKAP. These involved the last 500 patients who had undergone higher risk exposure-prone procedures. One of the investigations identified infected patients after the 2004 report was published. The numbers of patients potentially exposed and tested, prior to the identification of an infected patient, are included in this table. This investigation has also been included in Table 22, Epidemiologic investigations reporting transmission of HCV from infected HCW to patient with the numbers of potentially exposed and tested patients indicated as 'NR'.
L Companion articles provide supplementary information about the specific epidemiologic investigation. Where such articles exist, the additional information is included in the table. M Information obtained from Charles et al. (2007) (412) . In October 2005, the HCW was being investigated for 'unspecified ill health' and stopped work immediately. A Only articles published in 1992 or later are included as well as articles identified as part of the systematic review of the literature for risk of transmission of HBV from infected HCWs to patients. B Screening period: Time span selected by the investigators to screen patients. C Number excludes index case(s). D Includes index case(s); confirmation test for transmission include phylogenetic analysis, genotyping, or other epidemiologic evidence of transmission during surgery. E Transmission rate as reported in the study (R) or calculated by reviewer (C); formula for calculated transmission rate= *100 F HCW risk factors reported to be present at any point during the screening period. G Article met the eligibility criteria for data extraction to inform the systematic review of HBV exposure incidents with HCW to patient transmission. H Confirmed cases are: 1) Patients with a temporally-related active HBV infection that is genetically linked to the HBV-infected HCW; or 2) Patients with a serologic evidence of a previous infection consistent with timing of exposure or evidence of pre-exposure seronegative status; or 3) Reported as confirmed transmission cases by the authors.
I Undetermined cases: 1) Reported as undetermined by the authors; 2) serologic evidence of a previous infection with no evidence of pre-exposure seronegative status or no lifetime risk factors; or 3) no lookback investigation for sub-clinical infection was performed. J Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HBV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HBV infection. If so, a response of "Compatible with HBV" was recorded. K Indicates whether the HCW was aware of their HBV-positive serologic status at any time during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of "Not reported" (NR) was recorded. L Indicates whether IPC breaches were identified. A response of 'Yes' may also indicate any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Team and/or the Task Group determined that by current standards, an IPC breach was present. A response of 'No' indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. M Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table. N Includes the cases related to both clusters but excludes one case of secondary transmission identified in the first cluster. O Number applies to investigation of second cluster only. P The HCW was linked to both the first and second cluster when it was determined (during the second investigation) that the HCW had provided a blood sample taken from another person during the investigation for the first cluster. The HCW served a custodial sentence and was removed from the Medical Register. Q Positive for hepatitis Be antibodies. R Negative for hepatitis Be antibodies. S Ninety-nine potentially exposed patients received PEP. T Eleven potentially exposed patients received PEP. U Eighteen potentially exposed patients received PEP. V Hepatitis B e-antibody status was not reported. ICU, intensive care unit A Only articles published in 1992 or later are included as well as articles identified as part of the systematic review of the literature for risk of transmission of HBV from infected HCWs to patients. B Time span selected by the investigators to screen patients.
C HCW risk factors reported to be present at any point during the screening period. D Article met the eligibility criteria for data extraction to inform the systematic review on the risk for transmission of HBV from infected HCWs to patients. E Prospective study of patients of 9 HBV-infected HCWs, 6 with chronic infection (2 surgeons, 1 dialysis nurse, 1 pediatric ICU nurse, 1 pharmacist and 1 orderly) and 3 with acute infection (1 dental technician, 1 ICU nurse and 1 medical student) over a 30-month period. Only the information related to the two surgeons is contained in this table. The results of the study were pooled for all patients (n=246) and for all exposures (n=483) with no evidence of transmission identified. F Indicates whether the HCW was symptomatic at any point during the screening period. G Indicates whether the HCW was aware of their HBV-positive serologic status at any point during the screening period.
H Indicates whether IPC breaches were identified. I Potentially exposed patients were offered post-exposure prophylaxis if the time since potential exposure was within the incubation period for HBV infection. This is detected during the first 3 to 5 weeks after infection, but may take up to 9 weeks to be detectable (270) . The presence of HBsAg indicates that the person is infected but does not indicate level of infectivity. Persistence of HBsAg for 6 months or more indicates chronic infection (415) . Spontaneous resolution of the infection with clearance of HBsAg occurs in 0.1 to 0.8% of chronic carriers annually (416)(417)(418)(419)(420)(421) . Those with resolving acute HBV will clear HBsAg several months after initial infection (212) .
# Anti-HBs
The presence of anti-HBs is generally interpreted as indicating recovery and immunity from hepatitis B virus infection. Anti-HBs also develops in a person who has been successfully vaccinated against hepatitis B (270) . (270,415,(421)(422)(423)(424)(425) . B About 5%-10% of people will not respond to the vaccine or do not produce protective levels of antibody postvaccination (62) . C This marker is most often negative but may be positive in some individuals. D To ensure that this is not a false positive test, samples with repeatedly reactive HBsAg results should be tested with a licensed neutralizing confirmatory test (270) . A small percentage of people with chronic infection will have both HBsAg and anti-HBs markers present (62) . E This marker is most often positive but may be negative in some individuals. F Levels of anti-HBs may decline over time and become undetectable (212) . G Isolated anti HBc total is commonly the only serum marker detected indicating resolved infection. The reason for this test result is that anti-HBs titres fall with time and can become negative. Some earlier studies erroneously interpreted isolated anti HBc total as 1) a false positive result (based on an incorrect belief that hepatitis B was not that common); 2) "low level" chronic infection (if so, this would be HBsAg positive); 3) resolving acute infection (if so, this would be anti-HBc IgM positive or HBsAg positive or anti-HBs positive).
# IDENTIFICATION OF ARTICLES
Total articles from literature search of library databases n=4257
Articles excluded if not relevant to HIV transmission n=3272
Articles identified through: One of the 18 articles reports on two HCWs infected with HIV, for a total of 19 investigations. Sixteen out of 18 articles were eligible for the meta-analysis. One of the 16 articles reported two exposure incidents, therefore a total of 17 exposure incidents were included in the meta-analysis. Chamberland, 1992 (426) ; AIDS Committee SHEA, 1992 (427) ; Debry, 1993 (428) ; Robert, 1995 (154) ; Anonymous, 1995 (429) ; Schaffner, 1995 (93) ; Hansen, 1996 (53) ; PHLS, 1997 (430) ; PHLS, 1997 (401) ; Bartlett, 2000 (431) ; Puro, 2001 (238) ; McCarthy, 2002 (432) ; Tansley, 2004 (433) ; Department of Health and Children,2005 (370) ; Société française d'hygiène hospitalière, 2006 (434) ; Rogowska-Szadkowska, 2006 (435) ; Flint, 2011 (436) ; PHE, 2012 (107) ; PHE, 2014 (190)
# Language
Not English or French Hasselhorn, 2000 (28) ; Puro, 2003 (29) ; Stulhofer, 2006 (437) ; Ross, 2007 (438)
# Population
Did not report on HCWs infected with HIV who either: 1) performed EPPs; or 2) provided direct patient care not involving EPPs where transmission was reported Delwart, 1995 (439) ; Smith, 2002 (440) ; Bredell, 2003 (441) ; Roy, 2005 (442) ; Negut, 2007 (443) ; Jones, 2009 (444)
# Intervention
Did not report on any preventive or management intervention or measure for HCWs that may affect risk of transmission Irwin, 2002 (168) Not an analytic study (including trials and observational studies) or a descriptive study PHLS, 1997 (445) ; Aboulafia, 1998 (446) ; Bartlett, 2000 (431) ; PHE, 2005 (80) ; Criscione, 2012 (447) ; Herbeck, 2014 (448) ; Institut National de Santé Publique du Québec, 2015 (449)
# Outcome
# Did not report on indicators of transmission
# Language
Not English or French Anonymous, 1997 (450) ; Trenning-Himmelsbach, 1997 (451) ; Blazquez, 2001 (452) ; Resino, 2007 (453) ; Lucena, 2011 (454)
# Population
Belec, 1998 (455) ; Donnelly, 1999 (172) ; Kallenborn, 2001 (456) ; Blick,
Did not report on blood-to-blood 2007 (457) ; CDC, 2009 (178) ; Ding, 2009 (458) ; Hecht, 2010 (459) ; Miller, exposure and/or reported on sexual, 2013 (460) perinatal, transfusion or transplantationrelated exposures
Viral load data Robert, 1995 (154) ; Romea, 1995 (461) ; CDC, 1995 (462) ; Lot, 1995 (463) ;
Did not report the time between a
Bell, 1996 (464) ; Tereskerz, 1996 (465) ; Vidmar, 1996 (466) ; Cardo, person's exposure and viral load testing 1997 (467) ; CDC, 1997 (468) ; Dorozynski, 1997 (469) ; Lancaster, of the source individual
# Articles excluded for drug diversion n=6
Articles identified as companions to eligible articles n=6
A Companion articles provide supplementary information about specific epidemiologic investigations. B Nine out of 20 articles were eligible for the meta-analysis. Schaffner, 1995 (93) ; Roudot-Thoraval, 2000 (491) ; Bartlett 2000 (431) ; Ross, 2000 (65) ; Heptonstall, 2000 (492) ; Carbonne, 2006 (394) ; Roche, 2008 (493) ; Carlson, 2010 (33) ; Ramer, 2013 (494) ; Chen, 2016 (495) ; De Peyer, 2016 (232)
# Language
Not English or French Hasselhorn, 2000 (28) ; Puro, 2003 (29) ; Gerlich, 2004 (496)
# Population
Did not report on HCWs infected with HIV who either: 1) performed EPPs; or 2) provided direct patient care not involving EPPs where transmission was reported Hohne, 1994 (497) ; Dumpis, 2003 (498) ; PHLS, 2005 (230) ; Bonnal, 2010 (499)
# Intervention
Did not report on any preventive or management intervention or measure for HCWs that may affect risk of transmission PHLS, 2001 (229) ; Januszkiewicz-Lewandowska, 2003 (500) ; Ross, 2003 (235) ; Wrobel, 2006 (501)
# Outcome
Did not report on indicators of transmission Smith, 2002 (440) ; PHE, 2013 (502)
# Drug diversion
Reported drug diversion by the HCW Sehulster, 1997 (503) ; Akehurst, 1998 (504) ; Petruccelli 2005 (505) ; Shemer-Avni, 2007 (223) ; Hellinger, 2012 (506) ; Gonzalez-Candelas, 2013 (507)
# Duplicates removed n=379
Excluded for description of the same event, language, relevance and/ or article type n=1018
Excluded for study design, language, population and/ or viral load data n=137 Seeff, 1991 (508) ; Anonymous, 1996 (509) ; Canadian Medical Association, 2010 (381) ; CADTH, 2012 (510) ; American Society of Anesthesiologist, 2014 (511) ; GOV.UK, 2014 (512)
# Language
Berger, 1998 (513) ; Laufs, 1998 (514) ; Olaso, 1999 (515) ; Cordoba, 2000 (516) ;
Not English or French Del Poggio, 2000 (517) ; Hasselhorn, 2000 (28) ; Blázquez, 2001 (452) ; De Figueiredo, 2003 (518) ; Velasco, 2003 (519) ; Beran, 2004 (520) ; Castro Ferreiro, 2004 (521) ; Gerlich, 2004 (496) ; Husa, 2004 (522) ; Bilski, 2005 (523) ; Guglielmi, 2005 (524) ; Bilski, 2006 (525) ; Campins Martí, 2006 (526) ; Warley, 2006 (527) ; Anonymous, 2007 (528) ; Kubitschke, 2007 (40) Population Caporaso, 1998 (529) ; Anonymous, 2000 (530) ; File, 2003 (531) ; Keiserman,
Did not report on blood-to-blood 2003 (486) ; Nikolopoulou, 2005 (532) ; Patel, 2006 (533) ; CDC, 2009 (534) ; exposure and/or reported on sexual, Dawar, 2010 (77) perinatal, transfusion or transplantation-related exposures Articles identified as companions to eligible articles n=3
# Viral load data
Total articles from literature search of library databases n=4257
Articles excluded if not relevant to HBV n=3087
Excluded for description of the same event, language, relevance and/or article type n=1022
A Fifteen out of 23 articles were eligible for meta-analysis. Two articles included 3 incidents each and 1 article included 2 incidents, for a total of 20 incidents. Three articles were excluded for IPC breaches.
B Companion articles provide supplementary information about specific epidemiologic investigations. Bartlett, 2000 (431) ; Carbonne, 2006 (394) ; Danzmann, 2013 (611)
# Language
Not English or French Zaaijer, 1999 (612) ; Puro, 2003 (29) ; Bilski, 2005 (523)
# Population
Did not report on HCWs infected with HIV who either: 1) performed EPPs; or 2) provided direct patient care not involving EPPs where transmission was reported Zuckerman, 1995 (413) ; Curran, 2000 (613) ; Corden, 2003 (294) ; Buster, 2004 (614)
# Intervention
Did not report on any preventive or management intervention or measure for HCWs that may affect risk of transmission Ngui, 2000 (293) ; Carlson, 2010 (33) Sikora, 2010 (615)
# Outcome
# Did not report on indicators of transmission
# Language
Not English or French
# Nil
# Population
Did not report on blood-to-blood exposure and/or reported on sexual, perinatal, transfusion or transplantation-related exposures Zeuzem, 1997 (616) ; Datta, 2006 (617) ; Criscione, 2012 (618) ; Buchner, 2015 (619)
# Viral load data
Did not report the time between a person's exposure and viral load testing of the source individual Tedder, 1995 (620) ; Zucherman, 1995 (413) ; The incident control teams and others, 1996 (41) ; Mukerjee, 1996 (122) ; Sundkvist, 1998 (115) ; Oliver, 1999 (123) ; Nguyen, 2001 (43) ; Spijkerman, 2002 (121) ; Nguyen, 2003 (558) ; Kidd-Ljunggren, 2006 (621) ; Smellie, 2006 (133) ; Harling, 2007 (622) ; Laurenson, 2007 (124) ; Poujol, 2008 (139) ; Demirturk, 2014 (623) ; Du Plessis, 2014 (624) ; Dwibedi, 2014 (625) Abbreviation: HBV, hepatitis B virus
# Grade of Evidence
# Strength of Evidence
# Grades Criteria
Strong AI Direct evidence from meta-analysis or multiple strong design studies of high quality, with consistency of results
# AII
Direct evidence from multiple strong design studies of medium quality with consistency of results OR At least one strong design study with support from multiple moderate design studies of high quality, with consistency of results OR At least one strong design study of medium quality with support from extrapolation from multiple strong-design studies of high quality, with consistency of results
# Moderate BI
Direct evidence from multiple moderate design studies of high quality with consistency of results OR Extrapolation from multiple strong design studies of high quality, with consistency of results
# BII
Direct evidence from any combination of strong or moderate design studies of high/medium quality, with a clear trend but some inconsistency of results OR Extrapolation from multiple strong design studies of medium quality or moderate design studies of high/medium quality, with consistency of results OR One strong design study with support from multiple weak design studies of high/medium quality with consistency of results
# Weak CI
Direct evidence from multiple weak design studies of high/medium quality, with consistency of results OR Extrapolation from any combination of strong/moderate design studies of high/medium quality, with inconsistency of results (8) . (626) ; data for each profession and P/T was either obtained from CIHI documents or other reliable source (refer to hyperlinks in each cell). Yes -Profession is regulated in Province/Territory; No -Profession is not regulated in Province/Territory.
# CII
# Anti-HBc total
The presence of anti-HBc (IgG or IgM and IgG) indicates previous or ongoing infection with HBV (270) .
# Anti-HBc IgM
Anti-HBc IgM appears early in acute HBV infection and persists for about 6 months (270) . It may also be seen in chronic infection during flares of activity, so clinical / epidemiological correlation is required for interpretation (62,270) .
# Anti-HBc IgG
Anti-HBc IgG appears shortly after infection and usually persists for life in the majority of persons, sometimes showing up as the antibodies to all other proteins fade (62) .
# HBeAg
This is a secreted product of the nucleocapsid gene of HBV that is found in the serum during acute and chronic HBV infection (270) . It is a marker of active viral replication and its presence indicates high infectivity (62,237,270) . Some individuals infected with HBV, carry a viral strain with a nucleotide substitution in the precore region of the viral genome. This mutation prevents transcription of the precore region and therefore, the release of HBeAg from the hepatocyte which results in a negative serum test for HBeAg. This mutation is important because infections caused by these viruses are difficult to treat, can cause prolonged infections, and are associated with a higher risk of liver cirrhosis.
# Anti-HBe
Appears with recovery from acute infection, but may disappear over time. In chronic infection, the presence of anti-HBe is generally a marker of reduced viral replication, indicating a less infectious state (62) . For individuals carrying the viral strain with a mutation preventing transcription of the precore region and therefore, the release of HBeAg from the hepatocyte, this allows anti-HBe to be detected but HBV DNA is still high.
# HBV DNA
Used to measure level of infectivity and response to treatment (270) . Unable to find PHLS, 1997 (489) ; Donnelly, 1998 (490) Abbreviations
# Society for Healthcare Epidemiology of America Société française d'hygiène hospitalière HIV Medicine Association
A Stakeholder organizations and international subject matter experts were identified with the assistance of the Guideline Development Task Group and key international guidelines or reports. B Feedback provided as a subject matter expert and does not necessarily represent the official position of the U.S. Federal Government or the Society for Healthcare Epidemiology of America. C Feedback provided as a subject matter expert does not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention. Exposure-prone procedure (EPP): An invasive procedure where there is a higher-than-average risk that injury to the HCW may result in the exposure of the patient's open tissues to the blood of the HCW.
Healthcare facility: Includes but is not limited to acute-care hospitals, emergency departments, rehabilitation hospitals, mental health hospitals, and long-term care facilities (19) .
# Healthcare organization:
The organizational entity that is responsible for establishing and maintaining healthcare services provided by HCWs and other staff in one or more healthcare settings throughout the healthcare continuum (19) .
Healthcare setting: Any location where health care is provided, including emergency care, prehospital care, hospital, long-term care, home care, ambulatory care and facilities and locations in the community where care is provided (e.g., infirmaries in schools, residential or correctional facilities) (19) .
Healthcare worker (HCW): Individuals who provide health care or support services, such as nurses, physicians, dentists, dental hygienists, physician assistants, nurse practitioners, paramedics and sometimes emergency first responders, allied health professionals, unregulated healthcare providers, clinical instructors and students, volunteers and housekeeping staff. Healthcare workers have varying degrees of responsibility related to the health care and support services they provide, depending on their level of education and their specific job and/or responsibilities (19) .
Lead authority: Within the context of this guideline, it is the healthcare organization, facility, public health unit or agency that coordinates a lookback investigation related to a HCW infected with a BBV.
# Lookback investigation (LB):
If a HCW has been identified as infected with HBV, HCV or HIV and has performed exposure-prone procedures that could have put patients at risk of exposure to an infection, then the organization employing the HCW or the local public health unit contacts patients at risk to give advice about testing and potential treatment and to discuss methods of preventing further transmission with those found to be infected (2) .
Outcome: A term used to refer to results of interest in a study such as infections, diseases, behaviours, effects or conditions (8) .
# Peer healthcare worker (HCW):
A HCW from the same area of practice as the infected HCW who assists: 1) the expert review panel to determine the need for practice restrictions or modifications; 2) the risk assessment team to determine if a lookback investigation is required; and 3) the investigation management team to assist with the coordination of the investigation.
The peer HCW provides information on the procedures performed by the infected HCW and whether there is a risk of patients being potentially exposed to the HCW's blood.
Regulated HCW: Within the context of this guideline, refers to any HCW whose work or practice is regulated by a provincial or territorial regulatory authority (legislation may vary by province and territory).
Regulatory authorities: Within the context of this guideline, refers to any agency established by provincial or territorial legislation to regulate the practice of health professionals (e.g., medicine, dentistry, nursing, etc.) (Adapted from the Federation of Medical Regulatory Authorities of Canada definition for Medical Regulatory Authority) (627) .
Routine Practices (synonymous with Standard Precautions (26) ): A comprehensive set of infection prevention and control measures that has been developed for use in the routine care of all patients at all times in all healthcare settings. Routine Practices aim to minimize or prevent healthcare-associated infections in all individuals in the healthcare setting, including patients, HCWs, other staff, visitors and contractors (19) .
Traceback investigation: If a patient has been identified as infected with a HBV, HCV or HIV and has no identifiable risk of infection from that virus, as assessed by the physician or local public health unit, but has undergone an exposure-prone procedure within the appropriate incubation period, then the local public health unit seeks to identify the HCW who has performed exposure-prone procedures and other infected or potentially infected patients in order to provide treatment and counselling on preventing further transmission (2) . Universal precautions: A set of infection prevention and control measures that was developed with the primary purpose of protecting the HCW from exposure to bloodborne viruses, and was based on the principle that it was not possible to know which patients harboured bloodborne viruses (19) . Universal precautions were used in conjunction with category -or disease-specific isolation systems for patients with specific symptoms or infections (628,629) .
Unregulated HCW: Within the context of this guideline, refers to any HCW whose work is not regulated by a provincial or territorial regulatory authority (legislation may vary by province and territory).
# Viral load:
Refers to the number of circulating viruses in a unit of blood.
|
Recommendations were developed by the Task Group and were based on available evidence as well as collective expert opinion (where there was limited or no published evidence).• This guideline provides criteria to help determine whether or not a procedure performed by a HCW is an exposure-prone procedure. It does not provide risk categories for these procedures. Refer to the section on Exposure-prone procedures for detailed information. • This guideline provides a viral load cut-off level to inform an infected HCW's fitness for practice, thus increasing patient safety and optimizing the work force.# LIST OF FIGURES
# LIST OF TABLES
# IV EXECUTIVE SUMMARY
# Background
Healthcare workers (HCWs) have an ethical and professional duty to care for their patients in accordance with established standards of practice and care, acting in good faith, and not allowing their personal interests to conflict with their professional obligations. This responsibility includes minimizing the risk of patient exposure to bloodborne viruses (BBVs) while receiving care.
The purpose of this guideline is to provide a national framework for developing policies and procedures to prevent the transmission of bloodborne viruses (BBVs), specifically human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) from infected HCWs to patients in the healthcare setting. Failure to adhere to infection prevention and control principles identified as Routine Practices could result in transmission of BBVs. This guideline assumes that HCWs will adhere to Routine Practices when providing care to all patients at all times and in all settings. Recommendations on these practices are provided in PHAC's guideline titled Routine Practices and Additional Precautions for Preventing the Transmission of Infection in Healthcare Settings. As long as infected HCWs adhere to these practices, the risk of transmission of BBVs from infected HCWs to patients is negligible, except during exposure-prone procedures (EPPs), which may pose an increased but minimal risk. Exposure-prone procedures are invasive procedures where there is a risk that injury to the infected HCW may result in the exposure of the patient's open tissues to the blood of the HCW and depending on the nature of that exposure and host factors (e.g. immunity) transmission of the BBV may occur.
# This document, Guideline on the Prevention of Transmission of Bloodborne Viruses from
# Scope
This guideline is a key part of PHAC's work to provide evidence-based recommendations within the context of the Canadian healthcare system; thus providing national leadership as well as the underpinnings for organizational policy and a consistent pan-Canadian approach to the management of HCWs infected with a BBV.
Recommendations provided in this guideline are intended to assist those involved with the assessment and management of HCWs infected with a BBV, either individually (e.g., treating physician, members of an Expert Review Panel) or generally (e.g., regulatory authorities). This guideline applies to all HCWs with specific recommendations for HCWs infected with a BBV. Implementation of these recommendations will increase patient safety while allowing HCWs infected with a BBV to continue to work safely.
# Risk factors
Although it is well documented that the risk of a BBV transmission from patient to HCW is significantly higher than the risk of transmission from HCW to patient, the focus of this guideline is to further reduce the minimal risk to patients and to provide guidance for the consistent management of HCWs infected with BBVs. Efforts to prevent HCW-to-patient transmission of BBVs involve understanding the factors that affect the HCWs' risk of occupational acquisition of a BBV and the subsequent risk of transmission of the BBV during an EPP.
With the availability of the hepatitis B vaccine, immune HCWs are protected from occupational acquisition of HBV. Therefore, ensuring HBV immunity among HCWs as early as possible and on admission into health professional training programs is paramount. Nevertheless, multiple percutaneous injuries throughout a HCW's career may place them at risk for occupational acquisition of HIV or HCV infection. Adequate training and education on the prevention and management of occupational injuries and potential exposures are fundamental to all HCWs as part of an occupational health program. In addition, ongoing awareness of their own serologic status is essential for HCWs who perform EPPs.
In defining the risk of transmission of a BBV from an infected HCW to a patient, it is necessary to consider both the actual risk informed by available evidence and the risk perceived by the public as these both inform what is considered acceptable risk. Patient safety studies show that the most frequent types of adverse events affecting hospitalized patients are adverse drug events, wound infections, and surgical complications. Some risks, such as those known to be associated with surgical procedures, are generally accepted by patients. Although a precise assessment of the real risk of HCW-to-patient transmission of BBVs has not been determined, factors described in reports involving potential patient exposure (with or without ensuing transmission) provided some evidence for the development of this guideline.
While zero risk of transmission is unattainable, the availability of a vaccine that prevents HBV infection, effective treatment for HCV resulting in a sustained virologic response, and suppression of HIV with strict adherence to antiviral therapy, could render this risk negligible.
# Methodology
A project protocol was developed to outline the steps and methods for conducting the systematic reviews and environmental scans to inform recommendations provided in this guideline. The project protocol was circulated for comments and refinement by the Guideline Development Task Group (Task Group) and PHAC, and retained for internal reference. Systematic reviews were then conducted for Key Questions to inform the risk of transmission of HIV, HCV, and HBV from infected HCWs to patients. Additional systematic reviews were conducted to address Key Questions examining infectivity of each virus related to the source serum viral load at time of exposure. The literature informing the systematic reviews consisted primarily of lookback investigations and other descriptive studies. A published systematic review of randomized controlled trials (RCTs) was available and therefore used, along with other studies, to inform the effectiveness of double gloving in preventing HCW-to-patient transmission of a BBV. Evidence from all eligible studies was reviewed and qualitatively synthesized. Where applicable, the body of evidence was graded using PHAC's Infection Prevention and Control Guidelines: Critical Appraisal Tool Kit.
Environmental scans of relevant literature were conducted for Key Questions where the topic dealt with organizational, regulatory, and/or ethical issues not solely or directly informed by scientific research. No grade of evidence was assigned to recommendations from the environmental scans.
Summaries of published epidemiologic investigations involving HCWs infected with a BBV globally, from the late 1980s to 2018, were tabulated and are provided in the guideline appendices.
# Key stakeholder input and expert review
The process of developing this guideline involved consultation with relevant federal, provincial and territorial (FPT) partners and key stakeholder organizations which included clinicians with relevant expertise. A preliminary consultation with a targeted group of key stakeholders involved a needs assessment conducted prior to the development of the guideline to inform its scope and key issues. Existing guidelines developed for use in other countries and relevant provincial and territorial policies in Canada were reviewed for scope and content prior to the development of this guideline. Upon completion of a preliminary draft guideline, an extensive consultation with FPT partners and key stakeholders was done to obtain feedback. All feedback received from the consultation processes were reviewed and addressed as deemed appropriate by the Task Group prior to finalizing the guideline.
# Limitations
For ethical and methodological reasons, RCTs are not feasible to assess potentially harmful situations such as the transmission of BBVs. Many studies informing this guideline were weak in study design, with their overall quality ranging from mostly low and medium to a few high quality studies. In some instances, comparator interventions used in the selection criteria for the systematic reviews did not allow for substantially minimizing confounding factors. Where graded, the grade of evidence ranged from CI to BII. For items where there was a paucity of published studies, inconclusive study results, or information was obtained solely from environmental scans, expert opinion of the Task Group members informed recommendations for practice.
# New approach and additional content: how this guideline differs from Health Canada's 1998 consensus document
In the past 20 years there has been remarkable progress in the prevention, diagnosis tools, treatment regimens, and management of infections due to BBVs as well as major improvements in guideline development methodology. These advancements were considered in developing this guideline. As a result, there are key differences in the approach used for the development of this guideline and Health Canada's 1998 consensus document. Some key items include:
• The Task Group was selected by PHAC based on identified expertise needed for the guideline topic -infectious diseases, medical microbiology and virology, infection prevention and control, public health, occupational health, hepatology, dentistry, medical ethics, and obstetrics and gynecology. The Task Group reported to PHAC's National Advisory Body on Infection Prevention and Control.
• An evidence-based approach involving rigorous review and synthesis of the evidence with expert interpretation of the evidence was used in the development of this guideline.
• The evidence base reviewed for the development of this guideline included publications of epidemiologic investigations of potential and confirmed exposure incidents; similar guidance developed by other organizations and governments; relevant policy documents, and reports from government institutions or professional organizations outside of the indexed medical literature.
• Six systematic reviews, a narrative review, and three environmental scans of the most current and relevant literature were conducted to inform the guideline content.
• Where possible, evidence from eligible studies in the systematic reviews was graded.
• Key stakeholder consultation was conducted prior to writing the guideline and an extensive consultation followed the development of the first draft of the guideline.
• The guideline is a comprehensive document providing extensive background information on each section and summary tables where applicable.
• This guideline provides detailed information for establishing Expert Review Panels to assess the risk of transmission of a BBV from an infected HCW to patients. If a HCW infected with a BBV has been reviewed by an Expert Review Panel and deemed safe to practice, this negates the need for disclosure of the HCW's serologic status to patients. Refer to the section on Expert Review Panels for detailed recommendations.
• This guideline provides detailed information for conducting lookback investigations if deemed necessary following the identification of an infected HCW or a HCW-to-patient transmission of a BBV. Refer to the section on Lookback investigations related to infected healthcare workers for detailed recommendations.
• Recommendations provided in this guideline were thought to be sufficient to prevent transmission from HCWs co-infected with two or all three of these BBVs. If a HCW who performs EPPs is co-infected, the HCW should meet the defined criteria recommended for safe practice by HCWs infected with each virus.
• This guideline made every reasonable effort to further reduce the minimal risk of HCWto-patient transmission of BBVs, with recommendations striking a balance between the reasonable expectations of the public (protection from harm) and the reasonable expectations of individual HCWs (right to privacy). The major recommendations supported by relevant background information and context are summarized here. Users of this guideline should refer to the appropriate section(s) for the full recommendation and the context provided in footnotes.
# Recommendations for healthcare worker students and trainees
1. Professional schools should provide counselling to students and trainees infected with a BBV on potential implications of their BBV status to their future career, in order to facilitate making an informed decision regarding their preferred stream of study.
2. Professional schools should provide all students and trainees with training and/or education on Routine Practices, including hand hygiene and sharps safety.
# Recommendations for healthcare worker and patient exposures
1. Every organization or jurisdiction should have a mechanism for risk assessment to determine whether a patient or HCW exposure has occurred.
2. Administrative control measures should include an obligation and mechanism for reporting patient and HCW exposure incidents in every organization or jurisdiction, and a mechanism for assessing the risk of transmission.
3. Healthcare organizations should have written policies and procedures for post-exposure prophylaxis and management of exposed patients and HCWs. 4. All HCWs should know that a patient's possible exposure to a HCW's blood requires further management and that such events are reported in their facility/organization/jurisdiction.
5. All HCWs have an ethical and professional obligation to report and be tested (as per institutional policy) following an exposure to a patient's blood or body fluid or a patient's exposure to the HCW's blood.
Recommendations for management of healthcare workers infected with HIV 1.
# 2.
All HCWs who perform EPPs have ethical and professional obligations to know their HIV status.
If negative, those performing EPPs should be tested at appropriate intervals as determined by their level of risk and whenever an exposure has occurred.
3. HCWs infected with HIV should seek medical care from a physician with expertise in HIV management for optimal health maintenance and should be managed according to current recommendations with regular monitoring of HIV RNA levels. 4. HCWs infected with HIV should be restricted from performing EPPs until: a) the HCW is under the care of a physician with expertise in HIV management; and b) the HCW is either on effective combination antiretroviral therapy or has been identified as an elite controller; and c) the HCW's viral load is undetectable. 5. HCWs infected with HIV who are on effective combination antiretroviral therapy (or are elite controllers), and have an undetectable viral load, should have no restrictions on practice based on HIV status alone.
6. HCWs infected with HIV who do not perform EPPs do not need any restrictions on practice based on HIV status alone. 7. If a HCW-to-patient transmission of HIV occurs, the HCW should cease clinical practice immediately until determination for fitness to return to practice is made.
# Recommendations for management of healthcare workers infected with HCV
1. All HCWs who perform EPPs have ethical and professional obligations to know their HCV status. 2. If negative, those performing EPPs should be tested at appropriate intervals as determined by their level of risk and whenever an exposure has occurred. 3. Confirmation of active HCV infection should be done using HCV RNA testing. HCWs infected with HCV should seek medical care from a physician with expertise in HCV management for optimal health maintenance and should be managed according to current recommendations.
4. HCWs testing positive for HCV RNA should be restricted from performing EPPs until: a) the HCW is under the care of a physician with expertise in HCV management; and b) the HCW has completed effective therapy; and c) the HCW has tested negative for HCV RNA at least 12 weeks post-treatment. Note: Expert Review Panels may individualize practice restrictions to allow a HCW to perform EPPs while on effective therapy provided the virus is undetectable; the HCW's practice should then be restricted post treatment until a sustained virologic response (SVR) is confirmed.
5. HCWs testing negative for HCV RNA 12 weeks post-treatment can be considered to have SVR and should have no restrictions on practice based on HCV status alone.
6. HCWs infected with HCV who do not perform EPPs do not need any restrictions on practice based on HCV status alone.
7. If a HCW-to-patient transmission of HCV occurs, the HCW should cease clinical practice immediately until determination for fitness to return to practice is made.
Recommendations for HBV immunization for healthcare workers (pre-exposure prevention)
1. All susceptible HCWs (including students or trainees) should be immunized with hepatitis B (HB) vaccine, unless a medical contraindication exists.
2. Students should complete their vaccination series and demonstrate immunity prior to starting any clinical rotations.
3. If a HCW has documentation of receiving a complete HB vaccine series but does not have documentation of anti-HBs serology following immunization, or, if a HCW reports HB immunization but has incomplete or no documentation of HB immunization, serologic testing for anti-HBs should be done and then:
• If an anti-HBs titre of at least 10 IU/L is confirmed, testing need not be repeated nor should further immunization be undertaken, with the exception of immunocompromised persons who should be tested periodically for waning immunity, and persons with chronic renal disease or on dialysis, who should be tested yearly. • If testing for anti-HBs is done 1 to 6 months after vaccination and the anti-HBs titre is less than 10 IU/L, a primary vaccine failure has occurred and the HCW should be given a second vaccine series. The HCW should be retested 1 to 6 months after completion of the second series.
• If the HCW is tested more than 6 months after the initial series and the anti-HBs titre is less than 10 IU/L, the cause may be either a primary vaccine failure or waning antibody. Evidence shows that, in immunocompetent people, immunity is long lasting although antibody may be non-detectable. The HCW should receive one booster dose and be retested one month later to document an anamnestic response. If the anti-HBs titre is still less than 10 IU/L, the HCW should be tested for HBsAg and anti-HBc to rule out pre-existing chronic HBV infection. If both tests are negative, then a second vaccine series is indicated followed by anti-HBs serology 1 to 6 months after completing the second series.
• HCWs who have documented evidence of failure to respond to two series of HB vaccine (i.e., anti-HBs titre of less than 10 IU/L) are unlikely to benefit from further immunization and will need passive immunization after potential exposure to HB. Occupational health or infectious disease specialists may be consulted regarding any new strategies that may be available such as intradermal vaccination or high potency vaccine.
4. If an HB exposure occurs, and a HCW has had a documented anti-HBs titre of at least 10 IU/L, no further testing is needed unless the HCW is immunocompromised or has chronic renal disease or is on dialysis. These HCWs should be tested for anti-HBs after a potential HB exposure and given additional vaccine and HBIg if their anti-HBs titre is less than 10 IU/L.
# Recommendations for management of healthcare workers infected with HBV
1. All HCWs who perform EPPs have ethical and professional obligations to know their HBV status.
2. HCWs who remain susceptible to HBV should be tested at appropriate intervals as determined by their level of risk and whenever an exposure has occurred.
3. HCWs born or previously residing in high HBV endemic countries should be tested for both anti-HBc and HBsAg to fully define HBV status. 4. HCWs infected with HBV should seek medical care from a physician with expertise in HBV management for optimal health maintenance and should be managed according to current recommendations with regular monitoring of HBV DNA level.
5. HCWs infected with HBV should be restricted from performing EPPs until a) the HCW is under the care of a physician with expertise in HBV management; and b) the HCW's HBV DNA level is below 10 3 IU/ml (5 x 10 3 GE/ml) or equivalent and monitored regularly (every 3 to 6 months).
6. HCWs infected with HBV who have HBV DNA levels less than or equal to 10 3 IU/ml (5 x 10 3 GE/ml) or equivalent should have no restrictions on practice based on HBV status alone.
7. HCWs infected with HBV who do not perform EPPs do not need restrictions on practice based on HBV status alone.
8. If a HCW-to-patient transmission of HBV occurs, the HCW should cease clinical practice immediately until determination for fitness to return to practice is made.
Abbreviations: anti-HBc, antibody to hepatitis B core antigen; HBcAg, Hepatitis B core antigen; HBsAg, Hepatitis B surface antigen
# Recommendations for double gloving for infected healthcare workers
There is insufficient evidence to recommend for or against double gloving to prevent HCW-topatient transmission of a BBV.
# Recommendations for healthcare workers' disclosure obligations and right to privacy
1. A HCW infected with a BBV who performs EPPs does not have an obligation to routinely disclose his or her serologic status to patients to obtain their informed consent provided that the HCW's health status and practice have been assessed by an Expert Review Panel and all the panel's recommendations are followed.
2. All HCWs, including those infected with a BBV, have a right to privacy and confidentiality of personal health information.
3. Regulatory authorities should have policies on the management of HCWs infected with a BBV that are transparent about and detail how the right to privacy of HCWs will be upheld.
4. When a patient has been exposed to the blood of a HCW, the HCW must seek follow-up through their organizational process and the patient must be promptly informed of the nature of the exposure and the appropriate post-exposure protocol. However, the identity and confidentiality of the HCW should be protected to the greatest extent possible.
# Summation
This guideline was developed with a rigorous methodology involving robust systematic reviews, a narrative review, environmental scans, summaries of published epidemiologic investigations, and grading of available evidence with consideration of collective expert opinion in the development of recommendations. Adhering to recommendations provided in this guideline will result in safer practice for HCWs infected with a bloodborne virus. As new evidence develops, it may be necessary to update the recommendations.
# FOREWORD
# Purpose of Guideline
The Public Health Agency of Canada (PHAC) develops evidence-based infection prevention and control (IPC) guidelines. These guidelines support IPC professionals, occupational health professionals, healthcare organizations, and healthcare providers in developing, implementing and evaluating IPC policies, procedures and programs that improve the quality and safety of health care and patient outcomes. Recommendations provided in these guidelines complement provincial and territorial public health efforts in monitoring, preventing, and controlling healthcare-associated infections.
# The purpose of this document, Guideline on the Prevention of Transmission of Bloodborne
Viruses from Infected Healthcare Workers in Healthcare Settings, is to provide a national framework for developing policies and procedures to prevent the transmission of three bloodborne viruses (BBVs), namely hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) from infected healthcare workers (HCWs) to patients in the healthcare setting. These three viruses account for most cases of healthcare-associated transmission of BBVs reported worldwide (1) .
This evidence-based guideline replaces PHAC's 1998 Proceedings of the Consensus Conference on Infected Health Care Workers: Risk for Transmission of Bloodborne Pathogens (2) . Recommendations provided in this guideline apply to all HCWs, including student and trainee HCWs.
Following these recommendations will result in safer practice for HCWs infected with a BBV.
The information in this guideline was current at the time of publication. Scientific knowledge and medical technology are constantly evolving. Therefore, research and revisions to keep pace with advances in the field are necessary.
Guidelines, by definition, include principles and recommendations and should not be regarded as rigid standards. This guideline may need to be adapted to meet local, provincial and territorial requirements, or particular individual circumstances.
# Target Audience
This guideline is intended to assist those involved with the assessment and management of HCWs infected with a BBV, either individually (e.g., treating physician, members of Expert Review Panels) or generally (e.g., regulatory authorities). Key stakeholders impacted by this guideline and their inter-relationship with respect to managing the risk of transmission of BBVs from infected HCWs to patients, is shown in Figure 1.
# P even on o an m on o BBV om n e ed HCW o pa en
Legend 1 Regulated HCWs employed federally must be registered with the regulatory authority in their province or territory of work. 2 In some P/T jurisdictions, students of regulated health professions are not regulated therefore responsibility for managing these HCWs lies with their educational institution.
Abbreviations: P/T, provinces and territories; HCWs, healthcare workers; BBVs, bloodborne viruses
# DESCRIPTION
The first section of this guideline describes the guideline development process. This is followed by a summary of the risk of transmission of BBVs, risk of injury to HCWs, student and trainee considerations, and definition of exposure-prone procedures (EPPs). The risk of HCW-to-patient transmission is discussed by type of virus, and recommendations to prevent transmission and to manage infected HCWs are provided. Finally, the roles and responsibilities of Expert Review Panels, considerations for conducting lookback investigations, and HCW's disclosure obligations and their right to privacy are discussed.
# 2.1Guideline Development Process and Methodology
The core methods applied to the development of this guideline included identifying and reviewing existing guidelines, conducting a needs assessment, systematically reviewing evidence, grading the body of evidence, and synthesizing the evidence. A Guideline Development Task Group (Task Group) consisting of experts from across the country, developed recommendations based on available peer-reviewed evidence and collective expert opinion (where there was an absence of evidence). A broad consultation was conducted with key stakeholders to obtain feedback on the draft guideline. Relevant expert review and feedback continued throughout the development of this guideline.
# Consultation
The Public Health Agency of Canada (PHAC) consulted with federal, provincial and territorial partners and key stakeholder organizations during the development of the guideline. This consultation consisted of two parts, a needs assessment conducted in 2011 and 2012 (prior to the development of the guideline), and a broad consultation conducted in 2017 and 2018 (upon completion of the first draft of the guideline).
The needs assessment was conducted to inform the scope and development of the guideline. Organizations with direct responsibilities for the assessment and management of HCWs infected with a BBV were invited to complete the Questionnaire on the Development of a Guidance Document for the Management of Healthcare Workers Infected with Bloodborne Pathogens.
The national organizations invited to complete or share the needs assessment questionnaire with their members were identified with the assistance of the Task Group based on the following criteria: 1) national scope; 2) health professional regulatory authorities with members who might perform EPPs; 3) health professional faculties with students and trainees who might perform EPPs; 4) organizations with subject matter experts that might participate in the expert review process of HCWs infected with a BBV; and 5) upon request of another organization. The organizations invited were: The needs assessment was conducted using an online questionnaire that could be completed by any individual from these organizations. Each organization determined their own process to complete the questionnaire therefore it was not possible to determine individual response rates for the needs assessment. In total, 120 questionnaires were returned with 82 of these completed in full and 38 partially completed. Respondents were from all provinces and territories in Canada. The data collected was exported to an Excel spreadsheet and an analysis was performed using qualitative and basic quantitative methods. A summary of issues identified from the needs assessment is presented in Figure 2.
•
# Figure 2: Key issues and/or controversies identified regarding the management of a healthcare worker infected with a bloodborne virus
A broad consultation with federal, provincial and territorial partners and key stakeholder organizations was conducted upon development of the draft guideline. This involved a thorough review of the draft guideline by individual(s) within a stakeholder organization with a goal to: 1) identify potential issues and/or concerns with any of the recommendations, including their feasibility and applicability; 2) correct erroneous information, if any; and 3) encourage broad support for the recommendations across the country. The organizations that were invited to provide feedback are summarized in Appendix III, Table 35. Each organization rolled up the individual feedback received into one organizational response and a completed feedback form was sent to PHAC. Each organization determined their own process to complete the feedback form therefore it was not possible to determine the response rates for the broad consultation.
The feedback received from the broad consultation primarily identified the need for:
• Clarity of terminology • Additional citations • Minor grammatical edits • Clear explanation of the guideline development methodology and consultation process • Correction of erroneous background information or provision of supplemental background information with references • Substantive edits to some technical content in the guideline • Consideration of the applicability and feasibility of some recommendations • Consideration of the potential impacts of some recommendations on existing organizational policies All feedback received was tabulated and each item reviewed by the Task Group and PHAC staff to determine the appropriate action needed. Revisions were made to the draft guideline where needed and a rationale was documented where revisions were not made because the suggested edits were considered to be unnecessary, erroneous, ambiguous or not supported by current evidence.
# Review of the Literature
A project protocol was developed to outline the steps and methods for reviewing relevant literature by conducting systematic reviews and environmental scans to inform recommendations provided in this guideline. The systematic review and environmental scan parameters, literature search strategy, and approach for evidence analysis were established prior to the initiation of the project. The project protocol was then circulated for internal comment and refinement by the Task Group and PHAC.
A series of Key Questions were needed to clearly address the identified issues from the needs assessment as well as the defined scope and objectives of the guideline. Ten Key Questions were drafted by the PHAC writing team and reviewed by the Task Group. Each question was structured to focus on a fundamental issue to be addressed in the guideline. A systematic review was conducted for questions where a clearly defined population, intervention, comparator and outcome (PICO) were identified and/or where it was considered necessary to review existing data for consideration in the development of recommendations. There were some limitations in identifying adequate comparator interventions and available data was qualitatively synthesized. Seven of the 10 questions developed were addressed using a systematic review process. A published systematic review of randomized controlled trials (RCTs) was available and therefore used, along with other studies, to inform one of the seven questions (i.e. clinical effectiveness of double gloving). Three questions were addressed by conducting environmental scans (refer to section 1.1.3).
# Systematic Reviews
Systematic reviews were conducted to summarize the evidence for the risk of transmission of HIV, HCV, and HBV from infected HCWs to patients. The literature search parameters were developed upon review of the project outline developed by the Task Group.
Prior to conducting the literature search, the Cochrane Collaboration Database of Systematic Reviews, the International Prospective Register of Systematic Reviews, the NIH Library of Systematic Review Protocols and Protocol Registries, the Database of Abstracts of Review of Effect, and the TRIP Database were searched for any previous systematic reviews that addressed this topic (3)(4)(5)(6)(7) . No published systematic review was found.
Literature search strategy concepts and keywords were selected for each topic. Four databases were reviewed: Ovid MEDLINE, EMBASE, Global Health and Scopus. Worldwide literature was searched from 1995 until the present. The literature search was conducted in 2013 and updated in 2015. Additional relevant references were obtained from supplemental sources and from manual search of reference lists of eligible studies.
The literature searches resulted in references. The references were screened for relevance and then sorted into topic-specific folders and sub-folders. All published research findings relevant to each sub-topic were reviewed. Scopus Search Alert, Global Health Search Alert, ProMED postings, Safe Injection Global Network, and the Public Health Agency of Canada Daily News were used to stay up-to-date with new studies after the formal literature searches were completed.
Relevant articles were screened for eligibility for each systematic review. For the systematic reviews informing the preventive or management measures to reduce the risk of transmission of a BBV, the criteria for selecting eligible population included infected HCWs performing or assisting with EPPs (irrespective of whether transmission occurred) and those providing direct patient care involving non-EPPs but where transmission occurred.
Critical appraisal of eligible studies was conducted using PHAC's Critical Appraisal Tool Kit (the Tool Kit) (8,9) . A grade was provided for the strength of the body of evidence informing each recommendation. This grade was based on a combination of strength of the individual study designs, quality of the individual studies, number of studies informing a recommendation, consistency of results from these studies, and directness of the body of evidence (i.e., assessing whether the evidence specifically researched the association of interest needed to inform the recommendation). The Tool Kit uses a grading scale that rates all levels of evidence from metaanalyses of randomized controlled trials to ecologic studies; and rates expert opinion lower than published scientific evidence. Within the hierarchy of scientific evidence, meta-analyses of RCTs are generally considered to be the best evidence available. For ethical and methodological reasons, RCTs are not feasible to assess potentially harmful situations such as the transmission of BBVs. In such situations, the best evidence becomes the evidence that exists at the highest level within the hierarchy of evidence. The body of evidence that exists to inform this guideline consists mostly of epidemiologic investigations of past exposure incidents. Although these studies are weak in design, they are nonetheless, the best available evidence informing this issue. As a result, the grade of evidence in this guideline falls within the range of CI to BII. Refer to Table 34, Appendix II, for further details on the criteria used for this rating. A grade of CII indicates where the evidence base consisted of low quality studies regardless of study design or existing studies reported contradictory results or there was a paucity of relevant studies thus the evidence was mostly based on expert opinion.
Evidence from eligible studies were reviewed and summarized. Companion articles providing additional information about eligible studies were identified in the systematic review literature database as well as from supplemental sources and/or manual search of reference list of eligible studies. Where relevant, the additional information reported in the companion articles was included in the tabular summary of the corresponding eligible study. A synthesis of evidence is provided along with the recommendations developed. Where there were insufficient published studies or inconclusive study results, a consensus of experts in the field provided recommendations specific to practice. In addition, current practice and complex ethical and legal issues were considered and discussed in the development of final recommendations.
# Environmental Scans
An environmental scan of relevant literature (limited to English and French) was conducted for three Key Questions where the topic dealt with organizational, regulatory, and/or ethical issues not solely or directly informed by scientific research. This included the sections on disclosure of a HCW's serologic status, establishing Expert Review Panels and conducting lookback investigations.
The core methods used for conducting the environmental scans included identification and review of relevant documents obtained from a search of grey literature including policy documents, guidance from other organizations, and reports from government institutions or professional organizations outside of the indexed medical literature. These sources were used to identify the general consensus of opinion regarding these issues (10) . These sections were written as a text and/or tabular summary of the relevant literature.
The literature searches related to the disclosure of serologic status and the expert review process were limited to English and French language articles worldwide. Information obtained facilitated the development of recommendations based on relevant national and/or international guidelines, as well as regulatory authorities' and professional associations' policy statements. Relevant national guidelines on conducting lookback investigations, publications of past investigations and expert opinion informed the section on lookback investigations, with recommendations developed to fit the Canadian context.
Recommendations not informed by a systematic review of the scientific literature or where the topic deals with organizational, regulatory, and/or ethical issues not solely or directly informed by scientific research have no grade of evidence assigned.
# Guideline Development Task Group (Task Group)
The Guideline on the Prevention of Transmission of Bloodborne Viruses from Infected Healthcare Workers in Healthcare Settings is one in a series of Infection Prevention and Control (IPC) guidelines developed by PHAC. Technical expertise for the review of the evidence and development of recommendations were provided by the Task Group. The Task Group for this guideline was composed of members with expertise in infectious diseases, medical microbiology and virology, infection prevention and control, public health, occupational health, hepatology, dentistry, medical ethics and obstetrics and gynecology. The Task Group reported to PHAC's National Advisory Committee on Infection Prevention and Control.
# List of Guideline Development Task Group Members
Participation in the Task Group does not constitute endorsement by affiliated organizations.
The following individuals formed the Task Group (affiliations were at time of development of the guideline):
# INTRODUCTION
# Background
Healthcare professionals, including physicians, dentists, nurses, physician assistants, dental hygienists and midwives, have an ethical and professional obligation to prioritize the well-being of their patients first, by providing safe, compassionate, competent and ethical care at all times (11)(12)(13)(14)(15)(16)(17)(18) .
This responsibility includes minimizing the risk of exposure to pathogens within healthcare settings (19) . Certain surgical procedures may pose a risk of healthcare worker (HCW) injury with the possibility of exposing a patient to the blood of a HCW (20)(21)(22)(23)(24) . In 1998, Health Canada released recommendations from a consensus conference that was held to address the risk of transmission of bloodborne viruses (BBVs) from infected HCWs to patients (2) . This prompted key stakeholder organizations to develop policies on the issue. The policies of the professional regulatory authorities are direct and binding regulation on regulated HCWs infected with a BBV in Canada (25) . In addition, Medical Officers of Health, under their respective provincial or territorial Public Health Act, may issue an order to stop practice when an imminent risk to public health has been identified. This evidence-based guideline is intended to provide a framework for a pan-Canadian approach to the management of HCWs infected with a BBV.
To minimize the risk of BBV transmission from HCWs to patients, all HCWs should adhere to Routine Practices (synonymous with Standard Precautions, refer to Glossary) (19,26) , including performing hand hygiene as required, using personal protective equipment as appropriate, and taking care in the use and disposal of needles and other sharp instruments (27) . This guideline assumes that HCWs will adhere to Routine Practices when providing care to all patients at all times and in all settings (19) . As long as infected HCWs adhere to these practices, the risk of transmission of BBVs from infected HCWs to patients is negligible except during exposureprone procedures (EPPs), which may pose minimal risk (28) . Efforts to prevent BBV transmission involve understanding the factors that increase or decrease the risk of transmission during an EPP, thus providing a framework for developing recommendations for the management of HCWs infected with a BBV who perform or assist with EPPs (29) . There are published reports of HCW-to-patient BBV transmission solely due to IPC breaches, with some cases involving egregious breaches such as the illicit diversion of patient medication involving reuse of needles for self-injection by a HCW (30) . Illicit diversion of injectable patient medication by a HCW is considered malpractice and is not within the scope of this document.
A review of the literature to inform this guideline revealed primarily lookback investigations and other descriptive studies. Inherent limitations with these study designs make it difficult to conclusively discern the contribution of various risk factors to the transmission of a BBV from an infected HCW to a patient. Information relating to exposure incidents and history of injection drug use or other personal risk factors reported in lookback investigations is generally obtained from interviews. Such reports do not allow for assessing the extent of recall bias (bias due to differences in accuracy of recollection of past events), interviewer bias (bias in how information is solicited, recorded, and interpreted), or social desirability bias (providing responses that are considered to be socially or politically desirable). The retrospective nature of lookback investigations limits the information obtained from the report to the data the authors had access to or chose to report. Moreover, incidences of transmission where no EPP was involved and IPC breaches were not reported pose additional questions and thus require careful review (31,32) . It is possible that an infected HCW who has very poor IPC practices could infect patients without doing exposure-prone procedures. Therefore, the situation of every infected HCW should be reviewed. This does not necessarily require a formal review by a panel, but at least a review of what procedures the HCW performs, how they follow IPC practices, and whether they are on treatment. It is also an opportunity to reinforce appropriate IPC practices.
# Determinants of Risk of Transmission of Bloodborne Viruses
Three determinants of risk influencing the likelihood of transmission of BBVs from infected HCWs to patients during an EPP have been previously outlined (2) . These include the risk of percutaneous injury for the HCW; risk of the contaminated instrument or HCW's blood contacting the patient's open tissues; and susceptibility of the patient. Although the HCW with high levels of circulating BBV may pose some risk if their blood contacts a patient, the risk approaches zero if that HCW is treated and eradicates (HCV) or decreases (HIV and HBV) circulating virus in their blood.
For each BBV, reported exposure incidents, regardless of whether transmission occurred, have been assessed to provide a comprehensive context for the development of this guideline. The extent of reporting bias for HCWs infected with a BBV and not implicated in transmission to patients via EPPs or non-EPPs is unknown. As a result, the risk of transmission of BBVs from HCWs to patients may be overestimated in the literature. A series of BBV transmission incidents have involved a chain of patient-to-HCW-to-patient transmissions (33) . The risk of transmission of BBVs from patients to HCWs during clinical activities is influenced by the prevalence of BBVs in the population, frequency of contact with infected patients, communicability of the BBV, immunologic status of the HCW, and years of experience with tasks that include blood exposure risk (34)(35)(36)(37) . An increased prevalence of BBVs in a population served by HCWs who perform EPPs increases the risk of occupational exposure of HCWs to BBVs (38) . One urban academic hospital in the US reported that up to 38% of all surgical procedures conducted there involved exposure to HBV, HCV, and HIV (39) .
Despite the perceived risk, a 2007 systematic review investigating a total of 6,956 HCW injuries with HCV-contaminated needles, found no cases of HCV seroconversion (40) . In one study, a total of 99 injuries occurred during 1,382 (7.1%) surgical procedures with 89% of these sustained by residents or attending surgeons. In 29 of the 99 injuries (32%) sustained by surgeons, the sharp instrument that caused the HCW injury contacted the patient after it had penetrated the HCW's skin (21) . Another study estimated that patients may be exposed to the blood of at least one HCW in as many as one in six cardiothoracic surgery procedures that carry a high exposure risk (41) . Many changes have occurred in the operating room environment since these studies were conducted, nonetheless, ongoing improvement to protect HCWs from sharps injuries will also protect patients from possible exposure to BBVs. Seroconversion of HCWs may not be recognized in a timely manner or prior to a patient exposure incident. In addition, published lookback investigations of patient exposure incidents show that very rarely is the exposure recognized during or immediately following the incident. If exposure is recognized, timely reporting of the exposure would allow for prompt initiation of post-exposure prophylaxis for the patient (for HIV and HBV) (42) .
From a review of cases of BBV transmission from infected HCWs to patients worldwide, the factors that influence the risk of percutaneous injury and/or the risk of transmission of BBVs given HCW injury have been identified. These factors include (29,38,(43)(44)(45)(46)(47)(48) :
• Reports of potential patient exposure to HCWs infected with a BBV have identified dermatitis on the HCW's hands as one factor that may amplify the risk of transmission (49)(50)(51) . In one of these incidents, atopic eczema lesions prevented the HCW from wearing gloves systematically (50) . Another incident reported severe dermatitis on the HCW's hand with episodes of serous or bloody drainage from nodular lesions during the exposure period (49) . Adherence to Routine Practices should prevent transmission of BBVs via dermatitis (19) .
# Perception and Comparison of Risk
Along with the actual risks of transmission of BBVs, the risk perceived by the public has to be considered in determining acceptable risk (52) . Generally, people are more fearful of things that are extremely unlikely but considered beyond their control (53) . While zero risk is unattainable, every reasonable effort should be made to reduce the risk to a minimum with recommendations striking a balance between the rights and reasonable expectations of the public (informed consent and protection from harm) and the rights and reasonable expectations of individual HCWs (privacy and freedom from discrimination) (54) .
Patient safety studies show that the most frequent types of adverse events affecting hospitalized patients are adverse drug events, wound infections, and surgical complications (55,56) . Risks associated with surgical procedures have been estimated and generally appear to have been accepted by patients (57) . Examples include the mortality risk of anesthesia for surgical inpatients, which is estimated at 0.82 in 100,000 (58) and the risk for surgical site infections, which is estimated to be between 2 to 5% (59,60) . The risk of transmission of BBVs from an infected HCW to a patient via an EPP is lower than the risk of acquiring a healthcare-associated infection while receiving health care or the risk of acquiring BBVs via other mechanisms such as sexual activity with infected partners (61,62) . In the 2004 report published by the UK Advisory Panel for Healthcare Workers Infected with Bloodborne Viruses (UKAP), the risk of HCW-to-patient transmission of a BBV was presented in comparison to the risk of patient-to-HCW transmission of a BBV based on modelling studies (refer to Table 1) (63)(64)(65) . These studies collectively show that the risk of a BBV transmission from patient to HCW is significantly higher than the risk of transmission from HCW to patient. ; if e-antigen negative, the risk is 1-6% (66,67) .
Considering HCW's access to both effective treatment for HCV and effective vaccine against HBV, and the minimal risk of HCW-to-patient transmission of HIV, it is reasonable to expect that measures taken to address the risk of a BBV transmission from HCW to patient should avoid triggering public fears, unduly restricting individual freedom, or violating human rights (68) .
It has been reported that the risk of physicians transmitting BBVs to patients will continue to fall as more effective methods of prevention and treatment are identified (69) . To date, there are no documented cases of transmission of any BBV from Canadian dentists to patients, and also no documented transmissions of either HIV or HCV from Canadian physicians to patients. There is only one report of a Canadian physician (an orthopedic surgeon) implicated in transmitting HBV to four patients; the surgeon was compliant with universal precautions (refer to Glossary) with no obvious breaks in technique (70) . This incident occurred prior to the availability of modern antiviral therapy for HBV (71) . In addition, there have been numerous investigations of infected HCWs that did not identify transmission of a BBV.
# Risk of Injury to a Healthcare Worker
With the introduction of routine hepatitis B (HB) vaccination, most HCWs are protected from infection with this BBV, virtually eliminating the risk of HCW-to-patient transmission. On the other hand, multiple percutaneous injuries throughout a HCW's career may place them at risk for occupational acquisition of HIV or HCV infection that may go unnoticed and therefore not treated. This in turn may pose minimal risk of transmission to patients in the event of a HCW injury while performing an EPP (72)(73)(74)(75)(76)(77)(78) .
Surveillance of HCW occupational exposures indicates that percutaneous injuries are the most commonly reported route of HCW exposure to blood or bodily fluid (79,80) . A modelling study conducted within the framework of the World Health Organization's Global Burden of Disease project in 2002 estimated the global burden of occupational infections with HIV, HCV and HBV attributable to sharps and injuries among HCWs (81) . Bloodborne infections and injuries occurring in the year 2000 in 14 geographical regions and four age groups were assessed.
Overall, it was estimated that 1,000 HIV, 16,000 HCV, and 66,000 HBV infections may have occurred among HCWs worldwide due to occupational exposure through percutaneous injuries (33,81) . This amounted to 4.4%, 39%, and 37% of all HCW injuries resulting in HIV, HCV, and HBV infections respectively. The true incidence of occupational exposure to BBVs due to a HCW injury is unknown but likely to be higher than currently available publications due to late reporting and unreported cases (80,82) . Of all HCWs, nurses report percutaneous injuries most often while doctors report them least often (83) .
Risk of injury, and by extrapolation risk of BBV transmission to HCWs who perform EPPs, is dependent on the types of procedures they do. Certain HCWs such as laboratory technologists, phlebotomists, and surgeons perform procedures that have an increased incidence of injury and occupational exposure. Sharps and needlestick injuries are reported to be about six times more common among surgical personnel compared with nonsurgical personnel (82,84) . The frequency of HCW injury also varies among surgical specialties. Based on reports, the most at-risk procedures for HCW injury have been identified during major vascular, intra-abdominal, gynecologic, and orthopedic surgeries (85,86) . A study investigating the numbers and circumstances of percutaneous injuries among surgical personnel found that the procedure injury rate ranged from 4% (orthopedic) to 10% (gynecologic) and was s ignificantly related to procedure duration (21) . The American College of Surgeons reported that patients' blood makes contact with the skin or mucous membranes of operating room personnel in as many as 50% of operations, with cuts or needlestick injuries occurring in up to 15% of operations (87) . Surgeons and first assistants were found to be at highest risk of injury, sustaining up to 59% of injuries in the operating room (87) . At one institution, needlestick injury prevalence increased from medical students to residents and fellows (100%) and 11% of these needlestick injuries involved patients infected with a BBV (88) . Although sharps injury rates among surgical residents have been shown to decrease with increasing surgical experience, non-compliance with sharps injury reporting protocols is most common among senior surgeons with about 50% or more of these injuries not reported (36,84,89,90) . At one institution, lack of time and fear of potential embarrassment or consequence were reported to be the two critical components of underreporting of needlestick injuries (82) .
It has been reported that most dental HCWs (dentists, hygienists, assistants and oral surgeons) experience approximately three injuries per year (91) . A survey of a random sample of 300 dentists found that all respondents had protocols in place for managing and reporting sharp injuries to dental team members but only 48% of respondents had protocols for reporting patient exposures to the blood of a member of the dental team (35) . Dental HCWs were previously reported to have a low risk for occupationally acquired HIV but a higher risk for acquiring HBV than the average citizen (92) . With the development of a vaccine against HBV, the risk for acquiring HBV has been mostly mitigated for HCWs.
Adequate training and education on the prevention and management of occupational exposures is fundamental for HCWs as part of an occupational health program for sharps safety and prevention of exposure to BBVs (19,80) . Healthcare worker injuries can be reduced by use of blunt suture needles, improved instruments, reinforced gloves, changes in surgical technique and use of less invasive procedures (29,93,94) . Safety-engineered sharp devices should be used wherever possible for the safety of patients and HCWs (19) . Further information and recommendations on sharps safety, prevention of HCW exposure to blood or body fluids, and first aid when there has been a HCW exposure can be found in PHAC's Routine Practices and Additional Precautions for Preventing the Transmission of Infection in Healthcare Settings (19) .
# HEALTHCARE WORKER STUDENT AND TRAINEE SPECIFIC ISSUES
Key issues that have been identified for the health and safety of HCW students and trainees include necessary training in IPC, reducing the risk of occupational injury, assessment of immunization status, and confirming immunity to vaccine-preventable diseases (e.g., HBV) as early as possible on admission into health professional training programs (19,(95)(96)(97)(98) .
A prospective cohort study showed that medical students had a high risk for needlestick injuries, which most commonly occurred in the operating room (99) . A more recent study reported that 28% of medical students, 83% of residents and/or fellows and 100% of faculty had been exposed to a sharp injury at some point in their career (45) . By the final year of training, 99% of surgical residents have had a needlestick injury, with 53% of these injuries involving a high risk patient (patient with a history of a BBV infection or injection drug use) (84) . Occupational injuries among HCWs in dentistry show the highest rate of exposure occurs among dental students and assistants, with needlestick injuries predominating (46,100) . Nursing students have also been reported to be at increased risk of occupational needlestick injury due to limited clinical experience (101) .
The increased risk of injury among medical, dental and nursing students and trainees, if not mitigated, could pose a concern for students, trainees and patients. Education of student and trainee HCWs on risks and precautions, immunizations, use of less invasive procedures, protection strategies to minimize risk of injuries (e.g., use of safety engineered devices), and procedures to manage exposures will improve student and trainee knowledge and reduce their exposure risk (34,36,81,90,99,102,103) .
Despite increased rates of occupational sharp injuries to students and trainees, the risk for this group of HCWs to acquire a BBV, followed by secondary transmission to patients is still considered to be minimal. Professional schools should provide education to all students and trainees regarding the implications of infection with a BBV. Medical students are very unlikely to be performing exposure-prone procedures and transmission in dental school has not been reported in the literature. Strategies to reduce student and trainee injuries are primarily for their health and safety.
# EXPOSURE-PRONE PROCEDURES
Exposure-prone procedures (EPPs) are invasive procedures where there is a risk that injury to the HCW may result in the exposure of the patient's open tissues to the blood of the HCW. For transmission of a BBV from an infected HCW to patient to occur during an EPP, three conditions are necessary (104) :
1. HCW must sustain an injury or have a condition that allows for exposure 2. HCW's blood must come in contact with a patient's wound, traumatized tissue, mucous membranes, or similar portal of entry 3. HCW must be sufficiently viremic EPPs with risk of transmission include (105) :
a. Digital palpation of a needle tip in a body cavity (a hollow space within the body or one of its organs); or the simultaneous presence of the HCW's fingers and a needle or other sharp instrument or object (such as bone splinters, sternal wires etc.) in a blind or highly confined anatomic site, e.g., as may occur during major abdominal, cardiothoracic, vaginal, pelvic and/or orthopedic operations b. Repair of major traumatic injuries c. Cutting or removal of any oral or perioral tissue, during which the patient's open tissues may be exposed to the blood of an injured infected HCW.
Transmission has been documented with several surgical and dental procedures, most of which meet the above definition of an EPP. There is insufficient evidence to accurately categorize most surgical, dental and medical procedures in terms of transmission risk (106) . As a result, risk categories developed so far have been based on expert consensus on the risk of contact between the HCW's blood and that of the patient (106,107) . This guideline does not provide risk categories for EPPs. The approach taken involves providing criteria to help experts determine whether or not a procedure is an EPP. When assessing the procedures performed by an infected HCW, experts in the appropriate specialties should be engaged in determining which procedures fit the criteria for an EPP (108) .
Failure to adhere to IPC principles identified as Routine Practices could result in transmission of BBVs during a procedure. For reference purposes only, a list of procedures reported to date which involved documented transmission of a BBV, is presented in Table 2. Documented transmissions via non-EPPs have to be assessed on a case-by-case basis in order to rule out IPC breaches, illicit diversion of patient medication involving reuse of needles for self-injection by a HCW, and determine the possible mechanism(s) of transmission.
# Specialty Procedures
Cardiothoracic Valve replacement surgery (41,76,(109)(110)(111) surgery Coronary artery bypass graft surgery (41,76,(110)(111)(112)(113)(114) Pulmonary surgery (76) Other bypass surgery (110) Valve and coronary artery replacement (41) Thymectomy (111) Open-lung biopsy (111) Repair of congenital heart defects (111) Orthotopic heart transplantation (111) Orthopedic Placement of a total hip prosthesis with bone graft (72)
surgery
Thompson's hip hemiarthroplasty (115) Hip replacement (75,116) Revision of total knee replacement (70) Total knee replacement (70,116) Obstetrics and Caesarian section (117)(118)(119) gynecology Hysterectomy (120) Hysterectomy and removal of ovarian cyst (119) Uterus/adnexa extirpation (121) General Repair of inguinal hernia (121)(122)(123) surgery Cholecystectomy (119) Cholecystectomy and nephrectomy (119) Sigmoid resection (121) Ileocecal resection (121) Creation or removal of intestinal stoma (121) Transanal drainage (121) Excision of ganglion (121) Hernia repair and bladder neck resection (124) Vascular surgery
Abdominal aortic aneurysm surgery (76) Aorta bifurcation prosthesis (121) Ligation and stripping of varicose veins (121)
# Specialty
# Procedures
Dentistry and Extraction of two maxillary third molars under local anaesthesia; prophylaxis, and cosmetic oral surgery bonding (125,126) Extractions, prophylaxis, periodontal scaling and root planing, and fixed and removable prosthodontics (126) Extractions, prophylaxis, periodontal scaling and root planing, and restorative fillings (126) Examination, prophylaxis, fluoride treatment, restorative fillings and crowns, and root canal therapy under local anaesthesia (127) Examination and radiographs, prophylaxis, extraction, restorative fillings and root canal therapy (127) Root canal therapy and restorative filling under local anesthesia (127) Examinations, radiographs, prophylaxes and restorative fillings under local anaesthesia (128) Dental extraction (129) Reduction of fractured mandible (129) Enucleation of maxillary cyst (129) Root canal and cyst enucleation (129) Surgery and dental extraction (130) Crown (130) Miscellaneous Acupuncture (131) Electroencephalogram with reusable subdermal electrodes (132) Administration of intravenous antibiotics (133) Monitoring of patient and administration of two subcutaneous injections of heparin with a non-safety injection device (32) Care of an implanted venous port and administration of intravenous antibiotics (134) Venepuncture and cannulation (135) Administration of anesthesia (31,(136)(137)(138)(139) Hemodialysis (140) Abbreviations: BBV, bloodborne virus; HCW, healthcare worker A Procedures reported in the literature which involved transmission of HIV, HCV or HBV. Only procedures that are named in the investigations are included and where multiple procedures were done on a patient, it was not indicated which procedure was involved in transmission. All procedures done on a single patient are listed as a single line item. Where more than one patient had identical procedures, it was listed only once.
# Recommendations for Healthcare Worker and Patient Exposures A
Recommendations 1. Every organization or jurisdiction should have a mechanism for risk assessment to determine whether a patient or HCW exposure has occurred.
2. Administrative control measures should include an obligation and mechanism for reporting patient and HCW exposure incidents in every organization or jurisdiction, and a mechanism for assessing the risk of transmission.
3. Healthcare organizations should have written policies and procedures for post-exposure prophylaxis and management of exposed patients and HCWs.
4. All HCWs should know that a patient's possible exposure to a HCW's blood requires further management and that such events are reported in their facility/organization/jurisdiction.
5. All HCWs have an ethical and professional obligation to report and be tested (as per institutional policy) following an exposure to a patient's blood or body fluid or a patient's exposure to the HCW's blood.
A The term 'HCWs' in this document includes students and trainees.
# RISK OF TRANSMISSION OF HIV
There is a lack of consistency in the body of evidence relating to viral load units of measurement for BBVs. In this document, HIV viral load is reported as copies/mL as this is the current reporting practice for Canadian laboratories.
# Incidence and Prevalence of HIV
The prevalence of HIV infection in the general Canadian population rose steadily during the 1980s, corresponding to the initial rise of HIV incidence in the Canadian population (141) . In 2016, PHAC reported an estimated 2,165 new HIV infections in Canada (142) . Approximately 63,110 people were living with HIV (including AIDS) by the end of 2016, representing a 5% increase from the estimate at the end of 2014 (142) . The number and rate (per 100,000) of reported cases of HIV infection in Canada from 2000 to 2016 based on data from the CNDSS can be found on PHAC's Notifiable Diseases Online page here: http://diseases.canada.ca/notifiable/charts?c=pl
Although surveillance data are limited by underreporting, an increase in numbers of people living with HIV has been observed since the late 1990s. This may largely be related to the development of more effective, less toxic and better-tolerated therapies. These developments delayed the progression of HIV to acquired immune deficiency syndrome (AIDS), resulting in reduced mortality (79,143) .
In addition to the potential risk for occupational exposure, HCWs can have the same risk factors for acquiring HIV as the general population (e.g., injection drug use, sexual contact). There are currently no published HIV prevalence data among HCWs in Canada. The total number of reported AIDS cases among adults in Canada (15 or older) due to occupational exposure from 1979 to 2012 is 9, with 7 of these cases occurring before 2006 (144) . The setting for these occupational transmissions was not reported.
# Estimated Risk of HIV Transmission
Studies have estimated the risk of HIV transmission from patients to HCWs after percutaneous injury to range from about 0% to 3% (27,145,146) . Several risk factors may collectively increase seroconversion risk by as much as 50 times (145) . A case-control study of 33 HCWs who acquired HIV from occupational percutaneous exposure, compared with 665 controls who were similarly exposed to HIV-infected blood but not infected, found that the significant risk factors for seroconversion were (146) :
-deep injury, -injury with a device that was visibly contaminated with the source's blood (larger volume of blood), -exposures involving a needle placed in the source's artery or vein, -exposure to a source who died of AIDS within two months after the exposure (possibly due to higher titre of HIV in the blood), and -lack of post-exposure prophylaxis.
It is reasonable to assume that the same risk factors for seroconversion apply to transmission of HIV from HCWs to patients. There is very limited evidence of transmission of HIV from an infected HCW to a patient during an EPP. Nonetheless, the few transmission incidents reported globally confirm that the risk is not zero nor should it be considered hypothetical (refer to Table 3). The development of effective antiretroviral therapies, and their use by HCWs or patients infected with HIV will minimize the risk of transmission in the event of an exposure during an EPP (69,147) . The HIV transmission rates calculated from two of four reported incidents involving HCW-topatient transmission of HIV were 0.1% and 0.4% (refer to Table 20, Appendix I) (72,117) . Transmission rates from the other two reported incidents are not helpful in assessing risk from EPPs as one incident involved a non-EPP (32) , and another incident reported IPC breaches, although it was unclear if this was applicable to all infected patients (148) . To determine the observed rate of transmission of HIV from infected HCWs to patients in previous HIV exposure incidents, a meta-analysis of eligible exposure incidents was conducted [manuscript in development]. A total of 17 incidents were eligible for the meta-analysis including 14 with no transmission of HIV. The pooled transmission rate for HIV using the random effects DerSimonian-Laird model was 0.0056% (95% CI: 0-0.026%). This corresponds to a chance of 5.6 per 100,000 individuals (95% CI: 0 to 26.2 per 100,000 individuals) becoming infected in the absence of IPC breaches and illicit diversion of intravenous patient medication. The range of the observed transmission rate from this meta-analysis is similar to calculations from previous modelling studies (53,64) .
# Review of Patient Exposure Incidents with Transmission of HIV
In the worldwide literature search conducted for this systematic review, published investigations reported HIV transmission from five infected HCWs to patients. For four of the infected HCWs, the exposure incidents involved an EPP.
In the early 1990s, a number of publications documented epidemiologic investigations involving patients of a dentist infected with HIV in the USA (125,126,128,148) . The dentist was symptomatic in late 1986 and diagnosed in 1987. The dentist practised while symptomatic with advanced HIV infection; therefore the viral load, although not reported at time of exposure, was most likely very high. The dentist continued to practise for a period of time prior to beginning antiretroviral therapy with Zidovudine (a less effective regimen than currently available therapy); but was not adherent to treatment while practising. A lookback investigation was conducted and involved testing 43% of potentially exposed patients. Phylogenetic analysis confirmed transmission of HIV from the infected dentist to six patients. Breaches in IPC were reported but attempts to determine the mechanism of transmission were inconclusive (126) .
The second transmission event was published in 1999 with a probable transmission of HIV from an orthopedic surgeon to a patient in France (72) . About 33% of his patients were tested, and one was found to be infected with HIV. This patient was operated on three times by the infected surgeon with prolonged duration of potential exposure during one difficult procedure that lasted over 10 hours (149) .
The third HIV transmission event was published in 2002 and involved a nurse in France (32) . The nurse was co-infected with HCV and had advanced cirrhosis. The nurse monitored the patient and gave two subcutaneous injections of heparin calcium with a non-safety injection device. The nurse denied having a history of injection drug use. The mechanism of transmission, although clearly not via an EPP, remains unknown.
The fourth HIV transmission event was published in 2003 (117,150) . An obstetrician/gynecologist in Spain transmitted HIV to a patient during a caesarean section. The HCW admitted to having sustained a percutaneous injury during the procedure. The patient and family were reported to have seen the injury during the procedure although it was not promptly reported by the HCW at the time of injury (151) .
The fifth incident of HCW-to-patient transmission of HIV was published in France in 2005 (149,152) . A thoracic surgeon was identified as HIV positive during an investigation of a newly acquired HIV infection in a patient who had undergone coronary artery bypass surgery. The patient had no other recognized risk factors and no percutaneous injuries to the surgeon were reported. The surgeon had tested negative for HIV two years earlier and had a viral load of 12,000 copies/mL at time of diagnosis. Details of the investigation of this event have not been published and are therefore not included in the tables provided in this guideline.
It is possible that other HIV transmission incidents from HCW to patient have occurred but have not been published. The published lookback investigations involving patients exposed to HCWs infected with HIV with documented transmission are summarized by HCW specialty in Table 3. A total of 12,550 patients were reported to be exposed to 4 HCWs infected with HIV. Of these patients, a total of 4,261 (34%) had their HIV status examined. Transmission of HIV from HCWs to patients occurred in 9 of these patients with 6 of these transmissions possibly involving IPC breaches. A detailed summary of the individual exposure incidents is presented in Table 20, Appendix I.
# Number of patients infected
Dentistry (128,148) 1 1691 735 (43) 6 Orthopedic surgery (72) 1 3004 983 (33) 1
Nursing (32) 1 7580 2293 ( 30) 1 Obstetrics and gynecology (117) 1 275 250 ( 91 For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HIV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where HCW-to-patient transmission was reported. Epidemiologic investigations of all four published investigations were eligible for inclusion in the systematic review. Three of the four investigations involved EPPs. Findings on key preventive measures and risk factors for transmission are summarized in Table 4.
) 1 (1) 1 (0) 2 (1) 1 (0) 0 (0) 1 (0) 0 (0) 1 (1) Total No EPP (non-EPP) 2 (0) 1 (0) 1 (0) 2 (1) 2 (1) 0 (1) 0 (0) 0 (0) Total NR EPP (non-EPP) 0 (0) 1 (1) 0 (0) 0 (0) 1 (0) 2 (0) 3 (1) 2 (0)
Abbreviations: HIV, human immunodeficiency virus; EPP, exposure-prone procedure; IPC: infection prevention and control; PEP, post-exposure prophylaxis; NR, not reported; HCW, healthcare worker A N=4 for total number of infected HCWs from all reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made.
H Percutaneous injury: Percutaneous injury potentially exposing patient to HCW's blood was reported. I Patient PEP: Post-exposure prophylaxis was offered to exposed patient(s). J Diversion ruled out: Illicit diversion of patient medication by HCW was ruled out. K The HCW was on and off treatment while practising (non-adherent). L Although no percutaneous injury potentially exposing the infected patient was recorded, the HCW reported frequent injuries and noted blood under his gloves more than once a week. M The HCW was unaware of their serologic status at the time of the index patient's exposure incident but was aware after being hospitalized and diagnosed in 1996 (32,153) .
# Review of Patient Exposure Incidents with No Transmission of HIV
In 1995, a summary of all published and unpublished investigations from the CDC database showed that among 22,171 patients who were treated by 51 HCWs infected with HIV (29 dentists and dental students, 8 physicians and medical students, 13 surgeons or obstetricians, and 1 podiatrist), a total of 113 patients with HIV were reported (154) . Results from epidemiologic and laboratory testing did not indicate that a HCW was the source of any of these infections.
The only publicly available HIV lookback investigation conducted in Canada was done in 2004 and involved 2,560 patients operated on by an infected HCW at a pediatric hospital (155) . In this report, a total of 2175 patients (85%) were tested and no HIV infections were identified.
A review of all investigations of potential exposure to BBVs in healthcare settings in Ireland was conducted between 2007 and 2011 (156) . This study identified one lookback investigation that involved testing 66 potentially exposed patients for HIV; no case of transmission from the infected HCW was identified.
Published lookback investigations, from 1985 to 2014, involving 36 incidents of patients exposed to HCWs infected with HIV with no documented transmission are summarized by HCW specialty in Table 5. A total of 41,939 patients were reported to be exposed to 36 HCWs infected with HIV in a variety of healthcare settings. Of these patients, a total of 18,391 (44%) had their HIV status examined and no transmission was found. A detailed summary of the individual exposure incidents is presented in Table 21, Appendix I. For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HIV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where no transmission was reported. Of the 44 epidemiologic investigations with no documented transmission of HIV, 15 investigations (all involving EPPs) were eligible for inclusion in the systematic review. Findings on key preventive measures and risk factors for transmission are summarized in Table 6.
) 11 (0) 1 (0) 1 (0) 0 (0) 0 (0) 1 (0) Total No EPP (non-EPP) 7 (0) 1 (0) 1 (0) 4 (0) 6 (0) 6 (0) 0 (0) 0 (0) Total NR EPP (non-EPP) 5 (0) 9 (0) 3 (0) 10 (0) 8 (0) 9 (0) 15 (0) 14 (0)
Abbreviations: HIV, human immunodeficiency virus; EPP, exposure-prone procedure; IPC: infection prevention and control; PEP, post-exposure prophylaxis; NR, not reported; HCW, healthcare worker A N=15 for total number of infected HCWs from all reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made. An obvious limitation in all lookback investigations is that only a percentage of potentially exposed patients are tested. Although it is not clear what the minimal criteria are to reliably conclude that there was no evidence of transmission in an exposure episode (e.g., magnitude of the lookback investigation or minimum percentage of exposed patients that should be tested), it has been indicated that available studies collectively provide evidence that the overall risk of transmission from HCWs infected with HIV to patients is "likely to be very low" (172) . Although this risk is not zero, it can be rendered negligible if HCWs infected with HIV who perform EPPs adhere to recommendations that have addressed the identified risk factors from previous exposure incidents.
Recommendations provided for minimizing risk of HCW-to-patient transmission of HIV have taken into consideration preventive measures and risk factors reported in exposure incidents to date.
# HIV Viral Load
Deciding on a viral load cut-off level to determine an infected HCW's fitness for practice increases patient safety and optimizes the work force. High viral load is associated with both the acute phase of the infection (which may go unnoticed) and with late-stage AIDS at which time the HCW is more likely to be symptomatic (179) . Currently, there is a paucity of empirical data relating viral load and occupational transmissibility of HIV in a quantitative manner. Instances of HIV transmission during an EPP without documented IPC breaches have not provided robust data to inform a viral load cut off. This is primarily because the HCW's viral load at time of patient exposure, although expected to be high was most often not reported or unknown (72,117,150,180) .
Although viral load at the time of an exposure incident is usually not available, studies discussed thus far indicate that regardless of viral load, the risk of HIV transmission through an EPP is minimal. A 10-year lookback investigation involving 545 of 1,669 patients operated on by a cardiothoracic surgeon infected with HIV found no transmission occurred despite a viral load over 100,000 copies/mL at time of diagnosis (178) .
In conducting the systematic review to inform HIV infectivity or transmissibility related to viral load, the selection criteria allowed for inclusion of studies with blood-to-blood exposure and the reported time between potential exposure and source viral load determination. As a result, data informing this section includes data from patient-to-HCW exposure via percutaneous or other sharps injury. This allows for an analysis of HIV transmission (or absence thereof) from one person to another with different viral loads reported during exposure. Table 7 shows the relevant information from eligible studies of this systematic review. Overall, the studies did not show a consistent trend between high viral load and increased infectivity or transmissibility. In one study involving a HCW exposed to a high viral load of 5.3 x 10 7 copies/mL (via a deep needlestick injury), HIV transmission did not occur (181) . The lowest viral load at which HIV transmission occurred from one individual to another via a definite blood-to-blood exposure was 1500 copies/mL (117) .
The demand for accurate, reproducible, and cost-effective viral load assays is recognized at a global level (182) . Studies have shown that certain assays are less reliable for accurate viral load measurements. Genetic variation in HIV subtypes or extreme divergence within HIV subtypes may also significantly affect the ability to detect and quantify the viral RNA in clinical specimens (182) . Due to the different assays used for viral load measurements or incomplete information reported on the assay used, it is not possible to accurately compare the viral loads across studies presented in Table 7. Standardizing assays and units for measuring BBV viral load will allow for more accurate comparison across studies.
Most individuals initiating antiretroviral therapy (ART) experience effective and prolonged control of viral replication in the plasma (183)(184)(185)(186) . The impact of time of initiation of therapy on viral suppression and optimization of treatment outcome has been discussed in several studies (79,183,(186)(187)(188)(189) . In a study investigating HCW's exposure risk during surgical procedures on patients infected with HIV, the patients' viral load was reduced prior to surgery. This was done in an effort to ensure the safety of the operating team and best possible conditions for patients (147) . Collectively, these studies suggest that antiretroviral therapy lowers viral load thus minimizing the risk of HCW-to-patient or patient-to-HCW transmission. To date, there has not been a single reported case of HCW-to-patient transmission of HIV from an infected HCW receiving and adhering to antiretroviral therapy (71) . The reported transmission incidents involved untreated or treatment non-adherent HCWs. This suggests that recommendations to minimize risk of transmission should focus on treatment of infected HCWs as a means to maintain a low viral load. Strict adherence to therapy is essential for sustained HIV suppression, reduced risk of drug resistance, improved overall health, quality of life, and survival, as well as decreased risk of HIV transmission.
# Elite Controllers
Elite controllers are defined as individuals infected with HIV who are not receiving therapy and have maintained undetectable viral load in the blood (HIV RNA < 50 copies/mL) for at least one year, based on three separate viral load assessments (190)(191)(192)(193) . This spontaneous control of viral replication in the absence of therapy is estimated to occur in approximately 1 in 300 individuals infected with HIV (191,192) .
Although elite controllers have undetectable viremia by standard clinical assays, when using more sensitive assays for RNA detection in the plasma, studies have reported that almost all elite controllers have detectable levels of plasma viremia and viral 'blips' of > 50 copies/mL occur (192,(194)(195)(196) . This shows that virus from elite controllers is replication-competent and has no substantial genetic defect. Additional studies involving elite controllers show that despite undetectable plasma RNA levels, residual viral replication occurs in the absence of therapy and contributes to a chronic inflammation state (192,197,198) . As a result, elite controllers (including HCWs who perform EPPs) should be followed closely, as some may experience CD4 + cell decline, loss of viral control, or complications related to HIV infection. (199) Patient A Articles reporting transmission linked to sexual, blood transfusion and perinatal routes have been excluded. B Different assays may yield different values in copies/mL. C Zidovudine for 4 years before the transmission. D Initiated PEP (zidovudine 1000 mg per day) within one hour of exposure but stopped after 5 days due to side effects. E Article identified during the systematic review for risk of transmission of HIV or viral load and infectivity for HCV or HBV. F Goujon et al (2000) report that the HCW's viral load was 1,800 x 10 2 copies/mL (153) . G Source asymptomatic at time of diagnosis however, had had 'severe glandular fever' two years before (and one month after likely exposure event). H Application of topical therapy to active psoriasis lesions without gloves. I Source with HIV-HCV co-infection. J Source had measurement of two plasma VL samples while being cared for by the exposed person. The exposed person was likely infected in 1999 with possible seroconversion illness seven months prior to source's death. During the exposure period, the source was not on treatment from February to July 1999. K The source individual was on highly active antiretroviral therapy at the time of the fight. L The source patient was HIV-HCV co-infected. The exposed person received an expanded 3-drug HIV PEP. There was no HIV transmission however, HCV was transmitted. M Coma in injection drug user. N The HCW delayed in reporting the injury so commencement of PEP was delayed for 84 hours. O Patient admitted with a diagnosis of dementia.
# Recommendations for Management of Healthcare Workers Infected with HIV
Recommendations A 1.
# 2.
All HCWs who perform EPPs have ethical and professional obligations to know their HIV status B .
If negative, those performing EPPs should be tested at appropriate intervals as determined by their level of risk and whenever an exposure has occurred.
# Grade of evidence: CI
A The grade of the body of evidence upon which a recommendation is based is shown here (refer to Table 34, Appendix II for the grading scale). The full critical appraisal tool informing this scale can be found in PHAC's Critical Appraisal Tool Kit (8) . B Ethical obligation may be traced to principles of non-maleficence (the duty to intentionally refrain from actions that cause harm), which includes an obligation for HCWs not to impose risks of harm to patients and creates a standard of due care (12)(13)(14)209) C There are variations in minimum detectable viral load thresholds for different assays. In addition, there may be situations where very low viral loads and/or transient blips (up to 400 copies/mL) may occur. These blips may not be clinically relevant and thus do not indicate treatment failure and will not necessarily trigger practice restrictions or lookback investigations. However, some jurisdictions may manage transient blips by maintaining stricter or more conservative thresholds (210) . D Refer to the section on Expert Review Panels.
# RISK OF TRANSMISSION OF HCV
There is a lack of consistency in the body of evidence relating to viral load units of measurement for BBVs. In this document, HCV viral load is reported as IU/mL (copies/mL) as this is the current reporting practice for Canadian laboratories and the WHO (211) .
# Incidence and Prevalence of HCV
The first Canadian study to report seroprevalence of HCV infection based on a nationally representative household sample was the Canadian Health Measures Survey (CHMS) conducted from 2007 to 2011 (212) . Estimates in this study are based on data collected from 8,434 survey respondents. Although the number of new cases of HCV in Canada has decreased in recent years, the number of prevalent cases remains high. Data from the CHMS, showed that an estimated 0.5% (95% CI: 0.3-0.9) of the population, representing a total of approximately 138,600 (95% CI: 55,800-221,300) people (aged 14-79 years) had laboratory evidence of an HCV infection as identified by HCV antibody (212) . Hepatitis C infection was more common in the 50-79 year old group compared to the 14-49 year old group and in individuals living in lower income households. A modelling study estimated that between 0.64 and 0.71% of the overall Canadian population was living with chronic HCV infection in 2011 and 44% of these individuals were undiagnosed (213) .
The number and rate (per 100,000) of reported cases of HCV infection in Canada from 1991 to 2016 based on data from the CNDSS can be found on PHAC's Notifiable Diseases Online page here: http://diseases.canada.ca/notifiable/charts?c=pl
The prevalence of anti-HCV positivity in HCWs worldwide ranges from 0% to 9.7% in different studies (48) . Several studies in western countries have concluded that the seroprevalence of HCV among HCWs is low and comparable to that of the general population (27,(214)(215)(216)(217) . On the other hand, a systematic review and meta-analysis of data from studies conducted internationally, generated different findings for the estimated prevalence of HCV among HCWs compared to the general population (218) . The study population was limited to HCWs in direct contact with patients or with blood. Results showed that the prevalence of HCV infection was significantly higher in HCWs than in the control general population. Stratification by occupational groups showed the highest prevalence was among medical and laboratory personnel, and HCWs who had a high risk of blood contact (surgeons, midwives, microbiologists, pathologists, blood bank and dialysis staff). Although a higher prevalence was also reported for dental HCWs (dentists and dental hygienists) than for the control group, the stratification for this group of HCWs was limited due to a paucity of published studies. Stratification by nursing staff did not show a significant increase in prevalence although results may have been confounded by blood exposure misclassification for this group of HCWs (218) . The study authors noted the need for prospective studies focusing on HCW-specific activity and personal risk factors for HCV infection.
In addition to the potential risk for occupational exposure, HCWs are subject to the same nonoccupational risk factors for HCV as the general population. It is not known if the prevalence of HCV among Canadian HCWs is similar to that reported for the general public. This information as well as a Canadian estimate of the rate of transmission from infected HCWs to patients is needed to determine the true risk of transmission in Canada.
# Estimated Risk of HCV Transmission
The risk of transmission of HCV through contaminated blood exposure, as estimated from modelling studies and lookback investigations has been found to be higher than that for transmission of HIV (65) .
Table 22, Appendix I, shows that the rate of transmission to patients estimated from epidemiologic lookback investigations following exposure episodes via an EPP varied, ranging from 0.04 to 3.7%. Generalizations regarding risk cannot be made from these transmission studies as the rates vary according to circumstances unique to each incident, such as viral load of infected HCW, sample size of the lookback investigation, and possible IPC breaches. As a result, mathematical modelling studies are also used to estimate the risk of transmission of HCV. One modelling study concluded that the risk of transmission of HCV from an infected surgeon to patient(s) is about 0.0062 to 0.057%, corresponding to 1 chance in 1,750 to 1 in 16,000 procedures (65) . When the surgeon's serologic status was unknown, the risk of transmission during a single operation was about 0.00008 to 0.000074%, corresponding to 1 chance in 135,000 to 1 in 1.2 million. This risk is comparable to the chance of acquiring HCV by receiving a blood transfusion from first-time donors who have previously screened negative for HCV antibodies (65) . Literature reviews show that the risk of HCW-to-patient HCV transmission (in incidents where illicit diversion of injectable patient medication by HCWs was considered unlikely) was less than 0.6% (30,33,219) .
To estimate the rate of transmission of HCV from infected HCWs to patients from reported HCV exposure incidents, a meta-analysis of eligible exposure incidents was conducted [manuscript in development]. A total of 9 incidents were eligible for the meta-analysis with 2 of them involving no transmission of HCV. The pooled transmission rate for HCV using the random effects DerSimonian-Laird model was 0.46% (95% CI: 0.07-1.17%). This corresponds to a chance of 460 per 100,000 individuals (95% CI: 70 to 1170 per 100,000 individuals) becoming infected in the absence of IPC breaches and illicit diversion of patient medication.
# Review of Patient Exposure Incidents with Transmission of HCV
There have been over 20 epidemiologic investigations of HCV transmission from infected HCWs to patients conducted between 1996 and 2016 (refer to Table 22, Appendix I). It is likely that other transmission incidents have occurred but were either not published or not reported as exposures are often unrecognized and the asymptomatic phase of HCV infection can last many years, so transmission is not easily detected. The majority of investigations were triggered by patients showing symptoms of acute hepatitis C or testing positive for HCV following surgical procedures. According to the reports from these investigations, a total of at least 13,494 patients were considered to be exposed to HCV during EPPs and in a few cases non-EPPs performed by HCWs infected with HCV. In most cases, the HCWs were either unaware of their HCV status or the study did not report on their awareness. As a result, the infected HCWs continued to perform EPPs without seeking medical attention for their infection. Of the exposed patients, a total of 8,652 (64%) were tested for HCV. Transmission of HCV from HCWs to patients occurred in 30 of these patients. Table 8 provides a breakdown of the number of patients exposed and the number of patients tested, grouped by HCW specialty. A detailed summary of the individual exposure incidents is presented in Table 22, Appendix I.
In comparison to HIV and HBV transmissions, cases of HCW-to-patient HCV transmission were disproportionately attributed to confirmed or suspected HCW illicit diversion of patient medications involving reuse of needles for self-injection by the HCW. These situations often involved infected anesthesiologists or nurse anesthetists. A recent systematic review of HCV infections from healthcare-associated outbreaks between 1999 to 2012 showed that up to 50% were attributable to HCW tampering (diversion, self-injection, and substitution) of anesthetic opioids (220) . Transmission risk from tampering was substantially higher than from surgery. Investigations reporting confirmed illicit diversion of patient medication by an infected HCW do not inform recommendations for risk of transmission during an EPP, and are therefore not included in the detailed summary of exposure investigations presented in Table 22, Appendix I (221)(222)(223) .
Some investigations revealed possible or known breaches in IPC practices as the mechanism of transmission, and therefore, may not inform recommendations for risk of transmission during an EPP (50,134,(136)(137)(138) . However, these studies may provide insight into possible mechanism(s) of HCV transmission during a non-EPP. In Canada, the only reported outbreak of HCV in a tertiary-care hospital involved IPC breaches by HCWs participating in and performing procedures on each other as part of a research study, which resulted in HCV transmission from one infected healthcare technologist to 4 other HCWs. A subsequent lookback investigation to assess for HCW-to-patient transmission did not identify any patients infected (51) .
A case report of HCV transmission from an infected anesthetist to a patient without EPPs was reported in 2005 (31) . This was the first case of transmission where the anesthetist was known to be HCV-RNA positive prior to the procedure and adhered to existing IPC protocols to minimize the risk of transmission. The anesthetist's HCV-RNA level was not available at the time of the exposure incident, but was found to be 11 million copies/mL when tested several years later. The anesthetist inserted a cuffed oral endotracheal tube and also inserted a peripheral cannula. The HCW denied any possibility of injection drug use, reported no open wounds, IPC breaches, or injuries during the procedure. The study authors postulated that transmission may have occurred by HCV shed from abrasions to the anesthetist and then inoculated to the patient via microabrasions. The study did not report on whether the anesthetist had undergone treatment for HCV infection. Another report of HCW-to-patient transmission of HCV during a non-EPP involved an infected home care nurse. This incident draws attention to the risk of transmission in home care settings and the challenges of confirming direction of transmission (134) . Identification of the mechanism and implications of transmission of HCV from an infected HCW to a patient in the absence of EPP and no reported IPC breach may require a closer review of these incidents (135) . Among patients with acute HCV infection in Italy and Spain, a documented risk factor was hospitalization without any invasive procedure in some patients (224,225) . Although it was very difficult to determine the exact mechanism of HCV transmission, the mechanisms reported included patient-to-patient transmission, an outbreak due to the use of multidose drug vials, or poor IPC practices. The prolonged viability of HCV in fomites and on hospital equipment has been hypothesized to contribute significantly to healthcare-associated transmission in the absence of invasive procedures (226) .
Several studies show that EPPs were the sole or major mechanism of transmission and are therefore the basis upon which risk of transmission of HCV from an infected HCW to a patient and recommendations for prevention are based (75,76,109,112,113,118,120,219,(227)(228)(229)(230)(231) .
The summary of epidemiologic investigations reporting HCW-to-patient transmission of HCV excludes studies that did not report the number of patients exposed and the number of patients tested (refer to Table 8). Most of the infected patients (21 out of 30) acquired their infection from either infected cardiothoracic surgeons or obstetrician/gynecologists.
A transmission incident that was recognized in 2012, involved a retired obstetrician / gynecologist who had practised for over 30 years and was unaware of an HCV infection until after retirement (78) . In an extensive lookback investigation spanning over 18 years, four out of 5500 patients (0.07%) were found to be infected (to date of writing this guideline) (78) . In another episode, an infected midwife who worked on the post-natal unit transmitted HCV to one patient (135) .
In the two transmission incidents involving anesthetists, no IPC breach was reported although drug diversion could not be ruled out in one investigation (31,137) . General surgery (231) 1 1,461 1,193 (82) 1 Orthopedics (75) 1 229 207 (90) 1 Hemodialysis (140) 1 In 2016, a lookback investigation was conducted on a HCW infected with HCV in the UK (232) . When the HCW was initially found to be seropositive, the UK Advisory Panel for Healthcare Workers Infected with Bloodborne Viruses (UKAP) advised that patients did not need to be notified as the risk of transmission was thought to be low. However, following the emergence of two infected patients, further investigations found it was "probable" the HCW transmitted the virus during a surgical procedure. In total, 8,383 patients across the UK received letters informing them of the situation and urging them to arrange a blood test.
For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HCV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where HCW-to-patient transmission was reported. Seventeen such investigations were eligible for inclusion in the systematic review. Nine of the 17 investigations involved an EPP. Findings on key preventive measures and risk factors for transmission are summarized in Table 9. 3) 7 (3) Abbreviations: HCV, hepatitis C virus; EPP, exposure-prone procedure; IPC, infection prevention and control; NR, not reported; HCW, healthcare worker A N=17 for total number of infected HCWs from all reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made. H Percutaneous injury: Percutaneous injury potentially exposing patient to HCW's blood was reported. I Diversion ruled out: Illicit diversion of patient medication by HCW was ruled out. J Several articles indicate that although a percutaneous injury during an EPP on a specific patient was not described, injuries were reported to occur during certain procedures. The HCWs could not recall ever bleeding into a patient's wound (75,109,118) . K The HCW denied drug abuse but the authors could not rule this out as an explanation for transmission (137) . L Several members of the care team were tested, including surgeons, anesthesiologists, and nurses (50) . The specialty of the infected HCW was not reported, however, as it was reported that the infected HCW did not wear gloves systematically, the data have been pooled in the non-EPP column.
# Review of Patient Exposure Incidents with No Transmission of HCV
Published epidemiologic investigations for HCV transmission from eleven infected HCWs to patients did not find any cases of transmission. Of these investigations, the nine incidents that reported the number of patients exposed and tested are summarized by HCW specialty in Table 10. Exposure incidents due to five of the infected HCWs are documented in a single report (63) . A total of 9,837 patients were reported to be exposed to the nine HCWs infected with HCV. Of these patients, a total of 5,738 (58%) had their HCV status examined and no transmission was found. A detailed summary of the 11 individual exposure incidents is presented in Table 23, Appendix I. Infection prevention and control breaches were reported in three of the investigations (173,233,234) . One investigation was conducted in Canada to determine possible HCV transmission from a general surgeon to patients who underwent high risk procedures in the three years before the surgeon was found to be seropositive (77) . Healthcare technology (51) 1 498 215 (43) Orthopedic surgery (235) 1 1,513 1,068 (71) Obstetrics and gynecology (63) B Staged lookback investigations related to the practices of 5 infected HCWs were recommended by the UKAP. These involved the last 500 patients (of each HCW) who had undergone higher risk EPPs. Upon extension of the lookback investigation related to one of the five infected HCWs, potentially exposed patients from 1987 onwards were tested for HCV and HCW-to-patient transmission was identified (234) . This information is captured in Table 22, Epidemiologic investigations reporting transmission of HCV from infected HCW to patient (Appendix I).
C Information on two additional HCWs infected with HCV is not included due to missing data on the number of potentially exposed and tested patients.
For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HCV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where no transmission was reported. Three such investigations were eligible for inclusion in the systematic review. Two of the three investigations involved an EPP. Findings on key preventive measures and risk factors for transmission are summarized in Table 11. Recommendations provided for minimizing risk of HCW-to-patient transmission of HCV have taken into consideration preventive measures and risk factors reported in exposure incidents to date.
) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0) 0 (0) Total No EPP (non-EPP) 2 (1) 1 (0) 1 (0) 1 (1) 0 (0) 0 (0) 0 (0) Total NR EPP (non-EPP) 0 (0) 1 (1) 1 (1) 1 (0) 2 (1) 1 (1) 2(
# HCV Viral Load
Acute HCV infection is often asymptomatic, therefore detection and diagnosis can be difficult. Studies show that intermittent low level HCV viremia can occur up to two months before the period of exponential increase in viral load and the high titre plateau-phase viremia that usually precede seroconversion (236) . In general, 50 to 85% of people infected with HCV develop chronic infections with some variability based on certain factors (212,237) . In the chronic phase of HCV infection, infected persons can transmit infection via blood and other infected body secretions (33) .
High viral load appears to be a major determinant influencing an infected individual's efficiency in transmitting HCV (238) . Most of the viral load testing conducted in lookback investigations of patients exposed to an infected HCW was done months after the exposure episode, perhaps making this information unreliable for determining infectivity based on viral load at the time of exposure.
Complete spontaneous or therapy-induced resolution of HCV infection can occur (239) . Spontaneous clearance of HCV is found to occur more frequently among those who experience symptomatic HCV with high viral titres, and occurs during the first 3 to 6 months of infection (240,241) . In a prospective cohort study, the spontaneous viral clearance rate after six months of infection was 18%; another study reported a 20 to 50% chance of spontaneous resolution of infection (242,243) .
Hepatitis C viremia is unusual after successful treatment, which is defined as sustained virologic response (SVR) or undetectable HCV RNA 8-12 weeks after therapy is completed (244)(245)(246)(247) . A meta-analysis reported that SVR appears durable in the majority of patients at 5 years posttreatment with a summary 5-year recurrence risk of 0.95% among HCV mono-infected "lowrisk" patients (248) . Notably, the higher pooled estimates of recurrence observed in high-risk and coinfected cohorts were driven by an increase in reinfection rather than late relapse. Sustained virologic response with undetectable HCV-RNA following completion of current HCV therapy is considered a durable and clinically significant endpoint (244,246,247,249) . Treatment for HCV continues to improve and published data shows success rates in treatment should be over 90% (212,248,(250)(251)(252)(253)(254)(255)(256)(257) .
There is not much variability reported in viral loads of HCWs infected with HCV involved in transmission incidents (between 10 5 to 10 7 IU/mL) and there is no viral load that is considered non-infective. In conducting the systematic review to inform HCV infectivity or transmissibility related to viral load, the selection criteria allowed for inclusion of studies with blood-to-blood exposure and the reported time between potential exposure and source viral load determination.
As a result, data informing this section includes data from patient-to-HCW exposure via percutaneous or other sharps injury. This allows for an analysis of HCV transmission (or absence thereof) from one person to another with different viral loads reported during exposure. Table 12 shows the relevant information from eligible studies of this systematic review.
The risk of transmission of HCV can be eliminated with treatment of the infected HCW resulting in no detectable HCV RNA in the blood. As a result, recommendations provided for managing HCWs infected with HCV are focused on treatment rather than identifying a viral load cut-off level for fitness-for-work. (134) Companion L : (263) HCW A Articles reporting transmission linked to sexual, blood transfusion, and maternal-child routes have been excluded. B Viral load as reported in study (R) or calculated using an assay-specific conversion factor (C). If the assay for quantification was not reported in the study or if unable to determine the conversion factor, 'NR' was included in the relevant cell. One copy is equal to 1 genome equivalent (266) . C Treatment failed. D The source patient underwent a colonoscopy with multiple biopsies on the same morning and prior to the two exposed patients who also underwent colonoscopies with either multiple biopsies or a polypectomy. Serious IPC breaches were identified related to the endoscope cleaning and disinfection procedures (between all patients) and for the administration of anesthesia (between the two exposed patients). E Quantiplex bDNA 2.00, Chiron Diagnostics Europe, Cergy Pontoise, France. F Quantiplex HCV RNA Assay [bDNA]; Chiron Corp, Emeryville, Calif. G Amplicor HCV Monitor Test and Quanti-Path Kit, Roche Diagnostics (one IU/mL is equal to 0.9 copy/mL therefore 1 copy/mL is equivalent 1.1 IU/mL). H Versant 3.0 b-DNA Assay (one IU/mL is equal to 5.2 copies/mL). I The HCW became symptomatic 3 days after the exposed patient's procedure. J Injury with tip of needle used to monitor capillary blood glucose in spouse with diabetes and known chronic hepatitis C infection. K In-house real-time (rt)-PCR (detection limit 600 IU/mL). L Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table.
M The authors report as a possible case of HCW-to-patient transmission during home care as they were not able to determine the direction of transmission as the serologic status of the HCW was not known prior to the investigation (134) . In 2010, the authors report that an audit of the HCW's IPC practices is ongoing (263) ; in 2011, they emphasize the importance of HCWs wearing gloves if exposed to blood, in addition to other routine IPC practices (134) . N (8) .
B Ethical obligation may be traced to principles of non-maleficence (the duty to intentionally refrain from actions that cause harm), which includes an obligation for HCWs not to impose risks of harm to patients and creates a standard of due care (12)(13)(14)209) . C Due to the availability of effective therapy for HCV with sustained virologic response, this guideline does not recommend a serum HCV RNA cut off level for practice restrictions as recommended in other guidelines. D The overarching principle for management of HCWs infected with HCV who perform EPPs is to restrict practice while the virus is detectable (267) . E Refer to the section on Expert Review Panels.
# RISK OF TRANSMISSION OF HBV
There is a lack of consistency in the body of evidence relating to viral load units of measurement for BBVs. In this document, HBV viral load is reported as IU/mL (GE/mL) as this is the current reporting practice for Canadian laboratories and WHO (268) .
# Incidence and Prevalence of HBV
Approximately two billion people worldwide have serologic evidence of past or present HBV infection and approximately 350 million people are currently chronically infected (269,270) . Canada is considered a country of low HBV endemicity; however, there are substantially more reported cases within the foreign-born population, Indigenous peoples of Canada, people who inject drugs and men who have sex with men (212) . In Canada, the rates of reported acute HBV infections declined from 1.0 to 0.6 per 100,000 between 2005 and 2012 (237) . Primary HBV infection can be self-limited, with elimination of the virus from blood and subsequent lasting immunity against reinfection, or it can progress to chronic infection (270) . The risk for progression to chronic infection is inversely related to age at the time of infection (270) . Persons with chronic HBV infection are the major source of new infections (270) . Chronic HBV is likely to occur in <5% of infected older children and adults, approximately 25 to 50% of infected children aged 1 to 5 years old, and >90% of infants infected at birth (212,237,270,271) . Reporting of chronic HBV infection was variable across provinces and territories until 2009, making interpretation of earlier trends difficult. The number and rate (per 100,000) of reported cases of HBV infection in Canada from 1969 to 2016 based on data from the CNDSS can be found on PHAC's Notifiable Diseases Online page here: http://diseases.canada.ca/notifiable/charts?c=pl
Approximately half of all HBV cases are asymptomatic and approximately half of individuals infected with HBV are unaware of their status. As a result, the true incidence of HBV infection is most likely significantly underestimated (212,269) .
The introduction of the HBV vaccine in 1982, followed by the implementation of routine childhood immunization programs in Canada in the 1990s and screening during pregnancy have all contributed to decreasing rates of HBV (95,212,237) . Results from the Canadian Health Measures Survey conducted from 2007 to 2011, showed that 72.6% (95% CI: 69.6-75.4) of children aged 14-19 years had vaccine-induced immunity, and this rate decreased with increasing age but natural immunity increased with age (212) . Overall, the incidence of hepatitis B infection has decreased in all age groups in recent years, and has virtually disappeared in the cohorts that have benefited from routine immunization programs (95) .
Several seroprevalence surveys conducted before the availability of the HBV vaccine showed that HCWs had prevalence rates of past or present HBV infection that were three to fivefold higher than the general US population (272) . Following the implementation of preventive measures including HB vaccine and universal precautions (refer to Glossary), there was a significant decline in the incidence rates among HCWs (270,273) .
In addition to potential risk of occupational exposure, HCWs who have not been vaccinated or who are nonimmune following vaccination are subject to the same risk factors for HBV infection as the general population. The rates of HBsAg and anti-HBc positivity in HCWs worldwide published in several studies over the last three decades range from 0.1% to 8.1% and 6.2% to 73.4% respectively (48) . It is not known if the seroprevalence of HBV among Canadian HCWs is similar to that reported for the general public.
# HBV Serologic Markers
HBV is a DNA virus with a core protein surrounded by a coat containing surface antigen (HBsAg). The serologic markers of chronic HBV infection are varied and complex. Antigens and antibodies associated with HBV infection include HBsAg and antibody to HBsAg (anti-HBs), antibody to HBcAg (anti-HBc), and hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe). At least one serologic marker is present during each of the different phases of HBV infection (270) . The serologic markers are briefly described in Table 26, Appendix I (62,270,(274)(275)(276) . Some individuals infected with HBV carry a viral strain with a nucleotide substitution in the precore region of the viral genome. This mutation prevents transcription of the precore region and therefore, the release of HBeAg from the hepatocyte which results in a negative serum test for HBeAg.
The serologic markers currently used to identify a person's HBV status are HBsAg, anti-HBc IgG, and anti-HBs (270) . The only way to definitively differentiate acute from chronic infection is if HBsAg persists for more than 6 months. Table 27, Appendix I describes the typical serologic patterns used to interpret HBV serologic status. HCWs infected with HBV have transmitted infection to patients while in the incubation period of infection, during acute hepatitis, a few months following acute hepatitis, and during the chronic phase of infection.
# Estimated Risk of HBV Transmission
HBV is highly infectious, can be transmitted in the absence of visible blood, and has been reported to remain infectious on environmental surfaces for at least 7 days (66,270,277,278) . Hepatitis B virus is approximately 100 times and 10 times more infectious than HIV and HCV respectively. Several instances of healthcare-associated transmission were documented in the 1980s and summarized in several articles (64,269,279) .
In a study involving 405 reported cases of acute HBV infection, 262 cases were interviewed for risk factors. A total of 1.9% reported percutaneous injury and 3.1% reported healthcareassociated risk factors (269) . In studies of HCWs who sustained injuries from needles contaminated with HBV, the risk of developing acute hepatitis if the blood was both HBsAg positive and HBeAg positive was 22-31%; and the risk for developing serologic evidence of HBV infection was 37-62%. By comparison, if the blood was HBsAg positive and HBeAg-negative, the risks decreased to 1-6% and 23-37% respectively (277) . It is reasonable to assume that the same risk for seroconversion, following patient exposure to an HBV-contaminated needle, apply to HBV transmission from HCWs to patients.
Results from prospective studies showed that the estimated risk of transmission during exposure of two groups of 1,000 patients each to HBsAg positive HCWs and to HBsAg negative HCWs were both estimated to be less than 1% (280) . Transmission rates ranging from 0.06-11.11% have been reported from retrospective lookback investigations (refer to Table 24, Appendix I). This highlights the limitation of retrospective studies (triggered by reported transmission events) in obtaining data on transmission rates. When an infected patient is the trigger for an investigation seeking to identify other potentially exposed patients, the study design will result in documented transmission (the index patient) (280) . On the other hand, if an infected HCW is the trigger for an investigation (lookback), results will indicate either transmission or no transmission to patients.
Although prospective studies provide an opportunity for appropriate controls, the infected HCWs' knowledge that they are being followed may influence them to follow more stringent precautions to prevent transmission (280) . Data informing the risk of transmission of HBV is mostly informed by published lookback investigations thus providing more incidents of transmission than no transmission of HBV.
Table 24 (Appendix I) shows the rates of transmission estimated from epidemiologic investigations following a transmission or exposure event. The risk of infection was positively associated with the invasiveness of the procedures (121,281) . Generalizations cannot be made from the transmission rates in these studies due to circumstances specific to each incident, including the viral load of the infected HCW, level of risk posed by the procedure(s) associated with transmission, sample size (which was very small in most studies), and possible IPC breaches (132,133,139,282,283) . As a result, mathematical modelling studies are also used to estimate the risk of transmission of HBV. A modelling study concluded that the risk of transmission of HBV from an infected surgeon is about 0.24-0.024%, corresponding to 1 chance in 420 to 1 in 4,200 per procedure (64) . The probability of transmission during a single procedure by an HBeAg positive surgeon is 0.24%. In one transmission incident, the risk of acquiring HBV from an infected surgeon did not significantly exceed the risk of acquiring HBV from other sources (284) .
To determine the observed rate of transmission of HBV from infected HCWs to patients in previous HBV exposure incidents, a meta-analysis of eligible exposure incidents was conducted [manuscript in development]. A total of 20 incidents were eligible for the meta-analysis including 3 with no transmission of HBV. The pooled transmission rate for HBV using the random effects DerSimonian-Laird model was 1.45% (95% CI: 0.601-2.658%). This corresponds to a chance of 1,450 per 100,000 individuals (95% CI: 601 to 2658 per 100,000 individuals) becoming infected in the absence of IPC breaches and illicit diversion of patient medication.
# Review of Patient Exposure Incidents with Transmission of HBV
Since the introduction of serologic testing in the 1970s, there have been over 45 reported incidents of HCW-to-patient transmission of HBV (273) . Published investigations (from 1986 to date) have been summarized in Table 24, Appendix I. A summary of these transmission incidents by HCW specialty is provided in Table 13. All levels of experience including trainees, clinical assistants and senior surgeons are represented; technical expertise or competence was not usually identified as a contributing factor in transmission incidents (285) . No dentist-to-patient transmission of HBV has been reported since the late 1980s. Two published incidents of HCWto-patient HBV transmission occurred in Canada. One involved transmission by an infected electroencephalogram technician due to IPC breaches during a non-EPP (132) and the other involved transmission by an infected orthopedic surgeon during an EPP (284) (refer to Table 24).
A review of reported HCW-to-patient HBV transmission incidents in medical and dental settings, suggests that HCWs infected with HBV who are not involved in EPPs do not transmit infection unless there are IPC breaches (285) .
A total of 35,665 patients were exposed to 21 HCWs infected with HBV from a variety of healthcare specialties. Out of this exposed group of patients, a total of 22,191 (62%) were tested and 216 of them were confirmed to be infected with HBV (refer to Table 13). The number of infected patients could be higher if one includes the additional 38 infected patients that were considered by the study authors to be probable or possible transmission from a HCW or were cases of undetermined origin where transmission during a procedure could not be ruled out.
# Eight of the investigation reports did not address the hepatitis B (HB) immunization status of the
HCWs who were infected. The remaining studies provided some information about whether the HCWs completed a full or partial vaccination series and whether they had documented serological confirmation of immune status as a result. Two HCWs had been vaccinated but most likely acquired their infection before vaccination. Of the incidents that reported immunization data, none of the infected HCWs implicated in transmission of HBV to their patients had completed a full HB vaccination series with documented serological confirmation of their immunity or there was inadequate investigation of nonresponder status after vaccination (116,121,123,124) . (119) . C Performed venepuncture, inserted intravenous lines and prepared and administered intravenous antibiotics. D HCW performed electroencephalograms with reusable needle electrodes.
For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HBV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where HCW-to-patient transmission was reported. Twenty-eight such investigations were eligible for inclusion in the systematic review. Twenty-three of the 28 investigations involved an EPP. Findings on key preventive measures and risk factors for transmission are summarized in Table 14. (41) EPP Yes
The Incident Investigation Teams and Others, 1997 (119) 5) 23 ( 5) Abbreviations: HBV, hepatitis B virus; EPP, exposure-prone procedure; IPC: infection prevention and control; PEP, post-exposure prophylaxis; NR, not reported; HCW, healthcare worker A N=28 for total number of infected HCWs from reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made. H HB vaccine: HCW had previous HBV vaccine. I Percutaneous injury: Percutaneous injury potentially exposing patient to HCW's blood was reported. J Patient PEP: Post-exposure prophylaxis was offered to exposed patient(s). K Diversion ruled out: Illicit diversion of patient medication by HCW was ruled out. L Response to HB vaccine not assessed post-vaccination for five HCWs (110,122,123,130,133) . M HCW was a known non-responder. Since the HCW was hepatitis B e antigen negative with hepatitis B e antibodies and there was no report of transmission, the HCW was allowed to practice as per existing guidelines (115) . N Evaluation of lack of response to vaccine not performed for four HCWs (116,121,123,124) . O One HCW was allowed to perform surgical procedures prior to confirmation of response to HB vaccine (123) . P Two incidents during a 6-month period when HCW cut hand while breaking a glass vial with frank bleeding on one occasion (133) . Q HCW was vaccinated in 1990 without prior serologic testing; testing in 1992 revealed chronic carrier status that did not require further follow up (139) . R HCW recalled several needlestick injuries but never reported them and did not recall an injury when providing care to the index case (290) .
# Review of Patient Exposure Incidents with No Transmission of HBV
There are very few reported HBV patient exposure incidents that describe a lack of transmission from the infected HCW. Three incidents reported in the literature are presented in Table 25, Appendix I. Only one study provided information on numbers of patients potentially exposed and tested related to a HCW infected with HBV (refer to Table 15). One study compared the risk factors for two infected surgeons, one who performed uncomplicated or low risk procedures and the other who performed higher risk procedures (122) . All patients who were seropositive for HBV infection were operated on by the surgeon who performed lower risk procedures, wore single gloves for operations and did not have post-exposure vaccination offered to his patients (refer to Table 16). An accelerated course of HB vaccine was offered to patients of the surgeon who performed higher risk procedures, under the premise that even if infection had already occurred, severe illness and the development of a chronic state may be prevented (refer to Table 16).
A second study was conducted prospectively to investigate possible transmission of HBV from nine infected HCWs to 246 patients (280) . Patients were exposed a total of 483 times and no transmission was documented. Two of the nine infected HCWs who were HBeAg positive and had circulating HBV DNA accounted for a total of two-thirds of patient contacts. This study reported aggregate data for number of patients exposed to all nine HCWs therefore could not be included in Table 15. (1 dental technician, 1 ICU nurse and 1 medical student) over a 30-month period. The results of the study were pooled for all patients of all HCWs (n=246) and for all exposures (n=483) with no evidence of transmission identified (280) .
For purposes of informing the systematic review question (What preventive or management measures can reduce the risk of transmission of HBV from infected HCWs to their patients?), data were extracted from all eligible epidemiologic investigations where no transmission was reported. Three such investigations were eligible for inclusion in the systematic review, all involving an EPP. Findings on key preventive measures and risk factors for transmission are summarized in Table 16.
) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0) 0 (0) Total No EPP (non-EPP) 1 (0) 0 (0) 0 (0) 1 (0) 1 (0) 0 (0) 0 (0) 0 (0) 0 (0) Total NR EPP (non-EPP) 0 (0) 3 (0) 3 (0) 2 (0) 2 (0) 3 (0) 3 (0) 2 (0)
3 (0) Abbreviations: HBV, hepatitis B (HB) virus; EPP, exposure-prone procedure; IPC: infection prevention and control; PEP, post-exposure prophylaxis; NR, not reported; HCW, healthcare worker A N=3 for total number of infected HCWs from all reported investigations. B If EPPs and non-EPPs performed by a HCW (e.g., dentistry), data from article was pooled under EPP. C Aware of status: HCW was aware of serologic status prior to exposure incident(s). D IPC compliance: HCW was compliant with current IPC standards. E Symptomatic: HCW was symptomatic during screening period. F Treatment: HCW was previously treated or was on treatment during screening period. G Practice review: HCW's practice was previously reviewed by independent expert(s) and recommendations made. H HB vaccine: HCW had previous HBV vaccine I Percutaneous injury: Percutaneous injury potentially exposing patient to HCW's blood was reported. J Patient PEP: Post-exposure prophylaxis was offered to exposed patient(s). K Diversion ruled out: Illicit diversion of patient medication by HCW was ruled out.
Recommendations provided for minimizing risk of HCW-to-patient transmission of HBV have taken into consideration preventive measures and risk factors reported in exposure incidents to date.
# HBV Viral Load
There was no clinical test for HBV viral load until the late 1990s. In general, the presence of eantigen is associated with high HBV viral load and was therefore used as a surrogate measure for infectivity in earlier recommendations (124,291) . However, a small subset of persons who are HBeAg negative may still have a high viral load (105,292) . Following reported transmission incidents from HBeAg negative HCWs (114,115,119,121,293) , and detection of HBV DNA in 64.5% of HBeAg-negative carriers (294) , the focus for assessing infectivity and risk of transmission has changed from HBeAg status to HBV DNA levels. Viral load and volume of blood determine the transmission risk of HBV and as a result, recent guidelines have indicated that viral loads are a more accurate measure on which to base recommendations for practice restrictions of HCWs infected with HBV who perform EPPs (105,190,273,295) . A comparison of various guidelines on this topic show a lack of consensus for the threshold above which practice restrictions are recommended for HCWs infected with HBV (44,105,273,(296)(297)(298) . This is likely the result of a very limited evidence base available to inform an optimal threshold (299,300) .
Several lookback investigations predate the availability of viral load testing. Information on viral load provided in some lookback investigations is limited by the inability to link HCW viral load at time of transmission with rate of transmission. The viral load is usually tested weeks or months after transmission has occurred. This has led to concerns that data on HBV DNA levels to inform a cut-off level for HCWs who perform EPPs is not sufficiently robust (47) .
There are considerable differences in results obtained from various HBV DNA quantitative assays for individual sera (301) . In addition, various publications use slightly different conversion factors for the unit(s) used to report HBV DNA, largely based on the assay used. For purposes of this guideline, HBV DNA is expressed in terms of IU/mL as recommended by the World Health Organization (WHO). The unit copies/mL is considered equivalent to genome equivalent (GE/mL) and one IU/mL is considered approximately equivalent to 5 GE/mL or copies/mL (105,266,302) .
Results from transmission incidents indicate that risk of transmission was higher with HBV DNA levels above 1.8 x 10 5 IU/mL (10 6 GE/mL) (292) . Analysis of HBV DNA levels in surgeons who transmitted HBV to their patients helped identify an HBV DNA level above which transmission of HBV during an EPP could not be excluded. The identified HBV DNA level was 6.9 x 10 3 IU/mL (4 x 10 4 GE/ml) (refer to Table 17) (294) . The study authors noted that assays for HBV DNA based on polymerase chain reaction (PCR) have a ½ log10 variance. In addition, fluctuations in HBV DNA levels up to 2 log10 have been reported in invidividuals infected with HBV who were HBeAg-negative and even higher fluctuations in individuals infected with HBV who are not on treatment. This necessitates allowing for in vitro variation in test results and in vivo fluctuations in HBV DNA levels (as demonstrated in HBeAg-negative individuals) before defining a cut-off HBV DNA level (294,303) . A review of available data showed that a minimal risk strategy would be to set a cut off level well below levels documented in transmission incidents to allow for fluctuations and a 3 log10 safety margin was considered sufficient to account for this (47) . A viral load cut-off level of 2,000 IU/mL (10 4 GE/mL) is recommended in Europe (273) , and 1,000 IU / ml (5x10 3 GE / mL) in the US (105) . The thresholds provided are thought to increase patient safety as well as optimize the workforce by preventing loss of HCWs who are safe to practice (273) .
Treatment with current antivirals reduces HBV DNA levels to undetectable or almost undetectable levels in most persons (105,268,(304)(305)(306)(307)(308) . Virtually all persons infected with HBV under treatment can expect reduction in HBV DNA viral loads within weeks or months of initiating therapy (105,306) . In a study involving 18 surgeons with chronic HBV infection monitored every three to six months for a median period of 5.6 years, antiviral therapy was offered if HBV DNA was above 10 5 copies/ml (57) . Sustained viral suppression was achieved in both HBeAg-negative and HBeAg-positive surgeons (57,300) . The provision of regular expert monitoring, including quantification of HBV DNA was considered a necessary aspect of successfully managing infected surgeons using antiviral therapy. A small proportion of untreated individuals infected with HBV who are HBeAg negative with low HBV DNA are at risk for having fluctuating HBV DNA levels. Regular monitoring of HBV DNA will assess for these fluctuations making it unnecessary to have a very high safety margin in setting a viral load cut off level for HBV infection (47) . If a HCW performing EPPs elects not to go on therapy, they would need to have their viral load checked frequently and would not be able to do EPPs if they go above the threshold. In addition, with a safety margin of 3 log10, there is no real difference between a HBV DNA cut-off level of 1000 IU/mL and 2000 IU/mL. HBV treatment is very effective at suppressing the viral load and HBV blips while on treatment would not go beyond 1000 IU/mL. The availability of safe and effective antiviral agents to treat chronic HB infection provides a greater imperative to identify persons who might benefit from medical evaluation, management, and treatment (270) . (266) . C One IU/mL is considered equivalent to 5 copies/mL (302) (therefore 1 copy/mL is equivalent to 0.2 IU/mL) except for studies described in Corden (2003) (294) where an assay-specific conversion factor of 5.82 was used as indicated by Roche. D Companion: Articles that provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table. E Semi-quantitative PCR dot-blot hybridization, with comparison serum containing 108 chimpanzee-infectious material (105) . F Liquid hybridization and enzyme-linked oligonucleotide assay (105) . G Lightcycler PCR (105) . H Semi-quantification by end-point dilution (105) . I Limited dilution PCR (105) . J Chiron Quantiplex Branched DNA assay and Roche Amplicor HBV DNA monitor (105) . K Versant HBV bDNA 3.0 assay. L Detection assay based on TaqMan technology.
# HBV Vaccination
Prior to the introduction of a vaccine in the 1980s, HBV was a major occupational risk to HCW with exposure to blood, blood products, and other body fluids. HBV infection is currently preventable by vaccination, and Canada has had high risk and universal childhood HBV immunization programs in place, in all provinces and territories, since the mid-1990s (62) . A survey conducted over a decade after the introduction of vaccines showed that 90% of dentists in Canada had completed an immunization series and an additional 3% had natural immunity (309,310) . A study to identify the proportion of transplant surgeons in the US who were adequately vaccinated against HBV was conducted in 2006 (311) . Out of 94 surgeons (27.3% of participants) who reported at least one needlestick exposure while operating on a patient infected with HBV, 14 (14.9%) were inadequately vaccinated. The authors concluded that the surgeons underestimated both the risk of percutaneous exposure while operating, and the risk of becoming infected with HBV if exposed. An inadequate vaccination series is likely to lead to antibody loss during long-term follow up of HCWs (312) .
Evidence-based strategies to improve compliance with HB immunization recommendations in the Canadian Immunization Guide have been successful (313) . Although the success of HB vaccination programs is well documented among the younger population (Figure 3), there may be many HCWs who remain at risk of acquiring HBV. The risk of HBV transmission to a HCW who has been fully immunized and has developed an immune response after vaccination is virtually zero (314,315) . Therefore, increasing the emphasis on universal HB vaccination programs among HCWs in Canada will reduce the future risk of HBV transmission from HCWs to patients and from patients to HCWs. and 2009 to 2011 Canadian Health Measures Survey (212) .)
Strategies applied by a university postgraduate medical school to improve medical trainee compliance with immunization standards led to very high compliance with statistically significant increases in compliance over a 3-year period (313) . Canada's National Advisory Committee on Immunization (NACI), recommends immunization with HB vaccine and postimmunization serologic testing within 1 to 6 months of completion of the vaccine series for people who are at increased risk of infection through occupational exposure to blood, blood products and bodily fluids that may contain HBV (95) . This group includes all HCWs exposed to blood and other body fluids. Detailed recommendations on HB vaccination can be found in the Canadian Immunization Guide (95) .
Response to HB vaccine after a 3-dose series is generally greater than 95% in young healthy people (95,316) . For cases of nonresponse, revaccination with ≥1dose of HB vaccine subsequent to the primary series increases the proportion of persons achieving vaccine-induced seroprotection and a cumulative response rates of 69% has been reported among initial nonresponders after three revaccination doses (277) . The vaccine response decreases with age and several factors have been used to predict risk of nonresponse or vaccine failure (317) . Although typical anti-HBs levels in the 100s to 1000s IU/L are achieved following vaccination, levels of anti-HBs above 10 IU/L have been documented to provide virtually complete protection against HBV (310) . HCWs who perform EPPs and do not have a protective level of antibody titre against HBsAg (anti-HBs > 10 IU/L) after vaccination require further investigation (95,116,119) . A potential cause of vaccine nonresponse is established chronic HBV infection. Other common causes include immune suppression (steroid therapy), chronic illness (hepatitis C infection, dialysis, rheumatoid inflammatory diseases), smoking and older age (318,319) .
Once there is a record of a complete vaccination series and seroconversion has been documented for a HCW, i.e., anti-HBs titre ≥ 10 IU/L, he/she can be considered immune and no further testing is required, even if an exposure occurs. HCWs who have not responded to appropriate vaccination should be counseled on their ongoing risk of infection as well as the use of measures to reduce the risk of transmission. They should also be regularly assessed for infection (e.g., annually and after exposure) (95) .
People who develop an anti-HBs titre of at least 10 IU/L (adequate anti-HBs titre) following the completion of a recommended vaccination schedule are considered protected for life (95) . Exceptions are some immunocompromised persons and people with chronic renal disease or on dialysis, who may require periodic booster doses if their anti-HBs titre falls below 10 IU/L. In immunocompetent individuals, although anti-HBs titres may become non-detectable over time, immune memory persists (95) . An assessment of evidence on long-term efficacy and effectiveness of HB vaccines in immunocompetent individuals, with particular focus on individuals immunized as infants and HCWs has been conducted (320,321) . NACI currently recommends that, following immunization of immunocompromised individuals, initial annual monitoring of HB antibody levels may be considered (322) . • If an anti-HBs titre of at least 10 IU/L is confirmed B , testing need not be repeated nor should further immunization be undertaken, with the exception of immunocompromised persons who should be tested periodically for waning immunity, and persons with chronic renal disease or on dialysis, who should be tested yearly. • If testing for anti-HBs is done 1 to 6 months after vaccination and the anti-HBs titre is less than 10 IU/L B , a primary vaccine failure has occurred and the HCW should be given a second vaccine series. The HCW should be retested 1 to 6 months after completion of the second series.
• If the HCW is tested more than 6 months after the initial series and the anti-HBs titre is less than 10 IU/L B , the cause may be either a primary vaccine failure or waning antibody. Evidence shows that, in immunocompetent people, immunity is long lasting although antibody may be non-detectable. The HCW should receive one booster dose and be retested one month later to document an anamnestic response (defined as anti-HBs titre ≥10 IU/L one to four weeks post booster vaccination). If the anti-HBs titre is still less than 10 IU/L B , the HCW should be tested for HBsAg and anti-HBc to rule out pre-existing chronic HBV infection. If both tests are negative, then a second vaccine series is indicated followed by anti-HBs serology 1 to 6 months after completing the second series B .
• HCWs who have documented evidence of failure to respond to two series of HB vaccine (i.e., anti-HBs titre of less than 10 IU/L) are unlikely to benefit from further immunization and will need passive immunization after potential exposure to HB B, C . Occupational health or infectious disease specialists may be consulted regarding any new strategies that may be available such as intradermal vaccination or high potency vaccine.
4. If an HB exposure occurs, and a HCW has had a documented anti-HBs titre of at least 10 IU/L, no further testing is needed unless the HCW is immunocompromised or has chronic renal disease or is on dialysis. These HCWs should be tested for anti-HBs after a potential HB exposure and given additional vaccine and HBIg if their anti-HBs titre is less than 10 IU/L B .
Abbreviations: HB, hepatitis B; anti-HBs, antibody to surface antigen; HBIg, hepatitis B immune globulin A Recommendations 3 (adapted) and 4 are excerpted from the Canadian Immunization Guide (95) . Additional information is provided in the 1993 NACI Hepatitis B statement (323) . This statement was published prior to the development of the NACI methodology for grading of recommendations (324) . As a result, these recommendations are not graded.
B Anti-HBs titre less than 10 IU/L is the international standard utilized by most laboratories but may vary by jurisdiction. Check with your local laboratory for the standard used locally. C The HCW should be referred to a specialist in immunization. (8) . B Ethical obligation may be traced to principles of non-maleficence (the duty to intentionally refrain from actions that cause harm), which includes an obligation for HCWs not to impose risks of harm to patients and creates a standard of due care (12)(13)(14)209) C Countries or areas with moderate to high risk of HBV are identified by the World Health Organization (325) . D Refer to the Canadian Immunization Guide for immunization of persons new to Canada (95) . E HBV antiviral therapy may be required to allow HCWs infected with HBV to perform EPPs. F One IU/mL is considered equivalent to 5 copies/mL (i.e., 1 copy/mL is equivalent to 0.2 IU/mL) (302) . G Because the focus is on patient safety, HCWs who perform EPPs should be treated at this serum level regardless of recommendations in current treatment guidelines. With adherence to treatment as part of the threshold for infected HCWs to perform EPPs, HBV DNA levels are reduced to almost undetectable in most people. As a result, several known inconsistencies (e.g., differences in recommended HBV DNA threshold in various international guidelines, in-vivo fluctuations in a person's HBV DNA levels without treatment, variation in HBV DNA test results based on different assays used, or variations in results from repeated test of the same blood sample using the same assay) will likely have minimal impact on decisions regarding practice restrictions.
H Refer to the section on Expert Review Panels.
# CO-INFECTION WITH BLOODBORNE VIRUSES
Due to similar routes of infection, co-infection with any combination of HIV, HCV or HBV is not uncommon, especially among individuals with high risk of blood exposure such as hemophiliacs and people who use injection drugs (32,184,(326)(327)(328)(329) . A review of published literature on co-infection involving any two or all three of these BBVs was conducted in order to summarize considerations or challenges associated with management of HCWs with a BBV co-infection related to the risk of BBV transmission to patients.
Reports of co-infection with HIV-HBV and HBV-HCV are limited (328,330) , while reports of coinfection with HIV-HCV are more extensive (326,327,327,(331)(332)(333)(334)(335)(336)(337)(338)(339) . There is limited published data on co-infection by all three viruses (340)(341)(342)(343) .
Overall, studies on BBV co-infection focus more on disease progression and prognosis and not much is reported on the effect of co-infection on infectivity or transmissibility of these viruses. Following the review of currently available publications on BBV co-infection, recommendations provided in this guideline for the management of individual BBVs were thought to be sufficient to prevent transmission from co-infected HCWs. This is because these recommendations primarily focus on treatment for the infections and setting viral load thresholds for safely performing EPPs. The effect of co-infection on disease progression and treatment is relevant primarily for the treating physician responsible for the clinical management of the infected HCW (184,344) .
If a HCW who performs EPPs is co-infected with any combination of these BBVs, the HCW should meet the defined criteria recommended for safe practice by HCWs infected with each virus (296) .
# DOUBLE GLOVING
Several studies investigating IPC practices of surgeons implicated in transmission of a BBV to patient(s) assessed the gloving practices of the infected HCW (116,118,122,345) . Glove failure due to perforations and/or HCW injury can result in exposure to blood and body fluids and therefore increased risk of transmission of a BBV. It is unclear if glove failure carries the same risk for both HCWs and patients when either is infected. The practice of double gloving (wearing two pairs of gloves) as an effort to mitigate this risk has been well documented and is discussed below.
Studies attempting to assess potential benefits of double gloving are mainly focused on protecting HCWs as data show they have a higher risk of acquiring a BBV from patients than vice versa (63) . Some studies report that due to paucity of evidence, no conclusions can be drawn regarding the comparative effectiveness of double versus single gloving for minimizing the risk of transmission of BBVs (346) . Other studies have drawn conclusions from the limited available evidence (347)(348)(349) . The different conclusions reached in these studies likely reflect differences in interpretation of the evidence as it relates to risk of BBV transmission.
Most relevant studies on gloving practices compared glove perforation rates by assessing for body fluid contact or leaks in gloves (20,347,348,(350)(351)(352)(353)(354)(355) . Glove perforation is particularly high during certain types of procedures. Healthcare workers performing orthopedic, cardiothoracic, gynecologic and trauma surgeries are more frequently involved in procedures with higher risk of glove perforations and percutaneous injury than other HCWs (20)(21)(22)(23)(24)86,356) .
When two pairs of gloves are worn, the number of perforations to the inner glove and consequently potential HCW exposure to patient blood, is significantly reduced (70-87%) compared to when a single pair of gloves is used (87,348,(355)(356)(357) . As a result, some literature and lookback investigations postulated that there would be a similar reduction in the risk of BBV transmission from HCW to patient, with double gloving more protective than a single pair of gloves (49,350,351) .
A systematic review of RCTs investigated whether double gloving reduced the incidence of infections including surgical site infections, and bloodborne infections in surgical patients and in the surgical team (356) . The secondary study objective was to determine if additional glove protection reduced the number of perforations to the innermost pair of surgical gloves. Eligible RCTs involving two or more types of gloving including single gloving, double gloving, triple gloving, glove liners, knitted outer gloves, steel weave outer gloves, and perforation indicator systems were compared. A total of 61 RCTs informed the authors' conclusions on the various outcomes measured. A meta-analysis of 14 of these trials which included 8,885 surgeries, demonstrated that the addition of a second pair of gloves significantly reduced perforations to the innermost gloves (odds ratio 4.10, 95% confidence interval 3.30-5.09) (356) . Collectively, these studies may indicate that double gloving is indeed important for procedures with high risk of glove perforations and may therefore be a relevant preventive measure for transmission of bloodborne infections.
Deterrents against the wide adoption of double gloving by HCWs who perform EPPs include the need to change a habit, decreased manual dexterity and tactile sensation, constriction of the hands and digits leading to discomfort, paucity of evidence, and low perceived personal risk by HCWs (20,349,350,353,(358)(359)(360) . In many cases, a period of adaptation and "retraining" seems to be required before practitioners feel comfortable with double gloving (87,361) . A prospective randomized controlled trial involving 53 surgeons concluded that double gloving did not have a substantial impact on manual dexterity or tactile sensitivity when compared to single gloves or no gloves (358) . Results from a survey of 155 surgeons and residents affiliated with two Canadian universities showed that 43% of them routinely double gloved in 75% or more of procedures (361) . Some professional organizations recommend double gloving as a standard of practice for invasive procedures in order to reduce body fluid exposure caused by glove tears and sharps injuries in surgeons and scrub personnel (87,(362)(363)(364)(365) . In a Canadian survey of 170 surgeons, 87% of orthopedic surgeons double gloved while none of the urologists surveyed did (349) . In certain types of surgery (such as neurosurgery), where delicate manipulation of instruments and tissues is required, double gloving may impair the surgeon's ability to safely perform the procedures. Thus, the surgeon may decide to forego double gloving. Although it is clear that double gloving reduces the risk of exposure to blood and body fluids due to glove perforations, the evidence is insufficient to determine how it affects the risk for BBV transmission from HCW to patient and vice versa (347,356) . As a result, it is not possible to conclusively state that double gloving is a critical element for preventing transmission of BBVs between HCWs and patients.
Double gloving by HCWs, to protect themselves and their patients, may best be addressed as a matter of preference until further studies are conducted. Factors to consider in making a decision whether or not to double glove based on identified risk factors for glove perforations are summarized below (24,351,353) :
• The addition of a second pair of surgical gloves significantly reduces perforations to innermost gloves (355,356,361) . • Sensitivity and manual dexterity may be improved by choosing a suitable combination of inner-and outer-glove size (358) .
• Wearing two pairs of gloves does not substantially impact tactile sensitivity or manual dexterity to the point of resulting in more perforations (356,358) .
• Wearing one pair of orthopedic gloves (thicker than standard latex) is as effective as wearing two pairs of standard latex gloves in reducing the number of perforations to innermost gloves (366) .
• Risk of glove perforation has been reported to increase with the length and complexity of the procedure as well as HCW expertise and risk of injury associated with the procedure (24,84) . Deep procedures carry a significantly higher risk of glove failure (up to sevenfold) compared with superficial procedures (348,359) .
• The frequency of glove changes depends on length of procedure, amount of blood loss, and HCW injury (347,351,367) . • Glove perforations are significantly higher for emergency procedures than they are for scheduled procedures (24,353,367) .
• If double gloving, wearing glove perforation indicator systems results in significantly more inner glove perforations being detected during surgery than when wearing standard double latex gloves (348,368) .
• If HCWs choose to double glove, they should do so routinely and not based on the risk status of a patient. Occasional double gloving would not provide the opportunity for the HCW to adapt to it thereby potentially posing a risk to both the HCW and the patient (87) .
# Recommendation for Double Gloving for Infected Healthcare Workers
Recommendation 1. There is insufficient evidence to recommend for or against double gloving to prevent HCW-to-patient transmission of a BBV. Grade of evidence: Not applicable due to insufficient data specific to BBV transmission
# INFECTION PREVENTION AND CONTROL MANAGEMENT OF INFECTED HEALTHCARE WORKERS
# Reporting Obligations
In all provinces and territories, certain HCWs are obligated by law to report patients infected with specified communicable diseases including HIV, HBV and HCV to public health (369) . There may be additional ethical, legal or regulatory reporting requirements related to patients infected with a BBV, who are also HCWs. As a result, all treating clinicians should be familiar with the reporting obligations in effect within their province or territory of practice (369) .
# Expert Review Panels
Within the context of this guideline, Expert Review Panels (ERPs) are advisory committees to the relevant jurisdictional authority (e.g., public health, regulatory authority) whose primary role is to assess the risk of transmission of a BBV from an infected HCW to patients and assess whether practice modifications or restrictions are needed if the infected HCW performs EPPs.
A review of existing guidelines from Canada, the United States, the United Kingdom, Europe, France, Ireland, Australia, and the Netherlands shows differences in approach to convening and/or implementing an expert review process (2,44,105,190,273,298,300,370,371) . The UK has a nationallevel ERP called The UK Advisory Panel for Healthcare Workers Infected with Bloodborne Viruses (UKAP), which has been in place since 1991 (234) . In 2011, France recommended a similar approach for the creation of an ERP at a national level (44) .
# Canadian Approach
The approach taken for the establishment of ERPs in Canada varies across provinces and territories (P/Ts). Table 36 (Appendix III) describes key elements of the expert review process in two provinces that have a centralized approach for all HCWs. ERPs have been convened by P/T ministries of health or public health agencies, as well as by university faculties (e.g., medicine) or regulatory authorities for HCW professional groups (274,(372)(373)(374)(375)(376)(377)(378)(379)(380) . Health Canada's 1998 consensus document recommended the creation of an ERP (2) . At the time of developing this guideline, not all HCWs infected with a BBV in Canada had access to an ERP. Where ERPs exist, the process for implementation and monitoring for compliance with recommendations provided by the panel also varies across P/Ts. The inconsistencies in establishing an ERP and developing a framework for their decision-making have led to inconsistent practices across Canada. This could result in movement of an infected HCW between provinces and territories, a situation where an infected HCW is not being managed, or management of an infected HCW using advice that is not based on available evidence regarding risk of transmission. A consistent evidence-based approach across the country will improve patient safety and support the effective and equal treatment of HCWs infected with a BBV irrespective of where they work in Canada. This guideline is intended to support consistency in availability of ERPs and their practices nationally.
For purposes of developing this guideline, an environmental scan of relevant literature was conducted to address the key question, What issues are relevant to the expert review process in Canada for the management of HCWs infected with HIV / HCV / HBV? Characteristics of ERPs in Canada were identified through an environmental scan of publicly available documents and personal communication where necessary. Upon review of relevant documents, current practice, and stakeholder engagement, essential components were identified to inform recommendations for establishment of effective ERPs by provincial and territorial health authorities. These recommendations prioritize patient safety using a consistent and evidence-based approach to decision-making regarding the management of infected HCWs while ensuring that each HCW's right to privacy and the confidentiality of their personal medical information are maintained.
# Recommendations for Expert Review Panels
Recommendations for the governance, authority, responsibility and processes for ERPs are provided below. These issues should be clearly defined for each P/T such that all HCWs (including students) who may be affected by the policies are afforded the opportunity to receive expert guidance related to their BBV infection. o The composition of the panel and who it reports to should be publicly available. • P/Ts and regulatory authorities without the necessary resources and expertise to establish an ERP, should partner with another P/T to ensure that all HCWs infected with a BBV have access to an ERP.
• Expert Review Panels should engage relevant stakeholders such as public health, health faculties and healthcare institutions.
• Indemnification should be provided for all ERP members.
• The ERP should be adequately resourced to complete its mandate. The governing authority for an ERP is responsible for addressing the remuneration of the ERP members.
• The ERP should be convened in a timely manner when an infected HCW is identified for review.
• There should be sufficient members on the ERP to provide the breadth of expertise required to assess the risk posed by a HCW infected with a BBV, and offer recommendations to mitigate the risk. Membership on an ERP should include an infectious disease physician and a public health professional. Other members may include: a hepatologist, surgeon, medical/clinical microbiologist, infection prevention and control professional, occupational health physician, bioethicist, member of the public, and peer HCW (in the same area of practice as the HCW infected with a BBV).
# Roles and Responsibilities
• An ERP should assess the risk that the HCW may pose to patients and make recommendations on fitness for practice based on the HCWs' health status and practice. • The HCW or their delegate should have an opportunity to present information during the assessment for fitness to practice.
• The HCW or their delegate should have an opportunity to discuss the recommendations prior to implementation and have an opportunity for clarification or a re-evaluation.
• The ERP processes should be conducted in a manner that protects the HCW's privacy and maintains confidentiality.
• The ERP or regulatory authority should sign a written agreement with the HCW that identifies the recommendations and specifies any practice modifications or restrictions, with whom the agreement will be shared with (regulatory authority, program director, etc.), who will be monitoring the HCW's compliance, and who will be responsible for monitoring the HCW's health status. Ensuring that the HCW is under the care of a clinician with expertise in management of the BBV(s) is an important aspect of care for the HCW; this care provider may have an ongoing role in receiving test results and communicating status updates with the regulatory authority at defined intervals.
• Recommendations of the ERP including the signed agreement should be in the possession of the regulatory authority that is responsible for monitoring the HCW's compliance with the recommendations.
• The relevant authority should have a process in place in the event a HCW wishes to request a re-evaluation of any ERP recommendation(s). Acceptable reasons for a reevaluation should be outlined and may include concerns with the process, availability of new treatment regimens, or new information about the HCW's health status or practice.
# Referral to an ERP
There are several mechanisms for initiating a referral to an ERP. The options provided here are not exhaustive.
• All HCWs, including students and trainees, may self-refer to an ERP.
• The referral to the ERP may be initiated by the Medical Officer of Health or the regulatory authority; with appropriate information communicated in writing, in person, or by phone. If initiated by the regulatory authority, their monitoring department may send a list of HCWs infected with BBVs to an ERP for review. • The referral to the ERP may be initiated by the HCW and done via telephone contact to maintain anonymity. Alternatively, the HCW may choose to initiate the referral via an advocate, surrogate, or legal representative. Most often the advocate is the treating physician.
• In the case of students and trainees, the referral may be initiated through the undergraduate or post-graduate office of the faculty.
• If the HCW is a student or trainee, a person in charge of the program or a faculty member may provide procedural advice and assistance to the student or trainee.
# Implementation, Monitoring and Compliance with ERP Recommendations
• The ERP should provide recommendations informed by Sections 6.6, 7.6 and 8.9
Recommendations for Management of HCWs infected with HIV, HCV and HBV respectively. • The HCW and treating clinician should provide the relevant authority with the necessary information to confirm compliance with the recommendations.
• The relevant regulatory authority may remove the HCW's licence if the HCW is noncompliant with practice restrictions. • In the event that a HCW who is being monitored changes jurisdictions or institutions, the regulatory authority or faculty should inform the appropriate jurisdictional authorities subject to applicable laws.
A sample flow chart providing an overview of the interactions and responsibilities of regulated HCWs infected with a BBV, an ERP, and relevant authorities is shown in Figure 4. Although local jurisdictions can adapt the referral and implementation processes within the context of the relevant authorities and available resources, specific guidelines and recommendations are provided above for each key step. Table 37 (Appendix III) lists select regulated and unregulated HCWs in Canada by P/T.
Policies regarding the management of HCWs infected with BBVs must comply, as appropriate, with applicable jurisdictional health and privacy legislation, employment law, Human Rights codes and the Canadian Charter of Rights and Freedoms.
Abbreviations: HCW, healthcare worker; BBV, bloodborne virus; EPPs, exposure-prone procedures; IPC, infection prevention and control; ERP, Expert Review Panel; P/T, provincial and territorial Regulated HCW infected with a BBV (1) Regulated HCW infected with a BBV (1) Yes No HCW consults with relevant authority (2) HCW consults with relevant authority (2) Does the HCW perform or wish to perform EPPs (4) ?
Does the HCW perform or wish to perform EPPs (4) ?
Restrictions on practice not needed based on BBV status alone Restrictions on practice not needed based on BBV status alone HCW notifies regulatory authority (5) HCW notifies regulatory authority (5) Relevant authority ensures review of HCW's general practice (including IPC) by an individual with the appropriate expertise (3) Relevant authority ensures review of HCW's general practice (including IPC) by an individual with the appropriate expertise (3)
# E p R w P ERP
R n 11 0 PC M g m d HCW d o mm d n E HCW h h d u n u u p b A k p d o p h o h du h HCW p o m w d k p o m M mm d h h HCW m mp w h d d p d R g mm d b d w m b HCW h h d p C mm n d d w h h h R p p d qu m d p g S d po o g g u h y R gu y ho y d n E u w o HCW PC p by n nd d w h h pp op p b E o p n Ob w g m w h h HCW
x ert evie anel ( ) (6) Expert Review Panel (ERP) (6) efer to sectio . I ana e ent of Infecte s for etails n reco en atio s: Refer to section 11.0 IPC Management of Infected HCWs for details on recommendations: a.
valuates 's ealt status an c rre t or f t re ractice a. Evaluates HCW's health status and current or future practice . ssesses ris ose t atients in t e course f t e ties t e erf r s or oul li e to erf r b. Assesses risk posed to patients in the course of the duties the HCW performs or would like to perform c.
akes reco en ations t at t e ust co ly it as a con ition of continue or future ractice c. Makes recommendations that the HCW must comply with as a condition of continued or future practice . e-evaluates ori inal reco en ations ase on ne infor ation a out 's ealt status an /or current or future ractice d. Re-evaluates original recommendations based on new information about HCW's health status and/or current or future practice e. o unicates as ee e it t e source of t e referral (7) e. Communicates as needed with the source of the referral (7) f. e orts as er juris ictional re ire ents an /or ractice (8) f. Reports as per jurisdictional requirements and/or practice (8) . en s re rt t overnin a t orit (9) g. Sends report to governing authority (9) e lator aut rit consi eratio s: Regulatory authority considerations: a.
ns res revie f 's I ractices a i ivi ual it t e a r riate ex ertise (3) a. Ensures review of HCW's IPC practices by an individual with the appropriate expertise (3) . nf rces ractice restrictio s b. Enforces practice restrictions c.
tains a ritten a ree ent it t e c. Obtains a written agreement with the HCW d. Refers back to the ERP should the HCW's health status or type of procedures they want to perform changes e. Monitors HCW compliance f. Receives necessary information to confirm compliance with ERP recommendations g. Restricts or puts conditions on licence as recommended by the ERP h. Informs relevant P/T regulatory authorities if the infected HCW who is being monitored changes jurisdictions, subject to applicable laws d. Refers back to the ERP should the HCW's health status or type of procedures they want to perform changes e. Monitors HCW compliance f. Receives necessary information to confirm compliance with ERP recommendations g. Restricts or puts conditions on licence as recommended by the ERP h. Informs relevant P/T regulatory authorities if the infected HCW who is being monitored changes jurisdictions, subject to applicable laws
Has the HCW and/or treating clinician provided the necessary information demonstrating compliance with and fulfillment of all ERP recommendations (10) ?
Has the HCW and/or treating clinician provided the necessary information demonstrating compliance with and fulfillment of all ERP recommendations (10) ?
HCW can practice in compliance with recommendations from the ERP (11) HCW can practice in compliance with recommendations from the ERP (11) HCW practice restrictions continue (11) HCW practice restrictions continue (11) Yes
# No
Legend 1. This model could be adapted to align with jurisdictional requirements and for unregulated HCWs, including students in some P/Ts, to ensure that all infected HCWs have access to the appropriate expertise in a timely manner. The process includes assessment for risk of transmission of the BBV during the provision of care; the provision of recommendations to the HCW, including practice restrictions if applicable; and the monitoring of the HCW's compliance with the recommendations.
# 2.
For example, regulatory authority, public health.
3. An individual with the appropriate expertise may vary depending on the types of procedures performed by the infected HCW. At a minimum, the review should include all the elements of Routine Practices for the prevention of transmission of infections in healthcare settings (i.e., hand hygiene, aseptic technique, sharps safety and prevention of exposure to BBVs, etc.). If a HCW should want to start performing EPPs, they will need to notify their regulatory authority again. 4. Question to be answered by the relevant authority (e.g., regulatory authority, public health). Other reasons for referral to an ERP may include: Confirmed HCW-to-patient transmission of a BBV; and presence of extenuating circumstances that may increase risk of exposure to patients (e.g., identified IPC breaches).
# 5.
The regulatory authority can be notified from other sources as well (e.g., a peer HCW, a Medical Officer of Health, a diagnosing or treating physician). 6. The Chair of the ERP may work with the regulatory authority to determine the need for practice restrictions and subsequent referral to the ERP. 7. Communication or notification beyond the source of referral should only be done with the consent of the infected HCW and subject to applicable laws. 8. May include communicating with or reporting to the faculty program director, P/T public health and/or the HCW's employer.
# DISCLOSURE OBLIGATIONS AND RIGHT TO PRIVACY
This section addresses the HCW's disclosure obligations to their patients and the HCW's right to privacy. Few Canadian guidelines and policies address the issue of disclosure obligations to patients. None of those reviewed regard routine disclosure of HCW serologic status to patients as a necessary requirement for the provision of care. When a HCW infected with a BBV has been reviewed by an ERP and deemed safe to practice, the issue of disclosure is not applicable.
# International Approach
The United States Centers for Disease Control and Prevention (CDC) previously required that HCWs infected with HBV or HIV who perform EPPs disclose their serologic status to their patients (291) . However, this is no longer a requirement in the CDC's updated recommendations for the management of HCWs infected with HBV (105) . These recommendations state that routine mandatory disclosure might be counterproductive to public health, as it might lead to avoidance of testing, vaccination, treatment and/or management, and may result in non-compliance with practice oversight from an ERP. The risk of transmission of a BBV is greater from unknown infections than from known infections. Mandatory disclosure was "accepted to be an insurmountable barrier to practice, and might limit patient and community access to quality medical care" (105) .
Internationally, none of the reviewed policy documents regard disclosure of a HCW's serologic status to patients as a necessary requirement for the provision of care (44,105,190,370,371) . The HCW right to privacy is comprehensively addressed, but the practical steps to ensure that this right is upheld are not included in most policies.
A harmonized, evidence-based approach to addressing HCW disclosure obligations and right to privacy is warranted, and stands to benefit HCWs, patients, and society. Ensuring safe medical care and protecting HCW privacy rights should be achieved in a consistent and transparent manner in all healthcare settings across Canada. An essential precursor for safe patient care is the ethical and professional obligations of the HCW performing EPPs to know their serologic status, and seek and receive necessary guidance accordingly (refer to section 11.0 Infection Prevention and Control Management of Infected Healthcare Workers) (11)(12)(13)(14)(15)(16)(17)(18) . This obligation of HCWs in Canada, whether ethical or professional, is increasingly recognized. Concurrently, policies are being developed to address issues related to HCW rights to privacy, and attenuate risks to patients in healthcare settings. This trend does not, however, extend to a disclosure obligation of serologic status from HCW to patient.
# Disclosure Obligations
Many of the current guidelines and policies that address HCWs and BBV infections do not contain explicit recommendations regarding disclosure obligations of HCWs to patients. None of the reviewed guidelines and policies recommends mandatory routine disclosure of HCW serologic status to patients, regardless of whether or not the HCW performs EPPs (13,54,71,274,377,(381)(382)(383)(384) .
Some publications suggest that mandatory disclosure of a HCW's serologic status to patients be restricted to cases arising when: (1) exposure from a HCW infected with a BBV to a patient has occurred;
(2) the HCW has been non-compliant with an ERP's recommendations or (3) viral load in the infected HCW constitutes a material risk to the patient. If the ERP has deemed the HCW safe to practice, this negates both material risk and a need for disclosure.
# Right to Privacy
The right to privacy of a HCW infected with a BBV is addressed in most relevant Canadian and international guidelines and policies. While the wording to describe this right varies, the guidelines and policies uniformly recognize the importance of maintaining HCW privacy without specifying mechanisms to achieve this.
# Ethical Aspects
There is an inherent ethical dilemma in considering disclosure. The risk of transmission of a BBV from HCW to patient is non-zero (i.e. the risk exists, even if minimal). Therefore patients have an interest in knowing about the risk, while HCWs have an interest in protecting their privacy; given the impact that disclosing to patients might have on their practice and personal lives.
Ethically, the interests of the patient and HCW must also be balanced against other competing rights and interests which, in this case, may include denying patients the services of HCWs without improving the safety of care, creating unfair hardship for HCWs, and creating an economic burden on the health system.
HCWs performing EPPs have ethical and professional obligations to know their serologic status, and to seek guidance and follow expert advice if infected (refer to section 11.0 Infection Prevention and Control Management of Infected Healthcare Workers). These obligations may be traced to principles of non-maleficence (the duty to intentionally refrain from actions that cause harm), respect for autonomy (the responsibility to obtain informed consent from patients for treatment, and provide all information material to their decision making), and the right to privacy (the obligation to minimize the extent to which HCWs may experience stigmatization, discrimination and/or reduced professional prospects as a result of disclosing their serologic status) (209) . It is expected that HCWs follow all the elements of code of practice of which informed consent and fitness to practice are included.
# Legal Context
In accordance with the Canadian legal system, policies regarding the management of HCWs infected with BBVs must comply, as appropriate, with applicable jurisdictional health and privacy legislation, employment law, Human Rights codes and the Canadian Charter of Rights and Freedoms (385) . Provincial Human Rights codes prohibit discrimination on several grounds, including "disability", a term that, under antidiscrimination law in Canada, includes infection with HBV, HIV and/or HCV.
In all provinces and territories in Canada, HIV (or AIDS), HBV and HCV are reportable diseases under public health legislation (386)(387)(388) . It has not been established, however, whether an obligation to disclose serologic status to patients exists under common law. Such an obligation would likely infringe upon the HCWs' rights to privacy and freedom from discrimination under the Charter and Human Rights codes. When such conflicts arise between the Charter, Human Rights Codes and common law, the courts recognize that rights are non-absolute and have limits, and evaluate the case on consideration of matters such as the balance between the provision of safe health care to patients and respect for the rights of HCWs (54) . Fiduciary duties may require HCWs to disclose their serologic status when performing EPPs. However, if the HCW takes reasonable steps to reduce the risk of transmission to acceptable levels, fiduciary duty obligations may be satisfied without having to disclose serologic status (54) .
A HCW infected with HBV, HCV and/or HIV could in theory face legal liability for failure to obtain informed consent if the HCW does not disclose their serologic status. To give informed consent, a patient must be provided with all information material to the proposed treatment plan, including all 'material, and special or unusual risks' (389,390) . The likelihood of risk and the consequences of the risk (impacts of the HIV, HBV or HCV infections) would be factors considered by the Courts to determine whether the HCW serologic status constitutes a material risk to be disclosed to the patient. In the context of EPPs, the risk could therefore be considered material for the purpose of informed consent. In previous cases, courts have affirmed that physicians did not have to routinely disclose their medical information to patients (391) , and that the informed consent requirement is to be judged by the "reasonable patient" standard, i.e., what a reasonable patient in that position would have expected to hear before consenting (390) . It has been suggested that the disclosure obligations may be better managed by regulatory authorities.
It is possible the courts may also take into account the public policy consequences of disclosure, and the special nature of the relationship between HCWs and patients, in determining whether and to what extent an obligation exists (392) .
The following recommendations are based on a review of existing Canadian and international guidelines and policies, taking into consideration the ethical and legal contexts.
12.6 Recommendations for HCW Disclosure Obligations and Right to Privacy Recommendations 1. A HCW infected with a BBV who performs EPPs does not have an obligation to routinely disclose his or her serologic status to patients to obtain their informed consent provided that the HCW's health status and practice have been assessed by an Expert Review Panel and all the panel's recommendations are followed.
2. All HCWs, including those infected with a BBV, have a right to privacy and confidentiality of personal health information.
3. Regulatory authorities should have policies on the management of HCWs infected with a BBV that are transparent about and detail how the right to privacy of HCWs will be upheld.
4. When a patient has been exposed to the blood of a HCW, the HCW must seek follow-up through their organizational process and the patient must be promptly informed of the nature of the exposure and the appropriate post-exposure protocol. However, the identity and confidentiality of the HCW should be protected to the greatest extent possible.
# LOOKBACK INVESTIGATIONS RELATED TO INFECTED HEALTHCARE WORKERS
# Overview of Lookback Investigations
This section addresses the principles and considerations for lookback investigations, which may be performed following the identification of a HCW-to-patient transmission or identification of an infected HCW with no known transmission to patients.
Complete reports on lookback investigations are rarely published in peer-reviewed journals (168) .
There have been five Canadian lookback investigations involving infected HCWs published to date. These involved two HCWs infected with HBV (70,132) , two HCWs infected with HCV (51,77) , and one HCW infected with HIV (155) . Key aspects from these investigations are summarized in Table 18. Although the majority of lookback investigations are initiated as a result of transmission of a BBV infection through exposure-prone procedures (EPPs), one significant Canadian lookback investigation identified transmission during non-EPPs due to IPC breaches (132) . Detailed information on relevant lookback investigations published internationally between 1985 and 2016 can be found in summary tables for each BBV in Appendix 1: Epidemiologic investigations summary tables.
Several countries have national regulations and/or policies that frame and guide decisions and risk assessments surrounding lookback investigations (2,190,370,393,394) .
Healthcare organizations have an obligation to inform patients of an exposure incident where there is a risk of transmission of a BBV (231,233,395) . Neglecting this patient right prevents them from obtaining an early diagnosis and treatment and minimizing risk of secondary transmission (165) . In a survey of patients involved in a large lookback investigation, the majority of patients stated that they wished to know about an exposure despite the anxiety that the knowledge caused them (395) .
A HCW's right to privacy and confidentiality of his or her personal health information must be respected during a lookback investigation (165) . It is feasible to conduct the investigation and publish a report without infringing on the rights of the affected HCW (155,393) . This is important to reassure and encourage potentially infected HCWs to come forward in the future (168) . Abbreviations: LB, lookback investigation; HCW, healthcare worker; EPP, exposure-prone procedure; HBV, hepatitis B virus; NR, not reported; IPC, infection prevention and control; HCV, hepatitis C virus; HIV, human immunodeficiency virus A Articles that provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table. B In addition to patients identified prior to the lookback investigation. C The report states that approximately 40 full-time equivalent positions were required in the first week alone. In addition, external expertise was obtained from the provincial ministry of health, public health, medical regulatory authority, legal counsel, and a communications consultant. D A phased approach by greatest risk of transmission and exposure was used. The parameters for the screening period were determined based on the HCW's abnormal laboratory findings and HCV mutation over time. E As there was no transmission identified in the first phase, the investigators decided not to pursue screening of patients with a lower risk of exposure thus permitting an efficient use of public health resources.
# Key Considerations and Objectives of a Lookback Investigation
Lookback investigations require resources to identify, notify, counsel and test all the potentially exposed patients (165) . These investigations often involve collaboration between a healthcare organization or facility where an infected HCW practiced and public health authorities. Although such collaborations may potentially pose a challenge for conducting the investigation, the process is generally coordinated by an Investigation Management Team with the expertise needed to successfully and efficiently manage the investigation (122,156,171,370) .
Lookback investigations are both time consuming and costly activities requiring significant financial and human resources (115) . Direct and indirect costs are associated with salaries for personnel, honoraria for expert advice, counseling and testing of patients, courier services and support services such as information technology, telephone services, security, and media relations. These resources can come at the expense of other institutional or public health activities (114) . One report stated that the cost of a lookback investigation was equivalent to a third of the state's entire annual budget for HIV and AIDS surveillance (excluding the costs to other organizations involved in the investigation) (49) . Investigations conducted in the early 1990s cost over US $100,000 (49,159) , with the cost for lab testing alone in one investigation estimated at US $76,000 (32) . In the UK, the total cost for lookback investigations, where reported, exceeded well over £200,000 (168,172) . Canadian healthcare organizations or facilities may not have sufficient resources, either human, laboratory or financial, to conduct a lookback investigation without support from public health authorities. Poor quality patient information retention by a health organization or facility (148) , or the lack of computerized information systems to assist with information retrieval, can also hinder an investigation.
Lookback investigations related to an infected HCW may be undertaken to: a. notify patients of their potential exposure b. identify infected patients and provide appropriate advice and treatment recommendations c. prevent secondary transmission d. reassure the public e. maintain the public's trust and confidence in the healthcare system f. contribute to the evidence base on risk of transmission.
# Recommendations for Conducting Lookback Investigations
Recommendations provided in this section are expert opinion informed by published lookback investigations and existing guidelines (2,190,298,393,394,396) as well as current practice.
Prior to initiating a lookback investigation, a risk assessment is conducted by a team with the expertise needed to determine the requirement for an investigation and if applicable, define its scope. Recommendations for conducting the risk assessment are provided below including supporting tools to facilitate decision making.
# Risk assessment to determine requirement for a lookback investigation
• If a HCW who performs EPPs is found to be infected with a BBV, a team should be assembled to perform a risk assessment. Some organizations may have a standing risk assessment panel or process that could be utilized. • The HCW should cease performing EPPs immediately and be referred to an ERP for practice evaluation while the risk assessment is underway.
• Although there is a necessary link between the tasks done by both groups, the team responsible for performing the risk assessment should be different from the Expert Review Panel (ERP).
• Members of the risk assessment team should be familiar with the legal obligations in effect within their jurisdiction that may impact the decision-making process related to lookback investigations.
• The risk assessment team should include individuals with sufficient expertise to assess both the risk of potential exposure and transmission and to identify the process required to address these risks (e.g., infectious disease physician with expertise in relevant BBV, infection control professional, public health physician, peer HCW, medical microbiologist, bioethics expert, facility senior management, and legal counsel).
• Processes should be in place to ensure there is no conflict of interest or bias with regards to conducting the lookback investigation.
• For a consistent and thorough approach to risk assessment, pre-developed tools should be used to perform the assessment. Refer to the following tools below: o A checklist to record relevant information (Table 19).
o An algorithm and legend for guidance on the risk assessment (Figure 5). Data collected in Table 19 will facilitate use of the risk assessment algorithm (Figure 5). The risk assessment team will need to consider the information compiled in Table 19 as well as any additional details unique to each event in order to make a decision regarding whether or not there was a risk of patient exposure and a lookback investigation is required. 12 Has the HCW's practice ever been reviewed by an ERP? Note: If yes, identify the ERP recommendations and whether the HCW was compliant with them.
# Questions to consider related to extenuating circumstances
13 Has the HCW complied with current infection prevention and control standards (i.e., Routine Practices)?
14 Does the HCW use technique(s) (e.g., surgical) that may increase his/her risk of percutaneous injuries during procedures that can put patients at risk of exposure to the HCW's blood?
15 Has the HCW had percutaneous injuries that exposed a patient to the HCW's blood (both reported and unreported)?
16 Has the HCW ever noted blood on his/her hands after removal of surgical gloves following procedures performed on patients?
17 Has the HCW ever had evidence of a skin condition on his/her hands that potentially created an exit portal for BBVs (e.g., dermatitis)?
Abbreviations: HCW, healthcare worker; BBV, bloodborne virus; ERP, Expert Review Panel; EPP, exposure-prone procedure A Adapted from UKAP (2004) enquiry pro forma (63) . Is there HCW-to-patient transmission? (2) Are there extenuating circumstances that may have amplified the risk of transmission? (3) Perform a LB Consider performing a LB (refer to Table 19) (4) Has the HCW ever performed an EPP while potentially infectious? (5) LB is not required based on risk of transmission of BBV (6) Has the HCW's practice been assessed by an ERP?
Were modifications in HCW practice recommended? (9) LB is not required based on risk of transmission of BBV (11) Abbreviations: HCW, healthcare worker; BBV, bloodborne virus; LB, lookback investigation; EPP, exposureprone procedure; ERP, Expert Review Panel; IPC, infection prevention and control
# Yes
Has the HCW demonstrated compliance with ERP recommendations? (10) No Yes Did the HCW's viral load at the time of potential patient exposure exceed recommended levels? (7) Yes Perform a LB Yes Consider performing a LB (refer to Table 19) (4) No Need for LB determined on a case-by-case basis (refer to Table 19) (8) Unknown Legend 1. Identification of a HCW infected with a BBV may trigger a risk assessment to determine if a lookback investigation is required. In addition, the HCW should be referred to an ERP as soon as possible to have their health status and practice reviewed (if not previously done). 2. As determined by a traceback investigation. Refer to Appendix V, Glossary for a definition of traceback investigation.
# 3.
Extenuating circumstances include IPC breaches by the HCW that put patients at risk of exposure during the provision of care or illicit diversion of patient medication. 4. Refer to Table 19: Checklist for risk assessment and lookback investigations related to a HCW infected with a BBV for questions to consider to assist the decision-making process. 5. Refer to section 5.0 Exposure-prone procedures. 6. A lookback investigation may not be required based solely on risk of transmission of BBV however, a risk assessment team may determine that a lookback investigation is necessary based on other considerations (e.g., contribute to evidence base, alleviate public anxiety). 7. HCW who, at the time of potential patient exposure, had: i) HBV viral load greater or equal to 10 3 IU/ml (5x10 3 GE/ml); ii) detectable HIV viremia; or iii) circulating HCV RNA. 8. The risk assessment team should determine the need for a LB on a case-by-case basis considering all relevant information. 9. Refer to relevant sections: 6.0 Risk of Transmission for HIV, 7.0 Risk of Transmission for HCV, 8.0 Risk of Transmission for HBV and 11.2 Expert Review Panels. 10. Refer to section 11.2 Expert Review Panels. 11. Although the risk of transmission is not zero, it can be rendered negligible if HCWs infected with a BBV who perform EPPs adhere to recommendations which have addressed the identified risk factors from previous exposure incidents.
# Figure 5: Risk assessment to determine requirement for a lookback investigation related to a HCW infected with a BBV
# Lookback investigation: scope, roles and functions
• A LB investigation management team with an identified lead should be assembled to coordinate the investigation. This may be the same group as the risk assessment team.
• The investigation management team should include individuals with expertise in infectious disease, infection prevention and control, public health, medical microbiology, bioethics, laboratory services, the relevant BBV and the types of procedures performed by the infected HCW. In addition, representatives from the facility's senior management, communications department, risk management, and legal counsel should be included. Members of the investigation management team should be familiar with the legal obligations in effect within their jurisdiction that may impact the decision-making process related to lookback investigations.
• Members of the investigation management team should sign a pledge of confidentiality.
• The lookback investigation should be undertaken in a reasonable amount of time.
• The lookback investigation should be a collaborative process between the healthcare organization or facility where the infected HCW practices and public health authorities.
• The healthcare settings and organizations or local public health could be the lead authority depending on: o whether the HCW has practiced in more than one healthcare organization or facility within the jurisdiction of the local public health authority o whether the HCW has practiced outside of a healthcare organization or facility (e.g., private practice) o whether the healthcare organization or facility has sufficient resources to conduct the lookback investigation. • The local public health authority may request assistance from their provincial or territorial counterparts, who may also request federal assistance if the investigation goes beyond their jurisdiction.
# Access to resources
• Lookback investigations can be resource intensive and impact on laboratory resources should be considered. The public health laboratory should be involved with the investigation, whenever possible, to ensure appropriate testing, reporting and accountability.
• Detailed molecular analysis of samples in the investigation should be done to confirm or exclude HCW-to-patient transmission.
• Members of the risk assessment and investigation management teams should have access to appropriate patient information to support the decision-making process as per relevant provincial and territorial legislation.
• Provincial or territorial public health authorities may request the assistance of their federal counterparts.
• Lookback investigations should be conducted in a manner that facilitates efficient and effective use of public health and institutional resources.
# Risk communications
• A well-developed and coordinated communication strategy should be in place prior to patient notification. o Consideration should be given to setting up a call centre with a telephone hotline for public inquiries with personnel trained to provide accurate information while managing the anxiety that may be generated. o A list of potentially exposed patients to be notified should be assembled such that all patients are notified simultaneously and prior to public announcements. o All information necessary to inform the advice and counselling provided to potentially exposed individuals and their families should be compiled prior to patient notification. o All reasonable steps should be taken to identify and contact potentially exposed patients and encourage them to be tested for their own benefit. o Communication via traditional news media (press releases and conferences) as well as use of social media should be well coordinated. o Communication strategies should consider the following stakeholders: facility or organization personnel, the media, healthcare providers in the community, political representatives of the district and the general public. • Reports on lookback investigations should be published to contribute to the evidence base on risk of transmission from HCW to patients, inform future policy development, estimate cost associated with these investigations and improve patient safety.
• A national repository to document all lookback investigations, including those where no transmission was found, should be created.
# HCW confidentiality and right to privacy A
• Every effort should be made to avoid revealing the identity or information that would allow deductive disclosure of the HCW infected with a BBV. However, there may be instances where patient safety precludes this.
• Members of the investigation management team have an obligation to keep the information they receive confidential and respect the HCW's right to privacy.
• The right to privacy still applies if the infected HCW has died, or has already been identified publicly.
• The number of individuals who know the identity of the infected HCW should be kept to a minimum at all stages. It may not be necessary for all members of the team(s) to be aware of the identity of the infected HCW. A Adapted from the UK's HIV Infected Health Care Workers: Guidance on Management and Patient Notification, 2005 (393) APPENDIX I: EPIDEMIOLOGIC INVESTIGATIONS SUMMARY TABLES F Article met the eligibility criteria for data extraction to inform the systematic review on the risk for transmission of HIV from infected HCWs to patients. G Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table.
H Total number of patients tested consisted of: 519 patients initially tested (which identified the second and third cases); plus three patients later tested (who were identified by cross-matching the patient list with the state's AIDS surveillance records, self-identification, and routine testing for application to the military); plus an additional 141 patients tested with no evidence of transmission amongst them (126,128) . I Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HIV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HIV infection. If so, a response of "Compatible with HIV" was recorded. J Indicates whether the HCW was aware of their HIV-positive serologic status at any time during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of "NR" was recorded. K Indicates whether IPC breaches were identified. A response of "Yes" indicates any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Task Group determined that by current standards, an IPC breach was present. A response of "No" indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. L The HCW was unaware of their serologic status at the time of the index patient's exposure incident but was aware after being hospitalized and diagnosed in 1996 (32,153) . (161) Companion H : (398) US (403) Companions H : (404)(405)(406) UK C Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HIV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HIV infection. If so, a response of "Compatible with HIV" was recorded. D Indicates whether the HCW was aware of their HIV-positive serologic status at any time during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of "NR" was recorded. E Indicates whether IPC breaches were identified. A response of "Yes" may also indicate any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Task Group determined that by current standards, an IPC breach was present. A response of "No" indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. F Article met the eligibility criteria for data extraction to inform the systematic review on the risk for transmission of HIV from infected HCWs to patients. G The severe dermatitis on the HCW's hands contributed to the decision to investigate potential transmission of HIV to his patients. H Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table.
I HCW with HIV-HBV co-infection. J Article reported on this HCW risk factor but did not report on the screening period. As a result, it is unclear if the HCW risk factor existed during the time span selected for screening potentially exposed patients. K Investigations providing information on HCW risk factors and/or data on number of exposed and tested patients are included in this table. In the UK, HCWs infected with HIV were restricted from performing any exposure-prone procedures until 2014 (190,393) . Public Health England reports that there were 39 investigations related to HCWs infected with HIV between 1998 and 2008 in the UK with no evidence of transmission (190) . Higher-risk exposure-prone procedures, where theatre scrub nurses infected with HIV had acted as first assistants, were a part of these investigations but were excluded from this table as no relevant information was reported (63,173,234) . L HCW with HIV-HBV co-infection identified as a result of screening. G Article met the eligibility criteria for data extraction to inform the systematic review of HCV exposure incidents with HCW to patient transmission. H Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HCV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HCV infection. If so, a response of "Compatible with HCV" was recorded. I Indicates whether the HCW was aware of their HCV-positive serologic status at any time during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of "NR" was recorded. J Indicates whether IPC breaches were identified. A response of "Yes" may also indicate any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Team and/or the Task Group determined that by current standards, an IPC breach was present. A response of "No" indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. K Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table. L Ross et al. (2000a) reported that the HCW did not wear gloves and had a weeping wound on a finger of his right hand which bled repeatedly and was not covered during the provision of care to patients (136) . M Two separate lookback investigations for the same infected HCW have been combined. The first investigation involved testing of potentially exposed patients in the 6 months before the HCW's acute illness. The HCW was not aware of their serologic status and was symptomatic during the screening period (1995). The second investigation involved testing of potentially exposed patients in the 18 months following unsuccessful treatment for hepatitis C infection (1996 to 1997). N Investigations providing information on HCW risk factors and/or data on number of exposed and/or tested patients are included in this table. In the United Kingdom, HCV RNA positive HCWs are restricted from performing EPPs unless they have been successfully treated (411) . Since 2005, if no evidence of transmission of HCV or other risk factor increasing risk of transmission from an HCV-infected HCW is present, the UKAP does not recommend that patients be notified or tested (173) . O The infected HCW's specialty is not described however it is reported that his atopic eczema prevented him from wearing gloves systematically. Based on this information, it was determined that cardiothoracic surgery was not the procedure where transmission occurred. Note that several HCWs were tested including a surgeon, 4 nurses, 2 cardiopulmonary bypass technicians, 2 surgical assistants and 4 anesthesiologists. P HCW was diagnosed as HCV positive in 2006 but had a subsequent negative PCR result. In 2010, the HCW's viral load was 2.4 x 10 6 IU/mL. Q Four of the 48 potentially exposed patients were known to be infected with HCV. (32) has also been excluded from this table as no viral sequencing and analysis of risk factors was undertaken for the 43 HCV-positive patients that were identified. B Screening period: Time span selected by the investigators to screen patients. C HCW risk factors reported to be present at any point during the screening period. D Article met the eligibility criteria for data extraction to inform the systematic review on the risk for transmission of HCV from infected HCWs to patients. E Although diagnosed in 2003, a stored sample of blood from April 1991, when the HCW was first denied for blood donation, was seropositive for HCV. F Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HCV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HCV infection. If so, a response of 'Compatible with HCV' was recorded. G Indicates whether the HCW was aware of their HCV-positive serologic status at any point during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of 'NR' was recorded.
H Indicates whether IPC breaches were identified. A response of 'Yes' may also indicate any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Team and/or the Task Group determined that by current standards, an IPC breach was present. A response of 'No' indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. I IPC breaches were reported during the research project which led to transmission however there was no report of IPC breach related to the HCW's practice during patient care. J Investigations providing information on HCW risk factors and/or data on number of exposed and/or tested patients are included in this table. In the United Kingdom, HCV RNA positive HCWs are restricted from performing exposure-prone procedures unless they have been successfully treated (411) . Since 2005, if no evidence of transmission of HCV or other risk factor increasing risk of transmission from a HCW infected with HCW is present, the UKAP does not recommend that patients be notified or tested (173) .
K Staged lookback investigations related to the practices of 5 infected HCWs were recommended by the UKAP. These involved the last 500 patients who had undergone higher risk exposure-prone procedures. One of the investigations identified infected patients after the 2004 report was published. The numbers of patients potentially exposed and tested, prior to the identification of an infected patient, are included in this table. This investigation has also been included in Table 22, Epidemiologic investigations reporting transmission of HCV from infected HCW to patient with the numbers of potentially exposed and tested patients indicated as 'NR'.
L Companion articles provide supplementary information about the specific epidemiologic investigation. Where such articles exist, the additional information is included in the table. M Information obtained from Charles et al. (2007) (412) . In October 2005, the HCW was being investigated for 'unspecified ill health' and stopped work immediately. A Only articles published in 1992 or later are included as well as articles identified as part of the systematic review of the literature for risk of transmission of HBV from infected HCWs to patients. B Screening period: Time span selected by the investigators to screen patients. C Number excludes index case(s). D Includes index case(s); confirmation test for transmission include phylogenetic analysis, genotyping, or other epidemiologic evidence of transmission during surgery. E Transmission rate as reported in the study (R) or calculated by reviewer (C); formula for calculated transmission rate= [number of confirmed infected/(number of tested + index case)]*100 F HCW risk factors reported to be present at any point during the screening period. G Article met the eligibility criteria for data extraction to inform the systematic review of HBV exposure incidents with HCW to patient transmission. H Confirmed cases are: 1) Patients with a temporally-related active HBV infection that is genetically linked to the HBV-infected HCW; or 2) Patients with a serologic evidence of a previous infection consistent with timing of exposure or evidence of pre-exposure seronegative status; or 3) Reported as confirmed transmission cases by the authors.
I Undetermined cases: 1) Reported as undetermined by the authors; 2) serologic evidence of a previous infection with no evidence of pre-exposure seronegative status or no lifetime risk factors; or 3) no lookback investigation for sub-clinical infection was performed. J Indicates whether the HCW was symptomatic at any point during the screening period. Where the article described the HCW's clinical symptoms but did not clearly state that they were linked to the HBV infection, experts reviewed the information provided to determine whether the HCW's symptoms were compatible with an HBV infection. If so, a response of "Compatible with HBV" was recorded. K Indicates whether the HCW was aware of their HBV-positive serologic status at any time during the screening period. If the article stated that the HCW was aware of their serologic status but it was unclear when they became aware of it, a response of "Not reported" (NR) was recorded. L Indicates whether IPC breaches were identified. A response of 'Yes' may also indicate any of the following: 1) there was a lack of adherence to standard IPC practices and protocols; or 2) the Guideline Development Team and/or the Task Group determined that by current standards, an IPC breach was present. A response of 'No' indicates that an independent review of the HCW's practice was undertaken with no IPC breaches noted. M Articles identified as companion articles provide supplementary information about the specific epidemiologic investigation included in the systematic review. Where such articles exist, the additional information is included in the table. N Includes the cases related to both clusters but excludes one case of secondary transmission identified in the first cluster. O Number applies to investigation of second cluster only. P The HCW was linked to both the first and second cluster when it was determined (during the second investigation) that the HCW had provided a blood sample taken from another person during the investigation for the first cluster. The HCW served a custodial sentence and was removed from the Medical Register. Q Positive for hepatitis Be antibodies. R Negative for hepatitis Be antibodies. S Ninety-nine potentially exposed patients received PEP. T Eleven potentially exposed patients received PEP. U Eighteen potentially exposed patients received PEP. V Hepatitis B e-antibody status was not reported. ICU, intensive care unit A Only articles published in 1992 or later are included as well as articles identified as part of the systematic review of the literature for risk of transmission of HBV from infected HCWs to patients. B Time span selected by the investigators to screen patients.
C HCW risk factors reported to be present at any point during the screening period. D Article met the eligibility criteria for data extraction to inform the systematic review on the risk for transmission of HBV from infected HCWs to patients. E Prospective study of patients of 9 HBV-infected HCWs, 6 with chronic infection (2 surgeons, 1 dialysis nurse, 1 pediatric ICU nurse, 1 pharmacist and 1 orderly) and 3 with acute infection (1 dental technician, 1 ICU nurse and 1 medical student) over a 30-month period. Only the information related to the two surgeons is contained in this table. The results of the study were pooled for all patients (n=246) and for all exposures (n=483) with no evidence of transmission identified. F Indicates whether the HCW was symptomatic at any point during the screening period. G Indicates whether the HCW was aware of their HBV-positive serologic status at any point during the screening period.
H Indicates whether IPC breaches were identified. I Potentially exposed patients were offered post-exposure prophylaxis if the time since potential exposure was within the incubation period for HBV infection. This is detected during the first 3 to 5 weeks after infection, but may take up to 9 weeks to be detectable (270) . The presence of HBsAg indicates that the person is infected but does not indicate level of infectivity. Persistence of HBsAg for 6 months or more indicates chronic infection (415) . Spontaneous resolution of the infection with clearance of HBsAg occurs in 0.1 to 0.8% of chronic carriers annually (416)(417)(418)(419)(420)(421) . Those with resolving acute HBV will clear HBsAg several months after initial infection (212) .
# Anti-HBs
The presence of anti-HBs is generally interpreted as indicating recovery and immunity from hepatitis B virus infection. Anti-HBs also develops in a person who has been successfully vaccinated against hepatitis B (270) . (270,415,(421)(422)(423)(424)(425) . B About 5%-10% of people will not respond to the vaccine or do not produce protective levels of antibody postvaccination (62) . C This marker is most often negative but may be positive in some individuals. D To ensure that this is not a false positive test, samples with repeatedly reactive HBsAg results should be tested with a licensed neutralizing confirmatory test (270) . A small percentage of people with chronic infection will have both HBsAg and anti-HBs markers present (62) . E This marker is most often positive but may be negative in some individuals. F Levels of anti-HBs may decline over time and become undetectable (212) . G Isolated anti HBc total is commonly the only serum marker detected indicating resolved infection. The reason for this test result is that anti-HBs titres fall with time and can become negative. Some earlier studies erroneously interpreted isolated anti HBc total as 1) a false positive result (based on an incorrect belief that hepatitis B was not that common); 2) "low level" chronic infection (if so, this would be HBsAg positive); 3) resolving acute infection (if so, this would be anti-HBc IgM positive or HBsAg positive or anti-HBs positive).
# IDENTIFICATION OF ARTICLES
Total articles from literature search of library databases n=4257
Articles excluded if not relevant to HIV transmission n=3272
Articles identified through: One of the 18 articles reports on two HCWs infected with HIV, for a total of 19 investigations. Sixteen out of 18 articles were eligible for the meta-analysis. One of the 16 articles reported two exposure incidents, therefore a total of 17 exposure incidents were included in the meta-analysis. Chamberland, 1992 (426) ; AIDS Committee SHEA, 1992 (427) ; Debry, 1993 (428) ; Robert, 1995 (154) ; Anonymous, 1995 (429) ; Schaffner, 1995 (93) ; Hansen, 1996 (53) ; PHLS, 1997 (430) ; PHLS, 1997 (401) ; Bartlett, 2000 (431) ; Puro, 2001 (238) ; McCarthy, 2002 (432) ; Tansley, 2004 (433) ; Department of Health and Children,2005 (370) ; Société française d'hygiène hospitalière, 2006 (434) ; Rogowska-Szadkowska, 2006 (435) ; Flint, 2011 (436) ; PHE, 2012 (107) ; PHE, 2014 (190)
# Language
Not English or French Hasselhorn, 2000 (28) ; Puro, 2003 (29) ; Stulhofer, 2006 (437) ; Ross, 2007 (438)
# Population
Did not report on HCWs infected with HIV who either: 1) performed EPPs; or 2) provided direct patient care not involving EPPs where transmission was reported Delwart, 1995 (439) ; Smith, 2002 (440) ; Bredell, 2003 (441) ; Roy, 2005 (442) ; Negut, 2007 (443) ; Jones, 2009 (444)
# Intervention
Did not report on any preventive or management intervention or measure for HCWs that may affect risk of transmission Irwin, 2002 (168) Not an analytic study (including trials and observational studies) or a descriptive study PHLS, 1997 (445) ; Aboulafia, 1998 (446) ; Bartlett, 2000 (431) ; PHE, 2005 (80) ; Criscione, 2012 (447) ; Herbeck, 2014 (448) ; Institut National de Santé Publique du Québec, 2015 (449)
# Outcome
# Did not report on indicators of transmission
# Language
Not English or French Anonymous, 1997 (450) ; Trenning-Himmelsbach, 1997 (451) ; Blazquez, 2001 (452) ; Resino, 2007 (453) ; Lucena, 2011 (454)
# Population
Belec, 1998 (455) ; Donnelly, 1999 (172) ; Kallenborn, 2001 (456) ; Blick,
Did not report on blood-to-blood 2007 (457) ; CDC, 2009 (178) ; Ding, 2009 (458) ; Hecht, 2010 (459) ; Miller, exposure and/or reported on sexual, 2013 (460) perinatal, transfusion or transplantationrelated exposures
Viral load data Robert, 1995 (154) ; Romea, 1995 (461) ; CDC, 1995 (462) ; Lot, 1995 (463) ;
Did not report the time between a
Bell, 1996 (464) ; Tereskerz, 1996 (465) ; Vidmar, 1996 (466) ; Cardo, person's exposure and viral load testing 1997 (467) ; CDC, 1997 (468) ; Dorozynski, 1997 (469) ; Lancaster, of the source individual
# Articles excluded for drug diversion n=6
Articles identified as companions to eligible articles n=6
A Companion articles provide supplementary information about specific epidemiologic investigations. B Nine out of 20 articles were eligible for the meta-analysis. Schaffner, 1995 (93) ; Roudot-Thoraval, 2000 (491) ; Bartlett 2000 (431) ; Ross, 2000 (65) ; Heptonstall, 2000 (492) ; Carbonne, 2006 (394) ; Roche, 2008 (493) ; Carlson, 2010 (33) ; Ramer, 2013 (494) ; Chen, 2016 (495) ; De Peyer, 2016 (232)
# Language
Not English or French Hasselhorn, 2000 (28) ; Puro, 2003 (29) ; Gerlich, 2004 (496)
# Population
Did not report on HCWs infected with HIV who either: 1) performed EPPs; or 2) provided direct patient care not involving EPPs where transmission was reported Hohne, 1994 (497) ; Dumpis, 2003 (498) ; PHLS, 2005 (230) ; Bonnal, 2010 (499)
# Intervention
Did not report on any preventive or management intervention or measure for HCWs that may affect risk of transmission PHLS, 2001 (229) ; Januszkiewicz-Lewandowska, 2003 (500) ; Ross, 2003 (235) ; Wrobel, 2006 (501)
# Outcome
Did not report on indicators of transmission Smith, 2002 (440) ; PHE, 2013 (502)
# Drug diversion
Reported drug diversion by the HCW Sehulster, 1997 (503) ; Akehurst, 1998 (504) ; Petruccelli 2005 (505) ; Shemer-Avni, 2007 (223) ; Hellinger, 2012 (506) ; Gonzalez-Candelas, 2013 (507)
# Duplicates removed n=379
Excluded for description of the same event, language, relevance and/ or article type n=1018
Excluded for study design, language, population and/ or viral load data n=137 Seeff, 1991 (508) ; Anonymous, 1996 (509) ; Canadian Medical Association, 2010 (381) ; CADTH, 2012 (510) ; American Society of Anesthesiologist, 2014 (511) ; GOV.UK, 2014 (512)
# Language
Berger, 1998 (513) ; Laufs, 1998 (514) ; Olaso, 1999 (515) ; Cordoba, 2000 (516) ;
Not English or French Del Poggio, 2000 (517) ; Hasselhorn, 2000 (28) ; Blázquez, 2001 (452) ; De Figueiredo, 2003 (518) ; Velasco, 2003 (519) ; Beran, 2004 (520) ; Castro Ferreiro, 2004 (521) ; Gerlich, 2004 (496) ; Husa, 2004 (522) ; Bilski, 2005 (523) ; Guglielmi, 2005 (524) ; Bilski, 2006 (525) ; Campins Martí, 2006 (526) ; Warley, 2006 (527) ; Anonymous, 2007 (528) ; Kubitschke, 2007 (40) Population Caporaso, 1998 (529) ; Anonymous, 2000 (530) ; File, 2003 (531) ; Keiserman,
Did not report on blood-to-blood 2003 (486) ; Nikolopoulou, 2005 (532) ; Patel, 2006 (533) ; CDC, 2009 (534) ; exposure and/or reported on sexual, Dawar, 2010 (77) perinatal, transfusion or transplantation-related exposures Articles identified as companions to eligible articles n=3
# Viral load data
Total articles from literature search of library databases n=4257
Articles excluded if not relevant to HBV n=3087
Excluded for description of the same event, language, relevance and/or article type n=1022
A Fifteen out of 23 articles were eligible for meta-analysis. Two articles included 3 incidents each and 1 article included 2 incidents, for a total of 20 incidents. Three articles were excluded for IPC breaches.
B Companion articles provide supplementary information about specific epidemiologic investigations. Bartlett, 2000 (431) ; Carbonne, 2006 (394) ; Danzmann, 2013 (611)
# Language
Not English or French Zaaijer, 1999 (612) ; Puro, 2003 (29) ; Bilski, 2005 (523)
# Population
Did not report on HCWs infected with HIV who either: 1) performed EPPs; or 2) provided direct patient care not involving EPPs where transmission was reported Zuckerman, 1995 (413) ; Curran, 2000 (613) ; Corden, 2003 (294) ; Buster, 2004 (614)
# Intervention
Did not report on any preventive or management intervention or measure for HCWs that may affect risk of transmission Ngui, 2000 (293) ; Carlson, 2010 (33) Sikora, 2010 (615)
# Outcome
# Did not report on indicators of transmission
# Language
Not English or French
# Nil
# Population
Did not report on blood-to-blood exposure and/or reported on sexual, perinatal, transfusion or transplantation-related exposures Zeuzem, 1997 (616) ; Datta, 2006 (617) ; Criscione, 2012 (618) ; Buchner, 2015 (619)
# Viral load data
Did not report the time between a person's exposure and viral load testing of the source individual Tedder, 1995 (620) ; Zucherman, 1995 (413) ; The incident control teams and others, 1996 (41) ; Mukerjee, 1996 (122) ; Sundkvist, 1998 (115) ; Oliver, 1999 (123) ; Nguyen, 2001 (43) ; Spijkerman, 2002 (121) ; Nguyen, 2003 (558) ; Kidd-Ljunggren, 2006 (621) ; Smellie, 2006 (133) ; Harling, 2007 (622) ; Laurenson, 2007 (124) ; Poujol, 2008 (139) ; Demirturk, 2014 (623) ; Du Plessis, 2014 (624) ; Dwibedi, 2014 (625) Abbreviation: HBV, hepatitis B virus
# Grade of Evidence
# Strength of Evidence
# Grades Criteria
Strong AI Direct evidence from meta-analysis or multiple strong design studies of high quality, with consistency of results
# AII
Direct evidence from multiple strong design studies of medium quality with consistency of results OR At least one strong design study with support from multiple moderate design studies of high quality, with consistency of results OR At least one strong design study of medium quality with support from extrapolation from multiple strong-design studies of high quality, with consistency of results
# Moderate BI
Direct evidence from multiple moderate design studies of high quality with consistency of results OR Extrapolation from multiple strong design studies of high quality, with consistency of results
# BII
Direct evidence from any combination of strong or moderate design studies of high/medium quality, with a clear trend but some inconsistency of results OR Extrapolation from multiple strong design studies of medium quality or moderate design studies of high/medium quality, with consistency of results OR One strong design study with support from multiple weak design studies of high/medium quality with consistency of results
# Weak CI
Direct evidence from multiple weak design studies of high/medium quality, with consistency of results OR Extrapolation from any combination of strong/moderate design studies of high/medium quality, with inconsistency of results (8) . (626) ; data for each profession and P/T was either obtained from CIHI documents or other reliable source (refer to hyperlinks in each cell). Yes -Profession is regulated in Province/Territory; No -Profession is not regulated in Province/Territory.
# CII
# Anti-HBc total
The presence of anti-HBc (IgG or IgM and IgG) indicates previous or ongoing infection with HBV (270) .
# Anti-HBc IgM
Anti-HBc IgM appears early in acute HBV infection and persists for about 6 months (270) . It may also be seen in chronic infection during flares of activity, so clinical / epidemiological correlation is required for interpretation (62,270) .
# Anti-HBc IgG
Anti-HBc IgG appears shortly after infection and usually persists for life in the majority of persons, sometimes showing up as the antibodies to all other proteins fade (62) .
# HBeAg
This is a secreted product of the nucleocapsid gene of HBV that is found in the serum during acute and chronic HBV infection (270) . It is a marker of active viral replication and its presence indicates high infectivity (62,237,270) . Some individuals infected with HBV, carry a viral strain with a nucleotide substitution in the precore region of the viral genome. This mutation prevents transcription of the precore region and therefore, the release of HBeAg from the hepatocyte which results in a negative serum test for HBeAg. This mutation is important because infections caused by these viruses are difficult to treat, can cause prolonged infections, and are associated with a higher risk of liver cirrhosis.
# Anti-HBe
Appears with recovery from acute infection, but may disappear over time. In chronic infection, the presence of anti-HBe is generally a marker of reduced viral replication, indicating a less infectious state (62) . For individuals carrying the viral strain with a mutation preventing transcription of the precore region and therefore, the release of HBeAg from the hepatocyte, this allows anti-HBe to be detected but HBV DNA is still high.
# HBV DNA
Used to measure level of infectivity and response to treatment (270) . Unable to find PHLS, 1997 (489) ; Donnelly, 1998 (490) Abbreviations
# Society for Healthcare Epidemiology of America Société française d'hygiène hospitalière HIV Medicine Association
A Stakeholder organizations and international subject matter experts were identified with the assistance of the Guideline Development Task Group and key international guidelines or reports. B Feedback provided as a subject matter expert and does not necessarily represent the official position of the U.S. Federal Government or the Society for Healthcare Epidemiology of America. C Feedback provided as a subject matter expert does not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention. Exposure-prone procedure (EPP): An invasive procedure where there is a higher-than-average risk that injury to the HCW may result in the exposure of the patient's open tissues to the blood of the HCW.
Healthcare facility: Includes but is not limited to acute-care hospitals, emergency departments, rehabilitation hospitals, mental health hospitals, and long-term care facilities (19) .
# Healthcare organization:
The organizational entity that is responsible for establishing and maintaining healthcare services provided by HCWs and other staff in one or more healthcare settings throughout the healthcare continuum (19) .
Healthcare setting: Any location where health care is provided, including emergency care, prehospital care, hospital, long-term care, home care, ambulatory care and facilities and locations in the community where care is provided (e.g., infirmaries in schools, residential or correctional facilities) (19) .
Healthcare worker (HCW): Individuals who provide health care or support services, such as nurses, physicians, dentists, dental hygienists, physician assistants, nurse practitioners, paramedics and sometimes emergency first responders, allied health professionals, unregulated healthcare providers, clinical instructors and students, volunteers and housekeeping staff. Healthcare workers have varying degrees of responsibility related to the health care and support services they provide, depending on their level of education and their specific job and/or responsibilities (19) .
Lead authority: Within the context of this guideline, it is the healthcare organization, facility, public health unit or agency that coordinates a lookback investigation related to a HCW infected with a BBV.
# Lookback investigation (LB):
If a HCW has been identified as infected with HBV, HCV or HIV and has performed exposure-prone procedures that could have put patients at risk of exposure to an infection, then the organization employing the HCW or the local public health unit contacts patients at risk to give advice about testing and potential treatment and to discuss methods of preventing further transmission with those found to be infected (2) .
Outcome: A term used to refer to results of interest in a study such as infections, diseases, behaviours, effects or conditions (8) .
# Peer healthcare worker (HCW):
A HCW from the same area of practice as the infected HCW who assists: 1) the expert review panel to determine the need for practice restrictions or modifications; 2) the risk assessment team to determine if a lookback investigation is required; and 3) the investigation management team to assist with the coordination of the investigation.
The peer HCW provides information on the procedures performed by the infected HCW and whether there is a risk of patients being potentially exposed to the HCW's blood.
Regulated HCW: Within the context of this guideline, refers to any HCW whose work or practice is regulated by a provincial or territorial regulatory authority (legislation may vary by province and territory).
Regulatory authorities: Within the context of this guideline, refers to any agency established by provincial or territorial legislation to regulate the practice of health professionals (e.g., medicine, dentistry, nursing, etc.) (Adapted from the Federation of Medical Regulatory Authorities of Canada definition for Medical Regulatory Authority) (627) .
Routine Practices (synonymous with Standard Precautions (26) ): A comprehensive set of infection prevention and control measures that has been developed for use in the routine care of all patients at all times in all healthcare settings. Routine Practices aim to minimize or prevent healthcare-associated infections in all individuals in the healthcare setting, including patients, HCWs, other staff, visitors and contractors (19) .
Traceback investigation: If a patient has been identified as infected with a HBV, HCV or HIV and has no identifiable risk of infection from that virus, as assessed by the physician or local public health unit, but has undergone an exposure-prone procedure within the appropriate incubation period, then the local public health unit seeks to identify the HCW who has performed exposure-prone procedures and other infected or potentially infected patients in order to provide treatment and counselling on preventing further transmission (2) . Universal precautions: A set of infection prevention and control measures that was developed with the primary purpose of protecting the HCW from exposure to bloodborne viruses, and was based on the principle that it was not possible to know which patients harboured bloodborne viruses (19) . Universal precautions were used in conjunction with category -or disease-specific isolation systems for patients with specific symptoms or infections (628,629) .
Unregulated HCW: Within the context of this guideline, refers to any HCW whose work is not regulated by a provincial or territorial regulatory authority (legislation may vary by province and territory).
# Viral load:
Refers to the number of circulating viruses in a unit of blood.
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For patients >age 60 years, 3-7 days of prednisone 100mg/day pre-R-CHOP as well as G-CSF prophylaxis are recommended to decrease toxicity.Limited-stage DLBCL is associated with favorable outcomes with long-term survival rates up to 80%, although a persistent pattern of late relapses has been described in up to 20-30% of patients. The stage-modified IPI score risk stratifies patients according to the following factors: age >60, stage II, elevated LDH, ECOG >1. In the pre-rituximab era, the phase III SWOG S8736 trial reported superior PFS and OS with CHOP×3 plus RT versus CHOP×8; 53 however, due to the occurrence of late relapses and treatment complications, there was no difference in PFS or OS between the two strategies with long-term follow-up. 54 In the rituximab era, the MInT trial established R-CHOP x6 as the standard of care for most patients with limited-stage DLBCL. 55 Given the favorable outcomes of limited-stage DLBCL, recent studies have assessed the role for treatment de-escalation to minimize toxicity while preserving efficacy. The LYSA/GOELAMS 02-03 trial of 334 patients with stage I-II nonbulky (<7cm) DLBCL demonstrated that R-CHOP alone is non-inferior to R-CHOP + RT if CR is achieved on interim PET after cycle 4; in addition, 4 cycles of R-CHOP was found to be sufficient for interim PET-negative patients with 0 sm-IPI risk factors (Blood 2018;131(2):174). The phase III FLYER trial found that 4 cycles of R-CHOP has reduced toxicity and non-inferior efficacy compared to 6 cycles for patients with stage I-II non-bulky (<7.5cm) DLBCL with no other sm-IPI risk factors. 56 In addition, the phase II SWOG S1001 trial and real-world data from BC Cancer demonstrated excellent PFS rates with 4 cycles of R-CHOP if CR is achieved after cycle 3, even in patients with up to 2 sm-IPI risk factors (# Table of Contents
Background
# Background
Lymphomas encompass a group of lymphoproliferative malignant diseases that originate from T-and B-cells in the lymphatic system. Traditionally, lymphomas have been subcategorized into two groups: Hodgkin lymphoma and non-Hodgkin lymphoma. It is now known however, that Hodgkin lymphoma is simply one of the numerous varieties of lymphoma, and that non-Hodgkin lymphoma is a fairly meaningless term, representing all of the other subtypes of this disease.
Non-Hodgkin lymphoma involves a heterogeneous group of over 40 lymphoproliferative malignancies with diverse patterns of behaviours and responses to treatments. Non-Hodgkin lymphoma is much less predictable than Hodgkin lymphoma and prognosis depends on the histologic type, stage, and treatment. In Canadian males and females, the incidence rates for non-Hodgkin lymphoma showed a marked increase by approximately 50% between 1978 and the late 1990s, but have since stabilized 1 . Mortality rates have followed a similar pattern. The clearest risk factor for the disease is immunosuppression associated with HIV infection, or medications used to prevent rejection in organ transplantation. Other factors that increase risk of non-Hodgkin lymphoma are poorly understood but may include occupational exposures to pesticides, herbicides, and dioxins, as well as chronic immune stimulation associated with autoimmune disorders (e.g. thyroiditis, Sjogren's Syndrome, SLE) or infections (e.g. Helicobacter pylori gastritis, hepatitis C virus) 2 . In 2015, it is estimated that 8200 new cases of non-Hodgkin lymphoma will be diagnosed in Canada, and 2650 deaths will occur, making non-Hodgkin lymphoma the sixth most common cause of cancer-related death in Canada 3 .
Hodgkin lymphoma is a malignancy characterized histopathologically by the presence of Reed-Sternberg cells in the appropriate cellular background. Although rare, Hodgkin lymphoma is one of the best-characterized malignancies of the lymphatic system and one of the most readily curable forms of malignant disease. 2 The incidence rate has remained fairly steady over time, it is estimated that approximately 1000 new cases of Hodgkin lymphoma are diagnosed in Canada each year 3 . It is important to note that lymphoma also represents the most commonly diagnosed non-epithelial cancers in adolescents and young adults in Canada. Between 1992 and 2005, 5577 new cases of Hodgkin and non-Hodgkin lymphoma were diagnosed in Canadians aged 15-29 years 1 . The following guidelines do not address lymphoma in the pediatric or adolescent populations.
# Guideline Questions
- What are the diagnostic criteria for the most common lymphomas?
- What are the staging and re-staging procedures for Hodgkin and non-Hodgkin lymphomas?
- What are the recommended treatment and management options for Hodgkin and non-Hodgkin lymphomas?
- What are the recommended follow-up procedures for patients with malignant Hodgkin and non-Hodgkin lymphoma?
# Search Strategy
Medical journal articles were searched using Medline (1950 to October Week 1, 2015), EMBASE (1980 to October Week 1, 2015), Cochrane Database of Systematic Reviews (3 rd Quarter, 2015), and PubMed electronic databases. An updated review of the relevant existing practice guidelines for lymphoma was also conducted by accessing the websites of the National Comprehensive Cancer Network (NCCN), Cancer Care Ontario (CCO), the British Columbia Cancer Agency (BCCA), the European Society for Medical Oncology (ESMO), and the British Committee for Standards in Haematology.
# Target Population
The following guidelines apply to adults over 18 years of age. Different principles may apply to pediatric and adolescent patients.
I. Diagnosis and Pathologic Classification An excisional lymph node biopsy of the largest regionally involved lymph node is the optimal specimen for initial diagnostic assessment. Similarly, a sizable biopsy from the organ of origin in extranodal lymphomas is also suitable. Compelling clinical contraindications to an open biopsy should be present before considering any other options. A careful clinical examination or radiological investigations for more accessible or palpable pathologic adenopathy could be useful in decision making prior to opting for a lesser diagnostic specimen. Fine needle aspirate biopsies are inadequate for the initial diagnosis of lymphoma. These latter specimens may provide adequate material for evaluating possible relapse, clarification of staging at questionable sites and as a source of additional specimen where required for further special testing or research. Occasionally, a generous core needle biopsy comprising many core samples with sufficient material to perform the appropriate ancillary techniques required for diagnostic assessment (immunohistochemistry, flow cytometry, PCR for IgH and TCR gene rearrangements, and FISH for major translocations) may supply adequate tissue, in cases when a lymph node is not easily accessible for excisional or incisional biopsy. A reference lymphoma pathologist should confirm lymphoma diagnoses in each and every case. This is particularly important in cases when only a core needle biopsy is available, and whenever requested by the treating clinician.
Table 1 describes the histologic subclassification of the malignant lymphomas, and is an adaptation of the most recent WHO classification 6 . This classification is based on the light microscopic interpretation complemented by special stains, immunophenotyping, cytogenetics and other ancillary information as available. The specific lymphomas are divided into three major groups, according to the degree of clinical aggressiveness, for treatment planning. All B-cell lymphomas should be immuno-phenotyped to determine if they are CD20 positive.
# Required Immunohistochemical and Ancillary Testing for Lymphoma
In general, guidelines for using the various ancillary methods, includingimmunohistochemical and fluorescence in situ hybridization (FISH) testing as outlined in the most recent version of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues should be followed so as to confirm a specific diagnosis and provide necessary prognostic and/or predictive information 6 . In addition, the following are recommended by the Alberta Provincial Hematology Tumour Team 7,8 :
- Classical Hodgkin Lymphoma: The immunohistochemical panel may include CD45/CD3/CD20/CD30/CD15/ PAX5/MUM1 and should be selected on a case by case basis at the discretion of the hematopathologist. EBV studies by in situ hybridization (EBER) may be considered if difficulty exists diagnostically, as most cases of the mixed-cellularity subtype of classical Hodgkin lymphoma are EBER positive.
# Diffuse Large B-Cell Lymphoma (DLBCL):
- Immunohistochemical (IHC) panels to distinguish between Activated B Cell (ABC) type and Germinal Centre B-cell (GCB) cell of origin (COO) types have limitations (regardless of which algorithm is employed)when compared to gene expression profiling 8,9 . However, GCB vs non-GCB COO by IHC does correlate with survival rates following RCHOP chemotherapy, and therefore adds prognostic information when managing DLBCL. The Alberta hematopathologists currently use a simple algorithm published by Hans et al, requiring IHC stains for CD10, BCL6 and MUM1, in which CD10+ or BCL6+/ MUM1-cases are designated as GCB COO, whereas cases negative for negative/BCL6+/MUM1+ phenotype are considered to have a non-GCB COO.
- EBER and CD5 expression confer worse prognosis, and may be used to identify various clinicalpathological entities with distinct implications. Determining CD5 expression should be considered on all DLBCL cases. EBER should be performed in patients with immune suppression related lymphomas, or those who possibly have EBV-related DLBCL (consider past the age of 50) 10 .
- Rearrangments of the C-MYC gene as determined by FISH, especially in association with BCL2 and/or BCL6 (so called "double hit" or "triple hit" disease) are associated with very poor outcomes following R-CHOP therapy, as well as high rates of central nervous system relapse.
Patients with a double-hit or triple-hit lymphoma under age 70 years should receive more aggressive therapy and possibly stem cell transplantation. Though it represents approximately only 5-10% of DLBCL cases 11 , it is very important to recognize these patients, and therefore, MYC rearrangement testing by FISH is to be performed on all patients younger than 70 y.o. with the appropriate lymphoma histology, i.e. DLBCL or lymphoma that are so called "unclassifiable" with intermediate morphological features between DLBCL and Burkitt. If MYC is rearranged, the case should also undergo BCL2 and BCL6 rearrangement testing by FISH. MYC and BCL2 test results are required within 2 weeks of diagnoses for all new patients within the appropriate diagnostic category and age group. FISH testing may also be performed in select instances at the discretion of the reporting hematopathologist if such studies are deemed diagnostically useful.
- Immunohistochemical studies cannot be used as a surrogate for MYC rearrangement.
- However, the detection of MYC and BCL2 concurrent overexpression by IHC in so-called "dual expressor" DLBCL, identifies a numerically significant subset of the DLBCL with potentially similar aggressive behavior compared to double-hit lymphoma cases, but representing a distinct group of patients (more often an ABC subtype as opposed to double hit DLBCL which are usually GCB). This group is also associated with a high rate of CNS relapse 11 . Therefore, provided adequate benchmarks and interpretation standards can be established for reproducibility, IHC for MYC and BCL2 expression should also be strongly considered on all DLBCL cases 9,12 .
- Follicular Lymphoma: must document grade (1-2, 3a or 3b), because all grade 3b should receive R-CHOP rather than other chemotherapy regimens. Also, if a diffuse pattern is present, this should be specified and a relative proportion noted, as outlined in the WHO Classification. 4. Peripheral T-Cell Lymphoma: cytotoxic T-cell markers (CD8/CD57/Granzyme B) correlate with poor prognosis and should be considered. Notably, however, peripheral T cell lymphomas are not classified on the basis of these phenotypic markers. EBV studies by in situ hybridization (EBER) should be performed in cases where angioimmunoblastic T cell lymphoma (AITL) and extranodal T/NK cell lymphoma, nasal type enter in the differential diagnosis. 5. Mantle Cell Lymphoma: Evidence of CyclinD1 deregulation confirmed by IHC (positive staining for CyclinD1) and/or FISH (positive for t (11;14)) is needed to confirm the diagnosis, provided other morphophenotypic findings are consistent with the diagnosis. Poor prognostic features must be mentioned in the report, including blastoid and pleomorphic morphologic variants. The proliferation index as measured by Ki67 or Mib-1 (used to calculate MIPI score) is to be reported. In cases where it is difficult to differentiate MCL from CLL, flow cytometry for CD200 and IHC for SOX11 may be performed 13 . For patients who are deemed transplant-eligible (i.e. age <65 and fit for intensive therapy), TP53 mutational testing should be performed at time of diagnosis to identify high-risk patients more appropriate for allogeneic stem cell transplantation 14 .
II. Staging Mandatory Staging Procedures
- Pathology review whenever possible (essential for core needle biopsies)
- Complete history and physical examination stating ECOG Performance Score, B symptoms
- CBC & differential, creatinine, electrolytes, Alk P, ALT, LDH, bilirubin, total protein, albumin, calcium
- Hepatitis B Surface Antigen (HBsAg), Hepatitis B Surface Antibody (anti-HBs), and Hepatitis B Core Antibody (total anti-HBc) must be done prior to initiating chemo/immunotherapy. Patients who are HBsAg positive are either acutely or chronically infected and require consultation with Hepatology. Patients who are HBsAg negative/anti-HBc positive (regardless of anti-HBs titre levels) and are going to be treated with B-cell depleting therapy (e.g. rituximab) should receive prophylactic therapy with entecavir or tenofovir. Those who are HBsAg negative/anti-HBc positive and fall under low or moderate risk as per Table 1 do not require prophylaxis and should undergo serial HBV DNA testing q6-12 months and serial ALT testing q3 months while on immunosuppressive therapy (see Figure 1). Hepatitis B prophylactic therapy should be continued for at least 6 months following the completion of immunosuppressive therapy, except for those treated with anti-CD20 agents who should continue for at least 12-18 months due to the lag in B-cell function recovery. Adapted from Coffin, Carla S., et al. 13 Anti-HBc = antibody to HBV core; anti-HBs = antibody to HBsAg; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; TNF = tumour necrosing factor.
- ESR (for early stage Hodgkin lymphoma)
- Beta-2-microglobulin
- Serum protein electrophoresis and quantitative IgG, IgA, and IgM for indolent B-cell lymphomas
- Pregnancy test: if at risk
- Bone marrow aspiration and 2cm biopsy (BMasp/bx) with flow cytometry for patients with indolent B-cell and a marrow biopsy (without flow cytometry) for aggressive T-cell non-Hodgkin lymphomas. BMasp/bx is not required for Hodgkin lymphoma or DLBCL if a staging PET/CT is performed.
- FDG-PET and Diagnostic CT NeckChestAbdomenPelvis for FDG-avid, nodal lymphomas, which includes all histologies except chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma, mycosis fungoides, and marginal zone NHLs (unless there is a suspicion of aggressive transformation). Nodal lymphomas that are not FDG avid should have a staging diagnostic CT scan of NCAP. PET-CT is especially important for patients who otherwise have non-bulky, stage I-IIA lymphoma, and are being considered for involved field radiation (IFRT) following abbreviated (or no) chemotherapy. PET/CT is not necessarily required for Follicular Lymphoma if the results will not change management, particularly for a patient who will likely undergo watchful waiting.
Restaging Schedule
- The following are to be performed prior to each chemotherapy treatment:
- Clinical parameters: brief history and physical examination, toxicity notation, ECOG status - Bloodwork: o CBC/differential/platelet o also consider EP/creatinine and LFTs 2. Requirements for CT scanning of chest/ abdomen/ pelvis:
- Routine CT scanning: o after 3 months (4 cycles) of therapy and again after completion of all therapy for Non-Hodgkin Lymphomas o if a residual mass is seen on the CT after completion of all therapy, then repeat a PET/CT for aggressive lymphoma to determine partial or complete remission. o a repeat CT scan should be considered 6-12 months post-treatment; otherwise, no further routine CT scans are required o Hodgkin lymphoma patients should undergo a PET/CT after 2 cycles ABVD (rather than CT after 4 cycles) as outlined below in the Hodgkin Lymphoma treatment guidelines.
- Other requirements for CT scanning: o as indicated to investigate clinical signs or symptoms, or abnormal laboratory tests 3. Bone marrow aspirate & biopsy (with sample sent for flow cytometry):
- Repeat for transplant-eligible patients with aggressive histology lymphomas who otherwise are in complete remission after completion of chemotherapy, if marrow was positive at diagnosis 4. PET/CT Imaging:
- Assessment of residual radiographic or clinical abnormalities of uncertain significance at the time of re-staging following completion of therapy.
- Hodgkin lymphoma patients should undergo a PET/CT after 2 cycles ABVD (rather than CT after 4 cycles) as outlined below in the Hodgkin Lymphoma treatment guidelines. For DLBCL, factors associated with high risk (>10%) for relapse in the central nervous system include 4-6 of the following factors: 1) Age >60 years, 2) elevated LDH, 3) ECOG=2-4, 4) Stage 3-4, 5) >1 extranodal site of involvement, and 6) kidney or adrenal involvement. Other high risk situations include double hit lymphoma (MYC + BCL2 and/or BCL6 translocations) and testicular lymphoma. Prophylactic intrathecal chemotherapy does not penetrate the brain parenchyma and has not been proven to decrease meningeal or parenchymal brain relapse of lymphoma in well-designed studies.
Due to the lack of proven benefit, intrathecal chemotherapy cannot be recommended even in highrisk situations where the risk of CNS relapse is 10% or higher.
For patients at high-risk of CNS involvement, we previously recommended CNS prophylaxis with high dose intravenous methotrexate (HD-MTX) 3.5g/m2 x 3 doses mid-cycle of R-CHOP following cycles 2, 4, 6. We recently reviewed our outcomes for patients who were treated according to our guidelines with a recommendation for incorporating intravenous HD-MTX for all patients with CNS-IPI score 4-6, double-hit lymphoma or testicular lymphoma. 67 Among 906 patients treated for DLBCL, with a median follow-up of 35.3 months, CNS relapse risk was similar with and without intravenous MTX (11.2% vs 12.2%, p=0.82), with rates in high-risk patients comparable to previous reports in patients who did not receive CNS prophylaxis (10-12%). However, the risk of CNS relapse trended lower in patients who received consolidative ASCT or intensified chemo-immunotherapy versus R-CHOP (6.0% vs 14.6%, p=0.09). The ineffectiveness of prophylactic HD-MTX has been confirmed in several other multiinstitutional retrospective studies, 68,69 71 CAR T-cell therapy is an established treatment for adult patients with relapsed/refractory large B-cell lymphoma after two or more lines of therapy, with two immune effector cellular therapies approved in Canada, namely axicabtagene ciloleucel (axi-cel, Yescarta) and tisagenlecleucel (Kyrmiah). In the pivotal phase I/2 Zuma-1 study, 110/111 enrolled patients with refractory DLBCL, primary mediastinal B-lymphoma, or transformed follicular lymphoma received a single infusion of axi-cel, with CR rate of 52% and ongoing CR of 40% at 15.4 months of follow-up, and OS of 52% at 18 months. 72 At 38.1 months median follow-up, the OS rate was 47% with median of 25.8 months. 73,74 In the phase 2 Juliet trial 93 patients with relapsed/refractory DLBCL or transformed follicular lymphoma received a single infusion of tisagenlecleucel, with CR of 40% and relapse-free survival of 65% at 12 months (79% in those who achieved CR). 75 Lisocabtagene maraleucel (Liso-cel) is a third immune effector cell therapy being studied, and the TRANSCEND NHL001 study presented at ASH 2019 demonstrated similar efficacy data, with CR rate of 53%, and OS 57.9% at 1 year (85/% in patients with CR). 76 The main toxicities of these therapies are cytokine release syndrome, neurotoxicity, cytopenias, and B-cell aplasia/hypogammaglobulinemia and as such this therapy is be administered only at centers approved for cellular therapy treatments.
Phase III trials with axi-cel and liso-cel as second line therapy compared to the standard salvage chemotherapy approach in patients with poor prognosis relapsed/refractory DLBCL 50% of these patients subsequently proceeded with CAR T therapy in 3 rd line, with inferior outcomes. Review of 125 southern Alberta patients between 2015 and 2019 with relapsed/refractory DLBCL after RCHOP chemotherapy demonstrated that of the 50 patients that were intended for salvage and HDT-ASCT, only 28 underwent a stem cell transplant, with long-term cure in only 9 of these patients. 78 These data suggest that while the current standard of care results in poor outcomes for most patients with relapsed/refractory DLBCL, the use of CAR T therapy second line could substantially increase the proportion of patients able to receive curative treatment at first progression.
# Patients unfit for intensive therapy:
The prognosis of patients with relapsed/refractory DLBCL who are not candidates for cellular therapy is extremely poor, with median survival rates of less than 6 months, thus palliation is the main goal of any chosen therapy. Palliative-intent regimens including R-GemOx, polatuzumab vedotin with bendamustine/rituximab, and tafasitamab with lenalidomide have been studied in phase II trials of patients with r/r DLBCL who are unfit for intensive therapy:
# Recommendations for treatment:
- R-GemOx is the preferred second-line treatment because it is a well-established outpatient platinum-based regimen that is better tolerated in older patients than other regimens such as GDP, DHAP, or ICE, although it is associated with significant myelosuppression.
Polatuzumab, bendamustine, and rituximab can be considered for second or later relapses, and for patients who are unfit for, or intolerant of, R-GemOx. Patients should have reasonable performance status (ECOG 0-2) and adequate hematologic function to be expected to benefit from and tolerate polatuzumab with BR. Tafasitamab-lenalidomide is also approved but is not yet funded in Alberta. Bendamustine and tafasitamab should be avoided in patients potentially eligible for CAR-T cell therapy due to the respective risks of lymphodepletion and CD19 downregulation.
Some palliative patients at or beyond second relapse may have symptomatic benefit from prednisone alone, or low dose daily oral chemotherapy with chlorambucil 0.1mg/kg/day or etoposide 50mg/day, or combination oral therapy such as PEPC.
Involved field radiotherapy (IFRT) to symptomatic sites or localized relapses may also benefit these palliative patients.
Addressing goals of care and ensuring timely integration of palliative care should be a priority for all patients with r/r DLBCL who are unfit for intensive therapy.
# Secondary CNS Lymphoma 79-82
Selected patients with CNS relapse/progression may be candidates for intensive therapy as outlined in Appendix A, subheading VIII. Favorable outcomes were reported in an Alberta study of 62 SCNSL patients with median age 58 years (range 20-75) intended for transplant, with ASCT rates of 84%, 5year PFS 53% and OS 65% for all patients, and 5-year PFS 62% and OS 73% for those undergoing R-TBuM conditioning and ASCT. One of 3 induction regimens is recommended for transplant-eligible patients and one of two options for transplant ineligible patients, based on presentation:
1) Isolated CNS lymphoma: HDMTX-based induction then RDHAP for stem cell mobilization and collection, then R-TBuM/ASCT for transplant eligible (
# High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements by FISH:
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double hit lymphoma or DHL) is associated with a poor prognosis, with a large multicenter retrospective analysis of 311 patients reporting an OS rate <50% if IPI=2-5 vs 65% for IPI=0-1 (Blood 2014;124(15):2354). The optimal treatment of DHL is unknown, but intensive induction regimens such as da-EPOCH-R or R-CODOX-M/R-IVAC are commonly used and have demonstrated PFS benefit over R-CHOP in some retrospective studies (Blood 2014;124(15):2354) but not others (Am J Hematol 2021; 96(3):302). In
# CAR T-cell Therapy
addition, the use of consolidative HDT/ASCT has been associated with superior outcomes among patients achieving CR after R-CHOP induction but not after intensive induction regimens. 83 This suggests that DHL patients treated with R-CHOP can be considered for ASCT consolidation, especially if IPI=2-5 at diagnosis, however other patients who achieve CR after an intensive induction regimen probably should not receive ASCT consolidation. A retrospective analysis of 99 patients with DHL in Alberta found relatively favorable outcomes with 4-year PFS 59% and OS 66%, with no significant difference in PFS or OS between patients treated with intensive induction regimens vs intention-to-transplant following R-CHOP induction. Among the 48 patients intended for ASCT, outcomes were excellent for the 75% of patients undergoing upfront ASCT with 4-year PFS 80-90%, whereas there were no survivors among the 25% of patients with primary refractory disease. This suggests that upfront ASCT can achieve durable remissions in the majority of DHL patients with chemosensitive disease, whereas alternative strategies such as CAR-T cell therapy should be strongly considered for patients with chemorefractory disease.
# Alberta recommendations for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements:
- IPI=0-1: R-CHOP x 6 cycles or da-EPOCH-R x 6 cycles - IPI=2-5: Options include:
- A. R-CHOP x 2-3
# Primary Mediastinal B-Cell Lymphoma
Primary mediastinal B-cell lymphoma (PMBCL) of thymic origin represents 6-10% of all DLBCLs, and most commonly affects young adults (median age ~35), women more than men. 84 It is frequently associated with a bulky mediastinal mass that directly extends into extranodal thoracic tissues such as pleura, pericardium and chest wall. Patients with distant lymphadenopathy or extranodal involvement outside the thorax should likely be diagnosed and treated as systemic DLBCL with secondary mediastinal involvement, rather than as PMBCL. 85 Overall, PMBCL is associated with a better prognosis than other DLBCLs, including GCB DLBCLs. The IPI score tends not to work well for PMBCL because most patients are young with fairly well-preserved performance status, and have elevated LDH. Therefore, limited vs advanced stage, and number extranodal sites (esp pleural effusions) tend to be the only factors that subdivide patients into excellent vs good prognosis. Likewise, because most patients have a very good prognosis, interim restaging PET imaging is associated with very high negative predictive value, but relatively low positive predictive value. 86 These findings were confirmed in 20 patients treated with R-CHOP in Alberta, where the PPV of a positive interim PET scan was only 20% for disease progression/relapse whereas a negative interim PET had NPV 100%. Therefore, a positive interim PET scan should probably not be used alone to guide further therapy. 87 There is no phase III evidence that RT after R-CHOP improves survival rates relative to R-CHOP alone, but this is being studied in the ongoing IELSG-37 clinical trial. Real-world data from the BCCA demonstrates that omitting RT for PETnegative patients at the end of R-CHOP therapy achieves similar TTP (80%) and OS (89%) as historical cohorts treated routinely with RT, with a reduction in RT use from 78% in the historical cohort to 28% in the PET-directed era. 88 Similarly, retrospective data for 91 consecutive patients in Alberta treated with R-CHOP from 2004-2020 found a 5-year overall survival rate of 86%, with similar outcomes for patients with advanced versus limited stage (86% vs 92%, p=0.31) or bulky versus nonbulky disease (83% vs 96%, p=0.12). For patients responding to R-CHOP, the 5-year OS rate was 93% with RT versus 100% without RT (p=0.17). Among 40 patients with a PET-defined complete metabolic response after R-CHOP, 5-year OS was 100% for all patients treated with (n=9) or without (n=31) RT.
Management of patients with partial metabolic response after R-CHOP is uncertain. Prospective data show that the majority of Deauville 4 end-of-treatment (EOT) PET scans after DA-EPOCH-R are false-positives which can be monitored with surveillance PET without RT, with progressive disease occurring in only 1/16 patients with Deauville. 89 Among the 34 patients in BC and Alberta with Deauville 4 EOT PET after R-CHOP (the majority of whom received RT), survival outcomes were excellent and similar to EOT PET-negative patients. It is likely that many cases of partial metabolic response after R-CHOP are false positives as well; indeed, 5 patients in Alberta and BC with Deauville 4 after R-CHOP were observed without RT and none relapsed. Extrapolating from this data, it has been proposed that surveillance imaging without radiation may be reasonable for young patients with Deauville 4 EOT PET after R-CHOP given the likely low risk of progression and long-term risks of toxicity from RT. 90 In conclusion, available evidence supports the use of R-CHOP for patients with PMBCL, with less toxicity but similar excellent outcomes as DA-EPOCH-R. End of treatment PET should be done 6-8 weeks after day 1 of the final cycle of chemoimmunotherapy to allow time for the post-treatment inflammatory response to resolve. 91 In view of the long-term risk of secondary malignancy and premature heart disease from RT in young patients, RT can probably be safely omitted for patients with PET-negative disease after R-CHOP. Omitting RT in favour of surveillance imaging in 6-8 weeks (CT is the preferred modality in Alberta) may be reasonable for patients <60 years old with Deauville 4 on EOT PET after R-CHOP, while older patients and those with Deauville 5 should receive RT. For the 10-20% of patients with suspected relapsed/refractory PMBCL, the diagnosis of progressive disease should be confirmed with biopsy or clear progression on CT, and not based on FDG uptake on PET alone. Treatment options at relapse include radiation for localized disease, salvage chemotherapy and autotransplant, radiation therapy, axicabtagene ciloleucel (funded only after 2 prior lines of therapy), and pembrolizumab. Follicular Lymphoma Throughout the following suggested treatment approach, three over-riding principles should be considered: 1. These are guidelines only. This disease often carries a long, incurable, remitting/relapsing natural history and, therefore, several treatment approaches are reasonable. 2. The mere presence of disease does not alone imply the need for treatment. 3. If therapy is required for predominantly localized disease, IFRT should be considered in lieu of systemic pharmacological treatment as long as the radiotherapy can be done with minimal early or delayed side-effects (e.g., xerostomia, severe nausea/vomiting) and without eliminating future treatment options (e.g., should not radiate ≥25% bone marrow). Figure 2 outlines the treatment algorithm for follicular lymphoma. For patients who do not have any of the above indications for therapy, the recommended approach is to observe with (or arrange) follow-up clinical assessments every 3-6 months ("watchful waiting"), and a CT CAP 1 year after diagnosis. For patients not meeting treatment criteria 1 year after diagnosis, another CT 2 years after diagnosis could be considered. Patients who have progressive disease on www.ahs.ca/guru follow-up should generally be treated, even if they do not fulfill any of the other indications for therapy.
A retrospective study of 238 Alberta follicular lymphoma patients managed with watchful waiting found that 24% developed transformed disease or significant organ dysfunction (at a median of 30months) prior to initiating initial therapy, and these patients had inferior survival rates compared to other patients requiring therapy who were initially managed with watchful waiting (10 yr OS 67.9% vs 85.7%, HR 3.000 (95%CI 1.696-7.126), p=0.0007). These watchful waiting patients did not undergo routine follow-up CT scans at 1 or 2 years to identify progression. It is possible that these adverse outcomes might have been avoided with closer monitoring by CT imaging and earlier initiation of chemoimmunotherapy 138 .
For grades 1,2,3a follicular lymphoma who have an indication for therapy, the recommended therapy involves 6 cycles of B-R (bendamustine-rituximab) chemotherapy, followed in responding patients by 2 years of maintenance rituximab (every 3 months for total of eight doses). In patients with previously untreated indolent lymphoma, B-R can be considered as a prefered first-line treatment approach to R-CHOP because of increased progression-free survival and fewer side-effects. Patients who have limited life-expectancy from serious co-morbid illness, or who do not want intravenous therapy, may be treated with oral chlorambucil or fludarabine monotherapy.
The GALLIUM clinical trial investigated the value of obinutuzumab in combination with chemotherapy followed by maintenance therapy compared to standard therapy with rituximab chemoimmunotherapy plus maintenance in the firstline treatment of follicular lymphoma. The study demonstrated superiority of obinutuzumab over rituximab in terms of PFS (3-year PFS was 81.9% (95%CI: 77.9-85.2%) vs. 77.9% (95%CI: 73.8-81.4%), with acceptable increased toxicity. ). As no OS advantage has yet been demonstrated, obinutuzumab is not funded in Canada for this indication and we continue to recommend rituximab. 139 .
Grade 3b follicular lymphoma should be treated as DLBCL with, R-CHOP. Rituximab maintenance has not been proven effective following R-CHOP therapy for large B-cell lymphoma, and therefore is not recommended.
Therapy of relapsed disease: Therapeutic recommendations for recurrent follicular lymphoma need to be individualized, and no one recommendation is suitable for all patients. Numerous factors need to be taken into consideration before recommending therapy for recurrent follicular lymphoma, including:
- Patient Factors: Age, co-morbidity, symptoms, short vs. long-term goals, preservation of future options, reimbursement/ability to pay for expensive treatments, acceptance of risks/toxicities of treatment option relative to potential benefit (RR, PFS, OS).
- Disease Factors: Stage, sites of involvement, grade, transformation, prior therapy, time from prior therapy (disease-free interval).
For example, previously healthy patients younger than 70 years who relapse within 2 years of initial chemotherapy have a median life expectancy of <5 years, and are best managed with HDCT/ autologous SCT. HDCT/SCT maximizes the length of disease control for all patients less than 70 years, regardless of length of initial remission, and as such is a reasonable treatment option for those who accept potential risks/toxicities. Therefore, patients younger than 70 years without serious comorbid disease, and who respond to salvage therapy should be considered for high dose chemotherapy and autologous (relapse 1-2) or allogeneic stem cell transplantation (relapse 3). A large retrospective study of consecutively treated relapsed follicular lymphoma patients in Alberta and BC reported 5 year overall survival rates following relapse of ~90% for those who received ASCT vs ~60% for those who did not receive ASCT. This marked difference in survival retained significance in multivariate as well as instrumental variable analyses 140 . While the study used bendamustine as a chemotherapy backbone, few patients on the study had received bendamustine as their frontline therapy. Given current practice ofBR for the frontline treatment of FL and the fact that there is no biological reason that the same clinical benefit of obinutuzumab would not be seen in combination with other chemotherapies, alternate NHL chemotherapy backbones can be considered for patients deemed inappropriate for bendamustine retreatment. Relatively frequent infections were noted so prophylactic antibiotics and antivirals should be considered, especially when obinutuzumab is combined with bendamustine.
Another option to consider for rituximab-refractory relapsed FL is radioimmunotherapy with 90Yibritumomab tiuxetan (Zevalin). This optionrequires Director's Privilege approval, and is not currently listed on the Alberta Cancer Drug Benefit List for funding. In a small study of 57 patients with rituximab-refractory FL (median 4 prior therapies), the overall response rate to 90Y-ibritumomab tiuxetan was 74% (CR 15%) and median duration of response of 8.7months. There may be small subset of patients (10-15%) who achieve long-term PFS following 90Y-ibritumomab tiuxetan 118,141 .
Idelalisib, a PI3Kδ inhibitor has also shown efficacy in a Phase 2 study of double-refractory FL patients (patients with lack of response or progression within 6 months of both rituximab and an alkylator). Idelalisib can lead to durable remissions in a minority of patients and is currently not funded in Canada but is available through a compassionate access program. Infectious complications and immune toxicities are frequent and prophylactic antibiotics and anti-virals are required to reduce the risk of serious infections. 142 Palliative, symptomatic care (possibly including palliative IFRT 4Gy/2 fractions) is usually the best option for patients who were refractory to their 2 most recent treatment regimens, those with CNS involvement, or those with an ECOG score of 3-4.
# Indolent Lymphomas (Excluding Follicular Histology) 1, 143-151
Indolent lymphomas should generally be treated similarly to follicular grade 1-2 lymphomas. - majority should receive B-R, then rituximab maintenance - alternatives in special situations include IFRT, fludarabine, or chlorambucil
# Splenic Marginal Zone Lymphoma
Splenic marginal zone lymphoma is an uncommon type of non-Hodgkin lymphoma characterized by splenomegaly, cytopenias, lymphocytosis, and less commonly lymphadenopathy. Revised diagnostic criteria now specify the typical blood and bone marrow findings of SMZL and splenic biopsy is not usually required to establish the diagnosis 152 . It is still reasonable, however, to proceed with splenectomy if the cause of splenomegaly is not determined following peripheral blood and bone marrow evaluation.
The disease course is indolent and many patients can be managed expectantly until symptomatic splenomegaly or pronounced cytopenias develop. SMZL prognostic scoring systems have been described, with low hemoglobin, low platelets, elevated lactate dehydrogenase and extra-hilar lymphadenopathy as adverse markers 153 .
In rare cases, SMZL has been associated with hepatitis C infection (HCV), so all patients should be screened at diagnosis. Those who are HCV+ should first be offered HCV-directed therapy, as the lymphoma may regress avoiding the immediate need for further therapy 154,155 . Splenectomy has previously been the standard approach to treat SMZL for over two decades 156 . The role of splenectomy as frontline treatment of SMZL is now controversial 157, 158 159 160 . Risks posed by splenectomy include operative morbidity and mortality, particularly in the elderly, or those with multiple comorbidities. However, surgical outcomes are improving at experienced centres. The risk of infection with encapsulated organisms is a serious concern, but may be mitigated with timely vaccination and long-term antibiotic prophylaxis 161 .
Monotherapy with rituximab has recently emerged as a non-operative alternative with reports suggesting survival outcomes similar to historical patients treated with splenectomy. Chemoimmunotherapy such as rituximab-bendamustine (BR) is also a rational approach for SMZL given the recent favourable results of a large scale RCT of iNHL, including marginal zone histology 136 .
Although existing evidence is inadequate to conclude which treatment approach is superior, we propose the following strategy for managing SMZL:
- Rituximab monotherapy is recommended as frontline therapy for most patients. A standard regimen is rituximab weekly for 4 weeks, followed by a response assessment 4-6 weeks later. a. Those achieving at least a partial response, defined by conventional response criteria 152 , should subsequently receive maintenance rituximab as per other iNHL subtypes. b. Non-responders or those with progressive disease should proceed with either: i. Splenectomy if the spleen is the major site of disease or ii. BR for those with additional nodal disease, extensive bone marrow involvement, or non-operative candidates, then followed by maintenance rituximab in responding patients.
- Select patients who require a splenectomy to establish the diagnosis and have no bone marrow, peripheral blood, or nodal involvement, do not require maintenance rituximab and may simply be observed.
# Lymphoplasmacytic Lymphoma (LPL)
Diagnostic criteria for Waldenström macroglobulinemia (WM):
- IgM monoclonal gammopathy of any concentration - Bone marrow infiltration by small lymphocytes showing plasmacytoid/plasma cell differentiation, usually with intertrabecular pattern of bone marrow infiltration predominantly lymphocytic to lymphoplasmacytic to overt plasma cells. 5. CT of the abdomen and pelvis: to detect organomegaly and lymphadenopathy (skeletal surveys and bone scans are not necessary in absence of symptoms). 6. Blood or plasma viscosity: if signs and symptoms of hyperviscosity syndrome (HVS) or IgM> 50 g/L. 7. Direct antiglobulin test and cold agglutinin titre if positive. 8. Cryoglobulins. 151 . Serum IgM monoclonal protein should be measured by serum protein electrophoresis. The use of nephelometry to determine total serum IgM should be discouraged because this method is unreliable, especially when the levels of monoclonal protein are high. The presence of cryoglobulin or cold agglutinin may affect determination of IgM; therefore, testing of cryoglobulin and cold agglutinin at baseline should be considered, and if present, serum samples should be reevaluated at 37°C to ensure accurate and consistent determination of the monoclonal protein levels.
- LPL immunophenotype: o surface IgM+ CD5-CD10-CD19+ CD20+ CD22+ CD23-CD25+ CD27+ FMC7+ CD103-CD138- - Recent
# IgM monoclonal protein response assessment in WM
# Hyperviscosity syndrome (HVS) in LPL
Symptoms and signs of hyperviscosity include spontaneous bleeding, neurological symptoms and retinopathy. Patients with HVS have an expanded plasma volume and cardiac failure may also occur. There are several published reports demonstrating the efficacy of plasmapheresis in HVS although randomised data are lacking. There is not, however, a simple linear relationship between paraprotein concentration and either plasma viscosity, whole blood viscosity or symptoms. An increase in IgM concentration from 20 to 30 g/L results in an increase in plasma viscosity of <2 centipoise (cP) but an increase from 40 to 50 g/L increases the plasma viscosity by around 5 cP. Indeed, a 1-volume plasma exchange results in a 35-40% decrease in IgM concentration but in up to a 60% reduction in plasma viscosity. In patients with WM the actual plasma volume may exceed that calculated and, given the data above, a 1-1.5 volume exchange is therefore advisable.
# General treatment guidelines for LPL/WM 151 .
The usual indications for starting patients with LPL/WM on active therapy consist of clinical evidence of adverse effects of the paraprotein (HVS with neurological or ocular disturbance, peripheral neuropathy, amyloidosis, symptomatic cryoglobulinemia), symptomatic anemia (Hb<100g/L beware of pseudo-anemia from hemodilution), platelets <100, progression to high-grade lymphoma, significant adenopathy or organomegaly, or constitutional symptoms.
- Plasmapheresis: 1-2 procedures, exchanging 1-1.5 calculated plasma volumes, are advised for the treatment of HVS in WM, followed by chemotherapy to prevent paraprotein re-accumulation. In patients who are drug-resistant, plasmapheresis may be indicated for long-term management.
Although there are few studies that consider the role of plasma exchange in the treatment of cryoglobulinemia, there is a clear rationale for its use. The treatment room should be warm and blood warmers used in the cell separator circuit to prevent precipitation during the procedure.
- Chemotherapy: The most common initial chemotherapy for LPL is B-R (Bendamustine-Rituximab) followed by rituximab maintenance, similar to other indolent B-cell lymphomas. For patients who do not tolerate B-R, CDR (Cyclophosphamide, Decadron, Rituximab) or Bortezomib-based therapy (eg. R-Bortezomib, R-CyBorD) should be considered. Rituximab is active in the treatment of WM but associated with the risk of transient exacerbation of disease-related complications and should be used with caution in patients with symptoms of hyperviscosity and/or IgM levels >40 g/L. In patient with hyperviscosity and/or IgM levels >40 g/L, it is advised to hold rituximab for cycle 1, and start rituximab with cycle 2 chemotherapy. In retrospective studies, purine analogue therapy is associated with higher rates of prolonged cytopenias, infections, secondary MDS/AML, and transformation to large cell lymphoma when compared to therapy with alkylating agents.
- New data supports the use of ibrutinib in LPL (both first line and for relapsed/refractory disease).
Given the tolerability and durable responses to ibrutinib monotherapy, this is the preferred second line therapy for most patients. 163,164 - Many second-line therapy options exist. Patients who have obtained lengthy first remissions can be re-treated with chemo-immunotherapy with or without the addition of bortezomib (eg. R-Bortezomib, R-CyBorD). Purine analogues (Fludarabine) are usually reserved for multiply relapsed disease.
# Hairy Cell Leukemia
Hairy cell leukemia (HCL) and HCL variant (HCL-V) are mature lymphoid B-cell disorders, characterized by the identification of hairy cells and a specific genetic profile. Diagnosis of HCL is based on morphological evidence of hairy cells, immunophenotypic positivity for CD11C, CD103, CD123, and CD25 expression and the presence of BRAF V600E somatic mutation. BRAF-V600E has not been identified in other B-cell chronic lymphoproliferative disorders except very rarely so the mutation is now considered as the molecular hallmark of the disease. Absence of the BRAF gene mutation is reported in approximately 10% of patients with HCL and appears to constitute a subgroup with a poor prognosis 165 .
Patients with asymptomatic HCL may be managed with active observation (watch & wait strategy). Symptomatic patients should be treated with symptoms commonly derived from cytopenias or splenomegaly. Most guidelines agree that even asymptomatic patients with marked cytopenias should be treated including at least one of the following: hemoglobin < 110 mg/dL, platelet count <100 000/µL, or an absolute neutrophil count <1000/µL.
In the first-line setting, purine analogs (cladribine or pentostatin) have been demonstrated to result in long overall survival. No randomized trials have been performed in HCL with no studies to suggest superiority of either drug but cladribine is available in Canada and is the most frequently used drug worldwide for HCL. Early studies used continuous intravenous dosing over 7 days 166 but more recent studies (non-comparative) have investigated subcutaneous dosing over 5 days and demonstrate excellent responses 167 . The recommended dose of cladribine is 0.1-0.14mg/kg daily for 5-7 days. We recommend sc dosing for convenience and reduced infusion times. Infection prophylaxis is recommended as with other purine analogues (PJP and viral prophylaxis for 6-12 months) and patients with active infections should have control of infection prior to therapy initiation if possible.
For relapsed HCL, cladribine can result in a second durable remission however, synergy has been demonstrated with rituximab such that we recommend combination therapy with rituximab and cladribine for relapsed disease 168 . Studies of rituximab have used a weekly schedule x 8 weeks, concurrent with cladribine. Careful attention for and prophylaxis against infection is recommended.
A recent study investigated the addition of rituximab to cladribine in the frontline setting. HCL patients treated with concurrent cladribine and 8 weekly doses of rituximab had higher MRD-free complete remission rates than patients treated without rituximab or with delayed rituximab. (JCO 2020; 38:1527) As improved responses are predicted to lead to longer remissions and given the proven benefit of rituximab in combination with chemotherapy frontline for other indolent NHLs, we recommend consideration of cladribine + rituximab for frontline HCL treatment. Infectious risks and lack of survival data should be considered with cladribine monotherapy favoured for frailer patients and those at high risk of infection.
Given the importance of BRAF V600E in this disease, BRAF inhibitors have been investigated in relapsed patients with high response rates. Low dose vemurafenib at 240mg twice daily was reported to result in complete remissions in 40% of patients. Unfortunately, results do not appear durable after drug discontinuation and retreatment or chronic treatment may be required 169 . We recommend BRAF inhibition for patients who are refractory to cladribine (relapse < 24 months) or relapse after cladribine + rituximab 170 . Vemurafenib has also been used successfully in previously untreated patients with active infections as a bridge to cladribine therapy during treatment of the infection.
Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin, which has also proven efficacy in highly refractory HCL patients. This agent is associated with severe adverse reactions including hemolytic-uremic syndrome (7.5%) and capillary leak syndrome (5%). (leukemia 2018; 32: 1768) Moxetumumab is not currently funded in Canada but could be considered in relapsed HCL patients who have exhausted all other therapeutic options.
# Special Lymphomas
Mantle cell lymphoma 136, 137, 171-186 : Characteristics of mantle cell lymphoma include: male predominance, median age approximately 65 years, advanced stage with multiple extranodal sites (marrow, blood, and intestinal tract), relative chemoresistance, no evidence for curability following R-CHOP chemotherapy, median time to relapse after initial chemotherapy of 12-18 months and median survival following RCHOP induction of 3-5 years. Significant improvements in PFS over RCHOP alone have been demonstrated with the addition of high dose cytarabine to RCHOP-like regimen induction followed by high dose therapy and ASCT for transplant eligible patients, and for B-R induction for transplant ineligible patients, as well as for prolonged rituximab maintenance after completing initial chemotherapy.
# Recommendation regarding Watchful Waiting for MCL
Although most patients with MCL have relatively aggressive disease, and even those asymptomatic patients initially managed with watchful waiting have median times to first systemic therapy of 11-12 months, a small proprotion of patients can be manged expectantly for over 5 years 187,188 . Features suggestive of indolent MCL include leukemic non-nodal presentations, predominantly hypermutated immunoglobulin heavy chain variable regions, non complex karyotypes and absence of SOX11 expression by immunohistochemistry 189 . Occasionally, nodal MCL can also follow an indolent course 187,188 . Prognostic indices such as the MIPI have not been shown to identify indolent MCL 187 .
Poor prognostic features associated with shorter survivals and response durations, for which expectant management is not appropriate, include high burden nodal disease, Ki-67 positivity >20-30%, blastoid histology, p53 or Notch1 mutation, gene expression profiling and altered microRNA signature 190 . No prospective randomized trials, or properly designed retrospective comparative effectiveness research studies have compared immediate treatment versus watch-and-wait for MCL patients without clear indications for therapy. Poorly designed retrospective studies suggest similar survival outcomes to immediate therapy, however these studies were biased because patients were selected for watchful waiting based upon better prognostic factors (eg. younger age, better performance status) and did not routinely administer immediate aggressive therapy according to current standards to all patients in the control groups 187,188 . Prospective randomized trials have demonstrated that more aggressive therapy improves PFS and OS rates relative to less aggressive therapy for MCL. Extrapolating these data to the hypothetical question of aggressive therapy vs no immediate therapy leads to the logical conclusion that immediate therapy is likely the superior approach for most MCL patients.
Given the lack of high quality evidence from properly conducted comparative studies to prove the W&W is non-inferior to immediate therapy, W&W should only be considered for patients who present with all of the following features:
1) Non-nodal disease such as CLL-like presentation (lymphocytosis without associated cytopenias) or stage IAE marginal zone-like presentation. Patients presenting with nodal disease should generally receive immediate chemo-immunotherapy as indicated in treatment sections below unless they have significant co-morbidity that will limit life-expectancy, low tumor burden, and meet other criteria listed in this section below. 2) No disease-related symptoms 3) No adverse pathology features such as blastoid variant, Ki67>20% of cells, or complex cytogenetic changes. Other adverse features include SOX11 expression and complex cytogenetic changes, however, SOX11 immunohistochemistry is not routinely available in Alberta. 4) Patient consent to forgo immediate therapy despite knowledge of demonstrated survival benefits of aggressive vs less aggressive therapy. Patient agreement to surveillance disease monitoring.
# Treatment -Transplant Eligible Patients (Age <65yrs)
The accepted standard of care for newly diagnosed MCL patients <65 years of age without major comorbidities involves chemoimmunotherapy followed by high dose therapy with ASCT and then 3 years of rituximab maintenance administered every 2 months. Progression free and overall survival benefit has been established in a prospective randomized trial for patients treated with myeloablative radiochemotherapy followed by autologous stem cell transplant in first remission as consolidation after CHOP-like chemotherapy 183,184 . This strategy was compared to interferon alpha maintenance and demonstrated a 22mo improvement in progression free survival and 20.5mo improvement in overall survival with ASCT. These benefits of ASCT were seen in patients who had low risk MIPI, and who attained CR after RCHOP induction. The addition of high dose cytarabine with rituximab (RC) to RCHOP-like regimens is associated with improved rates of CR, PFS, and OS relative to RCHOP alone. This is supported by studies from the GELA and the European MCL Network with R-CHOP/R-DHAP induction prior to ASCT (RCHOP-21 x 3 followed by R-DHAP x3 , or alternating RCHOP/RDHAP x 6 cycles) 185 , as well as the Nordic regimen published as a phase II trial involving RCHOP-21 alternating with Ara-C , for a total of 6 cycles, then ASCT 191 . Given the superiority of BR over RCHOP in terms of efficacy and tolerability in patients with MCL, a phase 2 study of BR and RC induction for transplant-eligible patients was conducted and demonstrated a favorable safety profile as well as efficacy (with CR 96% and 93% MRD negativity after ASCT) 192 . A pooled analysis of 89 patients who received BR/RC induction chemotherapy prior to ASCT demonstrated a high transplant rate (89%), and durable remissions (5-yr PFS 80% and OS 85%) thus confirming that BR/RC is an excellent choice for induction therapy in MCL 193 .
TP53 mutation is an uncommon (11%) but significant poor prognostic finding in patients with MCL, highly associated with blastoid morphology, Ki-67 >30%, and high risk MIPI 194 . Unfortunately, intensified standard-of-care regimens for younger patients with MCL do not overcome the deleterious effects of TP53 mutations, with a median OS of 1.8 years, compared to 12.7 years for TP53unmutated (p,0.0001) 194 . Response to ibrutinib is also less favorable in patients with mutated versus wild-type TP53, with median PFS of only 4 months 195 . As such, all patients who are transplant-eligible should undergo TP53 mutational testing, with allogeneic SCT preferred over autologous SCT for patients with available donors. Allogeneic SCT should also be considered in patients with relapsed disease or with high risk MIPI scores at diagnosis and significant blood/marrow involvement, especially with blastoid morphology.
Although maintenance rituximab has been shown to improve PFS and OS (4 year OS 87% vs. 63%) in the elderly population (age > 60) after induction with R-CHOP 196 , the role of rituximab maintenance after ASCT for younger patients was uncertain until results of the phase III trial (LyMa) were reported 182 . In the LyMa trial, 299 patients <66years of age with mantle cell lymphoma received 4 courses of R-DHAP followed by R-BEAM/ASCT (patients who did not achieve at least PR after R-DHAP could receive 4 additional courses of R-CHOP to facilitate ASCT) and 240 responders were then randomly assigned to receive 3 years of rituximab maintenance therapy (375 mg/m 2 , one injection every two months) or watch and wait. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Progression-free survival at 4 years was improved at 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001)and overall survival was improved at 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). In support of the LyMa trial, a retrospective review of 72 patients previously enrolled in a phase II trial showed a progression free survival benefit in patients who received maintenance Rituximab vs those who did not (2 year PFS 90% vs. 65%) 197 .
# Treatment -Transplant Ineligible Patients (Age >60-65yrs)
For patients with mantle cell lymphoma over 60-65 years of age, B-R induction x6 cycles is our standard of care. Results from a recently published open-label, multicentre, randomized, phase 3 non-inferiority trial found a significant benefit for progression-free survival in patients with mantle cell lymphoma treated with B-R versus R-CHOP (HR 0.61, 95%CI 0.42-0.87, p=0.0072) 136 . In addition the trial confirmed the improved toxicity profile of BR over RCHOP.
Regarding rituximab maintenance, there is no published trial examining its benefit following BR induction. The European Mantle Cell Lymphoma Elderly trial confirmed a benefit of rituximab q2 months until progression (vs. interferon-α 2a or 2b) following RCHOP induction. After a median follow-up of 30 months, rituximab maintenance was associated with a significantly longer remission duration compared to interferon maintenance (51 vs. 24 months; HR=0.56, 95% CI 0.36-0.88; p=0.0117). While there was no difference in overall survival between the two groups, a subcohort of patients treated with R-CHOP appeared to show an advantage in 3-year overall survival with rituximab versus interferon maintenance (85% vs. 70%, p=0.0375). The StiL group investigated the value of R maintenance following BR and reported a lack of benefit in terms of PFS or OS. 198 However, the study was underpowered to detect a difference. Further, a multicentre retrospective study reported superior outcomes of patients given R maintenance (vs. observation) after achieving CR or PR with BR, with an OS advantage for those who achieved PR only. 199 We favour following BR x 6 cycles with R maintenance but with a maximum duration of 4 years of rituximab maintenance given the balance between efficacy, toxicity and cost. Given the lack of strong data to support this approach, R maintenance could be omitted or truncated in patients for whom the benefits of extending a remission do not outweigh the inconvenience of maintenance therapy.
The rare patient who has stage I-IIA, non-bulky mantle cell lymphoma could be considered for B-R + IFRT, or even IFRT alone if they are older than 70 years of age or have significant co-morbidities.
# Summary Initial Treatment Recommendations for Mantle Cell Lymphoma:
Immediate chemoimmunotherapy is recommended for most patients. See Recommendation regarding Watchful Waiting for MCL for details on the minority of patients for whom watchful waiting is recommended.
Treatment -Transplant Eligible Patients (Age 60 ml/min, and no pre-existing neurotoxicity ii. 1.5 g/m 2 BID for age>60, or CrCl 46-60 ml/min, or pre-existing neurotoxicity iii. 1 g/m 2 BID for CrCl 31-45 ml/min 2) Autologous blood stem cell collection with high dose cytarabine and G-CSF mobilization 3) Consolidation: High dose therapy and ASCT 4) Maintenance rituximab 375mg/m2 IV or 1400mg sc (preferred) every 2 months x 3 years post ASCT
For patients with TP53-mutated MCL and/or blastoid variant, consolidation with an allogeneic SCT is recommended over autologous SCT.
Treatment -Transplant Ineligible Patients (Age >60-65yrs). 1) Induction: Bendamustine-Rituximab x6 cycles 2) Rituximab maintenance q2mo until progression or for maximum 4 years
The rare patient with stage I-IIA, non-bulky mantle cell lymphoma could be considered for B-R + IFRT, or even IFRT alone if they are older than 70 years of age or have significant co-morbidities.
# Treatment Relapsed Mantle Cell Lymphoma.
There is no standard treatment for relapsed MCL but there are many options, including chemotherapy and novel agents 200 . In general, treatment choice should take into consideration the duration of response to previous treatment.
The Bruton's tyrosine kinase (BTK) inhibitors have shown the most promise as therapeutic agents for relapsed MCL and are the preferred secondline therapy. A phase 3 trial that randomized relapsed or refractory MCL patients who previously received at least one rituximab-containing regimen showed superior PFS using ibrutinib over temsirolimus (mPFS 14.6 vs. 6.2 months, p<0.0001) but no significant advantage in OS 201 . Acalabrutinib has also been investigated in relapsed/refractory MCL in a Phase 2 study with 12 month PFS and OS of 67% and 87% respectively. 202 Similarly, in a phase 1/2 trial with zanubrutinib the median PFS was 21.1 months and median DOR was 18.5 months. 203 Patients who achieved 12-24 months PFS with previous chemotherapy may do well with a different noncross-resistant chemotherapy regimen (R-bendamustine or R-BAC if previous (R) CHOP, or vice versa 200,204,205 . Other treatment options include bortezomib combined with rituximab +/chemotherapy 206,207 . Maintenance rituximab prolongs PFS and OS in relapsed MCL 208 but has not been studied in patients that received it after first-line therapy.
Lenalidomide also has efficacy in this setting, particularly in combination with rituximab +/chemotherapy 207,209 .
Brexucabtagene autoleucel (brexu-cel) is a CAR T therapy that is Health Canada approved for patients with relapsed or refractory mantle cell lymphoma who have received treatment with a BTKi.
In the ZUMA-2 phase 2 trial, the estimated PFS was 61% and OS 83% at 12 months. 210 This will be an option in the future for patients who are progressing on BTKi who are fit for intensive therapy.
Allogeneic stem cell transplant has the potential to cure MCL, as is evident from a plateau in the survival curves that is often seen post transplant. Because most patients present over the age of 60 and with multiple comorbidities, allogeneic stem cell transplant is not often offered. It is suggested in relapsed or refractory disease for those patients who are young and fit, even after autologous stem cell transplant.
Several retrospective reviews have looked at the outcomes of allogeneic stem cell transplant in the relapsed/refractory setting. Le Gouill et al. have shown a 2 year EFS of 50%, 2 year OS of 53% and 1-and 2-year transplant related mortality of 22% and 32% respectively 211 . Longer term follow up has demonstrated 6 year PFS and OS rates of 46% and 53%, respectively confirming the plateau in response that is often seen to allogeneic stem cell transplantation 212 . Response to chemotherapy has consistently been shown to predict both success of allogeneic stem cell transplant and transplant related mortality, with the best outcomes in those who have achieved a CR or CRu. Chronic GVHD has been shown in retrospective reviews to reduce the risk of relapse and DLI has been shown to salvage some patient who relapse or progress post allogeneic stem cell transplant, suggesting a graft-versus-tumour effect in MCL. Reduced intensity Allo SCT in the MCL setting has also been looked at retrospectively with 5 year PFS and OS rates of 14% and 37% respectively, and 1 year non relapse mortality of 18% 213 . Ibrutinib bridging prior to allogeneic SCT has recently been shown to improve transplant outcomes, with 2 year PFS 76% and 2-year OS 86% in one published series 214 .
The Calgary experience suggests no difference in OS or PFS when allogeneic vs. autologous stem cell transplantation are used in front-line therapy however, in the relapsed/refractory setting, allogeneic stem cell transplantation appears to offer superior OS and PFS. iii. If responding to therapy (PR/CR), fit and eligible for allogeneic SCT, particularly if high risk disease (e.g. TP53+), refer for opinion regarding allogeneic SCT iv. If not responding to therapy, OR progressing on BTKi, refer for CAR T therapy (once available) . Patients could also be considered for initial ISRT in addition to H. pylori therapy if the tumour is associated with t (11;18). Rituximab or chemoimmunotherapy may be considered for patients ineligible for or relapsing after RT .
Lymphoblastic
2) Localized (stage I-II1) H. pylori negative gastric MALT lymphoma: For the minority of patients whose gastric biopsies are negative for H. pylori, non-invasive testing (e.g. stool antigen test, urea breath test, and/or serology) should be performed to confirm H. pylori status. H. pylori-negative gastric MALT lymphoma is more likely to be associated with t(11;18) 243,244 . A trial of H. pylori eradication may still be considered as up to 38% of cases of H. pylori negative gastric MALT lymphoma can respond to antibiotics 245 , presumably due to false negative testing or infection with other helicobacter species 246 ; these patients should receive ISRT if there is no evidence of lymphoma regression after 3-6 months on repeat endoscopy. Alternatively, initial treatment with ISRT can be considered since the majority will not respond to H. pylori eradication, whereas ISRT achieves complete responses in >95% of patients with long-term event-free survival rates of 80-90% 228, .
Repeat endoscopy should be done 3-6 months after ISRT to confirm response. The decision to treat with initial ISRT versus a trial of H. pylori eradication should be individualized and made in conjunction with patient wishes.
3) Advanced (stage II2, IIE or IV) gastric MALT lymphoma: These patients should be managed as advanced stage indolent B-cell lymphoma with active surveillance if asymptomatic or chemoimmunotherapy if symptomatic disease. These patients should also receive H. pylori eradication therapy.
Testicular lymphoma :
In contrast to other patients with localized large B-cell lymphoma, patients with stage IAE or IIAE testicular lymphoma are cured less than 50% of the time using brief chemotherapy and irradiation. Thus, the recommended treatment for all stages of testicular lymphoma is a full course of chemotherapy (R-CHOP x 6 cycles). An additional problem often seen in these patients is relapse in the opposite testicle. This can be prevented by scrotal irradiation (25-30Gy/10-15 fractions). Finally, these patients are at high risk for CNS relapse. Although some experts recommend prophylactic intrathecal chemotherapy, especially for stage 3-4 disease, this has not been proven effective. Unfortunately, many of the CNS relapses occur within the brain parenchyma, and are not prevented by intrathecal chemotherapy. For this reason, CNS prophylaxis should involve high dose intravenous methotrexate 3.5g/m 2 every 14-28 days x 2-3 doses after completion of all 6 cycles of R-CHOP. 255 .
Whole brain radiotherapy (WBRT) has fallen out of favour for PCNSL, based in part upon high rates of severe neurotoxcity following high-dose methotrexate, and in part due to the results of the G-PCNSL-SG1 randomized controlled trial, in which 551 immunocompetent PCNSL patients (median age 63 years) were randomized to chemotherapy followed by WBRT (arms A1, B1) or chemotherapy alone (arms A2, B2) 267 . 411 patients entered the post-high dose methotrexate phase, and 318 of these patients were treated per protocol. For this per protocol population, there were no differences in median OS (32.4 vs. 37.1 months, p=0.8) or median PFS (18.3 vs. 12 months, p=0.13) between the chemotherapy plus WBRT arms (A1+B1, n=154) or chemotherapy alone arms (A2+B2, n=164), respectively 267 . A recent study suggests neurotoxicity can be reduced by decreasing WBRT dose to 23.4Gy after CR to induction HDMTX-based chemotherapy. The 2-year PFS was 78% in these patients 266 .
Although patients with refractory or relapsed PCNSL typically have dismal outcomes, autologous stem cell transplantation (ASCT) has shown promising results in this setting. Soussain et al. (2001) have reported a 3-year event-free survival (EFS) rate of 53% for patients with relapsed/refractory PCNSL undergoing ASCT following high dose thiotepa, busulfan and cyclophosphamide (TBC) conditioning 265 .
Small studies have demonstrated durable remissions with ASCT for PCNSL, however, the optimal conditioning regimen remains undefined . With the knowledge of our initial encouraging experience with TBC/ASCT 268 , and the lack of any widely accepted standard treatment for PCNSL, TBC/ASCT consolidation was considered an acceptable option to treat consenting PCNSL patients at our centre. Review of our data proved the efficacy of this therapy (PFS 52% at 5 years post TBC/ASCT) but with significant toxicity (5 treatment-related deaths, all occurring in patients over 60 yrs). To reduce the TRM, we modified our protocol to omit cyclophosphamide starting in 2011. We recently completed a retrospective review of the outcomes of this protocol for patients treated between Nov 2011 and Dec 2017. 272 .Based on these data, we recommend TBu/ASCT consolidation therapy for all eligible PCNSL patients. 273,274 The role of Rituximab in treating PCNSL was evaluated in the International Extranodal Lymphoma Study Group (IELSG) 32 study 275 , which randomized patients with histologically-proven primary CNS lymphoma to receive a maximum of four 3-week cycles of methotrexate at 3.5 g/m2 on day 1 and cytarabine at 2 g/m2 twice daily on days 2 and 3, either alone (arm A; n = 75), in combination with 375 mg/m2 of rituximab on day -5 and 0 (arm B; n = 69), or combined with rituximab at the same dose plus 30 mg/m2 of thiotepa on day 4 (MATRIX arm; n = 75). The study was conducted at 52 locations across five countries. The median patient age was 58 years (range, 18-70) and all patients were HIVnegative. Overall, patients had an ECOG PS ≤3, with patients aged 66 to 70 years having an ECOG PS ≤2. Patient characteristics were well balanced among the study arms. Autologous stem cells were successfully collected after the second treatment course in 152 patients (94%). In the MATRIX arm C, the overall response rate was 87% (95% CI, 80-94) compared with 74% (95% CI, 64-84), and 53% (95% CI, 42-64) in arms B and A, respectively (P = .00001 for A vs C) 275 . As reported by Dr. Andrés Ferreri at the ASH 2016 conference (abstr 511), at a median follow-up of 40 months, the PFS rate was approximately 55% in the MATRIX arm C, 39% in arm B, and 29% in arm A, with OS rates of 63%, 46%, and 31%, respectively. Of the 219 enrolled patients, 118 (54%) patients without progressive disease (n=52) or excessive toxicity/poor mobilization/refusal (n=49) underwent a second randomization comparing consolidation with whole-brain irradiation (n=59) or ASCT (n=59). The CR rate similarly improved from 54% after induction up to 94% after either consolidation therapy, suggesting a very important role for consolidation therapy. There were no statistically significant differences in PFS after the two consolidation treatments (3yr PFS approximately 60-70%), however, neurotoxicity rates were higher in the WBRT arm.
The potential benefit of rituximab with induction chemotherapy was not confirmed in different phase III trial by HOVON 105/ALLG NHL 24 276 , in which 119 patients in Netherlands, Australia and New Zealand were randomized to 2 cycles of induction (MTX, BCNU, teniposide, prednisone) with or without rituximab, then followed by consolidation with cytarabine and WBRT 30Gy (+10Gy boost) if <60yrs of age. This study reported non-significantly different 1 year EFS rates of 49% and 52% for rituximab vs no rituximab (ORR 87% and CR 67%).
The Alberta Lymphoma Group established a provincial PCNSL Treatment Protocol in November 2011. The rationale behind the 2011 protocol included:
1) Induction chemotherapy: a. First 2 cycles: HDMTX 3.5g/m2 d1,15 with procarbazine 100mg/m2 po d1-7. This treatment had been shown to induce response and is tolerable for patients who may be debilitated at the time of initial diagnosis of PCNSL. Cytarabine was not added to first cycle HDMTX because patients may not tolerate intensive therapy well until performance status improves. b. Stem Cell Mobilization and Apheresis: to be done with first dose of Cytarabine because stem cells may not mobilize well after multiple cycles Cytarabine/G-CSF. Rituximab will be used in addition to Cytarabine due to reports that lymphoma cells can circulate in blood and marrow in patients with PCNSL 277 , and Rituximab may decrease risk of collecting contaminated autograft as has been shown for other B-cell lymphomas. c. Final 2 Cycles will combine Cytarabine with HDMTX as done in a prior IELSG study to improve response rates and decrease frequency of primary progressive disease 255 .
d. Rituximab was added in 2016 for a total of 6 doses during induction to improve response 2) High Dose Chemotherapy (patients 60% after induction therapy, and PCNSL not secondary to immune suppression): a. Thiotepa 300mg/m2 x2d and Busulfan 3.2mg/kg x3d without cyclophosphamide. Because cyclophosphamide does not penetrate the blood brain barrier particularly well, its omission may decrease treatment-related mortality without decreasing cure rates compared to the previous TBC regimen. 3) Ifosfamide consolidation (transplant refusal or ineligible patients):
a. Ifosfamide crosses BBB approximately 30%, and gives some exposure of PCNSL to alkylating agent therapy 278,279 .
# Recommendations: PCNSL Transplant-Eligible (Usually <70 years old)
The above evidence suggests that transplant-eligible patients are best treated with HDMTX/AraCbased induction followed by TBu/ASCT consolidation. There also is a potentially important role for the addition of rituximab to induction chemotherapy when ASCT consolidation is used. However, the optimal number of induction chemotherapy cycles is unknown, and perhaps as soon as a patient achieves a response and is physically well, they should proceed directly to ASCT before the disease starts to progress, or cumulative toxicity from further induction therapy prevents ASCT consolidation.
As such, the 2018 PCNSL guidelines have been modified to decrease the length of induction therapy prior to ASCT. We have not incorporated MATRIX induction, because the use of MATRIX may decrease the ability of patients to proceed to ASCT due to toxicity, increased likelihood of patient refusal due to treatment-fatigue, or due to poor stem cell mobilization. We believe the use of ASCT is more important than the use of MATRIX. Our real world outcomes using non-MATRIX induction and TBu/ASCT are numerically superior to those reported in the MATRIX study. We also increased the age limit for the transplant eligible protocol to 75 years, however, patients over age 70 years must be extremely healthy with no comorbidities and must also be highly motivated to receive TBu/ASCT. For a detailed description of recommended PCNSL treatment regimens, please refer to Appendix A, subheading VII, sections A and B.
For palliative therapy, doses of cranial radiotherapy should be 30Gy in 10-20 fractions.
# Eye lymphoma
Orbital or peri-orbital lymphoma 251,280 : Peri-orbital lymphoma of the bony orbit or the soft tissues in and around the orbit but outside of the globe and optic nerve should be managed as indicated in the earlier sections on aggressive lymphomas, marginal zone lymphomas or follicular lymphoma, as appropriate for the type and stage of the lymphoma. Approximately 40% of such patients have advanced disease discovered when carefully staged. In general, 25-30Gy/20 fractions radiotherapy to whole orbit/periorbital tissue is recommended for indolent peri-orbital lymphomas.
Conjunctival lymphoma 251,280 : Lymphoma involving the conjunctiva but not the structures within the globe or the optic nerve is usually of low grade and should be treated with 25-30Gy/20 fractions of radiotherapy. Doses, fields, and shielding specifically modified for treatment of the eye are necessary to minimize long-term complications such as xerophthalmia or cataract formation.
Intra-ocular and optic nerve lymphoma 251,281 :
- Lymphoma involving the vitreous, retina or other structures within the optic nerve or globe is usually of large cell type and is equivalent to PCNSL. Bilateral involvement is common. Evaluation and management should be the same as for PCNSL. Acceptable treatment involves induction chemotherapy with high dose methotrexate and high dose cytarabine as described for PCNSL in Appendix A.
- Lymphoma involving the uveal structures (choroid) is a rare presentation of lymphoma, and is usually of indolent type. This disease is best managed with treatment appropriate for stage and local extent of disease.
# Aggressive T-Cell Lymphomas:
NK/T-cell lymphoma, nasal type Natural killer (NK)/T-cell lymphoma, nasal type is a rare and aggressive extranodal neoplasm that almost exclusively affects Asian and South American adults in the fifth decade of life, with a male:female ratio of approximately 3:1. It typically arises in the nasal cavity or surrounding structures, such as the sinuses, palate, nasopharynx, tonsils, hypopharynx, and larynx. While the pathogenesis of NK/T-cell lymphoma, nasal type is not well understood, the Epstein-Barr virus (EBV) is implicated in almost all cases. Approximately 25% of cases show a p53 mutation; in addition, p21 overexpression is also frequent in nasal NK/T-cell lymphoma, and seems to be independent of p53 gene status 285 .
Hematopathological evaluation of a biopsy specimen from the site of involvement is the basis for diagnosis of nasal NK/T-cell lymphoma. The recommended immunohistochemistry panel includes 283,291 :
- B-cell: CD20
- T-lineage antigens: CD2, CD7, CD8, CD4, CD5, CD3
- NK lineage markers: CD56
- Cytotoxic granules (granzyme B and/or TIA-1)
- Ki-67
In situ hybridization for EBV-encoded RNA (EBER)
For patients with early-stage nasal NK/T-cell lymphoma (ENKTCL), early or upfront radiotherapy (intensive regimens such as a total dose ≥ 50 Gy) plays an essential role in therapy, and has been associated with higher overall survival and complete response rates compared to chemotherapy alone 286 . However, radiotherapy alone is also associated with high relapse rates. Combined modality therapy is recommended with sequential and concurrent chemo-radiotherapy regimens having relatively equivalent outcomes. No standard of care therapy exists for ENKTCL with our guidelines previously recommending VIPD consolidation after concurrent single agent cisplatin and radiotherapy. Local outcomes were poor with this approach and most novel regimens incorporate Lasparaginase into treatment due to high single agent activity. 292 Given the recent discontinuation of Lasparaginase, we favour the combination of peg-asparaginase with gemcitabine and oxaliplatin (P-GEMOX) for patients with limited stage disease. With this approach, treatment is initiated with 2 cycles of P-GEMOX, followed by radiotherapy (48-56 Gy) followed by 2 further cycles of P-GEMOX restarted 1 week after completion of radiotherapy. With this approach, in 33 patients, the ORR was 94% and 2 year PFS and OS were 77% and 83% respectively. Notably, Grade 3-4 toxicities were rare.
For patients with stage III-IV disease, complete remission rates are less than 15%, and the median overall survival is approximately 4 months 290 . The recommended options for therapy include either enrollment in a clinical trial or treatment with an L-asparaginase-based combination chemotherapy regimen. The most well-studied regimen is the SMILE regimen with several small series of patients reported . While the SMILE regimen was first reported to have excellent response rates (overall, and complete in 79% and 45%, respectively) in relapsed/refractory patients, an updated study of the use of the SMILE regimen as frontline therapy for advanced stage patients reported a short median OS (12.2 months; 1-year OS was 45%) with a high rate of TRM (5 of 87 patients died of sepsis) 293 .
While the GOLD regimen has less reported patients, the toxicity is significantly less (Grade 3-4 neutropenia of 16% compared to SMILE of 92% 294 with serious infections in 4% and 31-45% 293,294 of patients treated, respectively). For this reason, patients of advanced age or with comorbidities or a history of infections should be considered for therapy with GOLD for 2-4 cycles followed by SCT if possible while younger, fit patients can be treated with SMILE x 2 cycles with a goal of proceeding to SCT as consolidation. The role of allogeneic or autologous SCT is not yet well defined because of limited data; but it is suggested when possible for advanced stage or relapsed/refractory patients.
Peripheral T-cell lymphomas (PTCL) .
With the exception of ALK-positive anaplastic large cell lymphoma, CHOP chemotherapy cures less than 30% of patients with PTCL. Options that may be associated with higher cure rates include CHOP x 4-6 cycles followed by HDCT/ASCT in responding patients or brentuximab-vedotin + CHP or intensification of CHOP with etoposide (CHOEP). 305 The ECHELON-2 study was a Phase 3 of CD30+ (≥ 10% by immunohistochemistry) PTCL with IPI ≥ 2 comparing CHOP with BV-CHP. The median PFS was improved with BV-CHP at 48.2 months compared to 20.8 months with CHOP. Overall survival was also numerically superior in the BV-CHP arm. Important toxicities were comparable between the arms. Unfortunately, the study was not powered to detect differences between the different subtypes of PTCL and the study was biased to include a majority of patients with ALCL (70%). Patients with ALK+ ALCL were 22% of the population and had the largest noted benefit from the addition of BV-CHP. The subgroup of AITL patients appeared to do slightly worse with BV-CHP compared to CHOP but patient numbers were small. Given the lack of single agent efficacy in non-anaplastic subtypes, it remains unclear if there is any benefit to BV-CHF in non-anaplastic subtypes of PTCL such that it can not be recommended that BV be routinely implemented for those patients at this time. 297 .
Retrospective and prospective phase II trials support the use of SCT as part of upfront therapy for PTCL. Sieniawski and colleagues reported 5-year PFS rates of 60% for 26 patients with enteropathy associated T-cell lymphoma treated with IVE-methotrexate induction therapy followed by autologous SCT, compared to only 22% for 54 patients treated with CHOP-like therapy alone 297 . Two prospective trials have also been reported. In the first, Reimer and colleagues reported results of CHOP x 4-6 cycles followed by dexabeam or ESHAP followed by CyTBI/ASCT for 83 patients (including 32 with PTCL-not otherwise specified, and 27 with angioimmunoblastic T-cell lymphoma) 299 . Fifty-five of the 83 patients received transplantation. In an intent-to-treat analysis, with a median follow-up time of 33 months, the estimated 3-year OS, DFS, and PFS rate were 48%, 53%, and 36%, respectively 307 . In the second prospective trial, Rodriguez and colleagues from the Spanish Lymphoma and Autologous Transplantation Cooperative Group reported the results of 74 patients transplanted in the first complete response (65% had 2-3 aaIPI risk factors) 300 . With a median follow-up of 67 months from diagnosis, the 5-year OS and PFS rates were 68% and 63%, respectively.
For PTCL patients who relapse following CHOP-type induction and respond to salvage therapy, ASCT should be recommended, as several studies report similar ASCT outcomes to those seen with relapsed DLBCL. Brentuximab vedotin may be considered for those patients with CD30+ anaplastic large cell lymphoma who have had failure of initial chemotherapy 308 .
For patients who are ineligible for ASCT or who have failed ASCT, PFS and OS is extremely short and end of life care and planning should be implemented. Palliative therapy options include chemotherapy (with limited expectation of response or benefit), romidepsin and/or pralatrexate.
Alberta has funded only 1 of romidepsin or pralatrexate despite these agents have non-overlapping mechanisms of action for reasons of cost (due to unavailability of published data for responses to either drug in patients who failed the alternate). No quality evidence exists to direct the decision between romidepsin and pralatrexate however, durables responses to romidepsin have been most commonly seen in patients with AITL, favouring romidepsin in that group.
An open-label, single arm, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma (N=130) with a median two (range: 1-8) prior systemic therapies found an objective response rate of 25%, including 15% with CR/CRu. 309 An evaluation of longer term follow-up found median duration of response was 28 months (range: 1 to >48 months). 310 Patients who achieved CR/CRu had a median PFS of 29 months. The most common grade ≥3 AEs were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). Another phase II study of romidepsin in cutaneous and peripheral T-cell lymphoma (N=45; median 3 prior therapies) found complete response in n=8 and partial response in n=9 for an overall response rate of 38% (95%CI: 24-53%).
Median duration of overall response was 8.9 months (range: 2-74). Of note, 6 of the 18 responses were among patients with prior stem-cell transplant. 311 The prospective PROPEL trial evaluated the effectiveness of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma. N=111 patients received pralatrexate after a median 3 prior therapies (range: 1-12). The overall response rate was 29% with 11% achieving complete response.
The median duration of response was 10.1 months. Median PFS and OS were 3.5 months and 14.5 months, respectively. The most common grade ≥3 AEs were thrombocytopenia (32%), mucositis (22%), and anemia (18%). 312 Summary of treatment recommendations for PTCL. - recommendation for stage I-II NK/T cell lymphoma: P-GEMOX x 2 cycles (then IFRT (48-56 Gy) then 1 week later, 2 further cycles P-GEMOX (total 4 cycles) 313 AIDS-related lymphomas: In general, the treatment of AIDS-related lymphoma should be the same as for non-AIDS related lymphoma if the AIDS does not otherwise compromise the patient's performance status and he/she is free of coincident serious opportunistic infection. HAART should be given with CHOP chemotherapy.
Treatment should be planned in conjunction with the patient's HIV physician and an antiviral regimen without overlapping toxicity should be chosen. R-CHOP results in the highest rates of disease-free survival, but may also increase the risk of infectious complications and treatment-related mortality in patients with CD4 counts below 50.
# Post-transplant lymphoproliferative disease (PTLD) after Solid Organ Transplant in Adults:
Epidemiology. Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous disease with clinical and pathologic manifestations ranging from benign lymphoid hyperplasia (ie. early lesions) to aggressive lymphoma (ie. monomorphic PTLD) 320,321 . PTLD and its treatment cause a high rate of mortality and graft loss in patients with solid organ transplants (SOT) 322 . The incidence of PTLD is highest in multivisceral (>10%) and lowest in renal transplants (1-5%), attributed to intensity of immunosuppression and amount of lymphoid tissue in the allograft . Epstein-Barr virus (EBV) infection drives the pathogenesis in PTLDs occurring early post-transplant; conversely, PTLDs occurring after prolonged immunosuppression tend to be monomorphic with no detectable EBV genome, calling an infectious etiology into question 326 . An epidemiologic shift in PTLD has occurred in the most recent decade: the median latency time from transplant to PTLD has increased from 1 to 3 years 327,328 and the proportion of EBV-positive vs. -negative PTLD has decreased 329 , attributed to EBV viral load monitoring in EBV seronegative (ie. high risk) patients.
Diagnosis and staging. Diagnostic tissue must be reviewed by expert pathologists and subtyped according to the WHO 330 . Several small case series have confirmed that PET-CT is an effective imaging modality for staging in PTLD . However, some subtypes of PTLD, such as early lesions and T-cell lymphomas, may not be FDG-avid, necessitating CT as an alternate staging modality.
Management. Recommendations for the management of PTLD in SOT are based on few phase II clinical trials, retrospective case series, and expert opinion . The mainstays of therapy for CD20-positive PTLD in SOT include reduction of immune suppression (RIS), rituximab, and chemotherapy; adoptive immunotherapy is promising but considered experimental and is unavailable in Alberta. All patients should undergo RIS to the lowest tolerated levels under the direction of the transplant physician as soon as the diagnosis of PTLD is confirmed 337 . A recommended strategy is to discontinue antiproliferative agents and reduce the calcineurin inhibitor by 25-50% while maintaining the steroid 337 . Published response rates vary widely (0-73%) and responses are seen within 2 to 4 weeks .
# 3a.
Early lesions, polymorphic and CD20-positive monomorphic PTLD. RIS may serve as definitive treatment of early lesions, but if response is incomplete further treatment with surgery or radiation is favored. In contrast, polymorphic and monomorphic PTLDs require definitive treatment along with RIS, discussed in further detail below (Figure 3).
# Surgery and radiation.
Patients with localized PTLD, such as isolated skin, GI or renal allograft lesions, can achieve prolonged remissions with surgery or localized radiation 340,343 . Some experts consider surgical resection of isolated GI lesions prior to initiating systemic therapy to reduce early mortality from bowel perforation 338 . Radiation alone is generally not curative, with exception of plasmacytoma-like PTLD 344 , and should not be used as primary treatment 337 . Radiation may be used for palliating obstructive or compressive symptoms where systemic therapy fails or is not possible 337 .
Chemotherapy. SOT patients do not tolerate chemotherapy well, often developing severe infection or prolonged cytopenias. Estimates of efficacy of chemotherapy in treatment of PTLD in SOT are limited by the almost entirely retrospective nature of publications. Results of retrospective studies of anthracycline-based chemotherapy, mainly CHOP, show ORRs of 65-73% and 5-year OS of 25-78%; however, treatment-related mortality (TRM) is up to 31% .
Rituximab. Several retrospective reviews and phase II clinical trials have confirmed the efficacy of rituximab monotherapy in CD20-positive PTLD post-SOT in patients that fail to respond to RIS. Phase II trials show overall response rates (ORR) of 44% to 71% and CR rates of 26% to 53% after 4 weekly doses with no reported TRM . However, 57% of patients treated with rituximab monotherapy in 2 prospective trials had progressive disease within 12 months; risk factors for survival and need for further treatment included age > 60, ECOG ≥ 2, elevated LDH, and lack of CR after rituximab 354 . Therefore rituximab causes minimal toxicity but remissions achieved are durable in only a minority of patients.
Sequential therapy. Efficacy of a sequential treatment regimen (4 weekly doses of rituximab followed by 4 cycles of CHOP) was established in a phase II international multicentre trial in adult CD20positive PTLD in SOT (n=70) in an attempt to improve upon the success of rituximab monotherapy and diminish the toxicity of chemotherapy 355 . The ORR was 60% after initial rituximab, increasing to 90% after sequential chemotherapy. EBV-positive and -negative PTLDs responded equally. OS was 61% at 3 years and time to progression was 69% at 3 years. There were no TRM events related to rituximab and 11% ascribed to CHOP. In a subsequent analysis, the authors concluded that patients who achieved CR and those in PR with a low-risk IPI score after rituximab monotherapy had a low risk of disease progression 356 .
A subsequent phase II trial utilized risk-stratified sequential therapy, in which patients in CR (by CT) after 4 doses of rituximab received 4 further 3-weekly doses of rituximab, and those not in CR after initial rituximab proceeded to RCHOP (4 cycles supported with GCSF). With 152 patients treated, endpoints were superior to sequential therapy (3-year OS 70%, 3-year TTP 73%, TRM 7%), and response to initial rituximab was highly predictive of OS, TTP and PFS (p<0.001) 357,358 .
In summary, rituximab monotherapy is effective first-line treatment in most CD20-positive PTLDs with minimal toxicity. Risk-stratified sequential therapy offers the highest survival rates published to date, and allows patients in CR after rituximab monotherapy to avoid chemotherapy. Close follow-up for disease progression is recommended for patients that received rituximab alone. For PTLD that behaves aggressively (ie. IPI 3-5) or progresses during initial treatment with rituximab, proceed directly to RCHOP before completing 4 doses of rituximab (Figure 3). 3b. Primary CNS PTLD. In the largest reported retrospective series of primary CNS PTLD (n=84), patients treated with rituximab and/or cytarabine (most often given after MTX) survived longer, but significant variation in regimens precluded firm conclusions 359 . Patients with acceptable renal function and performance status should be offered high-dose methotrexate and rituximab, and others may benefit from palliative radiation 338, 359 . 3c. Burkitt Lymphoma PTLD. Several case series cite acceptable outcomes in this rare subtype of PTLD with chemotherapy regimens ranging in intensity . However, no definite recommendations can be made and treatment should be considered individually.
3d. CD20-negative monomorphic PTLDs. Rare subtypes of PTLD that resemble non-transplant lymphomas, such as Hodgkin Lymphoma-like PTLD, T cell monomorphic PTLD, plasmablastic PTLD and plasma cell dyscrasias, require specific chemotherapeutic treatment similar to their nontransplant counterparts (reviewed by 337,338 ).
# Prognosis.
The risk of death from NHL is significantly higher in SOT compared to non-transplant patients 363 , and PTLD increases the graft failure rate 5-fold 364 . Retrospective series of PTLD post-SOT report OS of 30-68% at 5 years, with excess mortality in the first year post-diagnosis 323,328, . Adverse prognostic factors from retrospective studies include monomorphic subtype, monomorphic T-cell, bone marrow or CNS involvement, advanced stage, poor performance status, advanced age, elevated LDH, and hypoalbuminemia 327,328,351, . Risk factors for worsened OS in the PTLD-1 prospective trial include IPI 3-5, thoracic organ transplant and lack of CR after rituximab monotherapy 356 . A prognostic score developed from 500 PTLD cases in renal transplant patients is described in Table 8; the score was calculated with the exclusion of patients with monomorphic T-cell and CNS PTLD, both of which carried an adverse prognosis, but the score maintains its ability to discriminate risk groups in the whole population 364 .
# T3
One or more tumors (=>1-cm diameter)
# T4
Confluence of erythema covering =>80% body surface area N (lymph nodes) Abnormal peripheral lymph node indicates any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed or 1.5 cm or larger in diameter. Node groups examined on physical examination include cervical, supraclavicular, epitrochlear, axillary, and inguinal. Central nodes, which are not generally amenable to pathologic assessment, are not currently considered in the nodal classification unless used to establish N3 histopathologically.
# N0
No For viscera, spleen and liver may be diagnosed by imaging criteria
# M0
No visceral organ involvement
# M1
Visceral involvement (must have pathology confirmation and organ involved should be specified)
IIA IIB 1-2 3 1,2 0-2 0 0 0,1 0,189
IIIA IIIB 4 4 0-2 0-2 0 0 0 1 54 48 IVA1 IVA2 IVB 1-4 1-4 1-4 0-2 3 0-3 0 0 1 2 0-2 0-2 41 23 18
response modifiers (IFN-, retinoids) in cases of resistant or progressive skin disease. Local radiotherapy plays a key role in palliation and treating sanctuary sites. Total skin electron beam therapy is highly effective in T2 or T3 disease however its widespread use is limited by the availabilty of this technique. Predictably, chemotherapy leads to short remission durations and therefore should be reserved after other therapies have been tried. Its use should be limited to tumour (T3) or more advanced stages. It may be considered frontline in cases with histologic large-cell transformation and high risk features (see discussion below). Monotherapy (low-dose methotrexate, gemcitabine) is generally preferred over combination chemotherapy (e.g. CHOP) unless the patient has extensive burden of disease (nodal and extra-cutaneous and is fit to tolerate. Targeted therapies have demonstrated activity in MF/SS, and are currently reserved for the relapsed/refractory setting or in clinical trials. The optimal conditions for allogenic bone marrow transplant have not been elucidated, but may play a role in highly selected cases (see discussion below). Extracorporeal photopheresis is a unique treatment modality indicated for the treatment of erythrodermic MF/SS. Consensus recommendations for the treatment of MF/SS have recently been updated and are outlined elsewhere 30 . The following table intends to summarize a managment approach. - T1b: a solitary lesion with diameter >5cm T2
Regional skin involvement (multiple lesions limited to 1 body region or 2 contiguous body regions)
- T2a: skin lesions present in a 15-cm and 30-cm diameter circular area T3 Generalized skin involvement - T3a: multiple lesions involving 2 noncontiguous body regions - T3b: multiple lesions involving 3 or more body regions N N0 No clinical or pathologic lymph node involvement N1
Involvement of 1 peripheral lymph node region that drains an area of current or prior skin involvement N2
Involvement of 2 or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement N3
Involvement of central lymph nodes M M0 No evidence of organ disease M1
Extracutaneous organ disease
# Staging of other types of non-MF cutaneous lymphomas
# Special topics in CTCL
The role of transplantation in cutaneous lymphoma 8, 9, 14, 40-49 :
Existing studies of allogeneic stem cell transplantation in mycosis fungoides or sezary syndrome are limited to small, retrospective reports or case series. Autologous stem cell transplantation has not been associated with durable remissions and therefore has been largely abandoned for MF/SS. The following recommendations are based on best available outcome data and established consensus guidelines:
- Patients with MF/SS should be risk-stratified using the CTCL International Consortium prognosis score. Patients with high-risk disease (3 or 4 of age>60, elevated LDH, stage IV or LCT) should be considered for allogeneic transplantation as part of second line of therapy.
- Patients with advanced stage 3 or stage 4 MF/SS who progress after more than two lines of systemic therapy should be considered for allogenic transplantation. - Selected patients with stage 2 MF/SS or with large cell transformation may be considered for allogeneic BMT.. - Patients must meet other eligibility criteria for transplant prior to being considered. Issues such as chemosensitivity (CR or PR to last line of therapy), adequate performance status (ECOG 0-2) and preserved organ function apply. - TSEB before transplant may be considered prior to transplantation for improved skin control. - Transplantation in other rare and aggressive CTCL such as CD8+ epidermotropic aggressive T cell lymphoma or primary cutaneous gamma-delta T cell lymphoma is at this time a largely experimental approach - Relapses still occur after allogeneic transplants and may be treated adjustment of immunosuppression, DLI infusion, or further skin-directed treatments. Distinguishing CTCL from transplant associated GVHD requires multidisciplinary expertise.
# Large Cell Transformation in Mycosis Fungoides:
The pathologic definition of large cell transformation in mycosis fungoides (LCT-MF) is the presence of large cells (>= 4 times the size of a small lymphocyte) in 25% of more of the dermal infiltrate or forming microscopic nodules. The cells are often CD30+ by IHC however CD30-variants are also described. It is difficult to discriminate from other subtypes of cutaneous lymphoma, including cutaneous anaplastic large cell lymphoma (cALCL) or lymphomatoid papulosis (LyP), which may also coexist with mycosis fungoides.
The prognosis of LyP and cALCL is considerably more favourable than LCT-MF. Historical estimates for long-term survival with LCT-MF is less than 20%, and most series report a median survival of 2-36 months. However, a subset of patients with limited LCT-MF may follow a more indolent course. One large EORTC cohort analysis reported a median survival of 8.3 years for patients with LCT, and the authors concluded LCT is significant for disease progression but not survival outcome 26 .
Currently, there is a lack of prospective research to guide a standardized approach for management of LCT-MF. Most patients are treated with combination chemotherapy however it remains it is unclear which patients benefit from this approach.
Several clinical and pathological characteristics in LCT-MF have been associated with poor prognosis 28,31 , including advanced age (> 60 years), elevated LDH at transformation, advanced stage (III/IV), extra-cutaneous transformation, the presence of follicular mucinosis, folliculotropism, and CD30-negativity. Additional pathologic variables have been described but may not be routinely analyzable so have been omitted from these recommendations.
We recommend to consider intensive chemotherapeutic strategies (monotherapy or combination in suitable fit candidates) in patients with any of the following clinical or pathologic variables associated with high risk LCT-MF. In the absence of these, we recommend treatment as per MF guidelines (see Table I).
# Clinical variables for high risk LCT-MF:
- advanced age (> 60 years)
- elevated LDH at transformation - generalized tumours (versus solitary or regional)
# - advanced stage (III/IV) - extra-cutaneous transformation Adverse Pathologic variables in LCT
- absent papillary dermal involvement (assessment may be limited by provided tissues)
- folliculotropism - follicular mucinosis - absence of fibrosis - CD30 expression in less than 50% of neoplastic cells Brentuximab vedotin has activity in LCT-MF. A phase 2 study of brentuximab in a heavily pre-treated CD30+ MF/SS population, the majority of whom had LCT (30/32, 90%) showed a significant response rate of 70%. 35 A subsequent prospective, randomized controlled trial of brentuximab vedotin versus physician's choice (MTX or bexarotene) in CD30+ CTCL demonstrated a significant improvement in objective global response lasting atleast 4 months with brentuximab (56.3% versus 12.5%) 39 . The study included both previously treatment CD30+ MF and CD30+ ALCL. Although the histologic characteristics of the CD30+ MF patients were unreported, a proportion may have had transformed MF, as this was not an exclusion criteria. Brentuximab vedotin is indicated for previously treated CD30+ MF, and could be tried for high risk LCT-MF patients as defined above, who are either unsuitable for chemotherapy or refractory/relapsed folllowing chemotherapy.
# V. Hodgkin Lymphoma
# Pathologic Classification
The histological sub-classification of Hodgkin lymphoma is based on the light microscopic H&E interpretation. If problems with differential diagnosis arise, staining for CD15, CD30, T-cell and B-cell panels and EMA may be helpful. For lymphocyte predominant Hodgkin lymphoma, CD20, CD45, +/-CD57 are recommended.
# Staging
Mandatory staging procedures include 2-8 :
- Pathology review whenever possible (essential for core needle biopsies)
- Complete history and physical examination (B symptoms, Etoh intolerance, pruritis, fatigue, ECOG performance score, examination of nodes, Waldeyer's ring, spleen, liver, skin)
- CBC & differential, creatinine, electrolytes, Alk P, ALT, LDH, bilirubin, total protein, albumin, calcium - ESR (required for limited stage patients)
- If a PET/CT is not done, then perform a bone marrow aspiration and biopsy (2cm core preferable) for patients with stage IIB-IV or cytopenias (note: flow cytometry on the marrow aspirate does not add useful information and should not be done)
- Chest x-ray (PA and lateral)
- CT scan of the neck, chest, abdomen, and pelvis - A PET scan with body CT is preferred as initial staging and after 2 cycles of ABVD .
- Pregnancy test, if at risk (consider fertility and/or psychosocial counseling )
- Semen cryopreservation if chemotherapy or pelvic radiotherapy is contemplated - HIV: if HIV risk factors or unusual disease presentations Primary Treatment of Classical Hodgkin Lymphoma General principles: For treatment planning, supradiaphragmatic clinical stage (CS) I or II without bulk (mass >10cm or >1/3 maximal transthoracic diameter (MTD) on CXR) or significant B symptoms is considered limited stage. Initial treatment options for classical Hodgkin Lymphoma involve the chemotherapy regimens ABVD or escalated BEACOPP as well as involved field radiotherapy (IFRT).
Multiple phase III studies conducted by the German Hodgkin Study Group (GHSG) and other cooperative study groups have demonstrated that optimal cure rates are achieved with: 1) ABVD x2 cycles followed by 20Gy IFRT for favorable risk limited stage disease (5yr PFS >90%); 2) ABVD x4 cycles followed by 30Gy IFRT for unfavorable risk limited stage (> 3 nodal sites, ESR > 50 or >30 with B symptoms, or extranodal disease) (5yr PFS >85%); 3) escalated BEACOPP x 4-6 cycles for young healthy patients with advanced stage disease; and 4) ABVD x6 cycles for patients >60 years or with co-morbidities. Advanced stage patients also receive IFRT following chemotherapy to localized PET+ residual disease >2.5cm, and is considered for sites of prior bulk after ABVD.
# Data supporting escalated BEACOPP for advanced stage disease:
The GHSG HD9 trial conducted in the 1990s demonstrated that 8 cycles of an escalated-dose BEACOPP regimen were superior to 8 cycles of a COPP/ABVD regimen or 8 cycles of a baseline-dose BEACOPP regimen in terms of freedom from treatment failure and overall survival rates in patients with advanced-stage Hodgkin lymphoma 20 . Each regimen was followed by consolidative radiation therapy to sites of initial bulky disease greater than 5 cm. At the 10-year analysis, freedom from treatment failure was 64% for the COPP/ABVD group, 70% for the baseline BEACOPP group, and 82% for the escalated BEACOPP group (p<0.001); overall survival rates were 75%, 80%, and 86%, respectively (p<0.001) 21 . There were higher rates of hematologic toxicities, grades 25 .
In an attempt to reduce severe toxicities associated with escBEACOPP, an open-label, randomized, parallel-group, phase 3 trial investigated the utility of PET after two cycles of standard escBEACOPP to allow for adaptation of treatment intensity 26 . The trial included 18-60 year olds with newly diagnosed advanced-stage Hodgkin's lymphoma (N=1945), and assigned patients (1:1) to two parallel treatment groups on the basis of their PET results after cycle 2 of escBEACOPP (PET-2).
Patients with positive PET-2 were randomised to receive six additional cycles of either standard escBEACOPP (8 × escBEACOPP in total) or escBEACOPP with rituximab (8 × R-eBEACOPP) (rituximab abandoned mid-trial due to lack of efficacy). Patients with negative PET-2 were randomised between standard treatment with 4-6 additional cycles of escBEACOPP (6-8 × escBEACOPP… the trial switched from total 8 to total 6 escBEACOPP in the standard arm after the results of HD15) or experimental treatment with two additional cycles only (4 × escBEACOPP).
Patients with negative PET-2 randomly assigned to either 6-8 × escBEACOPP (n=504) or 4 × escBEACOPP (n=501) had 5-year progression-free survival of 908% (95% CI 879-937) and 922% (894-950), respectively (difference 14%, 95% CI -27 to 54). 4 × escBEACOPP was associated with fewer severe infections (8% vs 15%) and organ toxicities (8% vs 18%) as compared to patients receiving 6-8 × escBEACOPP. The trial supports reducing therapy to 4 escBEACOPP in patients who achieve PET-negative disease after 2 cycles of escBEACOPP.
Due to concerns of toxicity, escalated BEACOPP in Alberta should only be considered for the following patients 2,21,22,27-31 :
- Age 70 (ECOG 0-2)
- HIV negative, no other major co-morbidities - Patients must be made aware of infertility implications, and consent to proceed Although the above-described treatment approaches currently optimize cure rates from initial therapy, they result in: 1) the use of radiotherapy that contributes to late mortality from second cancers and cardiac disease; 2) the use of multiple cycles of Bleomycin that may cause serious lung toxicity; or 3) the use of escalated BEACOPP that increases the risk of serious infections and therapy-related MDS/AML. With the use of a PET-guided approach that minimizes therapy for patients whose lymphoma is highly sensitive to ABVD, we anticipate a reduction in toxicity of therapy and a need to only subject less responsive patients to the toxicities of IFRT or escalated BEACOPP.
arm of the study, patients received ABVD x2 then a PET scan, followed by ABVD x 2 (favorable) or 4 (unfavorable) if PET-, or escBEACOPP x2 cycles +INRT if PET+. Comparing control (INRT) and experimental (no INRT) arms for patients with negative PET after 2 cycles ABVD, the difference in PFS was -11.9% (95%CI -16.9%, -8.2%) for favorable risk (not meeting non-inferiority endpoint) and -2.5% (95%CI -6.6%, 0.5%) for unfavorable risk (not meeting non-inferiority endpoint). There was no difference in overall survival. For patients with PET+ disease after ABVD, the 5y PFS 77% vs 91% (p=0.002) and 5yr OS 89% vs 96% (p=0.06) favouring escBEACOPP compared to ABVD + INRT.
As neither the RAPID nor H10 trials confirmed non-inferiority of the PET-directed radiotherapy omission approach, this would support the use of radiotherapy despite a negative interim PET. However, given the lack of difference in OS and small differences in PFS, a PET-directed approach is recommended, accepting the risk of reduced local control with potential need for salvage chemotherapy and transplantation at relapse, reconciled by an expected late gain in OS due to avoidance of the long term sequelae of radiotherapy such as secondary malignancy and cardiovascular disease.
# Advanced Stage:
The UK RATHL trial treated patients with 2 cycles ABVD then performed a PET scan. 172 patients with PET+ disease (uptake > liver, Deauville 4-5) had therapy intensified to escBEACOPP whereas PET-patients were randomized to ABVD x4 (n=470) or AVD x4 (n=465). For PET-patients, 3yr PFS was 85.7% vs 84.4% for ABVD vs AVD (95%CI crossed 5% difference non-inferiority limit), the respective 3yr OS rates were 97.2% vs 97.6%, and the rate of grade 3-4 pneumonitis was 1% vs 0.2%, respectively. Of interest, a prior phase GHSG III trial found that omitting agents from ABVD x2 prior to IFRT for favorable risk limited stage HL resulted in lower 5 PFS rates (5yr FFTF 93.1% ABVD, 89.2% AVD, 77.1% AV, 81.4% ABV) and did not recommend this strategy. In view of the fact that the RATHL trial failed to meet its non-inferiority endpoint and only demonstrated a small reduction is serious pulmonary toxicity by eliminating bleomycin from the final 4 cycles of ABVD, it seems most reasonable to adopt this strategy only for those patients with risks factors for bleomycin lung toxicity (COPD / ↓PFTs, CrCl 40yr), or those with any clinical or PFT evidence of acquiring bleomycin lung toxicity at any time during therapy. Patients with PET2 positive status whose therapy was intensified to 4 additional cycles of BEACOPP (BEACOPP-14 or escBEACOPP) had a 3 yr PFS of 67.5% and 3 yr OS of 87.8%.
The aforementioned HD18 study by German Hodgkin Study Group confirmed that 4 escBEACOPP was as effective as 6-8 escBEACOPP but less toxic in patients who achieved PET-negative status after 2 cycles of escBEACOPP. 3 yr PFS in this group (PET-2 negative after escBEACOPP) was 95.3% and 3 yr OS was 98.8%.
Based upon the above data, it is reasonable to adopt a PET-guided therapy approach for advanced staged Hodgkin lymphoma. Initiation of escBEACOPP as per the HD18 study results in a higher overall survival and is the preferred approach for young, fit patients for whom the fertility implications are acceptable. For patients who initiate therapy with ABVD, PET-directed therapy will minimize the long-terms risks of cytotoxic chemotherapy and radiotherapy for PET-patients after ABVD x2, while maintaining PFS rates <5% inferior to conventional combined modality treatments. These PET-guided approaches are illustrated in Figure 1-2. For centres where PET scanning is not available, or in situations when patients prefer to prioritize their initial cure rate and avoidance of intensive salvage therapy with autologous SCT rather than prioritize a similar long-term survival while minimizing therapy-related second cancers, cardiovascular mortality or bleomycin lung toxicity, the more traditional therapy approach illustrated in Figure 3 is still very reasonable. A phase II study of N=102 patients treated with BV (1.8mg/kg, outpatient IV, 30min, every 3 weeks for up to 16 cycles) for relapsed/refractory Hodgkin lymphoma after failed hematopoietic autologous stem cell transplantion reported outcomes after approximately 3-years of follow-up. Median OS and PFS were estimated at 40.5 months and 9.3 months, respectively. The estimated 3-year OS and PFS rates were 73% (95%CI: 57-88%) and 58% (95%CI: 41-76%), respectively. Younger age, good performance status, and lower disease burden at baseline were favorable prognostic factors for OS. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea.
# Consolidation with Brentuximab Vedotin after ASCT
The AETHERA clinical trial evaluated a strategy of consolidation with brentuximab vedotin after autologous stem cell transplantation in high risk relapsed Hodgkin lymphoma patients. Patients were eligible for BV if they were either: refractory to frontline treatment, relapsed = 12 months with extranodal involvement. Patients were randomized to receive either BV (1.8mg/kg every 3 weeks for up to 16 cycles) or placebo. 5 year PFS was 59% for BV versus 41% for placebo. Grade 3-4 peripheral motor and sensory neuropathy was observed in 6 and 10% of patients receiving BV consolidation, however, improves or resolves in the majority of patients.
# PD1-inhibitors 56 :
The For primary prophylaxis of febrile neutropenic infection for similar indications above or co-morbidities that increase risk of infectious complications such as chronic obstructive pulmonary disease, or secondary prevention after a prior episode of febrile neutropenia:
- G-CSF 300 or 480µg/day starting 3 days after chemotherapy completed until post-nadir ANC>1.0 (usually 7-10 days) (though most patients require only 2-5 days of G-CSF support)
- Must monitor CBC - The alternative is one dose of pegfilgrastim (Neulasta) 6mg on day 4 (without CBC monitoring, but at a cost of ~$2500/dose)
# Erythropoeitin
Erythropoeitin is not recommended because of evidence suggesting increased mortality rates. Consider only for symptomatic anemia patients who cannot receive RBC transfusions (i.e., Jehovah's Witnesses, prior severe transfusion reactions or severe iron overload).
# Antimicrobial Prophylaxis for Immunosuppressive Regimens 6-8
- For patients receiving fludarabine, high dose cyclophosphamide, >5 days high dose corticosteroids every 21 days, bortezomib, and bendamustine, and for immune-compromised patients (i.e., HIV, post-organ transplant or autoimmune disease patients who develop hematologic cancers) use prophylaxis during and for 12 months post-treatment. CD4 count monitoring can be used to help determine if prophylaxis can be stopped earlier (should not be assessed until 3 or 6 months post-treatment). Patients withCD4 count > 200 / µL may have earlier discontinuation of antimicrobial prophylaxis.
# Immunizations
Patients should be encouraged to keep all immunizations up to date. The reactivation and/or seroreversion of viruses that patients have been previously vaccinated against, such as hepatitis B, is a major cause of morbidity and mortality in patients with hematologic malignancies treated with cytotoxic chemotherapy. Appendix G outlines the general principles and specific immunization schedules for recipients of blood and marrow transplantations. In addition, separate guidelines outlining influenza and pneumococcal immunization recommendations for all patients with cancer can be found at: www.albertahealthservices.ca/cancerguidelines.asp under the "Supportive Care" heading" Recombinant adjuvant herpes zoster vaccine is commercially available however cancer patients were excluded in the pivotal phase 3 trials (ZOE-50 and ZOE-70). Studies with use in cancer patients are not yet published, but results suggest that vaccination responses are better for patients not on treatment or given prior to chemotherapy, as opposed to during chemotherapy 9 . Other hematological malignancy patients had better vaccines responses than Non Hodgkin's Lymphoma and CLL patients for reasons not yet identified 10 . The AHS Hematology group consensus is that the recombinant adjuvant herpes zoster vaccine is not contraindicated in hematology patients. Patients may receive the vaccine if they have adequateimmune function to amount a response, and are 6-9 months post Rituximab due to the reduced vaccine responses seen in rituximab-treated patients.
Family members and health care providers in contact with patients who have undergone a transplant should also be strongly encouraged to keep all immunizations up to date.
For patients who have experienced reactivation or seroreversion of hepatitis B virus, prompt administration of nucleoside/nucleotide analogues is essential 11 . Entacavir or tenofovir following R-CVP or R-CHOP chemotherapy for lymphoma is recommended for all patients who have a positive hepatitis B surface antigen test.
Last Reviewed: September 2017 VIII. Follow-Up Care in the Treatment of Lymphoma The following late effects should be considered when patients are reviewed during follow-up:
- Relapse. Careful attention should be directed to lymph node sites, especially if previously involved with disease. Routine surveillance CT scans are not indicated. Most relapses have been demonstrated to occur between scheduled clinics visits and tests, and are detected by patients themselves. Highly anxious patients who wish surveillance tests could be considered for occasional CXR and abdominal/pelvic ultrasounds (if thin), especially in the setting of indolent lymphoma and prior retroperitoneal and mesenteric disease. - Dental caries. Neck or oropharyngeal irradiation may cause decreased salivation. Patients should have careful dental care follow-up and should make their dentist aware of the previous irradiation. - Hypothyroidism. After external beam thyroid irradiation to doses sufficient to cure malignant lymphoma, at least 50% of patients will eventually develop hypothyroidism. All patients whose TSH level becomes elevated should be treated with life-long T4 replacement in doses sufficient to suppress TSH levels to low normal. - Infertility. Multi-agent chemotherapy and direct or scatter radiation to gonadal tissue may cause infertility, amenorrhea, or premature menopause. However, with current chemotherapy regimens and radiation fields used, most patients will not develop these problems. All patients should be advised that they may or may not be fertile after treatment. In general, women who continue menstruating are fertile, but men require semen analysis to provide a specific answer. - Secondary neoplasms. Although quite uncommon, certain neoplasms occur with increased frequency in patients who have been treated for lymphoma. These include AML, thyroid, breast, lung, and upper GI carcinoma, melanoma and cervical carcinoma in situ. It is appropriate to screen for these neoplasms by careful history, physical examination, mammography and Pap smears for the rest of the patient's life because they may have a lengthy induction period. Patients should be counseled about the hazards of smoking and excessive sun exposure, and should be encouraged to perform careful breast and skin examinations on a regular basis.
Table 1 outlines the minimum follow-up tests and examinations that should be performed on all patients after treatment for malignant lymphoma. Visits should be scheduled with an oncologist or family physician educated in post-treatment lymphoma surveillance every 3-4 months for 2 years, then every 6 months for 3 years, then annually. - Rituximab 375mg/m 2 IV day 1 (premedications: Tylenol, Benadryl, Zantac, hydrocortisone 100mg), then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated well. - Rituximab 375mg/m 2 IV day 1 (premedications: Tylenol, Benadryl, Zantac, hydrocortisone 100mg) then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated well.
- Cyclophosphamide 750 mg/m 2 IV - Rituximab 375mg/m 2 IV day 1 (premedications: Tylenol, Benadryl, Zantac, hydrocortisone 100mg) then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated well. - weight (call MD if >2kg above day 1)
- CBC & differential, EP, creatinine, glucose - ALT,AlkP,LDH,bilirubin,Alb,Ca,Mg F) Transplant-ineligible patients (age >65 years, significant co-morbidities, or immune suppression) with late relapse (prior RCHOP x6) with relapsed systemic and CNS lymphoma. This situation is unfortunately associated with extremely poor prognosis, and generally should be treated with palliative intent. Treatments could include IT chemotherapy, radiotherapy, decadron, or best supportive care. Patients who received rituximab-based therapy as part of their initial treatment had a 3-year PFS of 70% and an OS of 73% compared with a 3-year PFS of 21% (p1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their short axis before treatment must have decreased to <1.0 cm in their short axis after treatment.
# Post-Transplantation Lymphoproliferative Disease (PTLD)
Prognostic
- The spleen and/or liver, if considered enlarged before therapy on the basis of a physical examination or CT scan, should not be palpable on physical examination and should be considered normal size by imaging studies, and nodules related to lymphoma should disappear. However, determination of splenic involvement is not always reliable because a spleen considered normal in size may still contain lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood volume, the use of hematopoietic growth factors, or causes other than lymphoma.
- If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is made must be adequate (with a goal of >20 mm unilateral core). If the sample is indeterminate by morphology, it should be negative by immunohistochemistry. A sample that is negative by immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow cytometry will be considered a CR until data become available demonstrating a clear difference in patient outcome.
# Partial Response (PR)
The designation of PR requires all of the following:
- At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. These nodes or masses should be selected according to all of the following: they should be clearly measurable in at least 2 perpendicular dimensions; if possible they should be from disparate regions of the body; and they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
- No increase should be observed in the size of other nodes, liver, or spleen.
- Splenic and hepatic nodules must regress by >50% in their SPD or, for single nodules, in the greatest transverse diameter.
- With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present.
- Bone marrow assessment is irrelevant for determination of a PR if the sample was positive before treatment. However, if positive, the cell type should be specified (e.g., large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria, but who have persistent morphologic bone marrow involvement will be considered partial responders. When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients should be considered partial responders.
progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must increase by >50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.
- At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.
- Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems (<1.5 cm in its long axis by CT).
- Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. For these recommendations, the spleen is considered nodal disease. Disease that is only assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent only, unless, while an abnormality is still noted by imaging studies or physical examination, it is found to be histologically negative.
- In clinical trials where PET is unavailable to the vast majority of participants, or where PET is not deemed necessary or appropriate for use (e.g., a trial in patients with MALT lymphoma), response should be assessed as above, but only using CT scans. However, residual masses should not be assigned CRu status, but should be considered partial responses.
Response and site PET-CT-Based Response CT-Based Response New lesions
# Bone Marrow
New FDG-avid foci consistent with lymphoma rather than another etiology (eg. Infection, inflammation). If uncertain regarding etiology or new lesions, biopsy or interval scan may be considered New or recurrent FDG-avid foci Regrowth of previously resolved lesions A new node > 1.5 cm in any axis A new extranodal site> 1.0cm in any axis; if mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.
# Ann Arbor Staging Nodal Sites
FLIPI
# ECOG Performance Status 0
Fully active, able to carry on all pre-disease activities without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
Ambulatory, capable of all self-care but unable to carry out any work activities. Up and about >50% waking hours.
Capable of only limited self-care. Confined to bed or chair more than 50% of waking hours.
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Disclaimer The recommendations contained in this guideline are a consensus of the Alberta Hematology Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2023) Alberta Health Services
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# Data Supporting Brentuximab vedotin for Primary Therapy of Hodgkin Lymphoma 36
An open-label, multicenter phase 3 trial of 1334 patients with previously untreated stage III/IV Hodgkin lymphoma, randomized (1:1) patients to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) or ABVD. After a median follow-up of 24.6 months, 2 year modified progression-free survival (primary end point) was 82.1% (95%CI: 78.8-85.0%) for the A+AVD group and 77.2% (95%CI: 73.7-80.4%) in the ABVD group (p=0.04). Neutropenia was higher in the A+AVD group (58% vs 45%), febrile neutropenia occurred in 83 patients (rate: 11% in those receiving prophylactic GCSF and 21% in those without GCSF). Peripheral neuropathy was also higher in the A+AVD group (67% vs. 43%), with resolution at last follow-up in 2/3 of patients. Pulmonary toxicity ≥grade 3 occurred in 1% of A+AVD patients vs. 3% in ABVD. No overall survival difference was observed. While this trial showed an improvement in its primary endpoint (modified PFS), this endpoint included patients who received IFRT after achieving a PR, which many would argue is appropriate curative therapy and should not have qualified as treatment failure. Additionally, Health Canada restricted approval to patients with Stage 4 disease, who are thus, the only patients currently eligible to receive this therapy in Canada. With the current analysis, the number needed to treat is very large (and would be even larger if the patients receiving adjuvant radiotherapy were excluded from the PFS calculation). BV has not been investigated using a PET-directed approach (the current standard for HL in Alberta), has not been proven superior to escBEACOPP (our recommended treatment for young and fit Stage 4 HL patients) and thus the costs of A-AVD are considered too high to justify a change in practice at this time.
We recommend A-AVD only for patients who are appropriate for intensive, curative HL therapy but refuse escBEACOPP for reasons of fertility preservation or personal choice or are ineligible for escBEACOPP due to age or comorbidities (but still suitable for full dose A-AVD).
Data Supporting a PET-Guided Treatment Approach :
# Limited Stage:
In the UK Rapid trial, patients with stage I-IIA non-bulky HL received ABVD x3 cycles then underwent a PET scan. If the PET was positive (uptake more than blood pool, Deauville score 3-5) the patients received one more cycle ABVD then IFRT, whereas if the PET was negative patients were randomized to observation or IFRT. The 3yr PFS was 85.9% in the 145 PET+ patients, 94.6% in the PET-patients who received IFRT and 90.8% in PET-patients who were observed. The difference in PFS was -3.8% (95%CI: -8.8%, 1.3%) exceeding -7% non-inferiority margin. Of interest, the perprotocol PFS was 97% vs 90.8% because 26 pts did not get allocated IFRT. The respective 3 year overall survival rates were 97.1% vs 99.0%. In the EORTC/LYSA/FIL H10 trial, stage I-II HL patients were randomized between control arm therapy with ABVD x3 +INRT (favorable risk) or ABVD x4 +INRT (unfavorable risk), with all patients undergoing PET after cycle 2 ABVD. In the experimental Future potential option for patients not eligible for PET-guided approach Brentuximab vedotin 36 :
An open-label, multicenter phase 3 trial of 1334 patients with previously untreated stage III/IV Hodgkin lymphoma, randomized (1:1) patients to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) or ABVD. After a median follow-up of 24.6 months, 2 year modified progression-free survival (primary end point) was 82.1% (95%CI: 78.8-85.0%) for the A+AVD group and 77.2% (95%CI: 73.7-80.4%) in the ABVD group (p=0.04). Neutropenia was higher in the A+AVD group (58% vs 45%), febrile neutropenia occurred in 83 patients (rate: 11% in those receiving prophylactic GCSF and 21% in those without GCSF). Peripheral neuropathy was also higher in the A+AVD group (67% vs. 43%), with resolution at last follow-up in 2/3 of patients. Pulmonary toxicity ≥grade 3 occurred in 1% of A+AVD patients vs. 3% in ABVD. No overall survival difference was observed. While this trial showed an improvement in its primary endpoint (modified PFS), this endpoint included patients who received IFRT after achieving a PR, which many would argue is appropriate curative therapy and should not have qualified as treatment failure. With the current analysis, the number needed to treat is very large (and would be even larger if the patients receiving adjuvant radiotherapy were excluded from the PFS calculation) and thus the costs of A-AVD are considered too high to justify a change in practice at this time. However, this regimen has been demonstrated as an effective and tolerable frontline therapy for advanced stage Hodgkin lymphoma and could become the standard against which future non-PET directed treatments are compared.
# Management of Recurrent Hodgkin Lymphoma 2,37-52 :
Similar to the initial workup, recurrent disease should involve re-staging tests.
# Initial relapse.
- Re-induction chemotherapy with GDP or DICEP then high dose therapy and autologous SCT + IFRT 20-30Gy to prior bulk site at relapse, or PET-positive residual disease post-ASCT
- Brentuximab vedotin consolidation post-ASCT for patients with primary refractory HL, relapse within 12 months or extranodal disease at relapse
- Pembrolizumab iv q3-6 weeks for older/unfit patients who are deemed ineligible for ASCT Second or subsequent relapse.
- IFRT if localized relapse in previously non-irradiated site - A PD1-inhibitor (eg. Nivolumab or Pembrolizumab) after prior failure of chemotherapy (and autologous SCT in transplant eligible patients) [data suggests longer remissions with PD1-inhibitor compared to Brentuximab vedotin making PD1i then BV the preferred sequencing)
- Brentuximab vedotin IV q21d for up to 16 doses if prior failure of initial chemotherapy (ABVD or BEACOPP) and prior autologous SCT (excluding patients who progress on BV consolidation post-ASCT)
- Palliative chemotherapy for symptomatic patients (GDP, COPP, ChlVPP, CEPP, vinblastine)
Reduce by 50% for grade 3 motor or sensory neuropathy For patients who develop ≥ grade 3 ileus, treatment should be delayed until recovery and vincristine introduced at 75% of the normal dose thereafter. If ≥ grade 3 ileus recurs, vincristine should be discontinued
# II. Initial Therapy For Indolent Histology Non-Hodgkin Lymphoma
# B-R:
- Bendamustine 90 mg/m 2 IV day 1, 2
- Rituximab 375 mg/m 2 IV day 1 then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated.
- Cycles: repeated every 3-4 weeks depending on blood counts (usually administered every 28 days) for a maximum of 6 cycles CVP:
- Cyclophosphamide 800 mg/m 2 IV day 1 (or 400 mg/m 2 /day p.o. days 1-5)
- Vincristine 2mg IV day 1
- Prednisone 100mg/day p.o. days 1-5
- Cycles: every 21 days
# R-CVP:
- Rituximab 375mg/m 2 IV day 1 (premeds: Tylenol, Benadryl, Zantac, hydrocortisone 100mg), then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated.
- Cyclophosphamide 750 mg/m 2 IV day 1
# Chlorambucil (options):
- 0.1-0.2 mg/kg/day for 4-8 weeks then usually reduce for maintenance - 10-14 mg/m² for 5 to 7 days each 28 days - 0.5 mg/kg days 1 and 15 q28d cycle Fludarabine:
- 25mg/m 2 IV days 1-5 q28 days (days 1-3 only if frail elderly or renal dysfunction)
- 40mg/m 2 p.o. days 1-5 q28 days (round down to nearest multiple of 10mg) (d1-3 only if frail or renal dysfunction)
# FND:
- Fludarabine 25mg/m 2
# Methotrexate should be omitted if creat clearance < 50 mL/min or if renal dysfunction with prior cycle Cytarabine should be reduced to q24hr if creat clearance < 50 mL/min or complications of myelosuppression
# VIII. Secondary CNS Lymphoma Protocol
A) Transplant-eligible patients (age <65 years, no significant co-morbidities, no immune suppression) with isolated CNS relapse/progression following complete response of systemic lymphoma to RCHOP.
Step 1
Step 2
Step Step 1
Step 2
Step 3
Week 1 2 3 4 5 6 7 8 9 10 11 12 15 or 16 Rituximab 375mg/m2 d0, 4 high-dose methotrexate 3.5 g/m 2 d1 procarbazine 100 mg/m 2 x 7 days d1-7
x x x Rituximab 375mg/m2 d0 high-dose methotrexate 3.5 g/m 2 day 1 cytarabine 1.5-2 g/m 2 bid days 2-3 - role of IMRT/VMAT/TOMO over 3DCRT is at discretion of treating radiation oncologist-this is determined on a case by case basis - the low dose bath is a consideration when using IMRT as it relates to potential long term risk of second malignancies The full analysis set was collected from eight phase 3 trials in France, Germany, the United Kingdom, the United States, and Poland (n=3,472 patients, median age 61 years (27-86 yrs)). 89% of patients had received treatment for CLL and median overall survival (OS) was 95 months. The model was externally validated in a third dataset comprising 845 patients with newly diagnosed CLL from the Mayo Clinic; 39% had received treatment for CLL. The final model of multivariate analysis identified 5 independent predictors for OS: TP53 (17p) mutation (deleted and/or mutated; hazard ratio : 4.2); IGHV mutation status (unmutated, HR: 2.6); B2M (>3.5 mg/L; HR: 2.0); clinical stage (Binet B/C or Rai I-IV, HR: 1.6); and age (>65 years, HR: 1.7). Using weighted grading, a prognostic score from 0 to 10 was derived that separated the patients into four different groups: low risk (score 0-1), intermediate risk (score 2-3), high risk (score 4-6), and very high risk (score 7-10). At 5 years, significantly different rates of OS were observed for the low to the very high risk group, 93%, 79%, 64%, and 23%, respectively (P<0.001; C-statistic c=0.72 ). The multivariable model was confirmed on the internal validation datasets; in addition, the four risk groups were reproduced with on the Mayo dataset, with 5-year OS rates of 97%, 91%, 68% and 21%, respectively (P<0.001; C-statistic c=0. 79
# Role of PET in
|
For patients >age 60 years, 3-7 days of prednisone 100mg/day pre-R-CHOP as well as G-CSF prophylaxis are recommended to decrease toxicity.Limited-stage DLBCL is associated with favorable outcomes with long-term survival rates up to 80%, although a persistent pattern of late relapses has been described in up to 20-30% of patients. The stage-modified IPI score risk stratifies patients according to the following factors: age >60, stage II, elevated LDH, ECOG >1. In the pre-rituximab era, the phase III SWOG S8736 trial reported superior PFS and OS with CHOP×3 plus RT versus CHOP×8; 53 however, due to the occurrence of late relapses and treatment complications, there was no difference in PFS or OS between the two strategies with long-term follow-up. 54 In the rituximab era, the MInT trial established R-CHOP x6 as the standard of care for most patients with limited-stage DLBCL. 55 Given the favorable outcomes of limited-stage DLBCL, recent studies have assessed the role for treatment de-escalation to minimize toxicity while preserving efficacy. The LYSA/GOELAMS 02-03 trial of 334 patients with stage I-II nonbulky (<7cm) DLBCL demonstrated that R-CHOP alone is non-inferior to R-CHOP + RT if CR is achieved on interim PET after cycle 4; in addition, 4 cycles of R-CHOP was found to be sufficient for interim PET-negative patients with 0 sm-IPI risk factors (Blood 2018;131(2):174). The phase III FLYER trial found that 4 cycles of R-CHOP has reduced toxicity and non-inferior efficacy compared to 6 cycles for patients with stage I-II non-bulky (<7.5cm) DLBCL with no other sm-IPI risk factors. 56 In addition, the phase II SWOG S1001 trial and real-world data from BC Cancer demonstrated excellent PFS rates with 4 cycles of R-CHOP if CR is achieved after cycle 3, even in patients with up to 2 sm-IPI risk factors (# Table of Contents
Background
# Background
Lymphomas encompass a group of lymphoproliferative malignant diseases that originate from T-and B-cells in the lymphatic system. Traditionally, lymphomas have been subcategorized into two groups: Hodgkin lymphoma and non-Hodgkin lymphoma. It is now known however, that Hodgkin lymphoma is simply one of the numerous varieties of lymphoma, and that non-Hodgkin lymphoma is a fairly meaningless term, representing all of the other subtypes of this disease.
Non-Hodgkin lymphoma involves a heterogeneous group of over 40 lymphoproliferative malignancies with diverse patterns of behaviours and responses to treatments. Non-Hodgkin lymphoma is much less predictable than Hodgkin lymphoma and prognosis depends on the histologic type, stage, and treatment. In Canadian males and females, the incidence rates for non-Hodgkin lymphoma showed a marked increase by approximately 50% between 1978 and the late 1990s, but have since stabilized 1 . Mortality rates have followed a similar pattern. The clearest risk factor for the disease is immunosuppression associated with HIV infection, or medications used to prevent rejection in organ transplantation. Other factors that increase risk of non-Hodgkin lymphoma are poorly understood but may include occupational exposures to pesticides, herbicides, and dioxins, as well as chronic immune stimulation associated with autoimmune disorders (e.g. thyroiditis, Sjogren's Syndrome, SLE) or infections (e.g. Helicobacter pylori gastritis, hepatitis C virus) 2 . In 2015, it is estimated that 8200 new cases of non-Hodgkin lymphoma will be diagnosed in Canada, and 2650 deaths will occur, making non-Hodgkin lymphoma the sixth most common cause of cancer-related death in Canada 3 .
Hodgkin lymphoma is a malignancy characterized histopathologically by the presence of Reed-Sternberg cells in the appropriate cellular background. Although rare, Hodgkin lymphoma is one of the best-characterized malignancies of the lymphatic system and one of the most readily curable forms of malignant disease. 2 The incidence rate has remained fairly steady over time, it is estimated that approximately 1000 new cases of Hodgkin lymphoma are diagnosed in Canada each year 3 . It is important to note that lymphoma also represents the most commonly diagnosed non-epithelial cancers in adolescents and young adults in Canada. Between 1992 and 2005, 5577 new cases of Hodgkin and non-Hodgkin lymphoma were diagnosed in Canadians aged 15-29 years 1 . The following guidelines do not address lymphoma in the pediatric or adolescent populations.
# Guideline Questions
• What are the diagnostic criteria for the most common lymphomas?
• What are the staging and re-staging procedures for Hodgkin and non-Hodgkin lymphomas?
• What are the recommended treatment and management options for Hodgkin and non-Hodgkin lymphomas?
• What are the recommended follow-up procedures for patients with malignant Hodgkin and non-Hodgkin lymphoma?
# Search Strategy
Medical journal articles were searched using Medline (1950 to October Week 1, 2015), EMBASE (1980 to October Week 1, 2015), Cochrane Database of Systematic Reviews (3 rd Quarter, 2015), and PubMed electronic databases. An updated review of the relevant existing practice guidelines for lymphoma was also conducted by accessing the websites of the National Comprehensive Cancer Network (NCCN), Cancer Care Ontario (CCO), the British Columbia Cancer Agency (BCCA), the European Society for Medical Oncology (ESMO), and the British Committee for Standards in Haematology.
# Target Population
The following guidelines apply to adults over 18 years of age. Different principles may apply to pediatric and adolescent patients.
I. Diagnosis and Pathologic Classification [1][2][3][4][5][6] An excisional lymph node biopsy of the largest regionally involved lymph node is the optimal specimen for initial diagnostic assessment. Similarly, a sizable biopsy from the organ of origin in extranodal lymphomas is also suitable. Compelling clinical contraindications to an open biopsy should be present before considering any other options. A careful clinical examination or radiological investigations for more accessible or palpable pathologic adenopathy could be useful in decision making prior to opting for a lesser diagnostic specimen. Fine needle aspirate biopsies are inadequate for the initial diagnosis of lymphoma. These latter specimens may provide adequate material for evaluating possible relapse, clarification of staging at questionable sites and as a source of additional specimen where required for further special testing or research. Occasionally, a generous core needle biopsy comprising many core samples with sufficient material to perform the appropriate ancillary techniques required for diagnostic assessment (immunohistochemistry, flow cytometry, PCR for IgH and TCR gene rearrangements, and FISH for major translocations) may supply adequate tissue, in cases when a lymph node is not easily accessible for excisional or incisional biopsy. A reference lymphoma pathologist should confirm lymphoma diagnoses in each and every case. This is particularly important in cases when only a core needle biopsy is available, and whenever requested by the treating clinician.
Table 1 describes the histologic subclassification of the malignant lymphomas, and is an adaptation of the most recent WHO classification 6 . This classification is based on the light microscopic interpretation complemented by special stains, immunophenotyping, cytogenetics and other ancillary information as available. The specific lymphomas are divided into three major groups, according to the degree of clinical aggressiveness, for treatment planning. All B-cell lymphomas should be immuno-phenotyped to determine if they are CD20 positive.
# Required Immunohistochemical and Ancillary Testing for Lymphoma
In general, guidelines for using the various ancillary methods, includingimmunohistochemical and fluorescence in situ hybridization (FISH) testing as outlined in the most recent version of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues should be followed so as to confirm a specific diagnosis and provide necessary prognostic and/or predictive information 6 . In addition, the following are recommended by the Alberta Provincial Hematology Tumour Team 7,8 :
1. Classical Hodgkin Lymphoma: The immunohistochemical panel may include CD45/CD3/CD20/CD30/CD15/ PAX5/MUM1 and should be selected on a case by case basis at the discretion of the hematopathologist. EBV studies by in situ hybridization (EBER) may be considered if difficulty exists diagnostically, as most cases of the mixed-cellularity subtype of classical Hodgkin lymphoma are EBER positive.
# Diffuse Large B-Cell Lymphoma (DLBCL):
• Immunohistochemical (IHC) panels to distinguish between Activated B Cell (ABC) type and Germinal Centre B-cell (GCB) cell of origin (COO) types have limitations (regardless of which algorithm is employed)when compared to gene expression profiling 8,9 . However, GCB vs non-GCB COO by IHC does correlate with survival rates following RCHOP chemotherapy, and therefore adds prognostic information when managing DLBCL. The Alberta hematopathologists currently use a simple algorithm published by Hans et al, requiring IHC stains for CD10, BCL6 and MUM1, in which CD10+ or BCL6+/ MUM1-cases are designated as GCB COO, whereas cases negative for negative/BCL6+/MUM1+ phenotype are considered to have a non-GCB COO.
• EBER and CD5 expression confer worse prognosis, and may be used to identify various clinicalpathological entities with distinct implications. Determining CD5 expression should be considered on all DLBCL cases. EBER should be performed in patients with immune suppression related lymphomas, or those who possibly have EBV-related DLBCL (consider past the age of 50) 10 .
• Rearrangments of the C-MYC gene as determined by FISH, especially in association with BCL2 and/or BCL6 (so called "double hit" or "triple hit" disease) are associated with very poor outcomes following R-CHOP therapy, as well as high rates of central nervous system relapse.
Patients with a double-hit or triple-hit lymphoma under age 70 years should receive more aggressive therapy and possibly stem cell transplantation. Though it represents approximately only 5-10% of DLBCL cases 11 , it is very important to recognize these patients, and therefore, MYC rearrangement testing by FISH is to be performed on all patients younger than 70 y.o. with the appropriate lymphoma histology, i.e. DLBCL or lymphoma that are so called "unclassifiable" with intermediate morphological features between DLBCL and Burkitt. If MYC is rearranged, the case should also undergo BCL2 and BCL6 rearrangement testing by FISH. MYC and BCL2 test results are required within 2 weeks of diagnoses for all new patients within the appropriate diagnostic category and age group. FISH testing may also be performed in select instances at the discretion of the reporting hematopathologist if such studies are deemed diagnostically useful.
• Immunohistochemical studies cannot be used as a surrogate for MYC rearrangement.
• However, the detection of MYC and BCL2 concurrent overexpression by IHC in so-called "dual expressor" DLBCL, identifies a numerically significant subset of the DLBCL with potentially similar aggressive behavior compared to double-hit lymphoma cases, but representing a distinct group of patients (more often an ABC subtype as opposed to double hit DLBCL which are usually GCB). This group is also associated with a high rate of CNS relapse 11 . Therefore, provided adequate benchmarks and interpretation standards can be established for reproducibility, IHC for MYC and BCL2 expression should also be strongly considered on all DLBCL cases 9,12 .
3. Follicular Lymphoma: must document grade (1-2, 3a or 3b), because all grade 3b should receive R-CHOP rather than other chemotherapy regimens. Also, if a diffuse pattern is present, this should be specified and a relative proportion noted, as outlined in the WHO Classification. 4. Peripheral T-Cell Lymphoma: cytotoxic T-cell markers (CD8/CD57/Granzyme B) correlate with poor prognosis and should be considered. Notably, however, peripheral T cell lymphomas are not classified on the basis of these phenotypic markers. EBV studies by in situ hybridization (EBER) should be performed in cases where angioimmunoblastic T cell lymphoma (AITL) and extranodal T/NK cell lymphoma, nasal type enter in the differential diagnosis. 5. Mantle Cell Lymphoma: Evidence of CyclinD1 deregulation confirmed by IHC (positive staining for CyclinD1) and/or FISH (positive for t (11;14)) is needed to confirm the diagnosis, provided other morphophenotypic findings are consistent with the diagnosis. Poor prognostic features must be mentioned in the report, including blastoid and pleomorphic morphologic variants. The proliferation index as measured by Ki67 or Mib-1 (used to calculate MIPI score) is to be reported. In cases where it is difficult to differentiate MCL from CLL, flow cytometry for CD200 and IHC for SOX11 may be performed 13 . For patients who are deemed transplant-eligible (i.e. age <65 and fit for intensive therapy), TP53 mutational testing should be performed at time of diagnosis to identify high-risk patients more appropriate for allogeneic stem cell transplantation 14 .
II. Staging [1][2][3][4][5][6][7][8][9][10][11][12] Mandatory Staging Procedures
• Pathology review whenever possible (essential for core needle biopsies)
• Complete history and physical examination stating ECOG Performance Score, B symptoms
• CBC & differential, creatinine, electrolytes, Alk P, ALT, LDH, bilirubin, total protein, albumin, calcium
• Hepatitis B Surface Antigen (HBsAg), Hepatitis B Surface Antibody (anti-HBs), and Hepatitis B Core Antibody (total anti-HBc) must be done prior to initiating chemo/immunotherapy. Patients who are HBsAg positive are either acutely or chronically infected and require consultation with Hepatology. Patients who are HBsAg negative/anti-HBc positive (regardless of anti-HBs titre levels) and are going to be treated with B-cell depleting therapy (e.g. rituximab) should receive prophylactic therapy with entecavir or tenofovir. Those who are HBsAg negative/anti-HBc positive and fall under low or moderate risk as per Table 1 do not require prophylaxis and should undergo serial HBV DNA testing q6-12 months and serial ALT testing q3 months while on immunosuppressive therapy (see Figure 1). Hepatitis B prophylactic therapy should be continued for at least 6 months following the completion of immunosuppressive therapy, except for those treated with anti-CD20 agents who should continue for at least 12-18 months due to the lag in B-cell function recovery. [13][14][15][16][17] Adapted from Coffin, Carla S., et al. 13 Anti-HBc = antibody to HBV core; anti-HBs = antibody to HBsAg; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; TNF = tumour necrosing factor.
• ESR (for early stage Hodgkin lymphoma)
• Beta-2-microglobulin
• Serum protein electrophoresis and quantitative IgG, IgA, and IgM for indolent B-cell lymphomas
• Pregnancy test: if at risk
• Bone marrow aspiration and 2cm biopsy (BMasp/bx) with flow cytometry for patients with indolent B-cell and a marrow biopsy (without flow cytometry) for aggressive T-cell non-Hodgkin lymphomas. BMasp/bx is not required for Hodgkin lymphoma or DLBCL if a staging PET/CT is performed.
• FDG-PET and Diagnostic CT NeckChestAbdomenPelvis for FDG-avid, nodal lymphomas, which includes all histologies except chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma, mycosis fungoides, and marginal zone NHLs (unless there is a suspicion of aggressive transformation). Nodal lymphomas that are not FDG avid should have a staging diagnostic CT scan of NCAP. PET-CT is especially important for patients who otherwise have non-bulky, stage I-IIA lymphoma, and are being considered for involved field radiation (IFRT) following abbreviated (or no) chemotherapy. PET/CT is not necessarily required for Follicular Lymphoma if the results will not change management, particularly for a patient who will likely undergo watchful waiting.
Restaging Schedule
1. The following are to be performed prior to each chemotherapy treatment:
• Clinical parameters: brief history and physical examination, toxicity notation, ECOG status • Bloodwork: o CBC/differential/platelet o also consider EP/creatinine and LFTs 2. Requirements for CT scanning of chest/ abdomen/ pelvis:
• Routine CT scanning: o after 3 months (4 cycles) of therapy and again after completion of all therapy for Non-Hodgkin Lymphomas o if a residual mass is seen on the CT after completion of all therapy, then repeat a PET/CT for aggressive lymphoma to determine partial or complete remission. o a repeat CT scan should be considered 6-12 months post-treatment; otherwise, no further routine CT scans are required o Hodgkin lymphoma patients should undergo a PET/CT after 2 cycles ABVD (rather than CT after 4 cycles) as outlined below in the Hodgkin Lymphoma treatment guidelines.
• Other requirements for CT scanning: o as indicated to investigate clinical signs or symptoms, or abnormal laboratory tests 3. Bone marrow aspirate & biopsy (with sample sent for flow cytometry):
• Repeat for transplant-eligible patients with aggressive histology lymphomas who otherwise are in complete remission after completion of chemotherapy, if marrow was positive at diagnosis 4. PET/CT Imaging:
• Assessment of residual radiographic or clinical abnormalities of uncertain significance at the time of re-staging following completion of therapy.
• Hodgkin lymphoma patients should undergo a PET/CT after 2 cycles ABVD (rather than CT after 4 cycles) as outlined below in the Hodgkin Lymphoma treatment guidelines. For DLBCL, factors associated with high risk (>10%) for relapse in the central nervous system include 4-6 of the following factors: 1) Age >60 years, 2) elevated LDH, 3) ECOG=2-4, 4) Stage 3-4, 5) >1 extranodal site of involvement, and 6) kidney or adrenal involvement. Other high risk situations include double hit lymphoma (MYC + BCL2 and/or BCL6 translocations) and testicular lymphoma. Prophylactic intrathecal chemotherapy does not penetrate the brain parenchyma and has not been proven to decrease meningeal or parenchymal brain relapse of lymphoma in well-designed studies.
Due to the lack of proven benefit, intrathecal chemotherapy cannot be recommended even in highrisk situations where the risk of CNS relapse is 10% or higher.
For patients at high-risk of CNS involvement, we previously recommended CNS prophylaxis with high dose intravenous methotrexate (HD-MTX) 3.5g/m2 x 3 doses mid-cycle of R-CHOP following cycles 2, 4, 6. We recently reviewed our outcomes for patients who were treated according to our guidelines with a recommendation for incorporating intravenous HD-MTX for all patients with CNS-IPI score 4-6, double-hit lymphoma or testicular lymphoma. 67 Among 906 patients treated for DLBCL, with a median follow-up of 35.3 months, CNS relapse risk was similar with and without intravenous MTX (11.2% vs 12.2%, p=0.82), with rates in high-risk patients comparable to previous reports in patients who did not receive CNS prophylaxis (10-12%). However, the risk of CNS relapse trended lower in patients who received consolidative ASCT or intensified chemo-immunotherapy versus R-CHOP (6.0% vs 14.6%, p=0.09). The ineffectiveness of prophylactic HD-MTX has been confirmed in several other multiinstitutional retrospective studies, 68,69 71 CAR T-cell therapy is an established treatment for adult patients with relapsed/refractory large B-cell lymphoma after two or more lines of therapy, with two immune effector cellular therapies approved in Canada, namely axicabtagene ciloleucel (axi-cel, Yescarta) and tisagenlecleucel (Kyrmiah). In the pivotal phase I/2 Zuma-1 study, 110/111 enrolled patients with refractory DLBCL, primary mediastinal B-lymphoma, or transformed follicular lymphoma received a single infusion of axi-cel, with CR rate of 52% and ongoing CR of 40% at 15.4 months of follow-up, and OS of 52% at 18 months. 72 At 38.1 months median follow-up, the OS rate was 47% with median of 25.8 months. 73,74 In the phase 2 Juliet trial 93 patients with relapsed/refractory DLBCL or transformed follicular lymphoma received a single infusion of tisagenlecleucel, with CR of 40% and relapse-free survival of 65% at 12 months (79% in those who achieved CR). 75 Lisocabtagene maraleucel (Liso-cel) is a third immune effector cell therapy being studied, and the TRANSCEND NHL001 study presented at ASH 2019 demonstrated similar efficacy data, with CR rate of 53%, and OS 57.9% at 1 year (85/% in patients with CR). 76 The main toxicities of these therapies are cytokine release syndrome, neurotoxicity, cytopenias, and B-cell aplasia/hypogammaglobulinemia and as such this therapy is be administered only at centers approved for cellular therapy treatments.
Phase III trials with axi-cel and liso-cel as second line therapy compared to the standard salvage chemotherapy approach in patients with poor prognosis relapsed/refractory DLBCL <12 months from RCHOP chemotherapy have demonstrated superior event-free survival outcomes. 77 Importantly, in both trials <50% of patients proceeded with an autologous stem cell transplantation, mainly due to lack of chemosensitive disease, and >50% of these patients subsequently proceeded with CAR T therapy in 3 rd line, with inferior outcomes. Review of 125 southern Alberta patients between 2015 and 2019 with relapsed/refractory DLBCL after RCHOP chemotherapy demonstrated that of the 50 patients that were intended for salvage and HDT-ASCT, only 28 underwent a stem cell transplant, with long-term cure in only 9 of these patients. 78 These data suggest that while the current standard of care results in poor outcomes for most patients with relapsed/refractory DLBCL, the use of CAR T therapy second line could substantially increase the proportion of patients able to receive curative treatment at first progression.
# Patients unfit for intensive therapy:
The prognosis of patients with relapsed/refractory DLBCL who are not candidates for cellular therapy is extremely poor, with median survival rates of less than 6 months, thus palliation is the main goal of any chosen therapy. Palliative-intent regimens including R-GemOx, polatuzumab vedotin with bendamustine/rituximab, and tafasitamab with lenalidomide have been studied in phase II trials of patients with r/r DLBCL who are unfit for intensive therapy:
# Recommendations for treatment:
1. R-GemOx is the preferred second-line treatment because it is a well-established outpatient platinum-based regimen that is better tolerated in older patients than other regimens such as GDP, DHAP, or ICE, although it is associated with significant myelosuppression.
# 2.
Polatuzumab, bendamustine, and rituximab can be considered for second or later relapses, and for patients who are unfit for, or intolerant of, R-GemOx. Patients should have reasonable performance status (ECOG 0-2) and adequate hematologic function to be expected to benefit from and tolerate polatuzumab with BR. Tafasitamab-lenalidomide is also approved but is not yet funded in Alberta. Bendamustine and tafasitamab should be avoided in patients potentially eligible for CAR-T cell therapy due to the respective risks of lymphodepletion and CD19 downregulation.
# 3.
Some palliative patients at or beyond second relapse may have symptomatic benefit from prednisone alone, or low dose daily oral chemotherapy with chlorambucil 0.1mg/kg/day or etoposide 50mg/day, or combination oral therapy such as PEPC.
# 4.
Involved field radiotherapy (IFRT) to symptomatic sites or localized relapses may also benefit these palliative patients.
# 5.
Addressing goals of care and ensuring timely integration of palliative care should be a priority for all patients with r/r DLBCL who are unfit for intensive therapy.
# Secondary CNS Lymphoma 79-82
Selected patients with CNS relapse/progression may be candidates for intensive therapy as outlined in Appendix A, subheading VIII. Favorable outcomes were reported in an Alberta study of 62 SCNSL patients with median age 58 years (range 20-75) intended for transplant, with ASCT rates of 84%, 5year PFS 53% and OS 65% for all patients, and 5-year PFS 62% and OS 73% for those undergoing R-TBuM conditioning and ASCT. One of 3 induction regimens is recommended for transplant-eligible patients and one of two options for transplant ineligible patients, based on presentation:
1) Isolated CNS lymphoma: HDMTX-based induction then RDHAP for stem cell mobilization and collection, then R-TBuM/ASCT for transplant eligible (
# High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements by FISH:
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double hit lymphoma or DHL) is associated with a poor prognosis, with a large multicenter retrospective analysis of 311 patients reporting an OS rate <50% if IPI=2-5 vs 65% for IPI=0-1 (Blood 2014;124(15):2354). The optimal treatment of DHL is unknown, but intensive induction regimens such as da-EPOCH-R or R-CODOX-M/R-IVAC are commonly used and have demonstrated PFS benefit over R-CHOP in some retrospective studies (Blood 2014;124(15):2354) but not others (Am J Hematol 2021; 96(3):302). In
# CAR T-cell Therapy
addition, the use of consolidative HDT/ASCT has been associated with superior outcomes among patients achieving CR after R-CHOP induction but not after intensive induction regimens. 83 This suggests that DHL patients treated with R-CHOP can be considered for ASCT consolidation, especially if IPI=2-5 at diagnosis, however other patients who achieve CR after an intensive induction regimen probably should not receive ASCT consolidation. A retrospective analysis of 99 patients with DHL in Alberta found relatively favorable outcomes with 4-year PFS 59% and OS 66%, with no significant difference in PFS or OS between patients treated with intensive induction regimens vs intention-to-transplant following R-CHOP induction. Among the 48 patients intended for ASCT, outcomes were excellent for the 75% of patients undergoing upfront ASCT with 4-year PFS 80-90%, whereas there were no survivors among the 25% of patients with primary refractory disease. This suggests that upfront ASCT can achieve durable remissions in the majority of DHL patients with chemosensitive disease, whereas alternative strategies such as CAR-T cell therapy should be strongly considered for patients with chemorefractory disease.
# Alberta recommendations for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements:
• IPI=0-1: R-CHOP x 6 cycles or da-EPOCH-R x 6 cycles • IPI=2-5: Options include:
o A. R-CHOP x 2-3
# Primary Mediastinal B-Cell Lymphoma
Primary mediastinal B-cell lymphoma (PMBCL) of thymic origin represents 6-10% of all DLBCLs, and most commonly affects young adults (median age ~35), women more than men. 84 It is frequently associated with a bulky mediastinal mass that directly extends into extranodal thoracic tissues such as pleura, pericardium and chest wall. Patients with distant lymphadenopathy or extranodal involvement outside the thorax should likely be diagnosed and treated as systemic DLBCL with secondary mediastinal involvement, rather than as PMBCL. 85 Overall, PMBCL is associated with a better prognosis than other DLBCLs, including GCB DLBCLs. The IPI score tends not to work well for PMBCL because most patients are young with fairly well-preserved performance status, and have elevated LDH. Therefore, limited vs advanced stage, and number extranodal sites (esp pleural effusions) tend to be the only factors that subdivide patients into excellent vs good prognosis. Likewise, because most patients have a very good prognosis, interim restaging PET imaging is associated with very high negative predictive value, but relatively low positive predictive value. 86 These findings were confirmed in 20 patients treated with R-CHOP in Alberta, where the PPV of a positive interim PET scan was only 20% for disease progression/relapse whereas a negative interim PET had NPV 100%. Therefore, a positive interim PET scan should probably not be used alone to guide further therapy. 87 There is no phase III evidence that RT after R-CHOP improves survival rates relative to R-CHOP alone, but this is being studied in the ongoing IELSG-37 clinical trial. Real-world data from the BCCA demonstrates that omitting RT for PETnegative patients at the end of R-CHOP therapy achieves similar TTP (80%) and OS (89%) as historical cohorts treated routinely with RT, with a reduction in RT use from 78% in the historical cohort to 28% in the PET-directed era. 88 Similarly, retrospective data for 91 consecutive patients in Alberta treated with R-CHOP from 2004-2020 found a 5-year overall survival rate of 86%, with similar outcomes for patients with advanced versus limited stage (86% vs 92%, p=0.31) or bulky versus nonbulky disease (83% vs 96%, p=0.12). For patients responding to R-CHOP, the 5-year OS rate was 93% with RT versus 100% without RT (p=0.17). Among 40 patients with a PET-defined complete metabolic response after R-CHOP, 5-year OS was 100% for all patients treated with (n=9) or without (n=31) RT.
Management of patients with partial metabolic response after R-CHOP is uncertain. Prospective data show that the majority of Deauville 4 end-of-treatment (EOT) PET scans after DA-EPOCH-R are false-positives which can be monitored with surveillance PET without RT, with progressive disease occurring in only 1/16 patients with Deauville. 89 Among the 34 patients in BC and Alberta with Deauville 4 EOT PET after R-CHOP (the majority of whom received RT), survival outcomes were excellent and similar to EOT PET-negative patients. It is likely that many cases of partial metabolic response after R-CHOP are false positives as well; indeed, 5 patients in Alberta and BC with Deauville 4 after R-CHOP were observed without RT and none relapsed. Extrapolating from this data, it has been proposed that surveillance imaging without radiation may be reasonable for young patients with Deauville 4 EOT PET after R-CHOP given the likely low risk of progression and long-term risks of toxicity from RT. 90 In conclusion, available evidence supports the use of R-CHOP for patients with PMBCL, with less toxicity but similar excellent outcomes as DA-EPOCH-R. End of treatment PET should be done 6-8 weeks after day 1 of the final cycle of chemoimmunotherapy to allow time for the post-treatment inflammatory response to resolve. 91 In view of the long-term risk of secondary malignancy and premature heart disease from RT in young patients, RT can probably be safely omitted for patients with PET-negative disease after R-CHOP. Omitting RT in favour of surveillance imaging in 6-8 weeks (CT is the preferred modality in Alberta) may be reasonable for patients <60 years old with Deauville 4 on EOT PET after R-CHOP, while older patients and those with Deauville 5 should receive RT. For the 10-20% of patients with suspected relapsed/refractory PMBCL, the diagnosis of progressive disease should be confirmed with biopsy or clear progression on CT, and not based on FDG uptake on PET alone. Treatment options at relapse include radiation for localized disease, salvage chemotherapy and autotransplant, radiation therapy, axicabtagene ciloleucel (funded only after 2 prior lines of therapy), and pembrolizumab. Follicular Lymphoma Throughout the following suggested treatment approach, three over-riding principles should be considered: 1. These are guidelines only. This disease often carries a long, incurable, remitting/relapsing natural history and, therefore, several treatment approaches are reasonable. 2. The mere presence of disease does not alone imply the need for treatment. 3. If therapy is required for predominantly localized disease, IFRT should be considered in lieu of systemic pharmacological treatment as long as the radiotherapy can be done with minimal early or delayed side-effects (e.g., xerostomia, severe nausea/vomiting) and without eliminating future treatment options (e.g., should not radiate ≥25% bone marrow). Figure 2 outlines the treatment algorithm for follicular lymphoma. For patients who do not have any of the above indications for therapy, the recommended approach is to observe with (or arrange) follow-up clinical assessments every 3-6 months ("watchful waiting"), and a CT CAP 1 year after diagnosis. For patients not meeting treatment criteria 1 year after diagnosis, another CT 2 years after diagnosis could be considered. Patients who have progressive disease on www.ahs.ca/guru follow-up should generally be treated, even if they do not fulfill any of the other indications for therapy.
A retrospective study of 238 Alberta follicular lymphoma patients managed with watchful waiting found that 24% developed transformed disease or significant organ dysfunction (at a median of 30months) prior to initiating initial therapy, and these patients had inferior survival rates compared to other patients requiring therapy who were initially managed with watchful waiting (10 yr OS 67.9% vs 85.7%, HR 3.000 (95%CI 1.696-7.126), p=0.0007). These watchful waiting patients did not undergo routine follow-up CT scans at 1 or 2 years to identify progression. It is possible that these adverse outcomes might have been avoided with closer monitoring by CT imaging and earlier initiation of chemoimmunotherapy 138 .
For grades 1,2,3a follicular lymphoma who have an indication for therapy, the recommended therapy involves 6 cycles of B-R (bendamustine-rituximab) chemotherapy, followed in responding patients by 2 years of maintenance rituximab (every 3 months for total of eight doses). In patients with previously untreated indolent lymphoma, B-R can be considered as a prefered first-line treatment approach to R-CHOP because of increased progression-free survival and fewer side-effects. Patients who have limited life-expectancy from serious co-morbid illness, or who do not want intravenous therapy, may be treated with oral chlorambucil or fludarabine monotherapy.
The GALLIUM clinical trial investigated the value of obinutuzumab in combination with chemotherapy followed by maintenance therapy compared to standard therapy with rituximab chemoimmunotherapy plus maintenance in the firstline treatment of follicular lymphoma. The study demonstrated superiority of obinutuzumab over rituximab in terms of PFS (3-year PFS was 81.9% (95%CI: 77.9-85.2%) vs. 77.9% (95%CI: 73.8-81.4%), with acceptable increased toxicity. ). As no OS advantage has yet been demonstrated, obinutuzumab is not funded in Canada for this indication and we continue to recommend rituximab. 139 .
Grade 3b follicular lymphoma should be treated as DLBCL with, R-CHOP. Rituximab maintenance has not been proven effective following R-CHOP therapy for large B-cell lymphoma, and therefore is not recommended.
Therapy of relapsed disease: Therapeutic recommendations for recurrent follicular lymphoma need to be individualized, and no one recommendation is suitable for all patients. Numerous factors need to be taken into consideration before recommending therapy for recurrent follicular lymphoma, including:
• Patient Factors: Age, co-morbidity, symptoms, short vs. long-term goals, preservation of future options, reimbursement/ability to pay for expensive treatments, acceptance of risks/toxicities of treatment option relative to potential benefit (RR, PFS, OS).
• Disease Factors: Stage, sites of involvement, grade, transformation, prior therapy, time from prior therapy (disease-free interval).
For example, previously healthy patients younger than 70 years who relapse within 2 years of initial chemotherapy have a median life expectancy of <5 years, and are best managed with HDCT/ autologous SCT. HDCT/SCT maximizes the length of disease control for all patients less than 70 years, regardless of length of initial remission, and as such is a reasonable treatment option for those who accept potential risks/toxicities. Therefore, patients younger than 70 years without serious comorbid disease, and who respond to salvage therapy should be considered for high dose chemotherapy and autologous (relapse 1-2) or allogeneic stem cell transplantation (relapse 3). A large retrospective study of consecutively treated relapsed follicular lymphoma patients in Alberta and BC reported 5 year overall survival rates following relapse of ~90% for those who received ASCT vs ~60% for those who did not receive ASCT. This marked difference in survival retained significance in multivariate as well as instrumental variable analyses 140 . While the study used bendamustine as a chemotherapy backbone, few patients on the study had received bendamustine as their frontline therapy. Given current practice ofBR for the frontline treatment of FL and the fact that there is no biological reason that the same clinical benefit of obinutuzumab would not be seen in combination with other chemotherapies, alternate NHL chemotherapy backbones can be considered for patients deemed inappropriate for bendamustine retreatment. Relatively frequent infections were noted so prophylactic antibiotics and antivirals should be considered, especially when obinutuzumab is combined with bendamustine.
Another option to consider for rituximab-refractory relapsed FL is radioimmunotherapy with 90Yibritumomab tiuxetan (Zevalin). This optionrequires Director's Privilege approval, and is not currently listed on the Alberta Cancer Drug Benefit List for funding. In a small study of 57 patients with rituximab-refractory FL (median 4 prior therapies), the overall response rate to 90Y-ibritumomab tiuxetan was 74% (CR 15%) and median duration of response of 8.7months. There may be small subset of patients (10-15%) who achieve long-term PFS following 90Y-ibritumomab tiuxetan 118,141 .
Idelalisib, a PI3Kδ inhibitor has also shown efficacy in a Phase 2 study of double-refractory FL patients (patients with lack of response or progression within 6 months of both rituximab and an alkylator). Idelalisib can lead to durable remissions in a minority of patients and is currently not funded in Canada but is available through a compassionate access program. Infectious complications and immune toxicities are frequent and prophylactic antibiotics and anti-virals are required to reduce the risk of serious infections. 142 Palliative, symptomatic care (possibly including palliative IFRT 4Gy/2 fractions) is usually the best option for patients who were refractory to their 2 most recent treatment regimens, those with CNS involvement, or those with an ECOG score of 3-4.
# Indolent Lymphomas (Excluding Follicular Histology) 1, 143-151
Indolent lymphomas should generally be treated similarly to follicular grade 1-2 lymphomas. • majority should receive B-R, then rituximab maintenance • alternatives in special situations include IFRT, fludarabine, or chlorambucil
# Splenic Marginal Zone Lymphoma
Splenic marginal zone lymphoma is an uncommon type of non-Hodgkin lymphoma characterized by splenomegaly, cytopenias, lymphocytosis, and less commonly lymphadenopathy. Revised diagnostic criteria now specify the typical blood and bone marrow findings of SMZL and splenic biopsy is not usually required to establish the diagnosis 152 . It is still reasonable, however, to proceed with splenectomy if the cause of splenomegaly is not determined following peripheral blood and bone marrow evaluation.
The disease course is indolent and many patients can be managed expectantly until symptomatic splenomegaly or pronounced cytopenias develop. SMZL prognostic scoring systems have been described, with low hemoglobin, low platelets, elevated lactate dehydrogenase and extra-hilar lymphadenopathy as adverse markers 153 .
In rare cases, SMZL has been associated with hepatitis C infection (HCV), so all patients should be screened at diagnosis. Those who are HCV+ should first be offered HCV-directed therapy, as the lymphoma may regress avoiding the immediate need for further therapy 154,155 . Splenectomy has previously been the standard approach to treat SMZL for over two decades 156 . The role of splenectomy as frontline treatment of SMZL is now controversial 157, 158 159 160 . Risks posed by splenectomy include operative morbidity and mortality, particularly in the elderly, or those with multiple comorbidities. However, surgical outcomes are improving at experienced centres. The risk of infection with encapsulated organisms is a serious concern, but may be mitigated with timely vaccination and long-term antibiotic prophylaxis 161 .
Monotherapy with rituximab has recently emerged as a non-operative alternative [158][159][160][161][162] with reports suggesting survival outcomes similar to historical patients treated with splenectomy. Chemoimmunotherapy such as rituximab-bendamustine (BR) is also a rational approach for SMZL given the recent favourable results of a large scale RCT of iNHL, including marginal zone histology 136 .
Although existing evidence is inadequate to conclude which treatment approach is superior, we propose the following strategy for managing SMZL:
1. Rituximab monotherapy is recommended as frontline therapy for most patients. A standard regimen is rituximab weekly for 4 weeks, followed by a response assessment 4-6 weeks later. a. Those achieving at least a partial response, defined by conventional response criteria 152 , should subsequently receive maintenance rituximab as per other iNHL subtypes. b. Non-responders or those with progressive disease should proceed with either: i. Splenectomy if the spleen is the major site of disease or ii. BR for those with additional nodal disease, extensive bone marrow involvement, or non-operative candidates, then followed by maintenance rituximab in responding patients.
2. Select patients who require a splenectomy to establish the diagnosis and have no bone marrow, peripheral blood, or nodal involvement, do not require maintenance rituximab and may simply be observed.
# Lymphoplasmacytic Lymphoma (LPL)
Diagnostic criteria for Waldenström macroglobulinemia (WM):
• IgM monoclonal gammopathy of any concentration • Bone marrow infiltration by small lymphocytes showing plasmacytoid/plasma cell differentiation, usually with intertrabecular pattern of bone marrow infiltration predominantly lymphocytic to lymphoplasmacytic to overt plasma cells. 5. CT of the abdomen and pelvis: to detect organomegaly and lymphadenopathy (skeletal surveys and bone scans are not necessary in absence of symptoms). 6. Blood or plasma viscosity: if signs and symptoms of hyperviscosity syndrome (HVS) or IgM> 50 g/L. 7. Direct antiglobulin test and cold agglutinin titre if positive. 8. Cryoglobulins. 151 . Serum IgM monoclonal protein should be measured by serum protein electrophoresis. The use of nephelometry to determine total serum IgM should be discouraged because this method is unreliable, especially when the levels of monoclonal protein are high. The presence of cryoglobulin or cold agglutinin may affect determination of IgM; therefore, testing of cryoglobulin and cold agglutinin at baseline should be considered, and if present, serum samples should be reevaluated at 37°C to ensure accurate and consistent determination of the monoclonal protein levels.
• LPL immunophenotype: o surface IgM+ CD5-CD10-CD19+ CD20+ CD22+ CD23-CD25+ CD27+ FMC7+ CD103-CD138- • Recent
# IgM monoclonal protein response assessment in WM
# Hyperviscosity syndrome (HVS) in LPL
Symptoms and signs of hyperviscosity include spontaneous bleeding, neurological symptoms and retinopathy. Patients with HVS have an expanded plasma volume and cardiac failure may also occur. There are several published reports demonstrating the efficacy of plasmapheresis in HVS although randomised data are lacking. There is not, however, a simple linear relationship between paraprotein concentration and either plasma viscosity, whole blood viscosity or symptoms. An increase in IgM concentration from 20 to 30 g/L results in an increase in plasma viscosity of <2 centipoise (cP) but an increase from 40 to 50 g/L increases the plasma viscosity by around 5 cP. Indeed, a 1-volume plasma exchange results in a 35-40% decrease in IgM concentration but in up to a 60% reduction in plasma viscosity. In patients with WM the actual plasma volume may exceed that calculated and, given the data above, a 1-1.5 volume exchange is therefore advisable.
# General treatment guidelines for LPL/WM 151 .
The usual indications for starting patients with LPL/WM on active therapy consist of clinical evidence of adverse effects of the paraprotein (HVS with neurological or ocular disturbance, peripheral neuropathy, amyloidosis, symptomatic cryoglobulinemia), symptomatic anemia (Hb<100g/L beware of pseudo-anemia from hemodilution), platelets <100, progression to high-grade lymphoma, significant adenopathy or organomegaly, or constitutional symptoms.
• Plasmapheresis: 1-2 procedures, exchanging 1-1.5 calculated plasma volumes, are advised for the treatment of HVS in WM, followed by chemotherapy to prevent paraprotein re-accumulation. In patients who are drug-resistant, plasmapheresis may be indicated for long-term management.
Although there are few studies that consider the role of plasma exchange in the treatment of cryoglobulinemia, there is a clear rationale for its use. The treatment room should be warm and blood warmers used in the cell separator circuit to prevent precipitation during the procedure.
• Chemotherapy: The most common initial chemotherapy for LPL is B-R (Bendamustine-Rituximab) followed by rituximab maintenance, similar to other indolent B-cell lymphomas. For patients who do not tolerate B-R, CDR (Cyclophosphamide, Decadron, Rituximab) or Bortezomib-based therapy (eg. R-Bortezomib, R-CyBorD) should be considered. Rituximab is active in the treatment of WM but associated with the risk of transient exacerbation of disease-related complications and should be used with caution in patients with symptoms of hyperviscosity and/or IgM levels >40 g/L. In patient with hyperviscosity and/or IgM levels >40 g/L, it is advised to hold rituximab for cycle 1, and start rituximab with cycle 2 chemotherapy. In retrospective studies, purine analogue therapy is associated with higher rates of prolonged cytopenias, infections, secondary MDS/AML, and transformation to large cell lymphoma when compared to therapy with alkylating agents.
• New data supports the use of ibrutinib in LPL (both first line and for relapsed/refractory disease).
Given the tolerability and durable responses to ibrutinib monotherapy, this is the preferred second line therapy for most patients. 163,164 • Many second-line therapy options exist. Patients who have obtained lengthy first remissions can be re-treated with chemo-immunotherapy with or without the addition of bortezomib (eg. R-Bortezomib, R-CyBorD). Purine analogues (Fludarabine) are usually reserved for multiply relapsed disease.
# Hairy Cell Leukemia
Hairy cell leukemia (HCL) and HCL variant (HCL-V) are mature lymphoid B-cell disorders, characterized by the identification of hairy cells and a specific genetic profile. Diagnosis of HCL is based on morphological evidence of hairy cells, immunophenotypic positivity for CD11C, CD103, CD123, and CD25 expression and the presence of BRAF V600E somatic mutation. BRAF-V600E has not been identified in other B-cell chronic lymphoproliferative disorders except very rarely so the mutation is now considered as the molecular hallmark of the disease. Absence of the BRAF gene mutation is reported in approximately 10% of patients with HCL and appears to constitute a subgroup with a poor prognosis 165 .
Patients with asymptomatic HCL may be managed with active observation (watch & wait strategy). Symptomatic patients should be treated with symptoms commonly derived from cytopenias or splenomegaly. Most guidelines agree that even asymptomatic patients with marked cytopenias should be treated including at least one of the following: hemoglobin < 110 mg/dL, platelet count <100 000/µL, or an absolute neutrophil count <1000/µL.
In the first-line setting, purine analogs (cladribine or pentostatin) have been demonstrated to result in long overall survival. No randomized trials have been performed in HCL with no studies to suggest superiority of either drug but cladribine is available in Canada and is the most frequently used drug worldwide for HCL. Early studies used continuous intravenous dosing over 7 days 166 but more recent studies (non-comparative) have investigated subcutaneous dosing over 5 days and demonstrate excellent responses 167 . The recommended dose of cladribine is 0.1-0.14mg/kg daily for 5-7 days. We recommend sc dosing for convenience and reduced infusion times. Infection prophylaxis is recommended as with other purine analogues (PJP and viral prophylaxis for 6-12 months) and patients with active infections should have control of infection prior to therapy initiation if possible.
For relapsed HCL, cladribine can result in a second durable remission however, synergy has been demonstrated with rituximab such that we recommend combination therapy with rituximab and cladribine for relapsed disease 168 . Studies of rituximab have used a weekly schedule x 8 weeks, concurrent with cladribine. Careful attention for and prophylaxis against infection is recommended.
A recent study investigated the addition of rituximab to cladribine in the frontline setting. HCL patients treated with concurrent cladribine and 8 weekly doses of rituximab had higher MRD-free complete remission rates than patients treated without rituximab or with delayed rituximab. (JCO 2020; 38:1527) As improved responses are predicted to lead to longer remissions and given the proven benefit of rituximab in combination with chemotherapy frontline for other indolent NHLs, we recommend consideration of cladribine + rituximab for frontline HCL treatment. Infectious risks and lack of survival data should be considered with cladribine monotherapy favoured for frailer patients and those at high risk of infection.
Given the importance of BRAF V600E in this disease, BRAF inhibitors have been investigated in relapsed patients with high response rates. Low dose vemurafenib at 240mg twice daily was reported to result in complete remissions in 40% of patients. Unfortunately, results do not appear durable after drug discontinuation and retreatment or chronic treatment may be required 169 . We recommend BRAF inhibition for patients who are refractory to cladribine (relapse < 24 months) or relapse after cladribine + rituximab 170 . Vemurafenib has also been used successfully in previously untreated patients with active infections as a bridge to cladribine therapy during treatment of the infection.
Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin, which has also proven efficacy in highly refractory HCL patients. This agent is associated with severe adverse reactions including hemolytic-uremic syndrome (7.5%) and capillary leak syndrome (5%). (leukemia 2018; 32: 1768) Moxetumumab is not currently funded in Canada but could be considered in relapsed HCL patients who have exhausted all other therapeutic options.
# Special Lymphomas
Mantle cell lymphoma 136, 137, 171-186 : Characteristics of mantle cell lymphoma include: male predominance, median age approximately 65 years, advanced stage with multiple extranodal sites (marrow, blood, and intestinal tract), relative chemoresistance, no evidence for curability following R-CHOP chemotherapy, median time to relapse after initial chemotherapy of 12-18 months and median survival following RCHOP induction of 3-5 years. Significant improvements in PFS over RCHOP alone have been demonstrated with the addition of high dose cytarabine to RCHOP-like regimen induction followed by high dose therapy and ASCT for transplant eligible patients, and for B-R induction for transplant ineligible patients, as well as for prolonged rituximab maintenance after completing initial chemotherapy.
# Recommendation regarding Watchful Waiting for MCL
Although most patients with MCL have relatively aggressive disease, and even those asymptomatic patients initially managed with watchful waiting have median times to first systemic therapy of 11-12 months, a small proprotion of patients can be manged expectantly for over 5 years 187,188 . Features suggestive of indolent MCL include leukemic non-nodal presentations, predominantly hypermutated immunoglobulin heavy chain variable regions, non complex karyotypes and absence of SOX11 expression by immunohistochemistry 189 . Occasionally, nodal MCL can also follow an indolent course 187,188 . Prognostic indices such as the MIPI have not been shown to identify indolent MCL 187 .
Poor prognostic features associated with shorter survivals and response durations, for which expectant management is not appropriate, include high burden nodal disease, Ki-67 positivity >20-30%, blastoid histology, p53 or Notch1 mutation, gene expression profiling and altered microRNA signature 190 . No prospective randomized trials, or properly designed retrospective comparative effectiveness research studies have compared immediate treatment versus watch-and-wait for MCL patients without clear indications for therapy. Poorly designed retrospective studies suggest similar survival outcomes to immediate therapy, however these studies were biased because patients were selected for watchful waiting based upon better prognostic factors (eg. younger age, better performance status) and did not routinely administer immediate aggressive therapy according to current standards to all patients in the control groups 187,188 . Prospective randomized trials have demonstrated that more aggressive therapy improves PFS and OS rates relative to less aggressive therapy for MCL. Extrapolating these data to the hypothetical question of aggressive therapy vs no immediate therapy leads to the logical conclusion that immediate therapy is likely the superior approach for most MCL patients.
Given the lack of high quality evidence from properly conducted comparative studies to prove the W&W is non-inferior to immediate therapy, W&W should only be considered for patients who present with all of the following features:
1) Non-nodal disease such as CLL-like presentation (lymphocytosis without associated cytopenias) or stage IAE marginal zone-like presentation. Patients presenting with nodal disease should generally receive immediate chemo-immunotherapy as indicated in treatment sections below unless they have significant co-morbidity that will limit life-expectancy, low tumor burden, and meet other criteria listed in this section below. 2) No disease-related symptoms 3) No adverse pathology features such as blastoid variant, Ki67>20% of cells, or complex cytogenetic changes. Other adverse features include SOX11 expression and complex cytogenetic changes, however, SOX11 immunohistochemistry is not routinely available in Alberta. 4) Patient consent to forgo immediate therapy despite knowledge of demonstrated survival benefits of aggressive vs less aggressive therapy. Patient agreement to surveillance disease monitoring.
# Treatment -Transplant Eligible Patients (Age <65yrs)
The accepted standard of care for newly diagnosed MCL patients <65 years of age without major comorbidities involves chemoimmunotherapy followed by high dose therapy with ASCT and then 3 years of rituximab maintenance administered every 2 months. Progression free and overall survival benefit has been established in a prospective randomized trial for patients treated with myeloablative radiochemotherapy followed by autologous stem cell transplant in first remission as consolidation after CHOP-like chemotherapy 183,184 . This strategy was compared to interferon alpha maintenance and demonstrated a 22mo improvement in progression free survival and 20.5mo improvement in overall survival with ASCT. These benefits of ASCT were seen in patients who had low risk MIPI, and who attained CR after RCHOP induction. The addition of high dose cytarabine with rituximab (RC) to RCHOP-like regimens is associated with improved rates of CR, PFS, and OS relative to RCHOP alone. This is supported by studies from the GELA and the European MCL Network with R-CHOP/R-DHAP induction prior to ASCT (RCHOP-21 x 3 followed by R-DHAP x3 , or alternating RCHOP/RDHAP x 6 cycles) 185 , as well as the Nordic regimen published as a phase II trial involving RCHOP-21 alternating with Ara-C [3gm 2 for patients under age 60 years or 2g/m 2 for patients over 60 years, repeated every 12 hours for a total of 4 doses], for a total of 6 cycles, then ASCT 191 . Given the superiority of BR over RCHOP in terms of efficacy and tolerability in patients with MCL, a phase 2 study of BR and RC induction for transplant-eligible patients was conducted and demonstrated a favorable safety profile as well as efficacy (with CR 96% and 93% MRD negativity after ASCT) 192 . A pooled analysis of 89 patients who received BR/RC induction chemotherapy prior to ASCT demonstrated a high transplant rate (89%), and durable remissions (5-yr PFS 80% and OS 85%) thus confirming that BR/RC is an excellent choice for induction therapy in MCL 193 .
TP53 mutation is an uncommon (11%) but significant poor prognostic finding in patients with MCL, highly associated with blastoid morphology, Ki-67 >30%, and high risk MIPI 194 . Unfortunately, intensified standard-of-care regimens for younger patients with MCL do not overcome the deleterious effects of TP53 mutations, with a median OS of 1.8 years, compared to 12.7 years for TP53unmutated (p,0.0001) 194 . Response to ibrutinib is also less favorable in patients with mutated versus wild-type TP53, with median PFS of only 4 months 195 . As such, all patients who are transplant-eligible should undergo TP53 mutational testing, with allogeneic SCT preferred over autologous SCT for patients with available donors. Allogeneic SCT should also be considered in patients with relapsed disease or with high risk MIPI scores at diagnosis and significant blood/marrow involvement, especially with blastoid morphology.
Although maintenance rituximab has been shown to improve PFS and OS (4 year OS 87% vs. 63%) in the elderly population (age > 60) after induction with R-CHOP 196 , the role of rituximab maintenance after ASCT for younger patients was uncertain until results of the phase III trial (LyMa) were reported 182 . In the LyMa trial, 299 patients <66years of age with mantle cell lymphoma received 4 courses of R-DHAP followed by R-BEAM/ASCT (patients who did not achieve at least PR after R-DHAP could receive 4 additional courses of R-CHOP to facilitate ASCT) and 240 responders were then randomly assigned to receive 3 years of rituximab maintenance therapy (375 mg/m 2 , one injection every two months) or watch and wait. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Progression-free survival at 4 years was improved at 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001)and overall survival was improved at 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). In support of the LyMa trial, a retrospective review of 72 patients previously enrolled in a phase II trial showed a progression free survival benefit in patients who received maintenance Rituximab vs those who did not (2 year PFS 90% vs. 65%) 197 .
# Treatment -Transplant Ineligible Patients (Age >60-65yrs)
For patients with mantle cell lymphoma over 60-65 years of age, B-R induction x6 cycles is our standard of care. Results from a recently published open-label, multicentre, randomized, phase 3 non-inferiority trial found a significant benefit for progression-free survival in patients with mantle cell lymphoma treated with B-R versus R-CHOP (HR 0.61, 95%CI 0.42-0.87, p=0.0072) 136 . In addition the trial confirmed the improved toxicity profile of BR over RCHOP.
Regarding rituximab maintenance, there is no published trial examining its benefit following BR induction. The European Mantle Cell Lymphoma Elderly trial confirmed a benefit of rituximab q2 months until progression (vs. interferon-α 2a or 2b) following RCHOP induction. After a median follow-up of 30 months, rituximab maintenance was associated with a significantly longer remission duration compared to interferon maintenance (51 vs. 24 months; HR=0.56, 95% CI 0.36-0.88; p=0.0117). While there was no difference in overall survival between the two groups, a subcohort of patients treated with R-CHOP appeared to show an advantage in 3-year overall survival with rituximab versus interferon maintenance (85% vs. 70%, p=0.0375). The StiL group investigated the value of R maintenance following BR and reported a lack of benefit in terms of PFS or OS. 198 However, the study was underpowered to detect a difference. Further, a multicentre retrospective study reported superior outcomes of patients given R maintenance (vs. observation) after achieving CR or PR with BR, with an OS advantage for those who achieved PR only. 199 We favour following BR x 6 cycles with R maintenance but with a maximum duration of 4 years of rituximab maintenance given the balance between efficacy, toxicity and cost. Given the lack of strong data to support this approach, R maintenance could be omitted or truncated in patients for whom the benefits of extending a remission do not outweigh the inconvenience of maintenance therapy.
The rare patient who has stage I-IIA, non-bulky mantle cell lymphoma could be considered for B-R + IFRT, or even IFRT alone if they are older than 70 years of age or have significant co-morbidities.
# Summary Initial Treatment Recommendations for Mantle Cell Lymphoma:
Immediate chemoimmunotherapy is recommended for most patients. See Recommendation regarding Watchful Waiting for MCL for details on the minority of patients for whom watchful waiting is recommended.
Treatment -Transplant Eligible Patients (Age <65yrs) 1) Induction: BRx3 cycles, followed by RCx3 cycles a. High dose cytarabine dosing i. 2 g/m 2 BID daily x2 days for age <60, CrCl >60 ml/min, and no pre-existing neurotoxicity ii. 1.5 g/m 2 BID for age>60, or CrCl 46-60 ml/min, or pre-existing neurotoxicity iii. 1 g/m 2 BID for CrCl 31-45 ml/min 2) Autologous blood stem cell collection with high dose cytarabine and G-CSF mobilization 3) Consolidation: High dose therapy and ASCT 4) Maintenance rituximab 375mg/m2 IV or 1400mg sc (preferred) every 2 months x 3 years post ASCT
For patients with TP53-mutated MCL and/or blastoid variant, consolidation with an allogeneic SCT is recommended over autologous SCT.
Treatment -Transplant Ineligible Patients (Age >60-65yrs). 1) Induction: Bendamustine-Rituximab x6 cycles 2) Rituximab maintenance q2mo until progression or for maximum 4 years
The rare patient with stage I-IIA, non-bulky mantle cell lymphoma could be considered for B-R + IFRT, or even IFRT alone if they are older than 70 years of age or have significant co-morbidities.
# Treatment Relapsed Mantle Cell Lymphoma.
There is no standard treatment for relapsed MCL but there are many options, including chemotherapy and novel agents 200 . In general, treatment choice should take into consideration the duration of response to previous treatment.
The Bruton's tyrosine kinase (BTK) inhibitors have shown the most promise as therapeutic agents for relapsed MCL and are the preferred secondline therapy. A phase 3 trial that randomized relapsed or refractory MCL patients who previously received at least one rituximab-containing regimen showed superior PFS using ibrutinib over temsirolimus (mPFS 14.6 vs. 6.2 months, p<0.0001) but no significant advantage in OS 201 . Acalabrutinib has also been investigated in relapsed/refractory MCL in a Phase 2 study with 12 month PFS and OS of 67% and 87% respectively. 202 Similarly, in a phase 1/2 trial with zanubrutinib the median PFS was 21.1 months and median DOR was 18.5 months. 203 Patients who achieved 12-24 months PFS with previous chemotherapy may do well with a different noncross-resistant chemotherapy regimen (R-bendamustine or R-BAC if previous (R) CHOP, or vice versa 200,204,205 . Other treatment options include bortezomib combined with rituximab +/chemotherapy 206,207 . Maintenance rituximab prolongs PFS and OS in relapsed MCL 208 but has not been studied in patients that received it after first-line therapy.
Lenalidomide also has efficacy in this setting, particularly in combination with rituximab +/chemotherapy 207,209 .
Brexucabtagene autoleucel (brexu-cel) is a CAR T therapy that is Health Canada approved for patients with relapsed or refractory mantle cell lymphoma who have received treatment with a BTKi.
In the ZUMA-2 phase 2 trial, the estimated PFS was 61% and OS 83% at 12 months. 210 This will be an option in the future for patients who are progressing on BTKi who are fit for intensive therapy.
Allogeneic stem cell transplant has the potential to cure MCL, as is evident from a plateau in the survival curves that is often seen post transplant. Because most patients present over the age of 60 and with multiple comorbidities, allogeneic stem cell transplant is not often offered. It is suggested in relapsed or refractory disease for those patients who are young and fit, even after autologous stem cell transplant.
Several retrospective reviews have looked at the outcomes of allogeneic stem cell transplant in the relapsed/refractory setting. Le Gouill et al. have shown a 2 year EFS of 50%, 2 year OS of 53% and 1-and 2-year transplant related mortality of 22% and 32% respectively 211 . Longer term follow up has demonstrated 6 year PFS and OS rates of 46% and 53%, respectively confirming the plateau in response that is often seen to allogeneic stem cell transplantation 212 . Response to chemotherapy has consistently been shown to predict both success of allogeneic stem cell transplant and transplant related mortality, with the best outcomes in those who have achieved a CR or CRu. Chronic GVHD has been shown in retrospective reviews to reduce the risk of relapse and DLI has been shown to salvage some patient who relapse or progress post allogeneic stem cell transplant, suggesting a graft-versus-tumour effect in MCL. Reduced intensity Allo SCT in the MCL setting has also been looked at retrospectively with 5 year PFS and OS rates of 14% and 37% respectively, and 1 year non relapse mortality of 18% 213 . Ibrutinib bridging prior to allogeneic SCT has recently been shown to improve transplant outcomes, with 2 year PFS 76% and 2-year OS 86% in one published series 214 .
The Calgary experience suggests no difference in OS or PFS when allogeneic vs. autologous stem cell transplantation are used in front-line therapy however, in the relapsed/refractory setting, allogeneic stem cell transplantation appears to offer superior OS and PFS. iii. If responding to therapy (PR/CR), fit and eligible for allogeneic SCT, particularly if high risk disease (e.g. TP53+), refer for opinion regarding allogeneic SCT iv. If not responding to therapy, OR progressing on BTKi, refer for CAR T therapy (once available) [236][237][238][239] . Patients could also be considered for initial ISRT in addition to H. pylori therapy if the tumour is associated with t (11;18). Rituximab or chemoimmunotherapy may be considered for patients ineligible for or relapsing after RT [240][241][242] .
Lymphoblastic
2) Localized (stage I-II1) H. pylori negative gastric MALT lymphoma: For the minority of patients whose gastric biopsies are negative for H. pylori, non-invasive testing (e.g. stool antigen test, urea breath test, and/or serology) should be performed to confirm H. pylori status. H. pylori-negative gastric MALT lymphoma is more likely to be associated with t(11;18) 243,244 . A trial of H. pylori eradication may still be considered as up to 38% of cases of H. pylori negative gastric MALT lymphoma can respond to antibiotics 245 , presumably due to false negative testing or infection with other helicobacter species 246 ; these patients should receive ISRT if there is no evidence of lymphoma regression after 3-6 months on repeat endoscopy. Alternatively, initial treatment with ISRT can be considered since the majority will not respond to H. pylori eradication, whereas ISRT achieves complete responses in >95% of patients with long-term event-free survival rates of 80-90% 228,[247][248][249][250] .
Repeat endoscopy should be done 3-6 months after ISRT to confirm response. The decision to treat with initial ISRT versus a trial of H. pylori eradication should be individualized and made in conjunction with patient wishes.
3) Advanced (stage II2, IIE or IV) gastric MALT lymphoma: These patients should be managed as advanced stage indolent B-cell lymphoma with active surveillance if asymptomatic or chemoimmunotherapy if symptomatic disease. These patients should also receive H. pylori eradication therapy.
Testicular lymphoma [251][252][253][254] :
In contrast to other patients with localized large B-cell lymphoma, patients with stage IAE or IIAE testicular lymphoma are cured less than 50% of the time using brief chemotherapy and irradiation. Thus, the recommended treatment for all stages of testicular lymphoma is a full course of chemotherapy (R-CHOP x 6 cycles). An additional problem often seen in these patients is relapse in the opposite testicle. This can be prevented by scrotal irradiation (25-30Gy/10-15 fractions). Finally, these patients are at high risk for CNS relapse. Although some experts recommend prophylactic intrathecal chemotherapy, especially for stage 3-4 disease, this has not been proven effective. Unfortunately, many of the CNS relapses occur within the brain parenchyma, and are not prevented by intrathecal chemotherapy. For this reason, CNS prophylaxis should involve high dose intravenous methotrexate 3.5g/m 2 every 14-28 days x 2-3 doses after completion of all 6 cycles of R-CHOP. 255 .
Whole brain radiotherapy (WBRT) has fallen out of favour for PCNSL, based in part upon high rates of severe neurotoxcity following high-dose methotrexate, and in part due to the results of the G-PCNSL-SG1 randomized controlled trial, in which 551 immunocompetent PCNSL patients (median age 63 years) were randomized to chemotherapy followed by WBRT (arms A1, B1) or chemotherapy alone (arms A2, B2) 267 . 411 patients entered the post-high dose methotrexate phase, and 318 of these patients were treated per protocol. For this per protocol population, there were no differences in median OS (32.4 vs. 37.1 months, p=0.8) or median PFS (18.3 vs. 12 months, p=0.13) between the chemotherapy plus WBRT arms (A1+B1, n=154) or chemotherapy alone arms (A2+B2, n=164), respectively 267 . A recent study suggests neurotoxicity can be reduced by decreasing WBRT dose to 23.4Gy after CR to induction HDMTX-based chemotherapy. The 2-year PFS was 78% in these patients 266 .
Although patients with refractory or relapsed PCNSL typically have dismal outcomes, autologous stem cell transplantation (ASCT) has shown promising results in this setting. Soussain et al. (2001) have reported a 3-year event-free survival (EFS) rate of 53% for patients with relapsed/refractory PCNSL undergoing ASCT following high dose thiotepa, busulfan and cyclophosphamide (TBC) conditioning 265 .
Small studies have demonstrated durable remissions with ASCT for PCNSL, however, the optimal conditioning regimen remains undefined [268][269][270][271] . With the knowledge of our initial encouraging experience with TBC/ASCT 268 , and the lack of any widely accepted standard treatment for PCNSL, TBC/ASCT consolidation was considered an acceptable option to treat consenting PCNSL patients at our centre. Review of our data proved the efficacy of this therapy (PFS 52% at 5 years post TBC/ASCT) but with significant toxicity (5 treatment-related deaths, all occurring in patients over 60 yrs). To reduce the TRM, we modified our protocol to omit cyclophosphamide starting in 2011. We recently completed a retrospective review of the outcomes of this protocol for patients treated between Nov 2011 and Dec 2017. 272 .Based on these data, we recommend TBu/ASCT consolidation therapy for all eligible PCNSL patients. 273,274 The role of Rituximab in treating PCNSL was evaluated in the International Extranodal Lymphoma Study Group (IELSG) 32 study 275 , which randomized patients with histologically-proven primary CNS lymphoma to receive a maximum of four 3-week cycles of methotrexate at 3.5 g/m2 on day 1 and cytarabine at 2 g/m2 twice daily on days 2 and 3, either alone (arm A; n = 75), in combination with 375 mg/m2 of rituximab on day -5 and 0 (arm B; n = 69), or combined with rituximab at the same dose plus 30 mg/m2 of thiotepa on day 4 (MATRIX arm; n = 75). The study was conducted at 52 locations across five countries. The median patient age was 58 years (range, 18-70) and all patients were HIVnegative. Overall, patients had an ECOG PS ≤3, with patients aged 66 to 70 years having an ECOG PS ≤2. Patient characteristics were well balanced among the study arms. Autologous stem cells were successfully collected after the second treatment course in 152 patients (94%). In the MATRIX arm C, the overall response rate was 87% (95% CI, 80-94) compared with 74% (95% CI, 64-84), and 53% (95% CI, 42-64) in arms B and A, respectively (P = .00001 for A vs C) 275 . As reported by Dr. Andrés Ferreri at the ASH 2016 conference (abstr 511), at a median follow-up of 40 months, the PFS rate was approximately 55% in the MATRIX arm C, 39% in arm B, and 29% in arm A, with OS rates of 63%, 46%, and 31%, respectively. Of the 219 enrolled patients, 118 (54%) patients without progressive disease (n=52) or excessive toxicity/poor mobilization/refusal (n=49) underwent a second randomization comparing consolidation with whole-brain irradiation (n=59) or ASCT (n=59). The CR rate similarly improved from 54% after induction up to 94% after either consolidation therapy, suggesting a very important role for consolidation therapy. There were no statistically significant differences in PFS after the two consolidation treatments (3yr PFS approximately 60-70%), however, neurotoxicity rates were higher in the WBRT arm.
The potential benefit of rituximab with induction chemotherapy was not confirmed in different phase III trial by HOVON 105/ALLG NHL 24 276 , in which 119 patients in Netherlands, Australia and New Zealand were randomized to 2 cycles of induction (MTX, BCNU, teniposide, prednisone) with or without rituximab, then followed by consolidation with cytarabine and WBRT 30Gy (+10Gy boost) if <60yrs of age. This study reported non-significantly different 1 year EFS rates of 49% and 52% for rituximab vs no rituximab (ORR 87% and CR 67%).
The Alberta Lymphoma Group established a provincial PCNSL Treatment Protocol in November 2011. The rationale behind the 2011 protocol included:
1) Induction chemotherapy: a. First 2 cycles: HDMTX 3.5g/m2 d1,15 with procarbazine 100mg/m2 po d1-7. This treatment had been shown to induce response and is tolerable for patients who may be debilitated at the time of initial diagnosis of PCNSL. Cytarabine was not added to first cycle HDMTX because patients may not tolerate intensive therapy well until performance status improves. b. Stem Cell Mobilization and Apheresis: to be done with first dose of Cytarabine because stem cells may not mobilize well after multiple cycles Cytarabine/G-CSF. Rituximab will be used in addition to Cytarabine due to reports that lymphoma cells can circulate in blood and marrow in patients with PCNSL 277 , and Rituximab may decrease risk of collecting contaminated autograft as has been shown for other B-cell lymphomas. c. Final 2 Cycles will combine Cytarabine with HDMTX as done in a prior IELSG study to improve response rates and decrease frequency of primary progressive disease 255 .
d. Rituximab was added in 2016 for a total of 6 doses during induction to improve response 2) High Dose Chemotherapy (patients <70 yo with no significant co-morbidities, KPS>60% after induction therapy, and PCNSL not secondary to immune suppression): a. Thiotepa 300mg/m2 x2d and Busulfan 3.2mg/kg x3d without cyclophosphamide. Because cyclophosphamide does not penetrate the blood brain barrier particularly well, its omission may decrease treatment-related mortality without decreasing cure rates compared to the previous TBC regimen. 3) Ifosfamide consolidation (transplant refusal or ineligible patients):
a. Ifosfamide crosses BBB approximately 30%, and gives some exposure of PCNSL to alkylating agent therapy 278,279 .
# Recommendations: PCNSL Transplant-Eligible (Usually <70 years old)
The above evidence suggests that transplant-eligible patients are best treated with HDMTX/AraCbased induction followed by TBu/ASCT consolidation. There also is a potentially important role for the addition of rituximab to induction chemotherapy when ASCT consolidation is used. However, the optimal number of induction chemotherapy cycles is unknown, and perhaps as soon as a patient achieves a response and is physically well, they should proceed directly to ASCT before the disease starts to progress, or cumulative toxicity from further induction therapy prevents ASCT consolidation.
As such, the 2018 PCNSL guidelines have been modified to decrease the length of induction therapy prior to ASCT. We have not incorporated MATRIX induction, because the use of MATRIX may decrease the ability of patients to proceed to ASCT due to toxicity, increased likelihood of patient refusal due to treatment-fatigue, or due to poor stem cell mobilization. We believe the use of ASCT is more important than the use of MATRIX. Our real world outcomes using non-MATRIX induction and TBu/ASCT are numerically superior to those reported in the MATRIX study. We also increased the age limit for the transplant eligible protocol to 75 years, however, patients over age 70 years must be extremely healthy with no comorbidities and must also be highly motivated to receive TBu/ASCT. For a detailed description of recommended PCNSL treatment regimens, please refer to Appendix A, subheading VII, sections A and B.
For palliative therapy, doses of cranial radiotherapy should be 30Gy in 10-20 fractions.
# Eye lymphoma
Orbital or peri-orbital lymphoma 251,280 : Peri-orbital lymphoma of the bony orbit or the soft tissues in and around the orbit but outside of the globe and optic nerve should be managed as indicated in the earlier sections on aggressive lymphomas, marginal zone lymphomas or follicular lymphoma, as appropriate for the type and stage of the lymphoma. Approximately 40% of such patients have advanced disease discovered when carefully staged. In general, 25-30Gy/20 fractions radiotherapy to whole orbit/periorbital tissue is recommended for indolent peri-orbital lymphomas.
Conjunctival lymphoma 251,280 : Lymphoma involving the conjunctiva but not the structures within the globe or the optic nerve is usually of low grade and should be treated with 25-30Gy/20 fractions of radiotherapy. Doses, fields, and shielding specifically modified for treatment of the eye are necessary to minimize long-term complications such as xerophthalmia or cataract formation.
Intra-ocular and optic nerve lymphoma 251,281 :
• Lymphoma involving the vitreous, retina or other structures within the optic nerve or globe is usually of large cell type and is equivalent to PCNSL. Bilateral involvement is common. Evaluation and management should be the same as for PCNSL. Acceptable treatment involves induction chemotherapy with high dose methotrexate and high dose cytarabine as described for PCNSL in Appendix A.
• Lymphoma involving the uveal structures (choroid) is a rare presentation of lymphoma, and is usually of indolent type. This disease is best managed with treatment appropriate for stage and local extent of disease.
# Aggressive T-Cell Lymphomas:
NK/T-cell lymphoma, nasal type [282][283][284][285][286][287][288][289][290] Natural killer (NK)/T-cell lymphoma, nasal type is a rare and aggressive extranodal neoplasm that almost exclusively affects Asian and South American adults in the fifth decade of life, with a male:female ratio of approximately 3:1. It typically arises in the nasal cavity or surrounding structures, such as the sinuses, palate, nasopharynx, tonsils, hypopharynx, and larynx. While the pathogenesis of NK/T-cell lymphoma, nasal type is not well understood, the Epstein-Barr virus (EBV) is implicated in almost all cases. Approximately 25% of cases show a p53 mutation; in addition, p21 overexpression is also frequent in nasal NK/T-cell lymphoma, and seems to be independent of p53 gene status 285 .
Hematopathological evaluation of a biopsy specimen from the site of involvement is the basis for diagnosis of nasal NK/T-cell lymphoma. The recommended immunohistochemistry panel includes 283,291 :
• B-cell: CD20
• T-lineage antigens: CD2, CD7, CD8, CD4, CD5, CD3
• NK lineage markers: CD56
• Cytotoxic granules (granzyme B and/or TIA-1)
• Ki-67
•
In situ hybridization for EBV-encoded RNA (EBER)
For patients with early-stage nasal NK/T-cell lymphoma (ENKTCL), early or upfront radiotherapy (intensive regimens such as a total dose ≥ 50 Gy) plays an essential role in therapy, and has been associated with higher overall survival and complete response rates compared to chemotherapy alone 286 . However, radiotherapy alone is also associated with high relapse rates. Combined modality therapy is recommended with sequential and concurrent chemo-radiotherapy regimens having relatively equivalent outcomes. No standard of care therapy exists for ENKTCL with our guidelines previously recommending VIPD consolidation after concurrent single agent cisplatin and radiotherapy. Local outcomes were poor with this approach and most novel regimens incorporate Lasparaginase into treatment due to high single agent activity. 292 Given the recent discontinuation of Lasparaginase, we favour the combination of peg-asparaginase with gemcitabine and oxaliplatin (P-GEMOX) for patients with limited stage disease. With this approach, treatment is initiated with 2 cycles of P-GEMOX, followed by radiotherapy (48-56 Gy) followed by 2 further cycles of P-GEMOX restarted 1 week after completion of radiotherapy. With this approach, in 33 patients, the ORR was 94% and 2 year PFS and OS were 77% and 83% respectively. Notably, Grade 3-4 toxicities were rare.
For patients with stage III-IV disease, complete remission rates are less than 15%, and the median overall survival is approximately 4 months 290 . The recommended options for therapy include either enrollment in a clinical trial or treatment with an L-asparaginase-based combination chemotherapy regimen. The most well-studied regimen is the SMILE regimen with several small series of patients reported [293][294][295] . While the SMILE regimen was first reported to have excellent response rates (overall, and complete in 79% and 45%, respectively) in relapsed/refractory patients, an updated study of the use of the SMILE regimen as frontline therapy for advanced stage patients reported a short median OS (12.2 months; 1-year OS was 45%) with a high rate of TRM (5 of 87 patients died of sepsis) 293 .
While the GOLD regimen has less reported patients, the toxicity is significantly less (Grade 3-4 neutropenia of 16% compared to SMILE of 92% 294 with serious infections in 4% and 31-45% 293,294 of patients treated, respectively). For this reason, patients of advanced age or with comorbidities or a history of infections should be considered for therapy with GOLD for 2-4 cycles followed by SCT if possible while younger, fit patients can be treated with SMILE x 2 cycles with a goal of proceeding to SCT as consolidation. The role of allogeneic or autologous SCT is not yet well defined because of limited data; but it is suggested when possible for advanced stage or relapsed/refractory patients.
Peripheral T-cell lymphomas (PTCL) [296][297][298][299][300][301][302][303][304] .
With the exception of ALK-positive anaplastic large cell lymphoma, CHOP chemotherapy cures less than 30% of patients with PTCL. Options that may be associated with higher cure rates include CHOP x 4-6 cycles followed by HDCT/ASCT in responding patients or brentuximab-vedotin + CHP or intensification of CHOP with etoposide (CHOEP). 305 The ECHELON-2 study was a Phase 3 of CD30+ (≥ 10% by immunohistochemistry) PTCL with IPI ≥ 2 comparing CHOP with BV-CHP. The median PFS was improved with BV-CHP at 48.2 months compared to 20.8 months with CHOP. Overall survival was also numerically superior in the BV-CHP arm. Important toxicities were comparable between the arms. Unfortunately, the study was not powered to detect differences between the different subtypes of PTCL and the study was biased to include a majority of patients with ALCL (70%). Patients with ALK+ ALCL were 22% of the population and had the largest noted benefit from the addition of BV-CHP. The subgroup of AITL patients appeared to do slightly worse with BV-CHP compared to CHOP but patient numbers were small. Given the lack of single agent efficacy in non-anaplastic subtypes, it remains unclear if there is any benefit to BV-CHF in non-anaplastic subtypes of PTCL such that it can not be recommended that BV be routinely implemented for those patients at this time. 297 .
Retrospective and prospective phase II trials support the use of SCT as part of upfront therapy for PTCL. Sieniawski and colleagues reported 5-year PFS rates of 60% for 26 patients with enteropathy associated T-cell lymphoma treated with IVE-methotrexate induction therapy followed by autologous SCT, compared to only 22% for 54 patients treated with CHOP-like therapy alone 297 . Two prospective trials have also been reported. In the first, Reimer and colleagues reported results of CHOP x 4-6 cycles followed by dexabeam or ESHAP followed by CyTBI/ASCT for 83 patients (including 32 with PTCL-not otherwise specified, and 27 with angioimmunoblastic T-cell lymphoma) 299 . Fifty-five of the 83 patients received transplantation. In an intent-to-treat analysis, with a median follow-up time of 33 months, the estimated 3-year OS, DFS, and PFS rate were 48%, 53%, and 36%, respectively 307 . In the second prospective trial, Rodriguez and colleagues from the Spanish Lymphoma and Autologous Transplantation Cooperative Group reported the results of 74 patients transplanted in the first complete response (65% had 2-3 aaIPI risk factors) 300 . With a median follow-up of 67 months from diagnosis, the 5-year OS and PFS rates were 68% and 63%, respectively.
For PTCL patients who relapse following CHOP-type induction and respond to salvage therapy, ASCT should be recommended, as several studies report similar ASCT outcomes to those seen with relapsed DLBCL. Brentuximab vedotin may be considered for those patients with CD30+ anaplastic large cell lymphoma who have had failure of initial chemotherapy 308 .
For patients who are ineligible for ASCT or who have failed ASCT, PFS and OS is extremely short and end of life care and planning should be implemented. Palliative therapy options include chemotherapy (with limited expectation of response or benefit), romidepsin and/or pralatrexate.
Alberta has funded only 1 of romidepsin or pralatrexate despite these agents have non-overlapping mechanisms of action for reasons of cost (due to unavailability of published data for responses to either drug in patients who failed the alternate). No quality evidence exists to direct the decision between romidepsin and pralatrexate however, durables responses to romidepsin have been most commonly seen in patients with AITL, favouring romidepsin in that group.
An open-label, single arm, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma (N=130) with a median two (range: 1-8) prior systemic therapies found an objective response rate of 25%, including 15% with CR/CRu. 309 An evaluation of longer term follow-up found median duration of response was 28 months (range: 1 to >48 months). 310 Patients who achieved CR/CRu had a median PFS of 29 months. The most common grade ≥3 AEs were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). Another phase II study of romidepsin in cutaneous and peripheral T-cell lymphoma (N=45; median 3 prior therapies) found complete response in n=8 and partial response in n=9 for an overall response rate of 38% (95%CI: 24-53%).
Median duration of overall response was 8.9 months (range: 2-74). Of note, 6 of the 18 responses were among patients with prior stem-cell transplant. 311 The prospective PROPEL trial evaluated the effectiveness of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma. N=111 patients received pralatrexate after a median 3 prior therapies (range: 1-12). The overall response rate was 29% with 11% achieving complete response.
The median duration of response was 10.1 months. Median PFS and OS were 3.5 months and 14.5 months, respectively. The most common grade ≥3 AEs were thrombocytopenia (32%), mucositis (22%), and anemia (18%). 312 Summary of treatment recommendations for PTCL. • recommendation for stage I-II NK/T cell lymphoma: P-GEMOX x 2 cycles (then IFRT (48-56 Gy) then 1 week later, 2 further cycles P-GEMOX (total 4 cycles) 313 AIDS-related lymphomas: [314][315][316][317][318][319] In general, the treatment of AIDS-related lymphoma should be the same as for non-AIDS related lymphoma if the AIDS does not otherwise compromise the patient's performance status and he/she is free of coincident serious opportunistic infection. HAART should be given with CHOP chemotherapy.
Treatment should be planned in conjunction with the patient's HIV physician and an antiviral regimen without overlapping toxicity should be chosen. R-CHOP results in the highest rates of disease-free survival, but may also increase the risk of infectious complications and treatment-related mortality in patients with CD4 counts below 50.
# Post-transplant lymphoproliferative disease (PTLD) after Solid Organ Transplant in Adults:
1.
Epidemiology. Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous disease with clinical and pathologic manifestations ranging from benign lymphoid hyperplasia (ie. early lesions) to aggressive lymphoma (ie. monomorphic PTLD) 320,321 . PTLD and its treatment cause a high rate of mortality and graft loss in patients with solid organ transplants (SOT) 322 . The incidence of PTLD is highest in multivisceral (>10%) and lowest in renal transplants (1-5%), attributed to intensity of immunosuppression and amount of lymphoid tissue in the allograft [323][324][325] . Epstein-Barr virus (EBV) infection drives the pathogenesis in PTLDs occurring early post-transplant; conversely, PTLDs occurring after prolonged immunosuppression tend to be monomorphic with no detectable EBV genome, calling an infectious etiology into question 326 . An epidemiologic shift in PTLD has occurred in the most recent decade: the median latency time from transplant to PTLD has increased from 1 to 3 years 327,328 and the proportion of EBV-positive vs. -negative PTLD has decreased 329 , attributed to EBV viral load monitoring in EBV seronegative (ie. high risk) patients.
# 2.
Diagnosis and staging. Diagnostic tissue must be reviewed by expert pathologists and subtyped according to the WHO 330 . Several small case series have confirmed that PET-CT is an effective imaging modality for staging in PTLD [331][332][333][334][335][336] . However, some subtypes of PTLD, such as early lesions and T-cell lymphomas, may not be FDG-avid, necessitating CT as an alternate staging modality.
# 3.
Management. Recommendations for the management of PTLD in SOT are based on few phase II clinical trials, retrospective case series, and expert opinion [337][338][339] . The mainstays of therapy for CD20-positive PTLD in SOT include reduction of immune suppression (RIS), rituximab, and chemotherapy; adoptive immunotherapy is promising but considered experimental and is unavailable in Alberta. All patients should undergo RIS to the lowest tolerated levels under the direction of the transplant physician as soon as the diagnosis of PTLD is confirmed 337 . A recommended strategy is to discontinue antiproliferative agents and reduce the calcineurin inhibitor by 25-50% while maintaining the steroid 337 . Published response rates vary widely (0-73%) and responses are seen within 2 to 4 weeks [340][341][342] .
# 3a.
Early lesions, polymorphic and CD20-positive monomorphic PTLD. RIS may serve as definitive treatment of early lesions, but if response is incomplete further treatment with surgery or radiation is favored. In contrast, polymorphic and monomorphic PTLDs require definitive treatment along with RIS, discussed in further detail below [337][338][339] (Figure 3).
# Surgery and radiation.
Patients with localized PTLD, such as isolated skin, GI or renal allograft lesions, can achieve prolonged remissions with surgery or localized radiation 340,343 . Some experts consider surgical resection of isolated GI lesions prior to initiating systemic therapy to reduce early mortality from bowel perforation 338 . Radiation alone is generally not curative, with exception of plasmacytoma-like PTLD 344 , and should not be used as primary treatment 337 . Radiation may be used for palliating obstructive or compressive symptoms where systemic therapy fails or is not possible 337 .
Chemotherapy. SOT patients do not tolerate chemotherapy well, often developing severe infection or prolonged cytopenias. Estimates of efficacy of chemotherapy in treatment of PTLD in SOT are limited by the almost entirely retrospective nature of publications. Results of retrospective studies of anthracycline-based chemotherapy, mainly CHOP, show ORRs of 65-73% and 5-year OS of 25-78%; however, treatment-related mortality (TRM) is up to 31% [345][346][347][348][349] .
Rituximab. Several retrospective reviews and phase II clinical trials have confirmed the efficacy of rituximab monotherapy in CD20-positive PTLD post-SOT in patients that fail to respond to RIS. Phase II trials show overall response rates (ORR) of 44% to 71% and CR rates of 26% to 53% after 4 weekly doses with no reported TRM [350][351][352][353] . However, 57% of patients treated with rituximab monotherapy in 2 prospective trials had progressive disease within 12 months; risk factors for survival and need for further treatment included age > 60, ECOG ≥ 2, elevated LDH, and lack of CR after rituximab 354 . Therefore rituximab causes minimal toxicity but remissions achieved are durable in only a minority of patients.
Sequential therapy. Efficacy of a sequential treatment regimen (4 weekly doses of rituximab followed by 4 cycles of CHOP) was established in a phase II international multicentre trial in adult CD20positive PTLD in SOT (n=70) in an attempt to improve upon the success of rituximab monotherapy and diminish the toxicity of chemotherapy 355 . The ORR was 60% after initial rituximab, increasing to 90% after sequential chemotherapy. EBV-positive and -negative PTLDs responded equally. OS was 61% at 3 years and time to progression was 69% at 3 years. There were no TRM events related to rituximab and 11% ascribed to CHOP. In a subsequent analysis, the authors concluded that patients who achieved CR and those in PR with a low-risk IPI score after rituximab monotherapy had a low risk of disease progression 356 .
A subsequent phase II trial utilized risk-stratified sequential therapy, in which patients in CR (by CT) after 4 doses of rituximab received 4 further 3-weekly doses of rituximab, and those not in CR after initial rituximab proceeded to RCHOP (4 cycles supported with GCSF). With 152 patients treated, endpoints were superior to sequential therapy (3-year OS 70%, 3-year TTP 73%, TRM 7%), and response to initial rituximab was highly predictive of OS, TTP and PFS (p<0.001) 357,358 .
In summary, rituximab monotherapy is effective first-line treatment in most CD20-positive PTLDs with minimal toxicity. Risk-stratified sequential therapy offers the highest survival rates published to date, and allows patients in CR after rituximab monotherapy to avoid chemotherapy. Close follow-up for disease progression is recommended for patients that received rituximab alone. For PTLD that behaves aggressively (ie. IPI 3-5) or progresses during initial treatment with rituximab, proceed directly to RCHOP before completing 4 doses of rituximab (Figure 3). 3b. Primary CNS PTLD. In the largest reported retrospective series of primary CNS PTLD (n=84), patients treated with rituximab and/or cytarabine (most often given after MTX) survived longer, but significant variation in regimens precluded firm conclusions 359 . Patients with acceptable renal function and performance status should be offered high-dose methotrexate and rituximab, and others may benefit from palliative radiation 338, 359 . 3c. Burkitt Lymphoma PTLD. Several case series cite acceptable outcomes in this rare subtype of PTLD with chemotherapy regimens ranging in intensity [360][361][362] . However, no definite recommendations can be made and treatment should be considered individually.
3d. CD20-negative monomorphic PTLDs. Rare subtypes of PTLD that resemble non-transplant lymphomas, such as Hodgkin Lymphoma-like PTLD, T cell monomorphic PTLD, plasmablastic PTLD and plasma cell dyscrasias, require specific chemotherapeutic treatment similar to their nontransplant counterparts (reviewed by 337,338 ).
# Prognosis.
The risk of death from NHL is significantly higher in SOT compared to non-transplant patients 363 , and PTLD increases the graft failure rate 5-fold 364 . Retrospective series of PTLD post-SOT report OS of 30-68% at 5 years, with excess mortality in the first year post-diagnosis 323,328,[365][366][367] . Adverse prognostic factors from retrospective studies include monomorphic subtype, monomorphic T-cell, bone marrow or CNS involvement, advanced stage, poor performance status, advanced age, elevated LDH, and hypoalbuminemia 327,328,351,[367][368][369] . Risk factors for worsened OS in the PTLD-1 prospective trial include IPI 3-5, thoracic organ transplant and lack of CR after rituximab monotherapy 356 . A prognostic score developed from 500 PTLD cases in renal transplant patients is described in Table 8; the score was calculated with the exclusion of patients with monomorphic T-cell and CNS PTLD, both of which carried an adverse prognosis, but the score maintains its ability to discriminate risk groups in the whole population 364 .
# T3
One or more tumors (=>1-cm diameter)
# T4
Confluence of erythema covering =>80% body surface area N (lymph nodes) Abnormal peripheral lymph node indicates any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed or 1.5 cm or larger in diameter. Node groups examined on physical examination include cervical, supraclavicular, epitrochlear, axillary, and inguinal. Central nodes, which are not generally amenable to pathologic assessment, are not currently considered in the nodal classification unless used to establish N3 histopathologically.
# N0
No For viscera, spleen and liver may be diagnosed by imaging criteria
# M0
No visceral organ involvement
# M1
Visceral involvement (must have pathology confirmation and organ involved should be specified)
0 0 0 0 0,1 0,198
89
IIA IIB 1-2 3 1,2 0-2 0 0 0,1 0,189
56
IIIA IIIB 4 4 0-2 0-2 0 0 0 1 54 48 IVA1 IVA2 IVB 1-4 1-4 1-4 0-2 3 0-3 0 0 1 2 0-2 0-2 41 23 18
response modifiers (IFN-, retinoids) in cases of resistant or progressive skin disease. Local radiotherapy plays a key role in palliation and treating sanctuary sites. Total skin electron beam therapy is highly effective in T2 or T3 disease however its widespread use is limited by the availabilty of this technique. Predictably, chemotherapy leads to short remission durations and therefore should be reserved after other therapies have been tried. Its use should be limited to tumour (T3) or more advanced stages. It may be considered frontline in cases with histologic large-cell transformation and high risk features (see discussion below). Monotherapy (low-dose methotrexate, gemcitabine) is generally preferred over combination chemotherapy (e.g. CHOP) unless the patient has extensive burden of disease (nodal and extra-cutaneous and is fit to tolerate. Targeted therapies have demonstrated activity in MF/SS, and are currently reserved for the relapsed/refractory setting or in clinical trials. The optimal conditions for allogenic bone marrow transplant have not been elucidated, but may play a role in highly selected cases (see discussion below). Extracorporeal photopheresis is a unique treatment modality indicated for the treatment of erythrodermic MF/SS. Consensus recommendations for the treatment of MF/SS have recently been updated and are outlined elsewhere 30 . The following table intends to summarize a managment approach. • T1b: a solitary lesion with diameter >5cm T2
Regional skin involvement (multiple lesions limited to 1 body region or 2 contiguous body regions)
• T2a: skin lesions present in a <15-cm diameter circular area • T2b: skin lesions present in a >15-cm and <30-cm diameter circular area • T2c: skin lesions present in a >30-cm diameter circular area T3 Generalized skin involvement • T3a: multiple lesions involving 2 noncontiguous body regions • T3b: multiple lesions involving 3 or more body regions N N0 No clinical or pathologic lymph node involvement N1
Involvement of 1 peripheral lymph node region that drains an area of current or prior skin involvement N2
Involvement of 2 or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement N3
Involvement of central lymph nodes M M0 No evidence of organ disease M1
Extracutaneous organ disease
# Staging of other types of non-MF cutaneous lymphomas
# Special topics in CTCL
The role of transplantation in cutaneous lymphoma 8, 9, 14, 40-49 :
Existing studies of allogeneic stem cell transplantation in mycosis fungoides or sezary syndrome are limited to small, retrospective reports or case series. Autologous stem cell transplantation has not been associated with durable remissions and therefore has been largely abandoned for MF/SS. The following recommendations are based on best available outcome data and established consensus guidelines:
• Patients with MF/SS should be risk-stratified using the CTCL International Consortium prognosis score. Patients with high-risk disease (3 or 4 of age>60, elevated LDH, stage IV or LCT) should be considered for allogeneic transplantation as part of second line of therapy.
• Patients with advanced stage 3 or stage 4 MF/SS who progress after more than two lines of systemic therapy should be considered for allogenic transplantation. • Selected patients with stage 2 MF/SS or with large cell transformation may be considered for allogeneic BMT.. • Patients must meet other eligibility criteria for transplant prior to being considered. Issues such as chemosensitivity (CR or PR to last line of therapy), adequate performance status (ECOG 0-2) and preserved organ function apply. • TSEB before transplant may be considered prior to transplantation for improved skin control. • Transplantation in other rare and aggressive CTCL such as CD8+ epidermotropic aggressive T cell lymphoma or primary cutaneous gamma-delta T cell lymphoma is at this time a largely experimental approach • Relapses still occur after allogeneic transplants and may be treated adjustment of immunosuppression, DLI infusion, or further skin-directed treatments. Distinguishing CTCL from transplant associated GVHD requires multidisciplinary expertise.
# Large Cell Transformation in Mycosis Fungoides:
The pathologic definition of large cell transformation in mycosis fungoides (LCT-MF) is the presence of large cells (>= 4 times the size of a small lymphocyte) in 25% of more of the dermal infiltrate or forming microscopic nodules. The cells are often CD30+ by IHC however CD30-variants are also described. It is difficult to discriminate from other subtypes of cutaneous lymphoma, including cutaneous anaplastic large cell lymphoma (cALCL) or lymphomatoid papulosis (LyP), which may also coexist with mycosis fungoides.
The prognosis of LyP and cALCL is considerably more favourable than LCT-MF. Historical estimates for long-term survival with LCT-MF is less than 20%, and most series report a median survival of 2-36 months. However, a subset of patients with limited LCT-MF may follow a more indolent course. One large EORTC cohort analysis reported a median survival of 8.3 years for patients with LCT, and the authors concluded LCT is significant for disease progression but not survival outcome 26 .
Currently, there is a lack of prospective research to guide a standardized approach for management of LCT-MF. Most patients are treated with combination chemotherapy however it remains it is unclear which patients benefit from this approach.
Several clinical and pathological characteristics in LCT-MF have been associated with poor prognosis 28,31 , including advanced age (> 60 years), elevated LDH at transformation, advanced stage (III/IV), extra-cutaneous transformation, the presence of follicular mucinosis, folliculotropism, and CD30-negativity. Additional pathologic variables have been described but may not be routinely analyzable so have been omitted from these recommendations.
We recommend to consider intensive chemotherapeutic strategies (monotherapy or combination in suitable fit candidates) in patients with any of the following clinical or pathologic variables associated with high risk LCT-MF. In the absence of these, we recommend treatment as per MF guidelines (see Table I).
# Clinical variables for high risk LCT-MF:
• advanced age (> 60 years)
• elevated LDH at transformation • generalized tumours (versus solitary or regional)
# • advanced stage (III/IV) • extra-cutaneous transformation Adverse Pathologic variables in LCT
• absent papillary dermal involvement (assessment may be limited by provided tissues)
• folliculotropism • follicular mucinosis • absence of fibrosis • CD30 expression in less than 50% of neoplastic cells Brentuximab vedotin has activity in LCT-MF. A phase 2 study of brentuximab in a heavily pre-treated CD30+ MF/SS population, the majority of whom had LCT (30/32, 90%) showed a significant response rate of 70%. 35 A subsequent prospective, randomized controlled trial of brentuximab vedotin versus physician's choice (MTX or bexarotene) in CD30+ CTCL demonstrated a significant improvement in objective global response lasting atleast 4 months with brentuximab (56.3% versus 12.5%) 39 . The study included both previously treatment CD30+ MF and CD30+ ALCL. Although the histologic characteristics of the CD30+ MF patients were unreported, a proportion may have had transformed MF, as this was not an exclusion criteria. Brentuximab vedotin is indicated for previously treated CD30+ MF, and could be tried for high risk LCT-MF patients as defined above, who are either unsuitable for chemotherapy or refractory/relapsed folllowing chemotherapy.
# V. Hodgkin Lymphoma
# Pathologic Classification
The histological sub-classification of Hodgkin lymphoma is based on the light microscopic H&E interpretation. If problems with differential diagnosis arise, staining for CD15, CD30, T-cell and B-cell panels and EMA may be helpful. For lymphocyte predominant Hodgkin lymphoma, CD20, CD45, +/-CD57 are recommended.
# Staging
Mandatory staging procedures include 2-8 :
• Pathology review whenever possible (essential for core needle biopsies)
• Complete history and physical examination (B symptoms, Etoh intolerance, pruritis, fatigue, ECOG performance score, examination of nodes, Waldeyer's ring, spleen, liver, skin)
• CBC & differential, creatinine, electrolytes, Alk P, ALT, LDH, bilirubin, total protein, albumin, calcium • ESR (required for limited stage patients)
• If a PET/CT is not done, then perform a bone marrow aspiration and biopsy (2cm core preferable) for patients with stage IIB-IV or cytopenias (note: flow cytometry on the marrow aspirate does not add useful information and should not be done)
• Chest x-ray (PA and lateral)
• CT scan of the neck, chest, abdomen, and pelvis • A PET scan with body CT is preferred as initial staging and after 2 cycles of ABVD [9][10][11][12][13][14] .
• Pregnancy test, if at risk (consider fertility and/or psychosocial counseling )
• Semen cryopreservation if chemotherapy or pelvic radiotherapy is contemplated • HIV: if HIV risk factors or unusual disease presentations Primary Treatment of Classical Hodgkin Lymphoma [15][16][17][18][19] General principles: For treatment planning, supradiaphragmatic clinical stage (CS) I or II without bulk (mass >10cm or >1/3 maximal transthoracic diameter (MTD) on CXR) or significant B symptoms is considered limited stage. Initial treatment options for classical Hodgkin Lymphoma involve the chemotherapy regimens ABVD or escalated BEACOPP as well as involved field radiotherapy (IFRT).
Multiple phase III studies conducted by the German Hodgkin Study Group (GHSG) and other cooperative study groups have demonstrated that optimal cure rates are achieved with: 1) ABVD x2 cycles followed by 20Gy IFRT for favorable risk limited stage disease (5yr PFS >90%); 2) ABVD x4 cycles followed by 30Gy IFRT for unfavorable risk limited stage (> 3 nodal sites, ESR > 50 or >30 with B symptoms, or extranodal disease) (5yr PFS >85%); 3) escalated BEACOPP x 4-6 cycles for young healthy patients with advanced stage disease; and 4) ABVD x6 cycles for patients >60 years or with co-morbidities. Advanced stage patients also receive IFRT following chemotherapy to localized PET+ residual disease >2.5cm, and is considered for sites of prior bulk after ABVD.
# Data supporting escalated BEACOPP for advanced stage disease:
The GHSG HD9 trial conducted in the 1990s demonstrated that 8 cycles of an escalated-dose BEACOPP regimen were superior to 8 cycles of a COPP/ABVD regimen or 8 cycles of a baseline-dose BEACOPP regimen in terms of freedom from treatment failure and overall survival rates in patients with advanced-stage Hodgkin lymphoma 20 . Each regimen was followed by consolidative radiation therapy to sites of initial bulky disease greater than 5 cm. At the 10-year analysis, freedom from treatment failure was 64% for the COPP/ABVD group, 70% for the baseline BEACOPP group, and 82% for the escalated BEACOPP group (p<0.001); overall survival rates were 75%, 80%, and 86%, respectively (p<0.001) 21 . There were higher rates of hematologic toxicities, grades 25 .
In an attempt to reduce severe toxicities associated with escBEACOPP, an open-label, randomized, parallel-group, phase 3 trial investigated the utility of PET after two cycles of standard escBEACOPP to allow for adaptation of treatment intensity 26 . The trial included 18-60 year olds with newly diagnosed advanced-stage Hodgkin's lymphoma (N=1945), and assigned patients (1:1) to two parallel treatment groups on the basis of their PET results after cycle 2 of escBEACOPP (PET-2).
Patients with positive PET-2 were randomised to receive six additional cycles of either standard escBEACOPP (8 × escBEACOPP in total) or escBEACOPP with rituximab (8 × R-eBEACOPP) (rituximab abandoned mid-trial due to lack of efficacy). Patients with negative PET-2 were randomised between standard treatment with 4-6 additional cycles of escBEACOPP (6-8 × escBEACOPP… the trial switched from total 8 to total 6 escBEACOPP in the standard arm after the results of HD15) or experimental treatment with two additional cycles only (4 × escBEACOPP).
Patients with negative PET-2 randomly assigned to either 6-8 × escBEACOPP (n=504) or 4 × escBEACOPP (n=501) had 5-year progression-free survival of 90•8% (95% CI 87•9-93•7) and 92•2% (89•4-95•0), respectively (difference 1•4%, 95% CI -2•7 to 5•4). 4 × escBEACOPP was associated with fewer severe infections (8% vs 15%) and organ toxicities (8% vs 18%) as compared to patients receiving 6-8 × escBEACOPP. The trial supports reducing therapy to 4 escBEACOPP in patients who achieve PET-negative disease after 2 cycles of escBEACOPP.
Due to concerns of toxicity, escalated BEACOPP in Alberta should only be considered for the following patients 2,21,22,27-31 :
• Age < 60 years • KPS score > 70 (ECOG 0-2)
• HIV negative, no other major co-morbidities • Patients must be made aware of infertility implications, and consent to proceed Although the above-described treatment approaches currently optimize cure rates from initial therapy, they result in: 1) the use of radiotherapy that contributes to late mortality from second cancers and cardiac disease; 2) the use of multiple cycles of Bleomycin that may cause serious lung toxicity; or 3) the use of escalated BEACOPP that increases the risk of serious infections and therapy-related MDS/AML. With the use of a PET-guided approach that minimizes therapy for patients whose lymphoma is highly sensitive to ABVD, we anticipate a reduction in toxicity of therapy and a need to only subject less responsive patients to the toxicities of IFRT or escalated BEACOPP.
arm of the study, patients received ABVD x2 then a PET scan, followed by ABVD x 2 (favorable) or 4 (unfavorable) if PET-, or escBEACOPP x2 cycles +INRT if PET+. Comparing control (INRT) and experimental (no INRT) arms for patients with negative PET after 2 cycles ABVD, the difference in PFS was -11.9% (95%CI -16.9%, -8.2%) for favorable risk (not meeting non-inferiority endpoint) and -2.5% (95%CI -6.6%, 0.5%) for unfavorable risk (not meeting non-inferiority endpoint). There was no difference in overall survival. For patients with PET+ disease after ABVD, the 5y PFS 77% vs 91% (p=0.002) and 5yr OS 89% vs 96% (p=0.06) favouring escBEACOPP compared to ABVD + INRT.
As neither the RAPID nor H10 trials confirmed non-inferiority of the PET-directed radiotherapy omission approach, this would support the use of radiotherapy despite a negative interim PET. However, given the lack of difference in OS and small differences in PFS, a PET-directed approach is recommended, accepting the risk of reduced local control with potential need for salvage chemotherapy and transplantation at relapse, reconciled by an expected late gain in OS due to avoidance of the long term sequelae of radiotherapy such as secondary malignancy and cardiovascular disease.
# Advanced Stage:
The UK RATHL trial treated patients with 2 cycles ABVD then performed a PET scan. 172 patients with PET+ disease (uptake > liver, Deauville 4-5) had therapy intensified to escBEACOPP whereas PET-patients were randomized to ABVD x4 (n=470) or AVD x4 (n=465). For PET-patients, 3yr PFS was 85.7% vs 84.4% for ABVD vs AVD (95%CI crossed 5% difference non-inferiority limit), the respective 3yr OS rates were 97.2% vs 97.6%, and the rate of grade 3-4 pneumonitis was 1% vs 0.2%, respectively. Of interest, a prior phase GHSG III trial found that omitting agents from ABVD x2 prior to IFRT for favorable risk limited stage HL resulted in lower 5 PFS rates (5yr FFTF 93.1% ABVD, 89.2% AVD, 77.1% AV, 81.4% ABV) and did not recommend this strategy. In view of the fact that the RATHL trial failed to meet its non-inferiority endpoint and only demonstrated a small reduction is serious pulmonary toxicity by eliminating bleomycin from the final 4 cycles of ABVD, it seems most reasonable to adopt this strategy only for those patients with risks factors for bleomycin lung toxicity (COPD / ↓PFTs, CrCl <80ml/min, Stage IV, Age >40yr), or those with any clinical or PFT evidence of acquiring bleomycin lung toxicity at any time during therapy. Patients with PET2 positive status whose therapy was intensified to 4 additional cycles of BEACOPP (BEACOPP-14 or escBEACOPP) had a 3 yr PFS of 67.5% and 3 yr OS of 87.8%.
The aforementioned HD18 study by German Hodgkin Study Group confirmed that 4 escBEACOPP was as effective as 6-8 escBEACOPP but less toxic in patients who achieved PET-negative status after 2 cycles of escBEACOPP. 3 yr PFS in this group (PET-2 negative after escBEACOPP) was 95.3% and 3 yr OS was 98.8%.
Based upon the above data, it is reasonable to adopt a PET-guided therapy approach for advanced staged Hodgkin lymphoma. Initiation of escBEACOPP as per the HD18 study results in a higher overall survival and is the preferred approach for young, fit patients for whom the fertility implications are acceptable. For patients who initiate therapy with ABVD, PET-directed therapy will minimize the long-terms risks of cytotoxic chemotherapy and radiotherapy for PET-patients after ABVD x2, while maintaining PFS rates <5% inferior to conventional combined modality treatments. These PET-guided approaches are illustrated in Figure 1-2. For centres where PET scanning is not available, or in situations when patients prefer to prioritize their initial cure rate and avoidance of intensive salvage therapy with autologous SCT rather than prioritize a similar long-term survival while minimizing therapy-related second cancers, cardiovascular mortality or bleomycin lung toxicity, the more traditional therapy approach illustrated in Figure 3 is still very reasonable. A phase II study of N=102 patients treated with BV (1.8mg/kg, outpatient IV, 30min, every 3 weeks for up to 16 cycles) for relapsed/refractory Hodgkin lymphoma after failed hematopoietic autologous stem cell transplantion reported outcomes after approximately 3-years of follow-up. Median OS and PFS were estimated at 40.5 months and 9.3 months, respectively. The estimated 3-year OS and PFS rates were 73% (95%CI: 57-88%) and 58% (95%CI: 41-76%), respectively. Younger age, good performance status, and lower disease burden at baseline were favorable prognostic factors for OS. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea.
# Consolidation with Brentuximab Vedotin after ASCT
The AETHERA clinical trial evaluated a strategy of consolidation with brentuximab vedotin after autologous stem cell transplantation in high risk relapsed Hodgkin lymphoma patients. Patients were eligible for BV if they were either: refractory to frontline treatment, relapsed < 12months after frontline therapy, or relapsed >= 12 months with extranodal involvement. Patients were randomized to receive either BV (1.8mg/kg every 3 weeks for up to 16 cycles) or placebo. 5 year PFS was 59% for BV versus 41% for placebo. Grade 3-4 peripheral motor and sensory neuropathy was observed in 6 and 10% of patients receiving BV consolidation, however, improves or resolves in the majority of patients.
# PD1-inhibitors 56 :
The For primary prophylaxis of febrile neutropenic infection for similar indications above or co-morbidities that increase risk of infectious complications such as chronic obstructive pulmonary disease, or secondary prevention after a prior episode of febrile neutropenia:
• G-CSF 300 or 480µg/day starting 3 days after chemotherapy completed until post-nadir ANC>1.0 (usually 7-10 days) (though most patients require only 2-5 days of G-CSF support)
• Must monitor CBC • The alternative is one dose of pegfilgrastim (Neulasta) 6mg on day 4 (without CBC monitoring, but at a cost of ~$2500/dose)
# Erythropoeitin
Erythropoeitin is not recommended because of evidence suggesting increased mortality rates. Consider only for symptomatic anemia patients who cannot receive RBC transfusions (i.e., Jehovah's Witnesses, prior severe transfusion reactions or severe iron overload).
# Antimicrobial Prophylaxis for Immunosuppressive Regimens 6-8
• For patients receiving fludarabine, high dose cyclophosphamide, >5 days high dose corticosteroids every 21 days, bortezomib, and bendamustine, and for immune-compromised patients (i.e., HIV, post-organ transplant or autoimmune disease patients who develop hematologic cancers) use prophylaxis during and for 12 months post-treatment. CD4 count monitoring can be used to help determine if prophylaxis can be stopped earlier (should not be assessed until 3 or 6 months post-treatment). Patients withCD4 count > 200 / µL may have earlier discontinuation of antimicrobial prophylaxis.
# Immunizations
Patients should be encouraged to keep all immunizations up to date. The reactivation and/or seroreversion of viruses that patients have been previously vaccinated against, such as hepatitis B, is a major cause of morbidity and mortality in patients with hematologic malignancies treated with cytotoxic chemotherapy. Appendix G outlines the general principles and specific immunization schedules for recipients of blood and marrow transplantations. In addition, separate guidelines outlining influenza and pneumococcal immunization recommendations for all patients with cancer can be found at: www.albertahealthservices.ca/cancerguidelines.asp under the "Supportive Care" heading" Recombinant adjuvant herpes zoster vaccine is commercially available however cancer patients were excluded in the pivotal phase 3 trials (ZOE-50 and ZOE-70). Studies with use in cancer patients are not yet published, but results suggest that vaccination responses are better for patients not on treatment or given prior to chemotherapy, as opposed to during chemotherapy 9 . Other hematological malignancy patients had better vaccines responses than Non Hodgkin's Lymphoma and CLL patients for reasons not yet identified 10 . The AHS Hematology group consensus is that the recombinant adjuvant herpes zoster vaccine is not contraindicated in hematology patients. Patients may receive the vaccine if they have adequateimmune function to amount a response, and are 6-9 months post Rituximab due to the reduced vaccine responses seen in rituximab-treated patients.
Family members and health care providers in contact with patients who have undergone a transplant should also be strongly encouraged to keep all immunizations up to date.
For patients who have experienced reactivation or seroreversion of hepatitis B virus, prompt administration of nucleoside/nucleotide analogues is essential 11 . Entacavir or tenofovir following R-CVP or R-CHOP chemotherapy for lymphoma is recommended for all patients who have a positive hepatitis B surface antigen test.
Last Reviewed: September 2017 VIII. Follow-Up Care in the Treatment of Lymphoma [1][2][3][4][5][6][7][8][9][10][11] The following late effects should be considered when patients are reviewed during follow-up:
• Relapse. Careful attention should be directed to lymph node sites, especially if previously involved with disease. Routine surveillance CT scans are not indicated. Most relapses have been demonstrated to occur between scheduled clinics visits and tests, and are detected by patients themselves. Highly anxious patients who wish surveillance tests could be considered for occasional CXR and abdominal/pelvic ultrasounds (if thin), especially in the setting of indolent lymphoma and prior retroperitoneal and mesenteric disease. • Dental caries. Neck or oropharyngeal irradiation may cause decreased salivation. Patients should have careful dental care follow-up and should make their dentist aware of the previous irradiation. • Hypothyroidism. After external beam thyroid irradiation to doses sufficient to cure malignant lymphoma, at least 50% of patients will eventually develop hypothyroidism. All patients whose TSH level becomes elevated should be treated with life-long T4 replacement in doses sufficient to suppress TSH levels to low normal. • Infertility. Multi-agent chemotherapy and direct or scatter radiation to gonadal tissue may cause infertility, amenorrhea, or premature menopause. However, with current chemotherapy regimens and radiation fields used, most patients will not develop these problems. All patients should be advised that they may or may not be fertile after treatment. In general, women who continue menstruating are fertile, but men require semen analysis to provide a specific answer. • Secondary neoplasms. Although quite uncommon, certain neoplasms occur with increased frequency in patients who have been treated for lymphoma. These include AML, thyroid, breast, lung, and upper GI carcinoma, melanoma and cervical carcinoma in situ. It is appropriate to screen for these neoplasms by careful history, physical examination, mammography and Pap smears for the rest of the patient's life because they may have a lengthy induction period. Patients should be counseled about the hazards of smoking and excessive sun exposure, and should be encouraged to perform careful breast and skin examinations on a regular basis.
Table 1 outlines the minimum follow-up tests and examinations that should be performed on all patients after treatment for malignant lymphoma. Visits should be scheduled with an oncologist or family physician educated in post-treatment lymphoma surveillance every 3-4 months for 2 years, then every 6 months for 3 years, then annually. • Rituximab 375mg/m 2 IV day 1 (premedications: Tylenol, Benadryl, Zantac, hydrocortisone 100mg), then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated well. • Rituximab 375mg/m 2 IV day 1 (premedications: Tylenol, Benadryl, Zantac, hydrocortisone 100mg) then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated well.
• Cyclophosphamide 750 mg/m 2 IV • Rituximab 375mg/m 2 IV day 1 (premedications: Tylenol, Benadryl, Zantac, hydrocortisone 100mg) then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated well. • weight (call MD if >2kg above day 1)
• CBC & differential, EP, creatinine, glucose • ALT,AlkP,LDH,bilirubin,Alb,Ca,Mg F) Transplant-ineligible patients (age >65 years, significant co-morbidities, or immune suppression) with late relapse (prior RCHOP x6) with relapsed systemic and CNS lymphoma. This situation is unfortunately associated with extremely poor prognosis, and generally should be treated with palliative intent. Treatments could include IT chemotherapy, radiotherapy, decadron, or best supportive care. Patients who received rituximab-based therapy as part of their initial treatment had a 3-year PFS of 70% and an OS of 73% compared with a 3-year PFS of 21% (p<0.0001) and an OS of 33% (p=0.0001) for patients who did not receive rituximab. 2b. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on CT to normal size (<1.5 cm in their greatest transverse diameter for nodes >1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their short axis before treatment must have decreased to <1.0 cm in their short axis after treatment.
# Post-Transplantation Lymphoproliferative Disease (PTLD)
Prognostic
3. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical examination or CT scan, should not be palpable on physical examination and should be considered normal size by imaging studies, and nodules related to lymphoma should disappear. However, determination of splenic involvement is not always reliable because a spleen considered normal in size may still contain lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood volume, the use of hematopoietic growth factors, or causes other than lymphoma.
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is made must be adequate (with a goal of >20 mm unilateral core). If the sample is indeterminate by morphology, it should be negative by immunohistochemistry. A sample that is negative by immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow cytometry will be considered a CR until data become available demonstrating a clear difference in patient outcome.
# Partial Response (PR)
The designation of PR requires all of the following:
1. At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. These nodes or masses should be selected according to all of the following: they should be clearly measurable in at least 2 perpendicular dimensions; if possible they should be from disparate regions of the body; and they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
2. No increase should be observed in the size of other nodes, liver, or spleen.
3. Splenic and hepatic nodules must regress by >50% in their SPD or, for single nodules, in the greatest transverse diameter.
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present.
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was positive before treatment. However, if positive, the cell type should be specified (e.g., large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria, but who have persistent morphologic bone marrow involvement will be considered partial responders. When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients should be considered partial responders.
progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must increase by >50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.
4. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.
5. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems (<1.5 cm in its long axis by CT).
6. Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. For these recommendations, the spleen is considered nodal disease. Disease that is only assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent only, unless, while an abnormality is still noted by imaging studies or physical examination, it is found to be histologically negative.
7. In clinical trials where PET is unavailable to the vast majority of participants, or where PET is not deemed necessary or appropriate for use (e.g., a trial in patients with MALT lymphoma), response should be assessed as above, but only using CT scans. However, residual masses should not be assigned CRu status, but should be considered partial responses.
Response and site PET-CT-Based Response CT-Based Response New lesions
# Bone Marrow
New FDG-avid foci consistent with lymphoma rather than another etiology (eg. Infection, inflammation). If uncertain regarding etiology or new lesions, biopsy or interval scan may be considered New or recurrent FDG-avid foci Regrowth of previously resolved lesions A new node > 1.5 cm in any axis A new extranodal site> 1.0cm in any axis; if < 1.0 cm in any axis, its presence must be unequivocal and must be attributable to lymphoma Assessable disease of any size unequivocally attributable to lymphoma New or recurrent involvement Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. * A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Nonnodal lesions include those in solid organs (eg. liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal masses, as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone, marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (eg. with marrow activation as a result of chemotherapy or myeloid growth factors). ꝉPET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.
# Ann Arbor Staging Nodal Sites
FLIPI
# ECOG Performance Status 0
Fully active, able to carry on all pre-disease activities without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
2
Ambulatory, capable of all self-care but unable to carry out any work activities. Up and about >50% waking hours.
3
Capable of only limited self-care. Confined to bed or chair more than 50% of waking hours.
# 4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Disclaimer The recommendations contained in this guideline are a consensus of the Alberta Hematology Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2023) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Data Supporting Brentuximab vedotin for Primary Therapy of Hodgkin Lymphoma 36
An open-label, multicenter phase 3 trial of 1334 patients with previously untreated stage III/IV Hodgkin lymphoma, randomized (1:1) patients to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) or ABVD. After a median follow-up of 24.6 months, 2 year modified progression-free survival (primary end point) was 82.1% (95%CI: 78.8-85.0%) for the A+AVD group and 77.2% (95%CI: 73.7-80.4%) in the ABVD group (p=0.04). Neutropenia was higher in the A+AVD group (58% vs 45%), febrile neutropenia occurred in 83 patients (rate: 11% in those receiving prophylactic GCSF and 21% in those without GCSF). Peripheral neuropathy was also higher in the A+AVD group (67% vs. 43%), with resolution at last follow-up in 2/3 of patients. Pulmonary toxicity ≥grade 3 occurred in 1% of A+AVD patients vs. 3% in ABVD. No overall survival difference was observed. While this trial showed an improvement in its primary endpoint (modified PFS), this endpoint included patients who received IFRT after achieving a PR, which many would argue is appropriate curative therapy and should not have qualified as treatment failure. Additionally, Health Canada restricted approval to patients with Stage 4 disease, who are thus, the only patients currently eligible to receive this therapy in Canada. With the current analysis, the number needed to treat is very large (and would be even larger if the patients receiving adjuvant radiotherapy were excluded from the PFS calculation). BV has not been investigated using a PET-directed approach (the current standard for HL in Alberta), has not been proven superior to escBEACOPP (our recommended treatment for young and fit Stage 4 HL patients) and thus the costs of A-AVD are considered too high to justify a change in practice at this time.
We recommend A-AVD only for patients who are appropriate for intensive, curative HL therapy but refuse escBEACOPP for reasons of fertility preservation or personal choice or are ineligible for escBEACOPP due to age or comorbidities (but still suitable for full dose A-AVD).
Data Supporting a PET-Guided Treatment Approach [32][33][34][35] :
# Limited Stage:
In the UK Rapid trial, patients with stage I-IIA non-bulky HL received ABVD x3 cycles then underwent a PET scan. If the PET was positive (uptake more than blood pool, Deauville score 3-5) the patients received one more cycle ABVD then IFRT, whereas if the PET was negative patients were randomized to observation or IFRT. The 3yr PFS was 85.9% in the 145 PET+ patients, 94.6% in the PET-patients who received IFRT and 90.8% in PET-patients who were observed. The difference in PFS was -3.8% (95%CI: -8.8%, 1.3%) exceeding -7% non-inferiority margin. Of interest, the perprotocol PFS was 97% vs 90.8% because 26 pts did not get allocated IFRT. The respective 3 year overall survival rates were 97.1% vs 99.0%. In the EORTC/LYSA/FIL H10 trial, stage I-II HL patients were randomized between control arm therapy with ABVD x3 +INRT (favorable risk) or ABVD x4 +INRT (unfavorable risk), with all patients undergoing PET after cycle 2 ABVD. In the experimental Future potential option for patients not eligible for PET-guided approach Brentuximab vedotin 36 :
An open-label, multicenter phase 3 trial of 1334 patients with previously untreated stage III/IV Hodgkin lymphoma, randomized (1:1) patients to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) or ABVD. After a median follow-up of 24.6 months, 2 year modified progression-free survival (primary end point) was 82.1% (95%CI: 78.8-85.0%) for the A+AVD group and 77.2% (95%CI: 73.7-80.4%) in the ABVD group (p=0.04). Neutropenia was higher in the A+AVD group (58% vs 45%), febrile neutropenia occurred in 83 patients (rate: 11% in those receiving prophylactic GCSF and 21% in those without GCSF). Peripheral neuropathy was also higher in the A+AVD group (67% vs. 43%), with resolution at last follow-up in 2/3 of patients. Pulmonary toxicity ≥grade 3 occurred in 1% of A+AVD patients vs. 3% in ABVD. No overall survival difference was observed. While this trial showed an improvement in its primary endpoint (modified PFS), this endpoint included patients who received IFRT after achieving a PR, which many would argue is appropriate curative therapy and should not have qualified as treatment failure. With the current analysis, the number needed to treat is very large (and would be even larger if the patients receiving adjuvant radiotherapy were excluded from the PFS calculation) and thus the costs of A-AVD are considered too high to justify a change in practice at this time. However, this regimen has been demonstrated as an effective and tolerable frontline therapy for advanced stage Hodgkin lymphoma and could become the standard against which future non-PET directed treatments are compared.
# Management of Recurrent Hodgkin Lymphoma 2,37-52 :
Similar to the initial workup, recurrent disease should involve re-staging tests.
# Initial relapse.
• Re-induction chemotherapy with GDP or DICEP then high dose therapy and autologous SCT + IFRT 20-30Gy to prior bulk site at relapse, or PET-positive residual disease post-ASCT
• Brentuximab vedotin consolidation post-ASCT for patients with primary refractory HL, relapse within 12 months or extranodal disease at relapse
• Pembrolizumab iv q3-6 weeks for older/unfit patients who are deemed ineligible for ASCT Second or subsequent relapse.
• IFRT if localized relapse in previously non-irradiated site • A PD1-inhibitor (eg. Nivolumab or Pembrolizumab) after prior failure of chemotherapy (and autologous SCT in transplant eligible patients) [data suggests longer remissions with PD1-inhibitor compared to Brentuximab vedotin making PD1i then BV the preferred sequencing)
• Brentuximab vedotin IV q21d for up to 16 doses if prior failure of initial chemotherapy (ABVD or BEACOPP) and prior autologous SCT (excluding patients who progress on BV consolidation post-ASCT)
• Palliative chemotherapy for symptomatic patients (GDP, COPP, ChlVPP, CEPP, vinblastine)
Reduce by 50% for grade 3 motor or sensory neuropathy For patients who develop ≥ grade 3 ileus, treatment should be delayed until recovery and vincristine introduced at 75% of the normal dose thereafter. If ≥ grade 3 ileus recurs, vincristine should be discontinued
# II. Initial Therapy For Indolent Histology Non-Hodgkin Lymphoma
# B-R:
• Bendamustine 90 mg/m 2 IV day 1, 2
• Rituximab 375 mg/m 2 IV day 1 then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated.
• Cycles: repeated every 3-4 weeks depending on blood counts (usually administered every 28 days) for a maximum of 6 cycles CVP:
• Cyclophosphamide 800 mg/m 2 IV day 1 (or 400 mg/m 2 /day p.o. days 1-5)
• Vincristine 2mg IV day 1
• Prednisone 100mg/day p.o. days 1-5
• Cycles: every 21 days
# R-CVP:
• Rituximab 375mg/m 2 IV day 1 (premeds: Tylenol, Benadryl, Zantac, hydrocortisone 100mg), then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated.
• Cyclophosphamide 750 mg/m 2 IV day 1
# Chlorambucil (options):
• 0.1-0.2 mg/kg/day for 4-8 weeks then usually reduce for maintenance • 10-14 mg/m² for 5 to 7 days each 28 days • 0.5 mg/kg days 1 and 15 q28d cycle Fludarabine:
• 25mg/m 2 IV days 1-5 q28 days (days 1-3 only if frail elderly or renal dysfunction)
• 40mg/m 2 p.o. days 1-5 q28 days (round down to nearest multiple of 10mg) (d1-3 only if frail or renal dysfunction)
# FND:
• Fludarabine 25mg/m 2
# Methotrexate should be omitted if creat clearance < 50 mL/min or if renal dysfunction with prior cycle Cytarabine should be reduced to q24hr if creat clearance < 50 mL/min or complications of myelosuppression
# VIII. Secondary CNS Lymphoma Protocol
A) Transplant-eligible patients (age <65 years, no significant co-morbidities, no immune suppression) with isolated CNS relapse/progression following complete response of systemic lymphoma to RCHOP.
Step 1
Step 2
Step Step 1
Step 2
Step 3
Week 1 2 3 4 5 6 7 8 9 10 11 12 15 or 16 Rituximab 375mg/m2 d0, 4 high-dose methotrexate 3.5 g/m 2 d1 procarbazine 100 mg/m 2 x 7 days d1-7
x x x Rituximab 375mg/m2 d0 high-dose methotrexate 3.5 g/m 2 day 1 cytarabine 1.5-2 g/m 2 bid days 2-3 • role of IMRT/VMAT/TOMO over 3DCRT is at discretion of treating radiation oncologist-this is determined on a case by case basis • the low dose bath is a consideration when using IMRT as it relates to potential long term risk of second malignancies The full analysis set was collected from eight phase 3 trials in France, Germany, the United Kingdom, the United States, and Poland (n=3,472 patients, median age 61 years (27-86 yrs)). 89% of patients had received treatment for CLL and median overall survival (OS) was 95 months. The model was externally validated in a third dataset comprising 845 patients with newly diagnosed CLL from the Mayo Clinic; 39% had received treatment for CLL. The final model of multivariate analysis identified 5 independent predictors for OS: TP53 (17p) mutation (deleted and/or mutated; hazard ratio [HR]: 4.2); IGHV mutation status (unmutated, HR: 2.6); B2M (>3.5 mg/L; HR: 2.0); clinical stage (Binet B/C or Rai I-IV, HR: 1.6); and age (>65 years, HR: 1.7). Using weighted grading, a prognostic score from 0 to 10 was derived that separated the patients into four different groups: low risk (score 0-1), intermediate risk (score 2-3), high risk (score 4-6), and very high risk (score 7-10). At 5 years, significantly different rates of OS were observed for the low to the very high risk group, 93%, 79%, 64%, and 23%, respectively (P<0.001; C-statistic c=0.72 [95% CI: 0.69, 0.76]). The multivariable model was confirmed on the internal validation datasets; in addition, the four risk groups were reproduced with on the Mayo dataset, with 5-year OS rates of 97%, 91%, 68% and 21%, respectively (P<0.001; C-statistic c=0. 79
# Role of PET in
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6fb5b0c9388fa36b9a4b5623099a676cff031404
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cma
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Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder involving both upper and lower motor neurons that results in progressive weakness of skeletal muscles. Regardless of site of first onset, death usually occurs as a result of progressive respiratory muscle involvement, with 50% of patients dying within three years of symptom onset. Mechanical ventilation is becoming increasingly accepted in ALS. In Canada, noninvasive ventilation is the most common form of ventilation applied, with tracheostomy ventilation being very uncommon. The current guideline addresses respiratory muscle testing, the benefits of mechanical ventilation in ALS, timing of initiation of ventilation and modes, settings and place of initiation. It also reviews diaphragm pacing and respiratory muscle training. Finally, given the challenges involved with tracheostomy ventilation in ALS, the question of tracheostomy ventilation is addressed.#
La scl erose lat erale amyotrophique est une affection neurod eg en erative impliquant les neurones moteurs sup erieurs et inf erieurs qui r esulte en une faiblesse progressive des muscles squelettiques. Ind ependamment de la premi ere r egion du corps o u elle se manifeste, elle entraine habituellement la mort en raison de l'implication progressive des muscles respiratoires : 50% des patients meurent dans les trois ans suivant l'apparition des symptômes. La ventilation m ecanique est de plus en plus accept ee dans les cas de SLA. Au Canada, la ventilation non invasive est la forme la plus commune de ventilation appliqu ee, tandis que la trach eotomie est tr es rare. Cette ligne directrice porte sur l' evaluation des muscles respiratoires, les avantages de la ventilation m ecanique dans les cas de SLA, le moment o u commencer la ventilation, les modes de ventilation, le param etrage et le lieu o u d ebuter la ventilation. Elle aborde aussi la stimulation du diaphragme et l'entraînement de la musculature respiratoire. Finalement, etant donn e les d efis que pr esente la ventilation par trach eotomie dans les cas de SLA, la question de la ventilation par trach eostomie est aussi abord ee.
# Introduction
The first Canadian Thoracic society (CTS) guideline for Home Mechanical Ventilation (HMV) was published in 2011 1 and included a section detailing recommendations for HMV for patients with Amyotrophic Lateral Sclerosis (ALS). This is the first update of the ALS section of that guideline and is intended for use as a standalone document making recommendations on the respiratory care of ALS patients. It excludes airway clearance and recruitment techniques in ALS and other neuromuscular disorders that were addressed in the 2011 guideline and that will be covered in an upcoming update by the CTS HMV clinical assembly. Airway clearance and recruitment are recognized to be of critical importance in the care of ALS patients.
ALS is a neurodegenerative disorder involving both upper and lower motor neurons that results in progressive weakness of skeletal muscles. Generally, onset of weakness is characterized as either limb or bulbar. Less commonly, approximately 3% of ALS cases in referral centres, the first presentation is with respiratory symptoms secondary to early respiratory muscle involvement. 2,3 Regardless of site of first onset, death usually occurs as a result of progressive respiratory muscle involvement, with 50% of patients dying within three years of symptom onset. 4 Patients with bulbar onset ALS generally have a shorter survival than those with limb onset. 5 The rapid progression to death separates ALS from most other neuromuscular disorders (NMDs) for which noninvasive ventilation (NIV) and tracheostomy ventilation are considered. ALS is also distinct from other medical conditions for which chronic mechanical ventilation is provided, including other neuromuscular disorders (NMDs), by virtue of having the poorest survival using ventilation. In one case series, only 5% of ALS patients using mechanical ventilation were alive after five years, as compared to more than 60% of patients with other neuromuscular diagnoses. 6 Ninety-five percent of the ALS patients using home ventilation in the Swedish Home Mechanical Ventilation registry 6 were using it noninvasively, a number similar to data from the North American ALS CARE database, which has remained largely unchanged since 1996 when it was created. 7 Use of home ventilation is increasing despite some debate regarding the ethics of prolonging survival in such a rapidly progressive disorder with poor survival on NIV. 6 In 1999, Melo published a survey of multidisciplinary ALS clinics and found that only 15% of eligible patients were using NIV. 8 This number was similar to that reported in the ALS CARE database two years later. 9 The ALS CARE database was reviewed again in 2006, following many reports of positive outcomes with the use of NIV and found that 36.2% of patients considered to be candidates were using NIV. 10 A Canadian survey of ALS centres published in 2010 found that NIV was used by 18.3% of patients, while only 1.5% were reported as tracheostomy ventilated. 11 The increasing trend in use of NIV in ALS was highlighted by a 2012 publication reviewing the UK experience. 12 They noted a 3.4 fold increase in NIV use in ALS between 2000 and 2012. An Australian database reporting on a large cohort of patients with ALS found 23% of their patients between 1991 and 2011 received NIV. 13 Some countries have reported particularly high incidences of NIV use. A recently published Japanese study reported that 52% of their patients used NIV after 2000. 14 Finally, a single center report from Denmark also reported a high incidence of 42.3% treated with NIV between 1998 and 2012. 15 Although there may be variability in its use, the focus in the ALS literature now is not whether or not to offer NIV, but rather the optimal timing and criteria for initiation of NIV.
# Differences from prior guideline published in 2011
This clinical practice guideline is an update from an earlier guideline that was published in 2011 by the Canadian Thoracic Society. 1 Changes in the content from the prior guideline include the following:
- Further reports of the benefits of HMV. 2. New techniques to evaluate respiratory muscles are discussed, and reevaluation of previously reported respiratory testing. 3. Exploration of the rationale for earlier timing, with less focus on a cut off value for vital capacity. 4. Review and recommendations regarding respiratory muscle training in the ALS population. 5. More conclusive evidence regarding diaphragm pacing after publication of two randomized controlled trials (RCTs) showing negative outcomes.
- Recommendation of mouthpiece ventilation as an option in a subgroup of ALS patients.
# Exclusion of any discussion of airway clearance in ALS.
This is recognized to be of critical importance, was addressed in the 2011 guideline, 1 and is currently under review by the HMV clinical assembly.
# Target patient population
The current clinical practice guideline applies to all adult individuals with Amyotrophic Lateral Sclerosis who are at risk for or are using HMV.
# Target users
The present clinical practice guideline is intended for use by the health care teams that care for individuals who are at risk for or require ventilatory assistance. Respirologists, physiatrists, neurologists, family practitioners, nurses, respiratory therapists, physiotherapists and other health care professionals can use this guideline to help inform their clinical practice with regard to HMV. This guideline is also intended for use by ventilator-assisted individuals (VAIs) and their caregivers to help them make informed decisions on HMV and by health care decision makers to aid in establishing policy and making funding decisions.
# Guideline panel composition
The CTS HMV guideline panel was interprofessional and was comprised of HMV clinicians and health care professionals with content expertise. The panel was chaired by one author and included seven adult respirologists, one physiatrist specializing in neurorehabilitation and one registered respiratory therapist. All author conflicts of interests are posted on the CTS website at /. Patient and caregiver input was not sought in development of this guideline, which is a weakness of the current guideline and which will be corrected in the next update of this document.
# Methodology
This clinical practice guideline was developed in accordance with the CTS guideline production methodology (). The panel utilized the AGREE II checklist 16 to guide the development of this guideline. Selection of key clinical questions: The primary author and the chair of the guideline panel determined key clinical questions based on their own knowledge of the literature and existing guidelines in the areas of benefits of mechanical ventilation in ALS; respiratory muscle testing and monitoring; timing of initiation of ventilation; modes, settings and place of initiation; diaphragm pacing; respiratory muscle training; and tracheostomy ventilation. Draft questions were then reviewed, discussed and revised by the panel with the final questions chosen to address significant changes since the last guideline, and gaps not addressed by prior guidelines in the area of ALS care. Using the PICO method, the panel took into consideration the Patient group or groups that should be addressed, the Intervention or interventions that should be examined, the Comparison groups that should be part of the studies of the various interventions and the Outcome or outcomes of interest. In the second part of the PICO process, panel members were asked to consider issues that influence implementability, when choosing PICO questions: the magnitude of the knowledge-tocare gap; target audiences; known barriers and supports to implementation; societal impact; and measurability of any implementation program. Members reached consensus on these questions over several teleconference meetings, webinars and email exchanges.
Literature search and screening of abstracts: An initial literature search was completed current to September 2017 using MEDLINE (OVID); Embase (OVID); HealthStar; the Cochrane Library: the Canadian Medical Association InfoBase; and the National Guideline Clearinghouse. The second literature search was conducted through to March 31, 2018 to include the most recent literature. Additional articles were found by review of the references in the articles accepted. Details of the search strategy are outlined in Appendix 1. The abstracts were assessed independently by two panel members for inclusion or exclusion and conflicts were resolved by discussion between panel members.
Study selection criteria: Following the completion of the abstract screening, the full text articles were retrieved and reviewed. Articles were selected for inclusion in the systematic review if they were directly relevant to one of the six PICO questions. All types of reports were considered and included guidelines, meta-analysis, systematic review, randomized controlled trial, cohort study, case control study, case series or case report.
Critical appraisal of identified studies: Data from all articles relevant to each PICO question were abstracted into tables by the lead author and can be found on the CTS website, at /. During discussion of each question via webinars held in June and July of 2018, the data were reviewed by the panel, and evidence addressing each clinical question was assessed according to the components of the GRADE 17 criteria (Table 1).
Synthesis of evidence-based clinical judgement of risk versus clinical benefit: For each clinical question, the panel considered the strength and directness of the published evidence supporting an intervention or treatment approach. The panel discussed the potential health benefit to the patient, the overall impact on the population burden of morbidity and mortality of ALS, and issues of risk, burden on a patient to adhere and cost effectiveness of an intervention or treatment. These discussions and the resulting synthesis of clinical judgement are presented for each recommendation.
Clinical remarks are included in association with each clinical question and are intended to offer experienced advice to the target user. Some of these good practice points may not have an evidence base, but are viewed as good clinical practice by the expert panel. All good practice points were arrived at by consensus, based on the clinical experience of the guideline panel members.
# Formulation of recommendations and classification:
Following the open and extensive discussions and review of evidence for each PICO question, a draft recommendation was proposed. The strength of the recommendation was based on consideration both of the GRADE quality of evidence, and the expert panel's synthesis of clinical judgement. In accordance with CTS methodology, the recommendations were then reviewed by the CTS Canadian Respiratory Guideline Committee (CRGC) Chair to optimize the language of each recommendation with a view to improving intrinsic implementability. 18 Next, a recommendation consensus process was completed by electronic survey using a six-point voting scale (Table 2). For a recommendation to be accepted, it had to be voted on by 75% of the panel members and achieve ratings of "wholeheartedly agree," "agree" or "can support" by ! 80% of the voting panelists. In the event of a failure to reach this threshold, another period of discussion ensued, whereby dissenting opinions were heard and considered. The recommendation was then revised, followed by a second round of electronic voting using a three-point scale (Table 2), with acceptance of a recommendation requiring ! 80% of the voting panelists choosing option 1 or 2. Through this process, all recommendations achieved acceptance, with a second round of voting required for only 3/22 recommendations.
# Applicability
Facilitators and barriers to its application: The tools exist for implementation of the recommendations of this guideline. Equipment is readily available and provincially funded in Canada in most, though not all, provinces and territories and the minimum required monitoring can be performed in both large and small centres. Unfortunately, not all ALS patients are cared for in multidisciplinary ALS clinics and, in ALS clinics, the model of respiratory care is inconsistent. This may be a barrier to application.
Advice and/or tools on how the recommendations can be put into practice: Optimally, all ALS patients should be regularly followed in multidisciplinary ALS clinics with experienced respiratory therapists and respirologists; however, this may not be an immediately achievable goal.
Protocolizing follow up and respiratory monitoring for ALS patients, whether followed by individual respirologists, neurologists or family physicians, can identify patients requiring intervention leading to timely initiation of noninvasive and the positive outcomes detailed in this document.
Registered Respiratory Therapists (RRTs) are excellent resources and individual health regions should be encouraged to capitalize on their expertise. Busy respirologists have come to rely on RRTs in health regions where they are trained to initiate and monitor noninvasive ventilation in association with a clinic specializing in HMV. RRTs alert team members to changes in status and needs and can be an excellent "early warning" system of a failing respiratory status in the ALS population. Health regions should be lobbied to include experienced RRTs in their ALS clinics and home care teams. The RRT community resource can be used for other ventilated and at risk populations making it valuable for a larger number of individuals.
Potential resource implications of this guideline: Excellent and timely care of the ALS population has the potential to reduce acute care needs and overall cost to the system. The equipment is already currently funded in most jurisdictions and the equipment costs are minor when compared to inpatient admission costs. The cost of adding newer monitoring equipment (eg, Sniff Nasal Inspiratory Pressure monitor) is small and can be absorbed by most of the larger centres.
Monitoring and/or auditing criteria: As care of the ALS patient may be by individual neurologists, respirologists or ALS centres, it will be challenging to monitor adoption of the guideline. The most reliable data collection at present is by ALS clinics and by the Canadian ALS Research network and it is for this reason that a survey of awareness and compliance will be done through ALS clinics and the Canadian ALS Research network. At 12-24 months post publication and distribution, ALS clinics across Canada will be surveyed to assess their knowledge of and compliance with recommendations.
# Review and approval process
In accordance with the CTS guideline review and approval process, before completion, CTS staff distributed the guideline for formal review by: 1) two international ALS content experts); and 2) two internal (CTS) reviewers with one reviewer performing an AGREE assessment of the guideline. The authors were blinded to the identities of the reviewers. The lead author considered AGREE II scores and reviewer comments, provided responses to the comments, and made corresponding changes to the manuscript. These reviews and the AGREE II scoresheet were provided to the CTS CRGC for review. The CRGC then reviewed these documents and provided further suggestions for edits that were considered by authors. The CRGC then recommended approval of a final draft of the guideline to the CTS Executive Committee. All reviews and author responses are posted on the CTS website at /.
# Living guideline/future updates
The HMV ALS guideline PICO questions will be uploaded in the CTS/McMaster Database, whereby authors will use the continuously updated McMaster Plus database to review Cannot supportblock it For a recommendation to be accepted, it has to be voted on by 75% of the eligible panel members and achieve ratings of wholeheartedly agree, agree, or can support by 80% of the voting panelists. If this is not achieved, additional discussion and revision of the recommendation(s) ensues, for which acceptance of a recommendation requires a majority (80%) for option 1 or 2.
new articles pertaining to these PICO questions published in top impact-factor journals as of April 2018. The studies are indexed according to the PICO questions, and made available to the guideline panel on a dedicated software platform for manual assignment to individual reviews. This evidence service will prompt guideline updates and facilitate year end reviews. The entire guideline will be reviewed every three years or sooner, to determine the need for guideline updates, in accordance with the CTS Living Guideline Model (details available at www.cts-sct.ca/guideline-library/).
# Summary of evidence
# Survival
The only randomized controlled trial (RCT) of noninvasive ventilation (NIV) with survival as a primary outcome was published by Bourke et al in 2006. 19 They screened 121 patients and ultimately recruited 92 patients to be followed every two months until randomization, which occurred if they met one or both of the pre-defined criteria: orthopnea with Peak inspiratory pressure (PImax) less than 60% predicted or symptomatic daytime hypercapnia. Ultimately, 41 were randomized and the data analyzed for all patients and also subdivided into "better" or "poor" bulbar function. All patients using NIV showed a modest survival advantage from randomization to death over those patients randomized to standard care excluding NIV: 219 (range 75-1382) days vs 171 (1-878) days. The subgroup with "better" bulbar function showed a much larger survival advantage with NIV compared to controls: 216 (range 94-681) days vs. 11 (1-283) days. There were six deaths of nine patients in the control group with better bulbar function within two weeks of enrollment. Five of the six had severe respiratory muscle weakness at enrollment. The "poor" bulbar function group showed improvement in health-related quality of life (HRQoL) if receiving NIV, but no survival benefit: 222 (range 75-1382) days vs 261 (6-878) days. The mean duration of daily use in this group, however, was less than four hours. In addition, the numbers were small and not powered to show survival benefit in the subgroup with poor bulbar function.
The Cochrane database of systematic reviews recently updated their review of mechanical ventilation in ALS in 2017 20 and found no new RCTs in this population addressing survival, disease progression or HRQoL. At the conclusion of their review, they commented that "more RCT evidence to support the use of NIV in ALS will be difficult to generate, as not offering NIV to the control group is no longer ethically justifiable." They commented that future studies should focus on the timing of initiation of NIV for maximal benefit.
Other prospective studies 6,24 and retrospective studies have reported prolonged survival in those using NIV. None of these studies was randomized, although attempts were made to provide a control group. The controls included patients refusing or intolerant of NIV or those using NIV less than 4 hours/day. 13,26,28 Historical controls were also considered. 29 An Australian group 13 reported the largest cohort of patients (n ¼ 929), 23% of whom received NIV. They found a survival advantage in patients treated with NIV, surviving 28 months from symptom onset as compared to 15 months in those who did not receive NIV. Interestingly, the subgroup demonstrating the clearest survival benefit was the bulbar onset group with a 19 month survival advantage, which is in contrast to most other studies reporting NIV outcomes in patients with severe bulbar dysfunction. One other recent study did, however, report a clear survival advantage in patients with severe bulbar dysfunction. 24 Numbers of bulbar patients were small (n ¼ 15 NIV vs n ¼ 6 controls) in this study. The control group was comprised of patients declining NIV. More severe bulbar dysfunction, as measured by the Norris Bulbar Score, was a prognostic factor in NIV failure, although a cut off value of the Norris Bulbar Score was not suggested. Despite this, prolonged survival from disease onset was found in the severe bulbar group with NIV: 40 months in the NIV group vs 16 months in those refusing NIV. This suggests that those accepting and tolerating NIV with severe bulbar dysfunction show a significant survival benefit.
The survival benefit was modest in most of the reported studies; however, in one retrospective descriptive study reported by Bach's group 27 the survival benefit in a subgroup of patients with preserved bulbar function could be measured in years even when requiring continuous NIV.
# Quality of life
In the single RCT of NIV in ALS, 19 improved HRQoL was reported for patients randomized to NIV compared with standard care with no NIV. For those with "better" bulbar function, NIV resulted in large improvement across several measures of HRQoL when compared to controls. Patients with "poor" bulbar function randomized to NIV also showed improvement in HRQoL, although the improvement was less marked.
In other prospective studies reporting HRQoL, 21,23,30-33 authors consistently reported improvements in HRQoL in certain domains for patients using NIV. These included sustained improvements in mental health, energy/vitality, social isolation, fatigue and mastery. Physical function domains generally worsened as would be expected with disease progression.
# Gas exchange and pulmonary function
All studies reporting gas exchange after initiation of NIV 31,32, show reduction of daytime partial pressure of carbon dioxide (pCO2) after initiation of nocturnal ventilation.
Five studies have reported the rate of decline of vital capacity (VC) before and after initiation of NIV. 13,23,27,28,30 Four of these studies 13,27,28,30 showed a slowing of decline of lung function after successful initiation of NIV, while in contrast, one study 23 reported a decrease in VC after initiation of NIV.
# Sleep
There are many reasons for sleep disruption in patients with ALS. Limited ability to change body position, pain and anxiety may all be factors. As with other neuromuscular disorders that involve respiratory muscles, sleep fragmentation by breathing related arousals has been reported. Early studies looking at sleep in patients with ALS sought to characterize the nature of the sleep disturbance that occurred, with recent studies looking more systematically at the effect of NIV on sleep parameters and HRQoL. Seven early studies that characterize breathing related sleep abnormalities specifically in patients with ALS 25,34, reported a decrease in total sleep time and sleep efficiency, increased stage 1 sleep and reduced REM sleep. The predominant pattern of sleep disordered breathing was not obstructive apneas, but rather, mixed apneas, central apneas and hypoventilation. Among these studies patient selection varied widely. In two of the studies, 25,34 patients selected had more advanced disease, with either very low VC (mean 52%) or symptoms suggesting sleep disordered breathing. Patients in other studies were asymptomatic 39 or had normal pulmonary function and diaphragm function. 41 Given bulbar involvement by ALS, the possibility of upper airway obstruction during sleep has been raised. Ferguson et al 38 found obstructive apneas did not occur; however, other investigators have noted obstructions in some subjects. In four of the seven early studies, 25,34,37,38 at least one subject was treated with NIV. Observations included improvement in sleep architecture, decreased breathing related arousals, improved oxygenation during sleep and improved symptoms related to sleep disordered breathing. In another, 31 cognitive impairment improved after NIV and was assumed to be related to correction of sleep disordered breathing.
More recent studies have reported the effect on HRQoL and sleep parameters with NIV. Sustained improvement in the Epworth Sleepiness Scale (ESS) and Pittsburg Sleep Quality Index (PSQI) and some subscales of the McGill QoL (MQoL) questionnaire were found and scores did not fall below baseline despite worsening ALSFRS scores. 36 One author 42 reported on the effect of NIV on sleep and showed that the minimum saturation improved by 7% with NIV. Time spent <90% also improved with NIV though other sleep parameters showed no significant change (sleep efficiency, AHI, arousal index or sleep architecture). Another report 45 found that those with bulbar dysfunction had better quality sleep at baseline with less change noted after NIV initiation compared to non-bulbar patients. PSQI did improve in bulbar patients though improvements in ESS, and MQoL were observed only in non-bulbar patients. In the entire cohort, N3 sleep and REM increased and arousal-awakening index (AAI) improved. The short form survey (SF-36) emotional health subscale also improved. A later report by the same authors 46 studied patient ventilator asynchrony, leaks and sleep quality. They noted the commonest asynchrony was ineffective efforts and that despite meticulous titration, patient ventilator asynchrony and leaks persisted, although interestingly, had a minor impact on sleep.
# Respiratory testing
Measuring lung function in ALS serves two purposes. First, it has been shown that some measures of lung function are better predictors of survival than functional rating scales. 5,6,47,48 This information could facilitate the design of studies evaluating new therapies, such as medications, in order to enrich the study population, possibly requiring fewer patients to achieve significance and aid in sample size calculations. Second, monitoring lung function helps guide the timing of interventions such as initiation of NIV. Earlier literature focused on measures of lung function which predicted daytime hypercapnia, a logical criterion to initiate mechanical ventilation. More recently, however, there has been a focus on predicting nocturnal sleep disordered breathing for the purpose of earlier initiation of ventilation before onset of daytime hypercapnia with the goal of improving outcomes such as survival or HRQoL.
An earlier study looked extensively at predictors of daytime hypercapnia. 49 It assessed VC, FEV1, peak inspiratory pressure (PImax), peak expiratory pressure (PEmax), sniff transdiaphragmatic pressure (Pdi), sniff esophageal pressure (Poes), sniff nasal pressure (SNP), cough gastric pressure (Pgas), bilateral cervical magnetic stimulation (CMS) Pdi and arterial blood gas (ABGs). Sniff Pdi and CMS Pdi had the greatest predictive power for the presence of daytime hypercapnia. Of the less invasive tests, Sniff nasal inspiratory pressure (SNP) had the best predictive power. This predictive power was limited to those patients without significant bulbar dysfunction. No test reliably predicted hypercapnia in the patients with bulbar dysfunction.
Hypercapnia, though a relatively late finding, remains an indication for initiation of HMV and can be determined by ABG, or capillary blood gas 50 or transcutaneous CO2. 51,52 A more recent assessment 53 of the predictive power of invasive and noninvasive respiratory muscle strength assessments for survival or ventilator free survival showed that VC had a good predictive power, but the cutoff value for a good outcome was in the normal range (>80% predicted) for all time intervals beyond 3 months. Although all tests of muscle strength predicted ventilator free survival, they had varying sensitivities. Sniff and Twitch transdiaphragmatic pressure were the best performing tests for ventilator free survival, although SNP also was shown to have a good predictive value. Maximal expiratory pressure (MEP) and MEP% predicted were also useful predictive tests. Supine forced vital capacity (FVC) was not assessed.
SNP has gained popularity in assessing the respiratory muscles as it is more sensitive to early muscle weakness than FVC 54 and can be performed by most patients, even those with advanced disease and bulbar dysfunction. 55 A SNP less (reduced strength 1 - ) than -40 cmH2O was shown to be significantly correlated with nocturnal hypoxemia and patients at this level had a median survival of only 6 months. 54 A more recent study 56 looked at SNP and other measures of lung function, including FVC, for predicting death at one year. A SNP -70 cmH2O resulted in improved survival at one year. Ultimately a SNP cutoff value of -34 cmH20 was found to have a sensitivity of 0.75 and a specificity of 0.72 for death at one year. The highest risk of death at one year was found in those with a sniff nasal pressure -18cmH2O. By comparison, the cut off value for FVC to predict death at one year was high at 75.9% and was less predictive for death at one year than SNP.
Maximal inspiratory pressure (MIP) is also a sensitive measure of early muscle dysfunction and can be used as the disease progresses to predict survival, but requires the patient to tolerate and be able to seal around the mouthpiece, or mask in order to perform the test. 53,57 Sitting VC is an insensitive measure of respiratory muscle weakness as it may remain normal even when respiratory muscle weakness is present. However, in one older study, when FVC falls to less than 50% predicted, survival was limited to nine months with most patients dying by six months. 47 Other authors have also noted the poor prognosis of patients with FVC < 50% predicted 48,58 and, therefore, it is recognized that FVC, when very low, is specific for impending respiratory failure and death. It has become increasingly recognized that sitting FVC or SVC are not the best predictors of muscle weakness and impending respiratory failure given that FVC may be normal or near normal when other measures of respiratory muscle strength may be significantly abnormal. 53,56,59 More sensitive to respiratory muscle weakness and diaphragmatic dysfunction, in particular, is supine VC. A correlation between the percentage fall in VC from the erect to the supine position and the lowest saturation during REM sleep 60 suggests that a drop in VC from the erect to the supine position may be used to predict abnormalities in breathing during sleep associated with diaphragm dysfunction. Others have found that the change in VC from the erect to supine posture correlates well with symptoms of dyspnea, orthopnea and daytime fatigue. 61 A normal supine FVC was highly predictive of survival at 2 years. 62 Another author found a Borg dyspnea scale !3 when supine to be a useful predictor of a SNP -40 cmH2O and impending respiratory failure. 63 Rate of decline of Slow Vital Capacity (SVC) has also been assessed 64 and shown to be strongly correlated with rate of decline of SNP and respiratory symptoms. The probability of respiratory failure free survival was estimated in this study by the rate of decline in the SVC suggesting that this is a useful prognostic tool. The finding of rate of decline of respiratory tests as a prognostic tool was confirmed by another study, 57 which looked at decline in VC, MIP or SNP, MEP and PCF and showed that the risk of death is significantly associated with the decline in pulmonary function regardless of the PFT parameter followed.
More recently the amplitude of the action potential with phrenic stimulation has been correlated with pulmonary function tests, symptoms and survival at one year. 65 When the amplitude of the action potential (Pamp) was 0.3mV of greater than 2 years. It was also found that a Pamp < 0.3mV correlated with symptoms of dyspnea, orthopnea and tachypnea. This threshold value of Pamp was also correlated with reduced FVC, MIP and SNP. Another study 66 also found that an abnormal Pamp was a predictor of death using a cutoff value of 0.4mV with a HR of 1.653 for those with a Pamp of <0.4mV. This is a non-volitional test and could aid in defining populations for future interventional studies in ALS.
Given the difficulty with volitional tests in this population, in particular the bulbar predominant patients, other non-volitional tests have been investigated. Diaphragm thickness by ultrasound has been found to correlate with other tests of respiratory function and to the compound muscle action potential (CMAP) of the diaphragm. 67,68 This correlation, unfortunately, was less evident in patients with bulbar dysfunction and relatively mild symptoms, a population in which it may have been particularly helpful.
Lung function is essential in the follow-up of ALS patients, but equally important is a history that focuses on symptoms of dyspnea, orthopnea, poor sleep, excessive daytime sleepiness, morning headache and fatigue. The onset of dyspnea and rate of decline of VC predicted survival in one series. 69 Excessive daytime sleepiness and poor sleep were very good in predicting sleep disordered breathing, though not specific enough to use alone. Finally, orthopnea was found in one study 34 to be a good predictor of sleep disordered breathing.
An excellent review of Respiratory measures in ALS was recently published by Lechtzin et al, which summarizes much of the aforementioned information. 70
# Timing of initiation of NIV
Early studies demonstrating the benefit of NIV in ALS patients with daytime respiratory failure have questioned whether earlier initiation of ventilation improves rate of decline in respiratory function, survival and HRQoL. Investigators have sought to define the optimal timing of initiation of NIV to maximize benefit.
Five earlier studies 29,30,33,69,71,72 addressed the issue of timing. Many other studies speak indirectly to this question as the indications for initiation of ventilation may include symptoms alone without the requirement for an abnormal measure of lung function or hypoventilation. 22,23,26,28,30 Orthopnea is often the symptom for which ventilation is started. 25,26,71 A study by Bourke et al. 30 supported initiation of ventilation for symptoms. They reported the greatest benefit and compliance in patients who complained of orthopnea. Also, in support of symptoms as an inclusion for initiation, they reported that four patients were initiated on NIV for the sole indication of nocturnal desaturation without symptoms. Of the four patients, only one was compliant with NIV and continued to use it.
A study exploring earlier initiation of NIV looked retrospectively at the survival of patients in whom NIV was started when FVC was greater than 65% predicted. 72 There were 67 patients in the standard therapy group and 25 in the early initiation group. There was a survival benefit from time of diagnosis to death in those starting NIV with FVC > 65% of predicted. Of note, however, the authors comment that patients in the "early" group frequently, though not always, had pulmonary function or ABG abnormalities that would have qualified them for NIV by other conventional measures.
In another study, 29 historical controls who received NIV for diurnal respiratory insufficiency were compared to ALS patients screened every three months with nocturnal oximetry and initiated on NIV when they demonstrated more than 15 periods of nocturnal desaturation per hour. The authors reported that survival was improved if NIV was started with evidence of nocturnal sleep disordered breathing, and prior to daytime blood gas abnormalities. However, for the subgroup with bulbar dysfunction, there was no survival benefit. The concept of NIV applied for nocturnal desaturation to improve survival, lead to studies which attempted to predict the presence of nocturnal disordered breathing or nocturnal desaturation or hypoventilation allowing for earlier initiation. Polygraphy was compared to FVC and symptoms. 59 This investigation suggested that the correlation between symptoms or FVC and the presence of nocturnal hypoventilation, as defined by prolonged desaturation or a nocturnal capillary pCO2 > 45, was poor. Eight of their 131 patients had FVC 75% of predicted with no symptoms of dyspnea, demonstrated nocturnal hypoventilation. It is not clear whether treatment of these asymptomatic patients with a normal or near normal FVC who demonstrate nocturnal hypoventilation will improve their survival or QoL.
A recent pilot, placebo controlled study looking at early NIV 73 demonstrated the feasibility of use of sham ventilation in their study design. They defined early as FVC > 50% and demonstrated no difference between groups in their study though, to ensure tolerance, pressures were very low with an inspiratory positive airway pressure (IPAP) of only 8 cm.
Timing of NIV initiation has also been indirectly addressed by the recent literature which focused more on patient factors or testing that predict survival with NIV, predictors of tolerance to NIV, the effect of NIV on sleep and models for initiation of NIV which improve outcomes. 36,74, These studies imply both indications and timing that should be used for ventilation by demonstrating positive outcomes with the protocols applied.
# Monitoring post initiation of NIV
Assessment of successful NIV has historically involved improvement in symptoms and gas exchange. More recently device download and assessment of nocturnal saturation or tCO2 have been reported. Two recent papers 43,44 focused on the effect of NIV in correcting nocturnal desaturation and obstructions on survival. In both studies, device download was a component of post initiation monitoring of successful ventilation. One study 43 found better survival in those with a saturation >90% for >95% of the night while on NIV when assessed at 1, 3 and 6 months after initiation. If the study participant was found to have persistent desaturation at 1 month after initiation of NIV, changes were made in an attempt to correct the desaturation. This was reassessed again at 3 and 6 months. In those that were corrected at 1, 3 or 6 months, survival was reported to be the same as those who were well ventilated at 1 month. Device download assisted in the evaluation of the leak, which was a component in the correction. In the subset of patients who could not be corrected, survival was shorter. A follow-up study 44 looked at obstructions as a cause for desaturations and found that those with persistent obstructions had a shorter survival than those without obstructions. This was the case even if the obstructions were not associated with desaturation. They concluded that the effectiveness of ventilation is important to survival.
# Section 3. Tracheostomy ventilation in ALS
# Conclusions
Many physiologic parameters including FVC, SVC, supine VC, MIP/MEP, SNP, PCF and CMAP on phrenic nerve stimulation have been correlated with survival and help to predict respiratory failure. A single parameter has not been identified as the most useful or predictive respiratory measure. Regular monitoring has been recommended to follow the decline in respiratory muscle function with most studies recommending repeated testing every 3 months. Recognizing the differences in rate of disease progression, regular monitoring every 2 to 6 months would be recommended. Nocturnal monitoring prior to initiation of NIV may be helpful in determining timing of NIV initiation though there is currently inadequate evidence to support regular and repeated nocturnal monitoring as part of routine follow-up. Follow-up with nocturnal assessment of oxygen saturation and device download to determine effectiveness of ventilation may prolong survival if effective ventilation can be achieved.
Optimal timing for NIV for maximal benefit has yet to be determined. Current literature supports initiation for the indications listed in PICO 2.2 recommendations.
PICO 2.1: What type of testing is required to predict survival, respiratory failure or need for home mechanical ventilation/non-invasive ventilation?
Recommendations:
- We recommend regular monitoring of ALS patients every two to six months from time of diagnosis (consensus based), depending on the anticipated rapidity of disease progression, including the following: - Clinical remark: Orthopnea may not be as specific for NIV initiation in individuals with significant bulbar weakness. If orthopnea is felt to be secondary to secretions in the setting of bulbar dysfunction, the secretions should be managed first.
Clinical remark: A FVC < 50% or SNP/MIP<-40cmH2O have been shown to be a predictor of death at 6 months and are therefore considered to be an indication for NIV. Clinical judgement is required if there are no associated symptoms or the reliability of the values is questionable.
* Clinical remark: The intention of device download review and monitoring of nocturnal oxygen saturation or TcCO2 (when available) is to correct leak, prevent excessive triggering (work of breathing), assure adequate volumes, prevent apneas and oxygen desaturation, and hypoventilation.
Historically, ventilation, if it was provided to ALS patients, was delivered via tracheostomy. Since the introduction of NIV, tracheostomy ventilation is less common and thought to be a less desirable option; 78 however, rates of tracheostomy ventilation throughout the world vary widely. The highest rates are seen in Japan and other Asian countries and are reported to be 27-45% of ALS patients, although a recent Italian study also reported a high rate of 31.3% in one region. 82 Lower rates are generally reported in American and European databases 6,7 and Canada reported a rate of 1.5% in 2010. 11 In studies reporting tracheostomy ventilation in ALS, the proportion of patients undergoing tracheostomy after advanced care planning varies from 0% to 63.5% 78, and survival also varies. One study 84 reported a mean survival from tracheostomy of 30.3 months, while another 82 reported a survival with tracheostomy ventilation from disease onset of 47 months. One group compared survival depending on choice of intervention 79 reporting survival from disease onset as 32 months with no ventilation, 48 months with noninvasive ventilation alone and 74 months if tracheostomy ventilation was accepted. Similarly, comparing survival between different therapies, another group 15 reported a survival of 22.9 months with no ventilation, 25.8 months with NIV alone, 56.8 months if initial NIV was followed by invasive ventilation and 33.8 months if invasive ventilation alone was used. Although reporting of survival varies from time of onset of disease, from time of diagnosis or from onset of ventilation making comparison more difficult, these reports suggest that tracheostomy ventilation can prolong survival.
Although chosen in advance by some, tracheostomy may result from an acute deterioration and intubation when a personal advance directive is unavailable. Following tracheostomy for acute respiratory failure, one group 84 reported that none of the patients died in hospital; however, 70% were discharged completely ventilator dependent, and 28% partially ventilator dependent. Only one patient was liberated from mechanical ventilation. None of the patients had their tracheostomy removed. An Italian study 85 reported on 134 patients with tracheostomy ventilation over a 10-year period. This represented 10.6% of their ALS population during this period. Of those patients receiving tracheostomy ventilation, 56% were considered to be elective. A total of 20.1% died before discharge from the hospital and 48.5% were discharged home with a relatively short survival post tracheostomy. For those patients surviving the first 30 days, the median survival was 339 days from tracheostomy. They found survival dependent on age, marital status, follow-up in an ALS center, the discharge destination, and duration of disease before tracheostomy.
Bach has described decannulation after tracheostomy for acute respiratory failure in a select group of ALS patients with preserved bulbar function and the ability to generate an assisted PCF of >160 L/min. 27,90 More recently, the same authors reported successful extubation regardless of measured PCF in patients with various NMDs, although this study included few patients with ALS. 91 Despite these occasional reports and the possibility of an extended period of NIV after decannulation, tracheostomy may be required in the future as bulbar function deteriorates, and if patients choose invasive ventilation in the hope of prolonged survival.
Concern has been raised regarding the patient and caregiver satisfaction with tracheostomy. In a retrospective review of patients using tracheostomy ventilation, an older American study found that 90% of patients were happy with their decision of tracheostomy and 94% of caregivers felt this way as well. 92 A 3-year survival of 58% was reported, with a five-year survival of 33% in this series of patients. A study comparing HRQoL of both patients and caregivers supported with either tracheostomy ventilation or NIV, found a good overall HRQoL in patients, but a very high burden of care for tracheostomy ventilated caregivers, 30% of whom rated their own HRQoL lower than the patient's. 83 Vianello et al 84 reported on a cohort of 60 patients who were invasively ventilated after an episode of acute respiratory failure. Thirteen of these patients participated in an assessment of HRQoL completing the Life Satisfaction Index (LSI-11) and Beck Depression Inventory (BDI). The cumulative score on the LSI-11 was 9.3, which was similar to a group of ALS patients without tracheostomy and to that of the general population. Fifteen percent were found to be severely depressed as assessed by the BDI. Eleven of the 13 patients completing the questionnaires reported that they would choose to have a tracheostomy if they had to make the decision again. This may be a biased sample, however, given this included only 13 of their 60 patients completing the questionnaire.
In the prior publication of this guideline, the section on clearance recommended deflated or uncuffed tracheostomy tubes when possible. A recent study 89 looked at the type of tracheostomy tube required for effective ventilation in ALS. It found that 35.7% of patients with advancing bulbar dysfunction required a cuffed tube as a result of excessive air leak and hypoventilation though the majority was able to use uncuffed tubes.
# Conclusions
Tracheostomy ventilation remains an option in carefully selected patients after lengthy discussion of the implications. It is strongly preferred that these discussions occur well in advance of acute respiratory failure. Tracheostomy ventilation can prolong survival in ALS and can provide an acceptable QoL for some patients. It does, however, impose a high burden for caregivers.
Recommendations:
- We suggest that practitioners discuss the option of tracheostomy ventilation with ALS patients. (GRADE 2B) 2. We strongly recommended that practitioners discuss this option well in advance à of acute respiratory failure. (GRADE 1C) - Clinical Remarks: Tracheostomy ventilation should be discussed with patients with ALS early in the disease and reviewed during disease progression as patients may revise their wishes with symptom progression. These discussions should occur well in advance of an acute indication such as lower respiratory tract infection which may acutely worsen respiratory status. Though tracheostomy is an option, in our experience, few ALS patients choose this option given that NIV can be applied even with advancing respiratory muscle dysfunction and given that care needs with tracheostomy are likely to require institutionalization or impose a high burden for home caregivers. If tracheostomy ventilation is chosen, discussions should occur early on with patients and families to establish the conditions under which ventilation will be withdrawn (eg, If a "locked in" state occurs.) 1. physiologic parameters 2. survival 3. rate of progression of disease 4. time to ventilation
The role of exercise in ALS remains unclear. There has been concern that compensatory overuse of surviving muscle groups may worsen neural dysfunction and potentially accelerate the loss of motor units. 93 In contrast, other studies have suggested that exercise may be safe and effective in slowing the decline in muscle strength. Inspiratory muscle training has been investigated in other neurological diseases such as spinal cord injury 97 and Duchenne muscular dystrophy, 98,99 but the results of these studies may not necessarily be relevant to a rapidly progressive degenerative neurological condition.
In a 2008 cohort study of ALS patients looking at a specific breathing pattern accentuating the diaphragmatic component of inspiration (Yoga breathing), 100 outcomes included QoL and FVC rate of decline. Patients served as their own controls with a 3 month run-in period measuring FVC monthly. They had difficulty in recruiting and, ultimately were able to analyze data from only 8 subjects. They found no improvement in FVC, QoL or rate of decline in FVC over 12 weeks.
A double blind RCT performed to address the question of safety and efficacy of inspiratory muscles training in ALS 101 recruited only 19 patients after screening 37 patients and looked at multiple outcomes including FVC, VC, SNIP, MIP, capillary blood gas, SF-36, ALSFRS-R and 6MWT. Although trends to improvement were seen, they found no significant difference between the groups and noted improvements in the MIP in both the training group and the control group. QoL was not impacted.
One trial looked at inspiratory muscle training (IMT) in ALS patients with early disease as defined by FVC > 70% predicted, MIP > 50% and an ALSFRS-R >24/40. 102 The trial design used a delayed intervention group as the comparator group. Group one started training at the onset of the study and group two started IMT 4 months after group one. The study lasted a total of 8 months. Their primary outcome was the ALS functional rating scale (ALSFRS) with secondary outcomes including multiple measures of respiratory function and QoL. There was no significant difference between groups in the ALSFRS or any other measure of respiratory function with the exception of the MVV, which was significantly different only at 4 months. Dyspnea was assessed using a visual analog scale and did not differ between groups. QoL showed no difference between groups using the Euro-QoL-5D questionnaire. There was also no difference in depression, fatigue or functional status, all assessed by questionnaires. In an extension of this study that included 18 patients from both groups 1 and 2, survival was measured and compared to historical controls. 103 The IMT group had a significantly longer survival from symptom onset than the historical controls: 36.99 months in the IMT group, 24.06 months in the historical controls.
Finally, the impact of expiratory strength training in ALS was studied in a delayed intervention open label trial. 104 After enrollment, there was a five week period during which no training occurred. Their primary outcome was MEP with secondary outcomes including analysis of swallowing, cough and aspiration risk. There was a significant increase in MEP and in maximal hyoid elevation after 5 weeks of treatment, but no change in cough or other parameters of the swallow assessment.
A systematic review 105 and a meta-analysis 106 have been published looking at the question of benefit of respiratory muscle training in ALS. The earlier systematic review 105 found no convincing evidence of benefit. The subsequent meta-analysis 106 looked at studies that included both ALS and Multiple Sclerosis patients. They found that MIP, MEP and FEV1 improved without change in FVC. Caution is recommended in applying this study to the ALS population given the small number of ALS patients included in the meta-analysis.
It is of note when reviewing the individual studies that the nature of the training varied from study to study in duration, intensity and training protocols. It can be noted that there did not appear to be harm associated with respiratory muscle training. 1. physiologic parameters 2. survival 3. rate of progression of disease 4. time to ventilation
# Conclusions
No convincing evidence was found to support improved physiologic parameters, longer survival or slowing in rate of progression of disease using respiratory muscle training. Delay in time to ventilation was not assessed. Small numbers of patients were included in the studies.
Recommendation:
- We do not suggest respiratory muscle training in ALS patients. (GRADE 2C)
# Clinical remark:
There does not appear to be harm associated with respiratory muscle training.
Section 5. Diaphragm pacing in ALS PICO 5: As compared to standard care, does diaphragm pacing, with or without concurrent noninvasive ventilation:
- Prolong survival 2. Delay the time to requirement for noninvasive ventilation 3. Slow disease progression or 4. Improve QoL?
A system for diaphragm pacing, which inserted electrodes into the inferior surface of the diaphragm adjacent to the motor end points to stimulate diaphragm contraction, has been developed primarily for ventilator dependent spinal cord injured patients. It was hypothesized that stimulating intact motor units in the diaphragm of ALS patients may prevent atrophy and slow rate of decline of respiratory muscle weakness resulting in improved survival or delayed time to ventilation. A pilot trial began implanting ALS patients in 2005 and subsequent reports of this surgical cohort suggested slowing in the rate of decline of FVC which was extrapolated to improvement in survival. 107 In 2012, 8 ALS patients paced with this pacing system were reported and compared to 354 patients that were not treated with pacing. 108 Poor tolerance was found to pacing, with 6 of their 8 patients decreasing the pacer settings and 4 of the 8 stopping pacing entirely. They also noted more rapid decline in VC and a shorter survival when compared to their cohort of ALS patients referred between 1996 and 2011.
Two RCTs of diaphragm pacing in ALS have now been reported.
The DiPALS study 109 compared NIV plus pacing (n ¼ 37) to NIV alone (n ¼ 37) with initiation when respiratory insufficiency was present as defined by one or more of the following: a VC 50-75% predicted, SNIP 6kPa in the day or 6.5kPa at night or nocturnal desaturation. A total of 37 patients were enrolled in each arm. Their primary endpoint was survival from randomization to death. They also reported survival from symptom onset, QoL, compliance and adverse events. The study was terminated prematurely when the Data Monitoring and Ethics Committee noted a concerning signal in overall survival figures. They found that survival from symptom onset in the paced plus NIV group was 28 months as compared to NIV alone, which was 45 months. The patient health utility score (EQ-5D-3L) was slightly lower with pacing, although other HRQoL questionnaires were similar between the two groups. They concluded that diaphragmatic pacing should not be a routine treatment for ALS patients in respiratory failure.
The RespiStimALS study 110 enrolled patients that did not require NIV and had FVC 60-80% of predicted with evidence of diaphragm function with a phrenic stimulus. Patients meeting these criteria were randomized to receive pacing or standard care with initiation of NIV in both groups when an indication occurred. All patients had pacer insertion soon after enrollment with the control group receiving an inactive cable and sham pacing. When criteria for NIV were met, the treatment was unmasked and all patients received both pacing and NIV. NIV was initiated when FVC 45, MIP or SNIP < 60% predicted, or nocturnal hypoxemia with 5% of recording time <90% or 5 consecutive minutes below a saturation of 88%. Decision to initiate NIV was established by an independent allocation committee. 37 patients were in each group. The study was terminated early by the study independent safety committee after becoming aware of the results of the DiPALS study and calling for a formal unplanned masked interim survival analysis which showed a mortality difference. The primary outcome was NIV free survival from randomization. They also reported survival from symptom onset, QoL and rate of decline of FVC, MIP and SNP. The median NIV free survival from randomization was 6.0 months in the early paced group and 8.8 months in the standard care group. Median survival from symptom onset in the early paced group was 51 months and this endpoint was not reached in the sham paced group. There was a more rapid decline in FVC, MIP and SNP in the early pacer group. QoL was not different between the two groups. It is interesting that the "pacer use" was higher in the sham group at the time of NIV initiation suggesting possible poor tolerance in the active pacing group. The authors concluded that there was no benefit to early pacing in terms of delay to NIV requirement or QoL and that it decreased survival.
These two RCTs both concluded that diaphragm pacing has no benefit and, in fact, may be harmful with a more rapid decline and shortened survival. The mechanism is unknown though both authors speculated on reasons for their findings. These studies are in contrast to the earlier positive reports in the surgical cohort studies. Both authors speculated that the 3 month run in period in the surgical cohort may have selected for patients with a slower disease progression, given that those with more rapid decline may have been excluded after the run-in period. In three older studies examining the benefit of NIV in ALS, both pressure and volume capable ventilators were used in the same study 22,23,71 implying that the authors considered the two modes were equivalent for the purpose of assessing benefit. Studies comparing the two modes have been reported in mixed populations. One study 113 included both restrictive and obstructive diseases, each having different respiratory mechanics. The conclusion of these studies reporting on mixed groups was that either mode is appropriate for use in most patients. It is interesting to note that in this study, approximately one-third of the patients were bilevel "non-responders" with elevated PCO2 and reduced nocturnal saturation when treated with Bi-level. In this study, "non-responders" were returned to volume ventilation. The conclusion was that the majority of patients successfully treated with volume-cycled ventilation could also be adequately maintained on pressure controlled ventilation; however, data showed that some were less well ventilated on pressure ventilation and required a volume targeted mode. In other studies comparing the two modes of ventilation, authors report a patient preference in some. Bach proposed volume cycled ventilators in one study looking at noninvasive support in the ALS population given that the ventilator could then be used to breath stack to Maximal Inspiratory Capacity (MIC) as an aid to airway clearance. 27 A more recent study 115 investigated whether the mode of noninvasive ventilation affected survival, gas exchange, and clinical outcomes in ALS. A French center using pressure targeted NIV was compared to a Spanish center using volume cycled NIV. The primary outcome was survival and there was no difference between centres. Symptom control appeared better with volume control NIV as well as gas exchange, time spent nocturnally with a saturation of less than 90%, mean saturation at night and minimum saturation. It is of note that the Norris Bulbar Score was significantly lower (poor bulbar function) in the pressure targeted group which may have influenced their secondary outcomes.
A study looking at tolerance of volume ventilation in ALS enrolled 87 patients who were initiated as inpatients. 116 Results showed that it was well tolerated by 92% of patients at 3 month assessment. The 8% who were intolerant were readmitted at 3 months for further habituation and remained intolerant. There was no comment on whether alternate modes were tried in the intolerant patients.
Prior studies have assessed ventilator pressure settings, including PEEP and EPAP. One evaluated the use of PEEP or end expiratory pressure in a dual limb circuit set up with a pressure targeted mode of ventilation. 117 End expiratory pressure of zero vs 4 cm was evaluated. Leaks were higher with PEEP 4 cm. They also noted increased auto-triggering and ineffective efforts with PEEP 4 cm. Decreased N3 sleep and higher sympathetic tone were also noted with the application of end expiratory pressure. On the other hand, EPAP pressure of up to 10 cm was allowed to abolish obstructions in one study, which suggested that unresolved obstructions were associated with higher mortality. 44 A recent study compared pressure support ventilation with volume assured pressure support (VAPS) in a retrospective review of ALS patients. 118 215 patients using pressure support were compared to 56 patients on volume assured pressure support. Both modes were well tolerated. Volume was more consistent with the volume assured group. It is likely the VAPS device was favored because the IPAP pressures in the pressure support mode were relatively low and the inspiratory times short (approximately 1 sec) and the rise times >600 msec, predisposing to smaller tidal volumes in those without a target volume.
Spontaneous timed (S/T) mode was compared to spontaneous (S) mode bilevel ventilation 119 in ALS patients and was found to improve gas exchange, respiratory events and patient ventilator synchrony when compared to the S mode.
Use of daytime mouthpiece ventilation 120 and nighttime bilevel pressure ventilation with a mask has been reported in a series of selected ALS patients. The authors defined this mode as an option in patients without significant bulbar dysfunction who require 24 hour ventilation. They noted that patients derived the greatest survival benefit if they could generate an assisted PCF > 180 L/min at initiation of mouthpiece ventilation.
Another question that remains unanswered is the optimal way to titrate NIV or to determine appropriate ventilator settings in this population. Many older studies did not describe how the ventilator settings were determined. Polysomnography to establish ventilator settings was previously rarely reported. More recently an ambulatory outpatient model of NIV initiation was described that involved an empiric daytime titration followed in 4-6 weeks by polysomnography for further titration. 75 Their comparator was an inpatient initiation model. The outpatient model showed shortened wait times for ambulatory initiation of NIV and improved survival. Other groups continue to admit patients for titrations and habituation. In the study by Martinez looking at tolerance of volume control ventilation, length of stay averaged 4.7 days for inpatient initiation of NIV. 116 Regardless of the method of initial titration, follow-up to assure adequate ventilation is suggested by 2 recent studies 43,44 reporting shortened survival with ineffective ventilation. Attention to initial titration and follow-up at 1, 3 and 6 months for evaluation and adjustment is suggested. In these studies, ventilator download with associated oximetry was used to assess adequacy of ventilation.
# Conclusions
There are limited data comparing modes of NIV, settings or initiation protocols. There is a trend in many centres across the world to use pressure targeted ventilators which generally can be purchased at lower cost than ventilators providing volume control ventilation. Pressure targeted and volume targeted modes had similar survival in one recent study. Volume controlled modes, however, offered some advantages in symptom control, gas exchange and nocturnal oxygenation, but the study specifically addressing this noted a lower Norris bulbar score in the pressure targeted group which may have influenced the effectiveness of ventilation. Pressure support is often felt to be better tolerated than volume control modes, though one study showed that 92% of patients tolerated a volume control mode. When using a pressure targeted ventilator, the mode should control inspiratory time for both spontaneous and machine delivered breaths.
Both inpatient and outpatient protocols for NIV initiation have been reported and both are effective, though outpatient initiation may be preferred by patients and associated with better survival (possibly because of a shorter duration to initiation) and less cost.
# Recommendations:
- We recommend S/T mode à over S mode when delivering ventilation with pressure targeted devices. (GRADE 1C) 2. No recommendation can be made for the preferred location of the initial titration (outpatient initiation, sleep lab, or inpatient admission are all acceptable); however, delays should not be incurred irrespective of selected location. (GRADE 1C) 3. Volume-controlled ventilation is an acceptable mode and we recommend that it be used if pressure targeted modes are not tolerated or ineffective. (GRADE 1C) 4. In patients with intact bulbar function who are receiving nocturnal ventilation, we recommend use of mouthpiece ventilation rather than tracheostomy when additional daytime ventilation is required. A nasal interface may be acceptable if preferred. (GRADE 1C) - Clinical remarks: Although S/T mode may improve gas exchange, respiratory events and synchrony when compared to S mode, care must be taken to assure that Ti (inspiratory time) is sufficiently long to provide adequate tidal volume and minute ventilation. In the S/T mode where the Ti is not controlled during spontaneous breaths, Ti may be too short to provide adequate tidal volume. If the percentage of triggered breaths is high, adequate support and ventilation may not be achieved. This can be resolved by use of the PC mode on ventilators that do not control Ti when the patient is triggering the device or breathing above the set rate. Other devices will control Ti on all breaths and an adequate inspiratory time may be achieved by setting a sufficiently long minimum Ti. Recommended Ti in neuromuscular patients without underlying airways disease is 1.2 to 1.5 seconds: up to a 1:1 ratio which is dependent on respiratory rate. (expert consensus)
# Summary
There is increasing evidence of benefit of HMV in patients with ALS. The current guideline reviews reported benefits and seeks to advise on monitoring of respiratory status in ALS and timing of initiation of noninvasive ventilation.
There is limited evidence on optimal settings and modes for patients using NIV in ALS though a timed or controlled mode is preferred. Tracheostomy remains an option for well-informed patients with ALS, but is associated with a high burden of care. Respiratory muscle training has not been shown to offer clear benefit and cannot be recommended at this time. RCTs, completed since the last publication of this guideline and addressing diaphragm pacing in ALS, have shown harm and pacing is not advised. Much research remains to be done. Device download remotely is increasingly available and its use to improve outcomes requires further assessment. Optimal timing of NIV to optimize benefit remains an ongoing question, in particular in bulbar predominant ALS.
The intention of the CTS guideline panel for HMV is to report on changes to this guideline going forward as new evidence is published and reviewed, creating a "living document" available on the CTS website.
# Implementation
The most relevant and important of the recommendations are those addressing monitoring before and after initiation of NIV and indications for initiation of noninvasive ventilation (PICO question 2).
# Implementation of these recommendations
- Wide dissemination given the variety of care providers for ALS patients An abridged online and electronic copy "quick reference" guide with reference link to the full document will be circulated to key stakeholders involved in care of the ALS patient. This includes: a. Directors and clinic coordinators of ALS clinics in Canada b. The Canadian ALS Research Network (CALS) who can distribute electronically and on their platform to corresponding members, as well as introduce and present it during their quarterly meetings c. The Canadian Association of Physical Medicine and Rehabilitation: neuromuscular Special Interest Group d. Respirologists in Canada with membership in the Canadian Thoracic Society e. ALS Canada with intent to distribute to provincial societies, and to make available in their online resources, accessible to clinicians, researchers and community via the ALS Canada website f. Canadian Society of Respiratory Therapists
# ALS clinic interaction nationally
Authors of this guideline are from across Canada and can present locally to respirologists, neurologists, physiatrists and ALS clinics. Annually, there is a national ALS Research symposium hosted by ALS Canada with participants and clinical leaders from centres across Canada. These guidelines will be presented, and a poster of the abridged recommendations and links will be available throughout the meeting.
Every ALS Clinic in Canada has representation at the Canadian ALS Research Network, and is typically linked to their respective provincial societies, and to ALS Canada. This strong network between researchers, clinicians, community advocates and patients/families will be instrumental in ensuring broad dissemination.
# Cost considerations
The aforementioned strategies are associated with minimal cost implications and maximal impact. The primary cost may be related to the purchase of equipment recommended for monitoring which is associated with a minimal initial cost outlay, but may have ongoing cost associated with disposables.
# Measures of successful implementation and dissemination
As care of the individual with ALS may be by individual neurologists, physiatrists, respirologists or ALS centres, it will be challenging to monitor adoption of the guideline. The most reliable data collection at present is by ALS clinics and by the Canadian ALS research network and it is for this reason that a survey of compliance will be done through ALS clinics and the research network. At 12-24 months post publication and distribution, ALS clinics across Canada will be surveyed to assess their knowledge of and compliance with recommendations.
# Current gaps and future research needs
The guideline panel identified areas where further research would improve the ability of clinicians to optimally manage patients with ALS.
- Evaluation of device download driven setting changes (both remotely and at clinic assessments) to improve outcomes such as adherence, optimal ventilation, hospital admissions and survival. 2. Ongoing evaluation of optimal timing, in particular, in bulbar predominant patients. Guideline Committee, Samir Gupta, for their guidance throughout the process. We would also like to acknowledge with deep appreciation our expert peer reviewers who made valuable contributions to the manuscript: J esus Gonzalez-Bermejo, Hôpitaux Universitaires Piti e Salpêtri ere-Charles Foix, Paris, France; Noah Lechtzin, John Hopkins Hospital, Baltimore, Maryland, United States; David Leasa, London Health Sciences Centre, London, Ontario, Canada; and Jeremy Road, Vancouver General Hospital, Vancouver, British Columbia, Canada.
# Editorial independence
The CTS HMV Clinical Assembly is accountable to the CTS Canadian Respiratory Guideline Committee and the CTS Board of Directors. The CTS HMV Clinical Assembly is functionally and editorially independent from any funding sources of the CTS and does not receive any direct funding from external sources. The CTS receives unrestricted grants which are combined into a central operating account to facilitate the knowledge translation activities of the CTS Clinical Assemblies. No funders played a role in the collection, review, analysis or interpretation of the scientific literature or in any decisions regarding the key messages presented in this document.
# Disclosures
Members of the CTS HMV Assembly declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy. Individual member conflict of interest statements are posted at /.
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Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder involving both upper and lower motor neurons that results in progressive weakness of skeletal muscles. Regardless of site of first onset, death usually occurs as a result of progressive respiratory muscle involvement, with 50% of patients dying within three years of symptom onset. Mechanical ventilation is becoming increasingly accepted in ALS. In Canada, noninvasive ventilation is the most common form of ventilation applied, with tracheostomy ventilation being very uncommon. The current guideline addresses respiratory muscle testing, the benefits of mechanical ventilation in ALS, timing of initiation of ventilation and modes, settings and place of initiation. It also reviews diaphragm pacing and respiratory muscle training. Finally, given the challenges involved with tracheostomy ventilation in ALS, the question of tracheostomy ventilation is addressed.#
La scl erose lat erale amyotrophique est une affection neurod eg en erative impliquant les neurones moteurs sup erieurs et inf erieurs qui r esulte en une faiblesse progressive des muscles squelettiques. Ind ependamment de la premi ere r egion du corps o u elle se manifeste, elle entraine habituellement la mort en raison de l'implication progressive des muscles respiratoires : 50% des patients meurent dans les trois ans suivant l'apparition des symptômes. La ventilation m ecanique est de plus en plus accept ee dans les cas de SLA. Au Canada, la ventilation non invasive est la forme la plus commune de ventilation appliqu ee, tandis que la trach eotomie est tr es rare. Cette ligne directrice porte sur l' evaluation des muscles respiratoires, les avantages de la ventilation m ecanique dans les cas de SLA, le moment o u commencer la ventilation, les modes de ventilation, le param etrage et le lieu o u d ebuter la ventilation. Elle aborde aussi la stimulation du diaphragme et l'entraînement de la musculature respiratoire. Finalement, etant donn e les d efis que pr esente la ventilation par trach eotomie dans les cas de SLA, la question de la ventilation par trach eostomie est aussi abord ee.
# Introduction
The first Canadian Thoracic society (CTS) guideline for Home Mechanical Ventilation (HMV) was published in 2011 1 and included a section detailing recommendations for HMV for patients with Amyotrophic Lateral Sclerosis (ALS). This is the first update of the ALS section of that guideline and is intended for use as a standalone document making recommendations on the respiratory care of ALS patients. It excludes airway clearance and recruitment techniques in ALS and other neuromuscular disorders that were addressed in the 2011 guideline and that will be covered in an upcoming update by the CTS HMV clinical assembly. Airway clearance and recruitment are recognized to be of critical importance in the care of ALS patients.
ALS is a neurodegenerative disorder involving both upper and lower motor neurons that results in progressive weakness of skeletal muscles. Generally, onset of weakness is characterized as either limb or bulbar. Less commonly, approximately 3% of ALS cases in referral centres, the first presentation is with respiratory symptoms secondary to early respiratory muscle involvement. 2,3 Regardless of site of first onset, death usually occurs as a result of progressive respiratory muscle involvement, with 50% of patients dying within three years of symptom onset. 4 Patients with bulbar onset ALS generally have a shorter survival than those with limb onset. 5 The rapid progression to death separates ALS from most other neuromuscular disorders (NMDs) for which noninvasive ventilation (NIV) and tracheostomy ventilation are considered. ALS is also distinct from other medical conditions for which chronic mechanical ventilation is provided, including other neuromuscular disorders (NMDs), by virtue of having the poorest survival using ventilation. In one case series, only 5% of ALS patients using mechanical ventilation were alive after five years, as compared to more than 60% of patients with other neuromuscular diagnoses. 6 Ninety-five percent of the ALS patients using home ventilation in the Swedish Home Mechanical Ventilation registry 6 were using it noninvasively, a number similar to data from the North American ALS CARE database, which has remained largely unchanged since 1996 when it was created. 7 Use of home ventilation is increasing despite some debate regarding the ethics of prolonging survival in such a rapidly progressive disorder with poor survival on NIV. 6 In 1999, Melo published a survey of multidisciplinary ALS clinics and found that only 15% of eligible patients were using NIV. 8 This number was similar to that reported in the ALS CARE database two years later. 9 The ALS CARE database was reviewed again in 2006, following many reports of positive outcomes with the use of NIV and found that 36.2% of patients considered to be candidates were using NIV. 10 A Canadian survey of ALS centres published in 2010 found that NIV was used by 18.3% of patients, while only 1.5% were reported as tracheostomy ventilated. 11 The increasing trend in use of NIV in ALS was highlighted by a 2012 publication reviewing the UK experience. 12 They noted a 3.4 fold increase in NIV use in ALS between 2000 and 2012. An Australian database reporting on a large cohort of patients with ALS found 23% of their patients between 1991 and 2011 received NIV. 13 Some countries have reported particularly high incidences of NIV use. A recently published Japanese study reported that 52% of their patients used NIV after 2000. 14 Finally, a single center report from Denmark also reported a high incidence of 42.3% treated with NIV between 1998 and 2012. 15 Although there may be variability in its use, the focus in the ALS literature now is not whether or not to offer NIV, but rather the optimal timing and criteria for initiation of NIV.
# Differences from prior guideline published in 2011
This clinical practice guideline is an update from an earlier guideline that was published in 2011 by the Canadian Thoracic Society. 1 Changes in the content from the prior guideline include the following:
1. Further reports of the benefits of HMV. 2. New techniques to evaluate respiratory muscles are discussed, and reevaluation of previously reported respiratory testing. 3. Exploration of the rationale for earlier timing, with less focus on a cut off value for vital capacity. 4. Review and recommendations regarding respiratory muscle training in the ALS population. 5. More conclusive evidence regarding diaphragm pacing after publication of two randomized controlled trials (RCTs) showing negative outcomes.
6. Recommendation of mouthpiece ventilation as an option in a subgroup of ALS patients.
# Exclusion of any discussion of airway clearance in ALS.
This is recognized to be of critical importance, was addressed in the 2011 guideline, 1 and is currently under review by the HMV clinical assembly.
# Target patient population
The current clinical practice guideline applies to all adult individuals with Amyotrophic Lateral Sclerosis who are at risk for or are using HMV.
# Target users
The present clinical practice guideline is intended for use by the health care teams that care for individuals who are at risk for or require ventilatory assistance. Respirologists, physiatrists, neurologists, family practitioners, nurses, respiratory therapists, physiotherapists and other health care professionals can use this guideline to help inform their clinical practice with regard to HMV. This guideline is also intended for use by ventilator-assisted individuals (VAIs) and their caregivers to help them make informed decisions on HMV and by health care decision makers to aid in establishing policy and making funding decisions.
# Guideline panel composition
The CTS HMV guideline panel was interprofessional and was comprised of HMV clinicians and health care professionals with content expertise. The panel was chaired by one author and included seven adult respirologists, one physiatrist specializing in neurorehabilitation and one registered respiratory therapist. All author conflicts of interests are posted on the CTS website at https://cts-sct.ca/guideline-library/. Patient and caregiver input was not sought in development of this guideline, which is a weakness of the current guideline and which will be corrected in the next update of this document.
# Methodology
This clinical practice guideline was developed in accordance with the CTS guideline production methodology (https://ctssct.ca/guidelines). The panel utilized the AGREE II checklist 16 to guide the development of this guideline. Selection of key clinical questions: The primary author and the chair of the guideline panel determined key clinical questions based on their own knowledge of the literature and existing guidelines in the areas of benefits of mechanical ventilation in ALS; respiratory muscle testing and monitoring; timing of initiation of ventilation; modes, settings and place of initiation; diaphragm pacing; respiratory muscle training; and tracheostomy ventilation. Draft questions were then reviewed, discussed and revised by the panel with the final questions chosen to address significant changes since the last guideline, and gaps not addressed by prior guidelines in the area of ALS care. Using the PICO method, the panel took into consideration the Patient group or groups that should be addressed, the Intervention or interventions that should be examined, the Comparison groups that should be part of the studies of the various interventions and the Outcome or outcomes of interest. In the second part of the PICO process, panel members were asked to consider issues that influence implementability, when choosing PICO questions: the magnitude of the knowledge-tocare gap; target audiences; known barriers and supports to implementation; societal impact; and measurability of any implementation program. Members reached consensus on these questions over several teleconference meetings, webinars and email exchanges.
Literature search and screening of abstracts: An initial literature search was completed current to September 2017 using MEDLINE (OVID); Embase (OVID); HealthStar; the Cochrane Library: the Canadian Medical Association InfoBase; and the National Guideline Clearinghouse. The second literature search was conducted through to March 31, 2018 to include the most recent literature. Additional articles were found by review of the references in the articles accepted. Details of the search strategy are outlined in Appendix 1. The abstracts were assessed independently by two panel members for inclusion or exclusion and conflicts were resolved by discussion between panel members.
Study selection criteria: Following the completion of the abstract screening, the full text articles were retrieved and reviewed. Articles were selected for inclusion in the systematic review if they were directly relevant to one of the six PICO questions. All types of reports were considered and included guidelines, meta-analysis, systematic review, randomized controlled trial, cohort study, case control study, case series or case report.
Critical appraisal of identified studies: Data from all articles relevant to each PICO question were abstracted into tables by the lead author and can be found on the CTS website, at https://cts-sct.ca/guideline-library/. During discussion of each question via webinars held in June and July of 2018, the data were reviewed by the panel, and evidence addressing each clinical question was assessed according to the components of the GRADE 17 criteria (Table 1).
Synthesis of evidence-based clinical judgement of risk versus clinical benefit: For each clinical question, the panel considered the strength and directness of the published evidence supporting an intervention or treatment approach. The panel discussed the potential health benefit to the patient, the overall impact on the population burden of morbidity and mortality of ALS, and issues of risk, burden on a patient to adhere and cost effectiveness of an intervention or treatment. These discussions and the resulting synthesis of clinical judgement are presented for each recommendation.
Clinical remarks are included in association with each clinical question and are intended to offer experienced advice to the target user. Some of these good practice points may not have an evidence base, but are viewed as good clinical practice by the expert panel. All good practice points were arrived at by consensus, based on the clinical experience of the guideline panel members.
# Formulation of recommendations and classification:
Following the open and extensive discussions and review of evidence for each PICO question, a draft recommendation was proposed. The strength of the recommendation was based on consideration both of the GRADE quality of evidence, and the expert panel's synthesis of clinical judgement. In accordance with CTS methodology, the recommendations were then reviewed by the CTS Canadian Respiratory Guideline Committee (CRGC) Chair to optimize the language of each recommendation with a view to improving intrinsic implementability. 18 Next, a recommendation consensus process was completed by electronic survey using a six-point voting scale (Table 2). For a recommendation to be accepted, it had to be voted on by 75% of the panel members and achieve ratings of "wholeheartedly agree," "agree" or "can support" by ! 80% of the voting panelists. In the event of a failure to reach this threshold, another period of discussion ensued, whereby dissenting opinions were heard and considered. The recommendation was then revised, followed by a second round of electronic voting using a three-point scale (Table 2), with acceptance of a recommendation requiring ! 80% of the voting panelists choosing option 1 or 2. Through this process, all recommendations achieved acceptance, with a second round of voting required for only 3/22 recommendations.
# Applicability
Facilitators and barriers to its application: The tools exist for implementation of the recommendations of this guideline. Equipment is readily available and provincially funded in Canada in most, though not all, provinces and territories and the minimum required monitoring can be performed in both large and small centres. Unfortunately, not all ALS patients are cared for in multidisciplinary ALS clinics and, in ALS clinics, the model of respiratory care is inconsistent. This may be a barrier to application.
Advice and/or tools on how the recommendations can be put into practice: Optimally, all ALS patients should be regularly followed in multidisciplinary ALS clinics with experienced respiratory therapists and respirologists; however, this may not be an immediately achievable goal.
Protocolizing follow up and respiratory monitoring for ALS patients, whether followed by individual respirologists, neurologists or family physicians, can identify patients requiring intervention leading to timely initiation of noninvasive and the positive outcomes detailed in this document.
Registered Respiratory Therapists (RRTs) are excellent resources and individual health regions should be encouraged to capitalize on their expertise. Busy respirologists have come to rely on RRTs in health regions where they are trained to initiate and monitor noninvasive ventilation in association with a clinic specializing in HMV. RRTs alert team members to changes in status and needs and can be an excellent "early warning" system of a failing respiratory status in the ALS population. Health regions should be lobbied to include experienced RRTs in their ALS clinics and home care teams. The RRT community resource can be used for other ventilated and at risk populations making it valuable for a larger number of individuals.
Potential resource implications of this guideline: Excellent and timely care of the ALS population has the potential to reduce acute care needs and overall cost to the system. The equipment is already currently funded in most jurisdictions and the equipment costs are minor when compared to inpatient admission costs. The cost of adding newer monitoring equipment (eg, Sniff Nasal Inspiratory Pressure monitor) is small and can be absorbed by most of the larger centres.
Monitoring and/or auditing criteria: As care of the ALS patient may be by individual neurologists, respirologists or ALS centres, it will be challenging to monitor adoption of the guideline. The most reliable data collection at present is by ALS clinics and by the Canadian ALS Research network and it is for this reason that a survey of awareness and compliance will be done through ALS clinics and the Canadian ALS Research network. At 12-24 months post publication and distribution, ALS clinics across Canada will be surveyed to assess their knowledge of and compliance with recommendations.
# Review and approval process
In accordance with the CTS guideline review and approval process, before completion, CTS staff distributed the guideline for formal review by: 1) two international ALS content experts); and 2) two internal (CTS) reviewers with one reviewer performing an AGREE assessment of the guideline. The authors were blinded to the identities of the reviewers. The lead author considered AGREE II scores and reviewer comments, provided responses to the comments, and made corresponding changes to the manuscript. These reviews and the AGREE II scoresheet were provided to the CTS CRGC for review. The CRGC then reviewed these documents and provided further suggestions for edits that were considered by authors. The CRGC then recommended approval of a final draft of the guideline to the CTS Executive Committee. All reviews and author responses are posted on the CTS website at https://cts-sct.ca/guideline-library/.
# Living guideline/future updates
The HMV ALS guideline PICO questions will be uploaded in the CTS/McMaster Database, whereby authors will use the continuously updated McMaster Plus database to review Cannot supportblock it For a recommendation to be accepted, it has to be voted on by 75% of the eligible panel members and achieve ratings of wholeheartedly agree, agree, or can support by 80% of the voting panelists. If this is not achieved, additional discussion and revision of the recommendation(s) ensues, for which acceptance of a recommendation requires a majority (80%) for option 1 or 2.
new articles pertaining to these PICO questions published in top impact-factor journals as of April 2018. The studies are indexed according to the PICO questions, and made available to the guideline panel on a dedicated software platform for manual assignment to individual reviews. This evidence service will prompt guideline updates and facilitate year end reviews. The entire guideline will be reviewed every three years or sooner, to determine the need for guideline updates, in accordance with the CTS Living Guideline Model (details available at www.cts-sct.ca/guideline-library/).
# Summary of evidence
# Survival
The only randomized controlled trial (RCT) of noninvasive ventilation (NIV) with survival as a primary outcome was published by Bourke et al in 2006. 19 They screened 121 patients and ultimately recruited 92 patients to be followed every two months until randomization, which occurred if they met one or both of the pre-defined criteria: orthopnea with Peak inspiratory pressure (PImax) less than 60% predicted or symptomatic daytime hypercapnia. Ultimately, 41 were randomized and the data analyzed for all patients and also subdivided into "better" or "poor" bulbar function. All patients using NIV showed a modest survival advantage from randomization to death over those patients randomized to standard care excluding NIV: 219 (range 75-1382) days vs 171 (1-878) days. The subgroup with "better" bulbar function showed a much larger survival advantage with NIV compared to controls: 216 (range 94-681) days vs. 11 (1-283) days. There were six deaths of nine patients in the control group with better bulbar function within two weeks of enrollment. Five of the six had severe respiratory muscle weakness at enrollment. The "poor" bulbar function group showed improvement in health-related quality of life (HRQoL) if receiving NIV, but no survival benefit: 222 (range 75-1382) days vs 261 (6-878) days. The mean duration of daily use in this group, however, was less than four hours. In addition, the numbers were small and not powered to show survival benefit in the subgroup with poor bulbar function.
The Cochrane database of systematic reviews recently updated their review of mechanical ventilation in ALS in 2017 20 and found no new RCTs in this population addressing survival, disease progression or HRQoL. At the conclusion of their review, they commented that "more RCT evidence to support the use of NIV in ALS will be difficult to generate, as not offering NIV to the control group is no longer ethically justifiable." They commented that future studies should focus on the timing of initiation of NIV for maximal benefit.
Other prospective studies 6,[21][22][23]24 and retrospective studies [13][14][15][25][26][27] have reported prolonged survival in those using NIV. None of these studies was randomized, although attempts were made to provide a control group. The controls included patients refusing or intolerant of NIV or those using NIV less than 4 hours/day. 13,[22][23][24]26,28 Historical controls were also considered. 29 An Australian group 13 reported the largest cohort of patients (n ¼ 929), 23% of whom received NIV. They found a survival advantage in patients treated with NIV, surviving 28 months from symptom onset as compared to 15 months in those who did not receive NIV. Interestingly, the subgroup demonstrating the clearest survival benefit was the bulbar onset group with a 19 month survival advantage, which is in contrast to most other studies reporting NIV outcomes in patients with severe bulbar dysfunction. One other recent study did, however, report a clear survival advantage in patients with severe bulbar dysfunction. 24 Numbers of bulbar patients were small (n ¼ 15 NIV vs n ¼ 6 controls) in this study. The control group was comprised of patients declining NIV. More severe bulbar dysfunction, as measured by the Norris Bulbar Score, was a prognostic factor in NIV failure, although a cut off value of the Norris Bulbar Score was not suggested. Despite this, prolonged survival from disease onset was found in the severe bulbar group with NIV: 40 months in the NIV group vs 16 months in those refusing NIV. This suggests that those accepting and tolerating NIV with severe bulbar dysfunction show a significant survival benefit.
The survival benefit was modest in most of the reported studies; however, in one retrospective descriptive study reported by Bach's group 27 the survival benefit in a subgroup of patients with preserved bulbar function could be measured in years even when requiring continuous NIV.
# Quality of life
In the single RCT of NIV in ALS, 19 improved HRQoL was reported for patients randomized to NIV compared with standard care with no NIV. For those with "better" bulbar function, NIV resulted in large improvement across several measures of HRQoL when compared to controls. Patients with "poor" bulbar function randomized to NIV also showed improvement in HRQoL, although the improvement was less marked.
In other prospective studies reporting HRQoL, 21,23,30-33 authors consistently reported improvements in HRQoL in certain domains for patients using NIV. These included sustained improvements in mental health, energy/vitality, social isolation, fatigue and mastery. Physical function domains generally worsened as would be expected with disease progression.
# Gas exchange and pulmonary function
All studies reporting gas exchange after initiation of NIV 31,32,[34][35][36] show reduction of daytime partial pressure of carbon dioxide (pCO2) after initiation of nocturnal ventilation.
Five studies have reported the rate of decline of vital capacity (VC) before and after initiation of NIV. 13,23,27,28,30 Four of these studies 13,27,28,30 showed a slowing of decline of lung function after successful initiation of NIV, while in contrast, one study 23 reported a decrease in VC after initiation of NIV.
# Sleep
There are many reasons for sleep disruption in patients with ALS. Limited ability to change body position, pain and anxiety may all be factors. As with other neuromuscular disorders that involve respiratory muscles, sleep fragmentation by breathing related arousals has been reported. Early studies looking at sleep in patients with ALS sought to characterize the nature of the sleep disturbance that occurred, with recent studies looking more systematically at the effect of NIV on sleep parameters and HRQoL. Seven early studies that characterize breathing related sleep abnormalities specifically in patients with ALS 25,34,[37][38][39][40][41] reported a decrease in total sleep time and sleep efficiency, increased stage 1 sleep and reduced REM sleep. The predominant pattern of sleep disordered breathing was not obstructive apneas, but rather, mixed apneas, central apneas and hypoventilation. Among these studies patient selection varied widely. In two of the studies, 25,34 patients selected had more advanced disease, with either very low VC (mean 52%) or symptoms suggesting sleep disordered breathing. Patients in other studies were asymptomatic 39 or had normal pulmonary function and diaphragm function. 41 Given bulbar involvement by ALS, the possibility of upper airway obstruction during sleep has been raised. Ferguson et al 38 found obstructive apneas did not occur; however, other investigators have noted obstructions in some subjects. [42][43][44] In four of the seven early studies, 25,34,37,38 at least one subject was treated with NIV. Observations included improvement in sleep architecture, decreased breathing related arousals, improved oxygenation during sleep and improved symptoms related to sleep disordered breathing. In another, 31 cognitive impairment improved after NIV and was assumed to be related to correction of sleep disordered breathing.
More recent studies have reported the effect on HRQoL and sleep parameters with NIV. Sustained improvement in the Epworth Sleepiness Scale (ESS) and Pittsburg Sleep Quality Index (PSQI) and some subscales of the McGill QoL (MQoL) questionnaire were found and scores did not fall below baseline despite worsening ALSFRS scores. 36 One author 42 reported on the effect of NIV on sleep and showed that the minimum saturation improved by 7% with NIV. Time spent <90% also improved with NIV though other sleep parameters showed no significant change (sleep efficiency, AHI, arousal index or sleep architecture). Another report 45 found that those with bulbar dysfunction had better quality sleep at baseline with less change noted after NIV initiation compared to non-bulbar patients. PSQI did improve in bulbar patients though improvements in ESS, and MQoL were observed only in non-bulbar patients. In the entire cohort, N3 sleep and REM increased and arousal-awakening index (AAI) improved. The short form survey (SF-36) emotional health subscale also improved. A later report by the same authors 46 studied patient ventilator asynchrony, leaks and sleep quality. They noted the commonest asynchrony was ineffective efforts and that despite meticulous titration, patient ventilator asynchrony and leaks persisted, although interestingly, had a minor impact on sleep.
# Respiratory testing
Measuring lung function in ALS serves two purposes. First, it has been shown that some measures of lung function are better predictors of survival than functional rating scales. 5,6,47,48 This information could facilitate the design of studies evaluating new therapies, such as medications, in order to enrich the study population, possibly requiring fewer patients to achieve significance and aid in sample size calculations. Second, monitoring lung function helps guide the timing of interventions such as initiation of NIV. Earlier literature focused on measures of lung function which predicted daytime hypercapnia, a logical criterion to initiate mechanical ventilation. More recently, however, there has been a focus on predicting nocturnal sleep disordered breathing for the purpose of earlier initiation of ventilation before onset of daytime hypercapnia with the goal of improving outcomes such as survival or HRQoL.
An earlier study looked extensively at predictors of daytime hypercapnia. 49 It assessed VC, FEV1, peak inspiratory pressure (PImax), peak expiratory pressure (PEmax), sniff transdiaphragmatic pressure (Pdi), sniff esophageal pressure (Poes), sniff nasal pressure (SNP), cough gastric pressure (Pgas), bilateral cervical magnetic stimulation (CMS) Pdi and arterial blood gas (ABGs). Sniff Pdi and CMS Pdi had the greatest predictive power for the presence of daytime hypercapnia. Of the less invasive tests, Sniff nasal inspiratory pressure (SNP) had the best predictive power. This predictive power was limited to those patients without significant bulbar dysfunction. No test reliably predicted hypercapnia in the patients with bulbar dysfunction.
Hypercapnia, though a relatively late finding, remains an indication for initiation of HMV and can be determined by ABG, or capillary blood gas 50 or transcutaneous CO2. 51,52 A more recent assessment 53 of the predictive power of invasive and noninvasive respiratory muscle strength assessments for survival or ventilator free survival showed that VC had a good predictive power, but the cutoff value for a good outcome was in the normal range (>80% predicted) for all time intervals beyond 3 months. Although all tests of muscle strength predicted ventilator free survival, they had varying sensitivities. Sniff and Twitch transdiaphragmatic pressure were the best performing tests for ventilator free survival, although SNP also was shown to have a good predictive value. Maximal expiratory pressure (MEP) and MEP% predicted were also useful predictive tests. Supine forced vital capacity (FVC) was not assessed.
SNP has gained popularity in assessing the respiratory muscles as it is more sensitive to early muscle weakness than FVC 54 and can be performed by most patients, even those with advanced disease and bulbar dysfunction. 55 A SNP less (reduced strength 1 * ) than -40 cmH2O was shown to be significantly correlated with nocturnal hypoxemia and patients at this level had a median survival of only 6 months. 54 A more recent study 56 looked at SNP and other measures of lung function, including FVC, for predicting death at one year. A SNP < -50 cmH2O was more likely to be associated with death at one year and a SNP of > -70 cmH2O resulted in improved survival at one year. Ultimately a SNP cutoff value of -34 cmH20 was found to have a sensitivity of 0.75 and a specificity of 0.72 for death at one year. The highest risk of death at one year was found in those with a sniff nasal pressure -18cmH2O. By comparison, the cut off value for FVC to predict death at one year was high at 75.9% and was less predictive for death at one year than SNP.
Maximal inspiratory pressure (MIP) is also a sensitive measure of early muscle dysfunction and can be used as the disease progresses to predict survival, but requires the patient to tolerate and be able to seal around the mouthpiece, or mask in order to perform the test. 53,57 Sitting VC is an insensitive measure of respiratory muscle weakness as it may remain normal even when respiratory muscle weakness is present. However, in one older study, when FVC falls to less than 50% predicted, survival was limited to nine months with most patients dying by six months. 47 Other authors have also noted the poor prognosis of patients with FVC < 50% predicted 48,58 and, therefore, it is recognized that FVC, when very low, is specific for impending respiratory failure and death. It has become increasingly recognized that sitting FVC or SVC are not the best predictors of muscle weakness and impending respiratory failure given that FVC may be normal or near normal when other measures of respiratory muscle strength may be significantly abnormal. 53,56,59 More sensitive to respiratory muscle weakness and diaphragmatic dysfunction, in particular, is supine VC. A correlation between the percentage fall in VC from the erect to the supine position and the lowest saturation during REM sleep 60 suggests that a drop in VC from the erect to the supine position may be used to predict abnormalities in breathing during sleep associated with diaphragm dysfunction. Others have found that the change in VC from the erect to supine posture correlates well with symptoms of dyspnea, orthopnea and daytime fatigue. 61 A normal supine FVC was highly predictive of survival at 2 years. 62 Another author found a Borg dyspnea scale !3 when supine to be a useful predictor of a SNP -40 cmH2O and impending respiratory failure. 63 Rate of decline of Slow Vital Capacity (SVC) has also been assessed 64 and shown to be strongly correlated with rate of decline of SNP and respiratory symptoms. The probability of respiratory failure free survival was estimated in this study by the rate of decline in the SVC suggesting that this is a useful prognostic tool. The finding of rate of decline of respiratory tests as a prognostic tool was confirmed by another study, 57 which looked at decline in VC, MIP or SNP, MEP and PCF and showed that the risk of death is significantly associated with the decline in pulmonary function regardless of the PFT parameter followed.
More recently the amplitude of the action potential with phrenic stimulation has been correlated with pulmonary function tests, symptoms and survival at one year. 65 When the amplitude of the action potential (Pamp) was < 0.3mV, the median survival was 1.07 years as compared to a Pamp > 0.3mV of greater than 2 years. It was also found that a Pamp < 0.3mV correlated with symptoms of dyspnea, orthopnea and tachypnea. This threshold value of Pamp was also correlated with reduced FVC, MIP and SNP. Another study 66 also found that an abnormal Pamp was a predictor of death using a cutoff value of 0.4mV with a HR of 1.653 for those with a Pamp of <0.4mV. This is a non-volitional test and could aid in defining populations for future interventional studies in ALS.
Given the difficulty with volitional tests in this population, in particular the bulbar predominant patients, other non-volitional tests have been investigated. Diaphragm thickness by ultrasound has been found to correlate with other tests of respiratory function and to the compound muscle action potential (CMAP) of the diaphragm. 67,68 This correlation, unfortunately, was less evident in patients with bulbar dysfunction and relatively mild symptoms, a population in which it may have been particularly helpful.
Lung function is essential in the follow-up of ALS patients, but equally important is a history that focuses on symptoms of dyspnea, orthopnea, poor sleep, excessive daytime sleepiness, morning headache and fatigue. The onset of dyspnea and rate of decline of VC predicted survival in one series. 69 Excessive daytime sleepiness and poor sleep were very good in predicting sleep disordered breathing, though not specific enough to use alone. Finally, orthopnea was found in one study 34 to be a good predictor of sleep disordered breathing.
An excellent review of Respiratory measures in ALS was recently published by Lechtzin et al, which summarizes much of the aforementioned information. 70
# Timing of initiation of NIV
Early studies demonstrating the benefit of NIV in ALS patients with daytime respiratory failure have questioned whether earlier initiation of ventilation improves rate of decline in respiratory function, survival and HRQoL. Investigators have sought to define the optimal timing of initiation of NIV to maximize benefit.
Five earlier studies 29,30,33,69,71,72 addressed the issue of timing. Many other studies speak indirectly to this question as the indications for initiation of ventilation may include symptoms alone without the requirement for an abnormal measure of lung function or hypoventilation. 22,23,26,28,30 Orthopnea is often the symptom for which ventilation is started. [21][22][23]25,26,71 A study by Bourke et al. 30 supported initiation of ventilation for symptoms. They reported the greatest benefit and compliance in patients who complained of orthopnea. Also, in support of symptoms as an inclusion for initiation, they reported that four patients were initiated on NIV for the sole indication of nocturnal desaturation without symptoms. Of the four patients, only one was compliant with NIV and continued to use it.
A study exploring earlier initiation of NIV looked retrospectively at the survival of patients in whom NIV was started when FVC was greater than 65% predicted. 72 There were 67 patients in the standard therapy group and 25 in the early initiation group. There was a survival benefit from time of diagnosis to death in those starting NIV with FVC > 65% of predicted. Of note, however, the authors comment that patients in the "early" group frequently, though not always, had pulmonary function or ABG abnormalities that would have qualified them for NIV by other conventional measures.
In another study, 29 historical controls who received NIV for diurnal respiratory insufficiency were compared to ALS patients screened every three months with nocturnal oximetry and initiated on NIV when they demonstrated more than 15 periods of nocturnal desaturation per hour. The authors reported that survival was improved if NIV was started with evidence of nocturnal sleep disordered breathing, and prior to daytime blood gas abnormalities. However, for the subgroup with bulbar dysfunction, there was no survival benefit. The concept of NIV applied for nocturnal desaturation to improve survival, lead to studies which attempted to predict the presence of nocturnal disordered breathing or nocturnal desaturation or hypoventilation allowing for earlier initiation. Polygraphy was compared to FVC and symptoms. 59 This investigation suggested that the correlation between symptoms or FVC and the presence of nocturnal hypoventilation, as defined by prolonged desaturation or a nocturnal capillary pCO2 > 45, was poor. Eight of their 131 patients had FVC < 50% predicted and demonstrated no hypoventilation. In contrast, 14 of the 29 patients with FVC > 75% of predicted with no symptoms of dyspnea, demonstrated nocturnal hypoventilation. It is not clear whether treatment of these asymptomatic patients with a normal or near normal FVC who demonstrate nocturnal hypoventilation will improve their survival or QoL.
A recent pilot, placebo controlled study looking at early NIV 73 demonstrated the feasibility of use of sham ventilation in their study design. They defined early as FVC > 50% and demonstrated no difference between groups in their study though, to ensure tolerance, pressures were very low with an inspiratory positive airway pressure (IPAP) of only 8 cm.
Timing of NIV initiation has also been indirectly addressed by the recent literature which focused more on patient factors or testing that predict survival with NIV, predictors of tolerance to NIV, the effect of NIV on sleep and models for initiation of NIV which improve outcomes. 36,[42][43][44][45]74,[75][76][77] These studies imply both indications and timing that should be used for ventilation by demonstrating positive outcomes with the protocols applied.
# Monitoring post initiation of NIV
Assessment of successful NIV has historically involved improvement in symptoms and gas exchange. More recently device download and assessment of nocturnal saturation or tCO2 have been reported. Two recent papers 43,44 focused on the effect of NIV in correcting nocturnal desaturation and obstructions on survival. In both studies, device download was a component of post initiation monitoring of successful ventilation. One study 43 found better survival in those with a saturation >90% for >95% of the night while on NIV when assessed at 1, 3 and 6 months after initiation. If the study participant was found to have persistent desaturation at 1 month after initiation of NIV, changes were made in an attempt to correct the desaturation. This was reassessed again at 3 and 6 months. In those that were corrected at 1, 3 or 6 months, survival was reported to be the same as those who were well ventilated at 1 month. Device download assisted in the evaluation of the leak, which was a component in the correction. In the subset of patients who could not be corrected, survival was shorter. A follow-up study 44 looked at obstructions as a cause for desaturations and found that those with persistent obstructions had a shorter survival than those without obstructions. This was the case even if the obstructions were not associated with desaturation. They concluded that the effectiveness of ventilation is important to survival.
# Section 3. Tracheostomy ventilation in ALS
# Conclusions
Many physiologic parameters including FVC, SVC, supine VC, MIP/MEP, SNP, PCF and CMAP on phrenic nerve stimulation have been correlated with survival and help to predict respiratory failure. A single parameter has not been identified as the most useful or predictive respiratory measure. Regular monitoring has been recommended to follow the decline in respiratory muscle function with most studies recommending repeated testing every 3 months. Recognizing the differences in rate of disease progression, regular monitoring every 2 to 6 months would be recommended. Nocturnal monitoring prior to initiation of NIV may be helpful in determining timing of NIV initiation though there is currently inadequate evidence to support regular and repeated nocturnal monitoring as part of routine follow-up. Follow-up with nocturnal assessment of oxygen saturation and device download to determine effectiveness of ventilation may prolong survival if effective ventilation can be achieved.
Optimal timing for NIV for maximal benefit has yet to be determined. Current literature supports initiation for the indications listed in PICO 2.2 recommendations.
PICO 2.1: What type of testing is required to predict survival, respiratory failure or need for home mechanical ventilation/non-invasive ventilation?
Recommendations:
1. We recommend regular monitoring of ALS patients every two to six months from time of diagnosis (consensus based), depending on the anticipated rapidity of disease progression, including the following: * Clinical remark: Orthopnea may not be as specific for NIV initiation in individuals with significant bulbar weakness. If orthopnea is felt to be secondary to secretions in the setting of bulbar dysfunction, the secretions should be managed first.
** Clinical remark: A FVC < 50% or SNP/MIP<-40cmH2O have been shown to be a predictor of death at 6 months and are therefore considered to be an indication for NIV. Clinical judgement is required if there are no associated symptoms or the reliability of the values is questionable.
*** Clinical remark: The intention of device download review and monitoring of nocturnal oxygen saturation or TcCO2 (when available) is to correct leak, prevent excessive triggering (work of breathing), assure adequate volumes, prevent apneas and oxygen desaturation, and hypoventilation.
Historically, ventilation, if it was provided to ALS patients, was delivered via tracheostomy. Since the introduction of NIV, tracheostomy ventilation is less common and thought to be a less desirable option; 78 however, rates of tracheostomy ventilation throughout the world vary widely. The highest rates are seen in Japan and other Asian countries and are reported to be 27-45% of ALS patients, [79][80][81] although a recent Italian study also reported a high rate of 31.3% in one region. 82 Lower rates are generally reported in American and European databases 6,7 and Canada reported a rate of 1.5% in 2010. 11 In studies reporting tracheostomy ventilation in ALS, the proportion of patients undergoing tracheostomy after advanced care planning varies from 0% to 63.5% 78,[83][84][85][86][87][88][89] and survival also varies. One study 84 reported a mean survival from tracheostomy of 30.3 months, while another 82 reported a survival with tracheostomy ventilation from disease onset of 47 months. One group compared survival depending on choice of intervention 79 reporting survival from disease onset as 32 months with no ventilation, 48 months with noninvasive ventilation alone and 74 months if tracheostomy ventilation was accepted. Similarly, comparing survival between different therapies, another group 15 reported a survival of 22.9 months with no ventilation, 25.8 months with NIV alone, 56.8 months if initial NIV was followed by invasive ventilation and 33.8 months if invasive ventilation alone was used. Although reporting of survival varies from time of onset of disease, from time of diagnosis or from onset of ventilation making comparison more difficult, these reports suggest that tracheostomy ventilation can prolong survival.
Although chosen in advance by some, tracheostomy may result from an acute deterioration and intubation when a personal advance directive is unavailable. Following tracheostomy for acute respiratory failure, one group 84 reported that none of the patients died in hospital; however, 70% were discharged completely ventilator dependent, and 28% partially ventilator dependent. Only one patient was liberated from mechanical ventilation. None of the patients had their tracheostomy removed. An Italian study 85 reported on 134 patients with tracheostomy ventilation over a 10-year period. This represented 10.6% of their ALS population during this period. Of those patients receiving tracheostomy ventilation, 56% were considered to be elective. A total of 20.1% died before discharge from the hospital and 48.5% were discharged home with a relatively short survival post tracheostomy. For those patients surviving the first 30 days, the median survival was 339 days from tracheostomy. They found survival dependent on age, marital status, follow-up in an ALS center, the discharge destination, and duration of disease before tracheostomy.
Bach has described decannulation after tracheostomy for acute respiratory failure in a select group of ALS patients with preserved bulbar function and the ability to generate an assisted PCF of >160 L/min. 27,90 More recently, the same authors reported successful extubation regardless of measured PCF in patients with various NMDs, although this study included few patients with ALS. 91 Despite these occasional reports and the possibility of an extended period of NIV after decannulation, tracheostomy may be required in the future as bulbar function deteriorates, and if patients choose invasive ventilation in the hope of prolonged survival.
Concern has been raised regarding the patient and caregiver satisfaction with tracheostomy. In a retrospective review of patients using tracheostomy ventilation, an older American study found that 90% of patients were happy with their decision of tracheostomy and 94% of caregivers felt this way as well. 92 A 3-year survival of 58% was reported, with a five-year survival of 33% in this series of patients. A study comparing HRQoL of both patients and caregivers supported with either tracheostomy ventilation or NIV, found a good overall HRQoL in patients, but a very high burden of care for tracheostomy ventilated caregivers, 30% of whom rated their own HRQoL lower than the patient's. 83 Vianello et al 84 reported on a cohort of 60 patients who were invasively ventilated after an episode of acute respiratory failure. Thirteen of these patients participated in an assessment of HRQoL completing the Life Satisfaction Index (LSI-11) and Beck Depression Inventory (BDI). The cumulative score on the LSI-11 was 9.3, which was similar to a group of ALS patients without tracheostomy and to that of the general population. Fifteen percent were found to be severely depressed as assessed by the BDI. Eleven of the 13 patients completing the questionnaires reported that they would choose to have a tracheostomy if they had to make the decision again. This may be a biased sample, however, given this included only 13 of their 60 patients completing the questionnaire.
In the prior publication of this guideline, the section on clearance recommended deflated or uncuffed tracheostomy tubes when possible. A recent study 89 looked at the type of tracheostomy tube required for effective ventilation in ALS. It found that 35.7% of patients with advancing bulbar dysfunction required a cuffed tube as a result of excessive air leak and hypoventilation though the majority was able to use uncuffed tubes.
# Conclusions
Tracheostomy ventilation remains an option in carefully selected patients after lengthy discussion of the implications. It is strongly preferred that these discussions occur well in advance of acute respiratory failure. Tracheostomy ventilation can prolong survival in ALS and can provide an acceptable QoL for some patients. It does, however, impose a high burden for caregivers.
Recommendations:
1. We suggest that practitioners discuss the option of tracheostomy ventilation with ALS patients. (GRADE 2B) 2. We strongly recommended that practitioners discuss this option well in advance à of acute respiratory failure. (GRADE 1C) * Clinical Remarks: Tracheostomy ventilation should be discussed with patients with ALS early in the disease and reviewed during disease progression as patients may revise their wishes with symptom progression. These discussions should occur well in advance of an acute indication such as lower respiratory tract infection which may acutely worsen respiratory status. Though tracheostomy is an option, in our experience, few ALS patients choose this option given that NIV can be applied even with advancing respiratory muscle dysfunction and given that care needs with tracheostomy are likely to require institutionalization or impose a high burden for home caregivers. If tracheostomy ventilation is chosen, discussions should occur early on with patients and families to establish the conditions under which ventilation will be withdrawn (eg, If a "locked in" state occurs.) 1. physiologic parameters 2. survival 3. rate of progression of disease 4. time to ventilation
The role of exercise in ALS remains unclear. There has been concern that compensatory overuse of surviving muscle groups may worsen neural dysfunction and potentially accelerate the loss of motor units. 93 In contrast, other studies have suggested that exercise may be safe and effective in slowing the decline in muscle strength. [94][95][96] Inspiratory muscle training has been investigated in other neurological diseases such as spinal cord injury 97 and Duchenne muscular dystrophy, 98,99 but the results of these studies may not necessarily be relevant to a rapidly progressive degenerative neurological condition.
In a 2008 cohort study of ALS patients looking at a specific breathing pattern accentuating the diaphragmatic component of inspiration (Yoga breathing), 100 outcomes included QoL and FVC rate of decline. Patients served as their own controls with a 3 month run-in period measuring FVC monthly. They had difficulty in recruiting and, ultimately were able to analyze data from only 8 subjects. They found no improvement in FVC, QoL or rate of decline in FVC over 12 weeks.
A double blind RCT performed to address the question of safety and efficacy of inspiratory muscles training in ALS 101 recruited only 19 patients after screening 37 patients and looked at multiple outcomes including FVC, VC, SNIP, MIP, capillary blood gas, SF-36, ALSFRS-R and 6MWT. Although trends to improvement were seen, they found no significant difference between the groups and noted improvements in the MIP in both the training group and the control group. QoL was not impacted.
One trial looked at inspiratory muscle training (IMT) in ALS patients with early disease as defined by FVC > 70% predicted, MIP > 50% and an ALSFRS-R >24/40. 102 The trial design used a delayed intervention group as the comparator group. Group one started training at the onset of the study and group two started IMT 4 months after group one. The study lasted a total of 8 months. Their primary outcome was the ALS functional rating scale (ALSFRS) with secondary outcomes including multiple measures of respiratory function and QoL. There was no significant difference between groups in the ALSFRS or any other measure of respiratory function with the exception of the MVV, which was significantly different only at 4 months. Dyspnea was assessed using a visual analog scale and did not differ between groups. QoL showed no difference between groups using the Euro-QoL-5D questionnaire. There was also no difference in depression, fatigue or functional status, all assessed by questionnaires. In an extension of this study that included 18 patients from both groups 1 and 2, survival was measured and compared to historical controls. 103 The IMT group had a significantly longer survival from symptom onset than the historical controls: 36.99 months in the IMT group, 24.06 months in the historical controls.
Finally, the impact of expiratory strength training in ALS was studied in a delayed intervention open label trial. 104 After enrollment, there was a five week period during which no training occurred. Their primary outcome was MEP with secondary outcomes including analysis of swallowing, cough and aspiration risk. There was a significant increase in MEP and in maximal hyoid elevation after 5 weeks of treatment, but no change in cough or other parameters of the swallow assessment.
A systematic review 105 and a meta-analysis 106 have been published looking at the question of benefit of respiratory muscle training in ALS. The earlier systematic review 105 found no convincing evidence of benefit. The subsequent meta-analysis 106 looked at studies that included both ALS and Multiple Sclerosis patients. They found that MIP, MEP and FEV1 improved without change in FVC. Caution is recommended in applying this study to the ALS population given the small number of ALS patients included in the meta-analysis.
It is of note when reviewing the individual studies that the nature of the training varied from study to study in duration, intensity and training protocols. It can be noted that there did not appear to be harm associated with respiratory muscle training. 1. physiologic parameters 2. survival 3. rate of progression of disease 4. time to ventilation
# Conclusions
No convincing evidence was found to support improved physiologic parameters, longer survival or slowing in rate of progression of disease using respiratory muscle training. Delay in time to ventilation was not assessed. Small numbers of patients were included in the studies.
Recommendation:
1. We do not suggest respiratory muscle training in ALS patients. (GRADE 2C)
# Clinical remark:
There does not appear to be harm associated with respiratory muscle training.
Section 5. Diaphragm pacing in ALS PICO 5: As compared to standard care, does diaphragm pacing, with or without concurrent noninvasive ventilation:
1. Prolong survival 2. Delay the time to requirement for noninvasive ventilation 3. Slow disease progression or 4. Improve QoL?
A system for diaphragm pacing, which inserted electrodes into the inferior surface of the diaphragm adjacent to the motor end points to stimulate diaphragm contraction, has been developed primarily for ventilator dependent spinal cord injured patients. It was hypothesized that stimulating intact motor units in the diaphragm of ALS patients may prevent atrophy and slow rate of decline of respiratory muscle weakness resulting in improved survival or delayed time to ventilation. A pilot trial began implanting ALS patients in 2005 and subsequent reports of this surgical cohort suggested slowing in the rate of decline of FVC which was extrapolated to improvement in survival. 107 In 2012, 8 ALS patients paced with this pacing system were reported and compared to 354 patients that were not treated with pacing. 108 Poor tolerance was found to pacing, with 6 of their 8 patients decreasing the pacer settings and 4 of the 8 stopping pacing entirely. They also noted more rapid decline in VC and a shorter survival when compared to their cohort of ALS patients referred between 1996 and 2011.
Two RCTs of diaphragm pacing in ALS have now been reported.
The DiPALS study 109 compared NIV plus pacing (n ¼ 37) to NIV alone (n ¼ 37) with initiation when respiratory insufficiency was present as defined by one or more of the following: a VC 50-75% predicted, SNIP<-65cm H2O in men and -55cm H2O in women in the presence of symptoms, SNIP <-40, or pCO2 > 6kPa in the day or 6.5kPa at night or nocturnal desaturation. A total of 37 patients were enrolled in each arm. Their primary endpoint was survival from randomization to death. They also reported survival from symptom onset, QoL, compliance and adverse events. The study was terminated prematurely when the Data Monitoring and Ethics Committee noted a concerning signal in overall survival figures. They found that survival from symptom onset in the paced plus NIV group was 28 months as compared to NIV alone, which was 45 months. The patient health utility score (EQ-5D-3L) was slightly lower with pacing, although other HRQoL questionnaires were similar between the two groups. They concluded that diaphragmatic pacing should not be a routine treatment for ALS patients in respiratory failure.
The RespiStimALS study 110 enrolled patients that did not require NIV and had FVC 60-80% of predicted with evidence of diaphragm function with a phrenic stimulus. Patients meeting these criteria were randomized to receive pacing or standard care with initiation of NIV in both groups when an indication occurred. All patients had pacer insertion soon after enrollment with the control group receiving an inactive cable and sham pacing. When criteria for NIV were met, the treatment was unmasked and all patients received both pacing and NIV. NIV was initiated when FVC <50% predicted, pCO2 > 45, MIP or SNIP < 60% predicted, or nocturnal hypoxemia with 5% of recording time <90% or 5 consecutive minutes below a saturation of 88%. Decision to initiate NIV was established by an independent allocation committee. 37 patients were in each group. The study was terminated early by the study independent safety committee after becoming aware of the results of the DiPALS study and calling for a formal unplanned masked interim survival analysis which showed a mortality difference. The primary outcome was NIV free survival from randomization. They also reported survival from symptom onset, QoL and rate of decline of FVC, MIP and SNP. The median NIV free survival from randomization was 6.0 months in the early paced group and 8.8 months in the standard care group. Median survival from symptom onset in the early paced group was 51 months and this endpoint was not reached in the sham paced group. There was a more rapid decline in FVC, MIP and SNP in the early pacer group. QoL was not different between the two groups. It is interesting that the "pacer use" was higher in the sham group at the time of NIV initiation suggesting possible poor tolerance in the active pacing group. The authors concluded that there was no benefit to early pacing in terms of delay to NIV requirement or QoL and that it decreased survival.
These two RCTs both concluded that diaphragm pacing has no benefit and, in fact, may be harmful with a more rapid decline and shortened survival. The mechanism is unknown though both authors speculated on reasons for their findings. These studies are in contrast to the earlier positive reports in the surgical cohort studies. Both authors speculated that the 3 month run in period in the surgical cohort may have selected for patients with a slower disease progression, given that those with more rapid decline may have been excluded after the run-in period. In three older studies examining the benefit of NIV in ALS, both pressure and volume capable ventilators were used in the same study 22,23,71 implying that the authors considered the two modes were equivalent for the purpose of assessing benefit. Studies comparing the two modes have been reported in mixed populations. [111][112][113][114] One study 113 included both restrictive and obstructive diseases, each having different respiratory mechanics. The conclusion of these studies reporting on mixed groups was that either mode is appropriate for use in most patients. It is interesting to note that in this study, approximately one-third of the patients were bilevel "non-responders" with elevated PCO2 and reduced nocturnal saturation when treated with Bi-level. In this study, "non-responders" were returned to volume ventilation. The conclusion was that the majority of patients successfully treated with volume-cycled ventilation could also be adequately maintained on pressure controlled ventilation; however, data showed that some were less well ventilated on pressure ventilation and required a volume targeted mode. In other studies comparing the two modes of ventilation, authors report a patient preference in some. Bach proposed volume cycled ventilators in one study looking at noninvasive support in the ALS population given that the ventilator could then be used to breath stack to Maximal Inspiratory Capacity (MIC) as an aid to airway clearance. 27 A more recent study 115 investigated whether the mode of noninvasive ventilation affected survival, gas exchange, and clinical outcomes in ALS. A French center using pressure targeted NIV was compared to a Spanish center using volume cycled NIV. The primary outcome was survival and there was no difference between centres. Symptom control appeared better with volume control NIV as well as gas exchange, time spent nocturnally with a saturation of less than 90%, mean saturation at night and minimum saturation. It is of note that the Norris Bulbar Score was significantly lower (poor bulbar function) in the pressure targeted group which may have influenced their secondary outcomes.
A study looking at tolerance of volume ventilation in ALS enrolled 87 patients who were initiated as inpatients. 116 Results showed that it was well tolerated by 92% of patients at 3 month assessment. The 8% who were intolerant were readmitted at 3 months for further habituation and remained intolerant. There was no comment on whether alternate modes were tried in the intolerant patients.
Prior studies have assessed ventilator pressure settings, including PEEP and EPAP. One evaluated the use of PEEP or end expiratory pressure in a dual limb circuit set up with a pressure targeted mode of ventilation. 117 End expiratory pressure of zero vs 4 cm was evaluated. Leaks were higher with PEEP 4 cm. They also noted increased auto-triggering and ineffective efforts with PEEP 4 cm. Decreased N3 sleep and higher sympathetic tone were also noted with the application of end expiratory pressure. On the other hand, EPAP pressure of up to 10 cm was allowed to abolish obstructions in one study, which suggested that unresolved obstructions were associated with higher mortality. 44 A recent study compared pressure support ventilation with volume assured pressure support (VAPS) in a retrospective review of ALS patients. 118 215 patients using pressure support were compared to 56 patients on volume assured pressure support. Both modes were well tolerated. Volume was more consistent with the volume assured group. It is likely the VAPS device was favored because the IPAP pressures in the pressure support mode were relatively low and the inspiratory times short (approximately 1 sec) and the rise times >600 msec, predisposing to smaller tidal volumes in those without a target volume.
Spontaneous timed (S/T) mode was compared to spontaneous (S) mode bilevel ventilation 119 in ALS patients and was found to improve gas exchange, respiratory events and patient ventilator synchrony when compared to the S mode.
Use of daytime mouthpiece ventilation 120 and nighttime bilevel pressure ventilation with a mask has been reported in a series of selected ALS patients. The authors defined this mode as an option in patients without significant bulbar dysfunction who require 24 hour ventilation. They noted that patients derived the greatest survival benefit if they could generate an assisted PCF > 180 L/min at initiation of mouthpiece ventilation.
Another question that remains unanswered is the optimal way to titrate NIV or to determine appropriate ventilator settings in this population. Many older studies did not describe how the ventilator settings were determined. Polysomnography to establish ventilator settings was previously rarely reported. More recently an ambulatory outpatient model of NIV initiation was described that involved an empiric daytime titration followed in 4-6 weeks by polysomnography for further titration. 75 Their comparator was an inpatient initiation model. The outpatient model showed shortened wait times for ambulatory initiation of NIV and improved survival. Other groups continue to admit patients for titrations and habituation. In the study by Martinez looking at tolerance of volume control ventilation, length of stay averaged 4.7 days for inpatient initiation of NIV. 116 Regardless of the method of initial titration, follow-up to assure adequate ventilation is suggested by 2 recent studies 43,44 reporting shortened survival with ineffective ventilation. Attention to initial titration and follow-up at 1, 3 and 6 months for evaluation and adjustment is suggested. In these studies, ventilator download with associated oximetry was used to assess adequacy of ventilation.
# Conclusions
There are limited data comparing modes of NIV, settings or initiation protocols. There is a trend in many centres across the world to use pressure targeted ventilators which generally can be purchased at lower cost than ventilators providing volume control ventilation. Pressure targeted and volume targeted modes had similar survival in one recent study. Volume controlled modes, however, offered some advantages in symptom control, gas exchange and nocturnal oxygenation, but the study specifically addressing this noted a lower Norris bulbar score in the pressure targeted group which may have influenced the effectiveness of ventilation. Pressure support is often felt to be better tolerated than volume control modes, though one study showed that 92% of patients tolerated a volume control mode. When using a pressure targeted ventilator, the mode should control inspiratory time for both spontaneous and machine delivered breaths.
Both inpatient and outpatient protocols for NIV initiation have been reported and both are effective, though outpatient initiation may be preferred by patients and associated with better survival (possibly because of a shorter duration to initiation) and less cost.
# Recommendations:
1. We recommend S/T mode à over S mode when delivering ventilation with pressure targeted devices. (GRADE 1C) 2. No recommendation can be made for the preferred location of the initial titration (outpatient initiation, sleep lab, or inpatient admission are all acceptable); however, delays should not be incurred irrespective of selected location. (GRADE 1C) 3. Volume-controlled ventilation is an acceptable mode and we recommend that it be used if pressure targeted modes are not tolerated or ineffective. (GRADE 1C) 4. In patients with intact bulbar function who are receiving nocturnal ventilation, we recommend use of mouthpiece ventilation rather than tracheostomy when additional daytime ventilation is required. A nasal interface may be acceptable if preferred. (GRADE 1C) * Clinical remarks: Although S/T mode may improve gas exchange, respiratory events and synchrony when compared to S mode, care must be taken to assure that Ti (inspiratory time) is sufficiently long to provide adequate tidal volume and minute ventilation. In the S/T mode where the Ti is not controlled during spontaneous breaths, Ti may be too short to provide adequate tidal volume. If the percentage of triggered breaths is high, adequate support and ventilation may not be achieved. This can be resolved by use of the PC mode on ventilators that do not control Ti when the patient is triggering the device or breathing above the set rate. Other devices will control Ti on all breaths and an adequate inspiratory time may be achieved by setting a sufficiently long minimum Ti. Recommended Ti in neuromuscular patients without underlying airways disease is 1.2 to 1.5 seconds: up to a 1:1 ratio which is dependent on respiratory rate. (expert consensus)
# Summary
There is increasing evidence of benefit of HMV in patients with ALS. The current guideline reviews reported benefits and seeks to advise on monitoring of respiratory status in ALS and timing of initiation of noninvasive ventilation.
There is limited evidence on optimal settings and modes for patients using NIV in ALS though a timed or controlled mode is preferred. Tracheostomy remains an option for well-informed patients with ALS, but is associated with a high burden of care. Respiratory muscle training has not been shown to offer clear benefit and cannot be recommended at this time. RCTs, completed since the last publication of this guideline and addressing diaphragm pacing in ALS, have shown harm and pacing is not advised. Much research remains to be done. Device download remotely is increasingly available and its use to improve outcomes requires further assessment. Optimal timing of NIV to optimize benefit remains an ongoing question, in particular in bulbar predominant ALS.
The intention of the CTS guideline panel for HMV is to report on changes to this guideline going forward as new evidence is published and reviewed, creating a "living document" available on the CTS website.
# Implementation
The most relevant and important of the recommendations are those addressing monitoring before and after initiation of NIV and indications for initiation of noninvasive ventilation (PICO question 2).
# Implementation of these recommendations
1. Wide dissemination given the variety of care providers for ALS patients An abridged online and electronic copy "quick reference" guide with reference link to the full document will be circulated to key stakeholders involved in care of the ALS patient. This includes: a. Directors and clinic coordinators of ALS clinics in Canada b. The Canadian ALS Research Network (CALS) who can distribute electronically and on their platform to corresponding members, as well as introduce and present it during their quarterly meetings c. The Canadian Association of Physical Medicine and Rehabilitation: neuromuscular Special Interest Group d. Respirologists in Canada with membership in the Canadian Thoracic Society e. ALS Canada with intent to distribute to provincial societies, and to make available in their online resources, accessible to clinicians, researchers and community via the ALS Canada website f. Canadian Society of Respiratory Therapists
# ALS clinic interaction nationally
Authors of this guideline are from across Canada and can present locally to respirologists, neurologists, physiatrists and ALS clinics. Annually, there is a national ALS Research symposium hosted by ALS Canada with participants and clinical leaders from centres across Canada. These guidelines will be presented, and a poster of the abridged recommendations and links will be available throughout the meeting.
Every ALS Clinic in Canada has representation at the Canadian ALS Research Network, and is typically linked to their respective provincial societies, and to ALS Canada. This strong network between researchers, clinicians, community advocates and patients/families will be instrumental in ensuring broad dissemination.
# Cost considerations
The aforementioned strategies are associated with minimal cost implications and maximal impact. The primary cost may be related to the purchase of equipment recommended for monitoring which is associated with a minimal initial cost outlay, but may have ongoing cost associated with disposables.
# Measures of successful implementation and dissemination
As care of the individual with ALS may be by individual neurologists, physiatrists, respirologists or ALS centres, it will be challenging to monitor adoption of the guideline. The most reliable data collection at present is by ALS clinics and by the Canadian ALS research network and it is for this reason that a survey of compliance will be done through ALS clinics and the research network. At 12-24 months post publication and distribution, ALS clinics across Canada will be surveyed to assess their knowledge of and compliance with recommendations.
# Current gaps and future research needs
The guideline panel identified areas where further research would improve the ability of clinicians to optimally manage patients with ALS.
1. Evaluation of device download driven setting changes (both remotely and at clinic assessments) to improve outcomes such as adherence, optimal ventilation, hospital admissions and survival. 2. Ongoing evaluation of optimal timing, in particular, in bulbar predominant patients. Guideline Committee, Samir Gupta, for their guidance throughout the process. We would also like to acknowledge with deep appreciation our expert peer reviewers who made valuable contributions to the manuscript: J esus Gonzalez-Bermejo, Hôpitaux Universitaires Piti e Salpêtri ere-Charles Foix, Paris, France; Noah Lechtzin, John Hopkins Hospital, Baltimore, Maryland, United States; David Leasa, London Health Sciences Centre, London, Ontario, Canada; and Jeremy Road, Vancouver General Hospital, Vancouver, British Columbia, Canada.
# Editorial independence
The CTS HMV Clinical Assembly is accountable to the CTS Canadian Respiratory Guideline Committee and the CTS Board of Directors. The CTS HMV Clinical Assembly is functionally and editorially independent from any funding sources of the CTS and does not receive any direct funding from external sources. The CTS receives unrestricted grants which are combined into a central operating account to facilitate the knowledge translation activities of the CTS Clinical Assemblies. No funders played a role in the collection, review, analysis or interpretation of the scientific literature or in any decisions regarding the key messages presented in this document.
# Disclosures
Members of the CTS HMV Assembly declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy. Individual member conflict of interest statements are posted at https://ctssct.ca/guideline-library/.
# Acknowledgments
The authors would like to thank Anne Van Dam from the CTS and the Chair of the CTS Canadian Respiratory
#
Appendix 1. Search strategy: HMV for patients with ALS guideline update
# Study types
Any. To be as inclusive as possible. Guidelines, meta-analysis, systematic review, randomized controlled trial, cohort study, case control study, case series, or case report Data sources MEDLINE V R (OVID); Embase V R (OVID); HealthStar V R ; Cochrane Library V R , Canadian Medical Association InfoBase V R ; and the National Guideline Clearinghouse
# Target users
Health care teams that care for individuals who are at risk for or require ventilatory assistance. Respirologists, physiatrists, neurologists, family practitioners, nurses, respiratory therapists, physiotherapists, and other health care professionals can use this guideline to help inform their clinical practice with regard to HMV. This guideline is also intended for use by ventilator-assisted individuals (VAIs) and their caregivers to help them make informed decisions on home mechanical ventilation and by health care decision makers to aid in establishing policy and making funding decisions
# Scope of this guideline
To address the benefits of mechanical ventilation in ALS, respiratory muscle testing, and monitoring required, timing of initiation of ventilation and modes, settings, and place of initiation To review diaphragm pacing and respiratory muscle training To address tracheostomy ventilation
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Primary Therapy Options A. External-beam radiotherapy 4,5 i. Include para-aortic and ipsilateral pelvic nodes to 20-25Gy ("dog leg" or "hockey stick"). ii. Boost grossly involved nodes by 10 Gy. B. Chemotherapy 6-8 i. Consider BEP × 3 cycles when optimal radiotherapy not possible; EP × 4 cycles may be considered in patients with contraindication to bleomycin. ii. Consider BEP × 3 cycles, in extensive stage IIB disease (same as stage IIC); EP × 4 cycles may be considered in patients with contraindication to bleomycin.A. P/E. B. Tumour markers. C. CXR (or CT thorax). D. CT abdomen/ pelvis (new baseline). Residual Disease (see section on residual disease below) Follow-up (click) T1-4, N3, M0, T1-4, Nx, M1 (Stages IIC, and III Seminomas): Indications include retro-peritoneal lymph node disease >5 cm in diameter, or distant metastases. Preparation for Therapy A. Baseline CBC, biochemistry, liver function tests, alkaline phosphatase. B. Discuss semen cryopreservation with the patient. Primary Therapy A. Cisplatin-based combination chemotherapy. 7, 8, 13 B. Good risk as per IGCCC: BEP × 3; EP × 4 may be considered if bleomycin is contraindicated. C. Intermediate risk as per IGCCC: BEP × 4; VIP x 4 may be considered if contraindication to# Background
Testicular germ cell tumours (GCTs) account for about 1% of all new cancer cases in men (agestandardized incidence rate of 5.5 per 100,000 men in Canada); however, they are the most common type of cancer in adolescents and young adults aged 15 to 29 years. There are approximately 120 new cases of all types of testicular cancer in Alberta each year, most of which are GCTs. Testicular GCTs are a highly curable type of cancer with five-year survival rates of over 95%. ii. Extensive lung metastases iii. Pure choriocarcinoma iv. B-HCG >5000 IU/L v. IGCCCG Poor risk disease G. Bone scan if relevant symptoms H. PET scans should only be used to evaluate residual masses post chemotherapy for seminoma; PET scan should not otherwise be routinely used Treatment A. Radical inguinal orchiectomy is the standard initial treatment. B. In rare instances, orchiectomy can be deferred in patients with life-threatening metastatic disease when a diagnosis of NSGCT (ex. unequivocally elevated AFP and/or B-HCG >5000) or seminoma (biopsy of metastatic site) is made, so as to not delay chemotherapy. Orchiectomy can be later performed after chemotherapy.
# Seminomas T1-4, N0, M0 (Stage I Seminomas):
Primary Therapy A. Management options include primary surveillance, adjuvant radiotherapy or adjuvant chemotherapy. 2 B. Surveillance is the preferred option and is indicated for the individual who will adhere with the surveillance protocol (below). C. Patients with a higher risk for recurrence (e.g. presence of a tumour >4 cm and/or rete testes involvement) should discuss risk factors with oncologists and could be offered radiotherapy; however, even patients in the high risk group have a 70-80% 3 chance of being relapse free without adjuvant treatment, as such surveillance remains the preferred option. D. Radiotherapy: 20-25 Gy in 10-20 fractions, to para-aortic ± ipsilateral pelvic lymph nodes ("dog leg" or "hockey stick"). E. Chemotherapy (carboplatin AUC 7 x 1-2 cycles) can be considered in select cases and should be reviewed in multidisciplinary rounds. F. The possibility of semen cryopreservation should be discussed.
# Follow-up (click) T1-4, N1-2, M0 (Stages IIA and IIB Seminomas):
Indications include retroperitoneal lymph node disease <5 cm in diameter. bleomycin. D. Consider prophylactic anticoagulation to reduce risk of venous thromboembolic disease during chemotherapy. E. Primary prophylaxis with G-CSF is required for patients receiving ifosfamide.
# Management of Residual Disease
A.If residual mass 3 cm, consider PET scan 6-12 weeks after day 21 of the last cycle. C. If PET is positive, cases should be reviewed in multidisciplinary rounds for discussion of best therapeutic approach. Generally, these can be observed over time, especially if mildly positive. In cases where FDG-PET remains strongly positive over time and/or the mass is growing, complete surgical resection or biopsy is the management of choice; Radiation is an option in select cases, although this has been inadequately studied.
Follow-Up: Table 1. Seminomas Follow-up 14,15 Year since treatment completion P/E = physical exam, CXR = chest x-ray, markers = alpha-fetoprotein (αFP), beta-human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH) hormone levels: LH (Luteinizing hormone), FSH (Follicular stimulating hormone), total testosterone A. To reduce radiation risk/exposure, consideration of low dose CT scans is recommended where possible/feasible. B. If abnormality with hormone testing, endocrinology and/or urology referral should be considered.
C. Unless high risk features are present (i.e. tumour size >4 cm, lymphovascular invasion, or rete testis invasion), consider discharge to primary care provider after year 5 (i.e. for year 7 and 9 surveillance). 16
# Nonseminoma T1-4, N0, M0, S0 (Stage I Nonseminomas):
Indications include disease localized to testicle only and normalization of tumour markers post radical orchidectomy (t ½ = 24-48 hours for β-hCG, 5-7 days for άFP).
Primary Therapy 18,19 A. Options include surveillance (see below), bilateral nerve sparing RPLND, or adjuvant chemotherapy. C. For patients in any risk group, surveillance is the preferred option. RPLND and adjuvant BEP chemotherapy x 1 cycle are options in select cases.
i. High risk features for relapse include pure embryonal histology, lymphovascular invasion, and rete testis invasion. 16 ii. If choosing surveillancemeasuring tumour markers monthly in year one is recommended. 16 iii. If RPLND is performed and lymph node metastases are present, adjuvant chemotherapy may be consideredsee section below on Stage II NSGCT. HDCT and PBSCT A. Refer patients to local stem cell transplant program for management of stem cell collection and transplant.
# Follow-up (click)
Adjunctive Care For All Patients A. Patients with brain metastases should be referred to multidisciplinary rounds for review. i. Management options may include radiotherapy and/or neurosurgery. B. After completion of all chemotherapy, resection of any residual masses should be performed.
# Unique Clinical Situations
Late Relapses: A. A late relapse is defined as relapse occurring >2 years after completion of primary chemotherapy. B. This does not occur frequently, and as such, all cases should be reviewed in a multidisciplinary setting. C. These patients have disease that is more chemotherapy resistant and immediate surgical resection of recurrent disease should be undertaken if feasible, irrespective of the level of tumour markers. D. Whether or not to offer chemotherapy post-surgical resection in this setting is controversial but could be considered. E. TIP has been used with modest success in patients who relapse late that are not surgical candidates.
# Non-Testicular Germ Cell Tumours (GCT
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including radiation oncologists, medical oncologists, urologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
# This guideline was originally developed in 2005.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
Abbreviations αFP, Alpha fetoprotein; β-hCG, Beta-human chorionic gonadotropin; CBC, Complete blood count; CT, Computed tomography; CXR, Chest X-ray; FSH, Follicular stimulating hormone; GCT, Germ cell tumour; LDH, Lactate dehydrogenase; LH, Luteinizing hormon; P/E, Physical exam;
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Primary Therapy Options A. External-beam radiotherapy 4,5 i. Include para-aortic and ipsilateral pelvic nodes to 20-25Gy ("dog leg" or "hockey stick"). ii. Boost grossly involved nodes by 10 Gy. B. Chemotherapy 6-8 i. Consider BEP × 3 cycles when optimal radiotherapy not possible; EP × 4 cycles may be considered in patients with contraindication to bleomycin. ii. Consider BEP × 3 cycles, in extensive stage IIB disease (same as stage IIC); EP × 4 cycles may be considered in patients with contraindication to bleomycin.A. P/E. B. Tumour markers. C. CXR (or CT thorax). D. CT abdomen/ pelvis (new baseline). Residual Disease (see section on residual disease below) Follow-up (click) T1-4, N3, M0, T1-4, Nx, M1 (Stages IIC, and III Seminomas): Indications include retro-peritoneal lymph node disease >5 cm in diameter, or distant metastases. Preparation for Therapy A. Baseline CBC, biochemistry, liver function tests, alkaline phosphatase. B. Discuss semen cryopreservation with the patient. Primary Therapy A. Cisplatin-based combination chemotherapy. 7, 8, 13 B. Good risk as per IGCCC: BEP × 3; EP × 4 may be considered if bleomycin is contraindicated. C. Intermediate risk as per IGCCC: BEP × 4; VIP x 4 may be considered if contraindication to# Background
Testicular germ cell tumours (GCTs) account for about 1% of all new cancer cases in men (agestandardized incidence rate of 5.5 per 100,000 men in Canada); however, they are the most common type of cancer in adolescents and young adults aged 15 to 29 years. There are approximately 120 new cases of all types of testicular cancer in Alberta each year, most of which are GCTs. Testicular GCTs are a highly curable type of cancer with five-year survival rates of over 95%. [link] ii. Extensive lung metastases iii. Pure choriocarcinoma iv. B-HCG >5000 IU/L v. IGCCCG Poor risk disease G. Bone scan if relevant symptoms H. PET scans should only be used to evaluate residual masses post chemotherapy for seminoma; PET scan should not otherwise be routinely used Treatment A. Radical inguinal orchiectomy is the standard initial treatment. B. In rare instances, orchiectomy can be deferred in patients with life-threatening metastatic disease when a diagnosis of NSGCT (ex. unequivocally elevated AFP and/or B-HCG >5000) or seminoma (biopsy of metastatic site) is made, so as to not delay chemotherapy. Orchiectomy can be later performed after chemotherapy.
# Seminomas T1-4, N0, M0 (Stage I Seminomas):
Primary Therapy A. Management options include primary surveillance, adjuvant radiotherapy or adjuvant chemotherapy. 2 B. Surveillance is the preferred option and is indicated for the individual who will adhere with the surveillance protocol (below). C. Patients with a higher risk for recurrence (e.g. presence of a tumour >4 cm and/or rete testes involvement) should discuss risk factors with oncologists and could be offered radiotherapy; however, even patients in the high risk group have a 70-80% 3 chance of being relapse free without adjuvant treatment, as such surveillance remains the preferred option. D. Radiotherapy: 20-25 Gy in 10-20 fractions, to para-aortic ± ipsilateral pelvic lymph nodes ("dog leg" or "hockey stick"). E. Chemotherapy (carboplatin AUC 7 x 1-2 cycles) can be considered in select cases and should be reviewed in multidisciplinary rounds. F. The possibility of semen cryopreservation should be discussed.
# Follow-up (click) T1-4, N1-2, M0 (Stages IIA and IIB Seminomas):
Indications include retroperitoneal lymph node disease <5 cm in diameter. bleomycin. D. Consider prophylactic anticoagulation to reduce risk of venous thromboembolic disease during chemotherapy. E. Primary prophylaxis with G-CSF is required for patients receiving ifosfamide.
# Management of Residual Disease
A.If residual mass <3cm, PET scan is not recommended; patients should be surveilled. B. If residual mass > 3 cm, consider PET scan 6-12 weeks after day 21 of the last cycle. C. If PET is positive, cases should be reviewed in multidisciplinary rounds for discussion of best therapeutic approach. Generally, these can be observed over time, especially if mildly positive. In cases where FDG-PET remains strongly positive over time and/or the mass is growing, complete surgical resection or biopsy is the management of choice; Radiation is an option in select cases, although this has been inadequately studied.
Follow-Up: Table 1. Seminomas Follow-up 14,15 Year since treatment completion P/E = physical exam, CXR = chest x-ray, markers = alpha-fetoprotein (αFP), beta-human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH) hormone levels: LH (Luteinizing hormone), FSH (Follicular stimulating hormone), total testosterone A. To reduce radiation risk/exposure, consideration of low dose CT scans is recommended where possible/feasible. B. If abnormality with hormone testing, endocrinology and/or urology referral should be considered.
C. Unless high risk features are present (i.e. tumour size >4 cm, lymphovascular invasion, or rete testis invasion), consider discharge to primary care provider after year 5 (i.e. for year 7 and 9 surveillance). 16
# Nonseminoma T1-4, N0, M0, S0 (Stage I Nonseminomas):
Indications include disease localized to testicle only and normalization of tumour markers post radical orchidectomy (t ½ = 24-48 hours for β-hCG, 5-7 days for άFP).
Primary Therapy 18,19 A. Options include surveillance (see below), bilateral nerve sparing RPLND, or adjuvant chemotherapy. C. For patients in any risk group, surveillance is the preferred option. RPLND and adjuvant BEP chemotherapy x 1 cycle are options in select cases.
i. High risk features for relapse include pure embryonal histology, lymphovascular invasion, and rete testis invasion. 16 ii. If choosing surveillancemeasuring tumour markers monthly in year one is recommended. 16 iii. If RPLND is performed and lymph node metastases are present, adjuvant chemotherapy may be consideredsee section below on Stage II NSGCT. HDCT and PBSCT [30][31][32] A. Refer patients to local stem cell transplant program for management of stem cell collection and transplant.
# Follow-up (click)
Adjunctive Care For All Patients A. Patients with brain metastases should be referred to multidisciplinary rounds for review. i. Management options may include radiotherapy and/or neurosurgery. B. After completion of all chemotherapy, resection of any residual masses should be performed.
# Unique Clinical Situations
Late Relapses: A. A late relapse is defined as relapse occurring >2 years after completion of primary chemotherapy. B. This does not occur frequently, and as such, all cases should be reviewed in a multidisciplinary setting. C. These patients have disease that is more chemotherapy resistant and immediate surgical resection of recurrent disease should be undertaken if feasible, irrespective of the level of tumour markers. D. Whether or not to offer chemotherapy post-surgical resection in this setting is controversial but could be considered. E. TIP has been used with modest success in patients who relapse late that are not surgical candidates.
# Non-Testicular Germ Cell Tumours (GCT
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including radiation oncologists, medical oncologists, urologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
# This guideline was originally developed in 2005.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
Abbreviations αFP, Alpha fetoprotein; β-hCG, Beta-human chorionic gonadotropin; CBC, Complete blood count; CT, Computed tomography; CXR, Chest X-ray; FSH, Follicular stimulating hormone; GCT, Germ cell tumour; LDH, Lactate dehydrogenase; LH, Luteinizing hormon; P/E, Physical exam;
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial GU Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2023) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of CancerControl Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerControl Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Nimira Alimohamed has nothing to disclose.
Dr. Naveen Basappa reports receiving grants from Pfizer, Merck, Janssen, AstraZeneca, Astellas, BMS, Bayer, Ipsen, Eisai and EMD Serono. *Dr. Bimal Bhindi has been an advisory board member for Verity Pharmaceuticals; and has received speaker honoraria from Merck; and consultancy for Ferring.
# Richard Littleton has nothing to disclose.
Cindy Railton has nothing to disclose.
Derek Tilley has nothing to disclose.
# Citation
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The following is an update of the 2016 Canadian Urological Association vasectomy guideline. The changes introduced are relatively minor, and include: -Clarified text on the optimal vasectomy occlusion technique, with a statement added about the surgeon being able to choose his/her preferred technique so long as outcomes are good. -Clarification of the recommendations on the number of post-vasectomy semen analyses.# Introduction
Vasectomy is a safe and effective method of birth control. Although it is a simple elective procedure, vasectomy is associated with potential minor and major complications. The early failure rate of vasectomy (presence of motile sperm in the ejaculate at 3-6 months post-vasectomy) is in the range of 0.2-5% and the late failure rate is in the range of 0.04-0.08%. The no-scalpel vasectomy technique is associated with a lower risk of early postoperative complications and the use of cautery or fascial interposition will reduce the risk of contraceptive failure. As such, detailed preoperative counselling and careful assessment of the post-vasectomy ejaculate (for presence of sperm) is imperative. Failure to provide and document adequate information and counselling to patients may lead to litigation.
The focus of this guideline is the management of men presenting for vasectomy. Specifically, the topics covered include preoperative counselling, vasectomy efficacy and complications, technical aspects of vasectomy, post-vasectomy semen testing, and interpretation-communication of post-vasectomy semen results. By performing an extensive literature review, we have generated an evidence-based consensus on the management of these men and have provided a recommendation grade based on the level of evidence (Table 1). The objective of this guideline is to help standardize the treatment of men presenting for vasectomy.
# Preoperative counselling
The procedure should be described during the initial consultation. Men must be informed about wound care and the potential for early complications: infection (0.2-1.5%), bleeding or hematoma (4-20%), and primary (early) surgical failure (0.2-5%) with motile sperm in the ejaculate at 3-6 months post-vasectomy. Men should also be made aware of late complications: chronic scrotal pain (1-14%) and delayed vasectomy failure after azoospermia at four months (0.05-1%). 1,5,6 Complications, such as bleeding and testicular pain, can often be managed medically but infrequently (<0.1%) these conditions may require a surgical intervention. 7,8 Exceptionally, surgical management of these complications may lead to testicular atrophy or an orchiectomy. Such information should be discussed verbally, and an information pamphlet should also be provided. The patient must be told that the vasectomy should be viewed as a permanent form of contraception with a high probability of reversibility. 9 Preoperative sperm banking and postoperative vasectomy reversal and sperm retrieval (for subsequent in vitro fertilization) can be discussed if patients are concerned about the permanent nature of the procedure.
Patients can be reassured that the data do not demonstrate a clear association between vasectomy and prostate cancer. 10 No other late complications have been associated with vasectomy (e.g., vascular disease, hypertension, testicular cancer) and, as such, these need not be discussed unless the patient inquires.
Most men are potentially fertile shortly after vasectomy. Moreover, in cases of early re-canalization or technical failure (e.g., missed vas deferens), men will remain fertile. Therefore, couples must be reminded about the rate of primary (early) surgical failure (0.2-5%) and instructed to use 4 A re-do vasectomy is recommended if motile spermatozoa continue to be present in the ejaculate six months after the procedure. Although the relationship between this finding (motile spermatozoa in the ejaculate at six months postoperatively) and subsequent pregnancy has not been established, pregnancies have been attributed to unprotected intercourse during the immediate post-vasectomy period. 11 While it is good practice to allow patients time for further reflection on their decision to undergo vasectomy, reconsider alternative contraceptive methods, and seek additional opinions from other healthcare providers, some patients may be fully ready to undergo vasectomy at the end of the initial consultation. In fact, it is logical to assume that many men in Canada seeking vasectomy have obtained information on the procedure from various sources, including the media, internet, friends/family, and/or other healthcare providers. Currently, there is no good data in the literature suggesting that providing a "cool-down" period after initial encounter of vasectomy counselling correlates to better surgical outcomes or better patient satisfaction. Thus, in the absence of valid medical reasons, such as time required to discontinue certain medications (e.g., anticoagulation) or recovery from temporary change of health status (e.g., acute infection), vasectomy may be performed (in most patients) shortly after the initial consultation.
With regards to the age limit of vasectomy, any man with the legal capacity to provide informed consent (this may vary from province to province) may undergo vasectomy. Studies in the U.S. indicate that it is rare for men below the age of 25 to choose vasectomy as a form of contraception. 12,13 An earlier study indicates that men who undergo vasectomy in their 20s have a 12.5 times greater likelihood of subsequently seeking vasectomy reversal. 14 Although data are lacking for men in their 20s seeking vasectomy, it is prudent to offer more time to these men (to reflect on their decision) prior to performing the surgery. Furthermore, when counselling about vasectomy in young patients, particularly minors and patients with an unclear level of understanding of or motivation to undergo vasectomy, surgeons should be prepared to offer consultations for psychosocial and ethical assessment prior to performing the surgery. Special consideration should be given when performing vasectomy in men with a clinical varicocele or with prior varicocelectomy. It has been estimated that varicoceles are found in 15% of the general male population, with a higher prevalence in men with primary or secondary infertility. Men who undergo surgical varicocelectomy for repair of a clinical varicocele may be left with only the deferential veins as the sole testicular venous return. In addition, during varicocelectomy, it is also possible to damage the testicular artery(ies), leaving the deferential artery as the principal arterial supply to the testis. Thus, when a vasectomy is performed in men who have undergone or may undergo varicocelectomy in the future, it is strongly advisable to isolate the vas deferens carefully and completely exclude the associated deferential arteries and veins to avoid potential injury to the deferential vasculature and minimize the risk of ipsilateral testicular injury. 15
# Vasectomy technique (access and occlusion)
The technique of vasectomy has undergone significant modifications over the years. Furthermore, the equipment, materials, and methods of anesthesia have also evolved over the years. Though experienced surgeons may prefer their own approach for vasectomies, it is advisable for surgeons to obtain regular continuing medical education focusing on various issues surrounding vasectomy, from surgical techniques to new studies in the latest peer-reviewed journals and clinical guidelines.
Local anesthesia is sufficient for most patients undergoing a vasectomy; however, anxious patients or those with complicating factors, such as a previous orchidopexy or other scrotal surgery, may require sedation or a general anesthetic. There is controversy regarding the benefit of topical anesthetic before injection of local anesthetic; 16,17 however, a small, 27-32-gauge needle is thought to be beneficial. Pneumatic injectors have not shown a clear benefit, 18,19 but may be suitable for patents with a needle phobia. The use of buffered xylocaine has not been studied in vasectomy patients.
# Isolation of the vas deferens
# Conventional vs. no scalpel vasectomy
The two most common surgical techniques for accessing the vas during vasectomy are the traditional incisional method and the no-scalpel vasectomy (NSV) technique. The conventional incisional technique involves the use of a scalpel to make one or two incisions in the scrotal skin to access the vas deferens; the NSV technique uses a sharp, forceps-like instrument to puncture the skin to access the vas deferens.
A Cochrane review of two randomized controlled trials found that compared to the standard incision technique, the NSV approach is associated with a significantly lower risk of postoperative hematoma (odds ratio 0.20, 95% The Cochrane review also found that NSV is a faster procedure than the standard incision technique; however, there was no significant difference in the effectiveness (azoospermic or absence of motile sperm) between the two procedures (1.6% vs. 1.8% early failure rate for the NSV and the conventional scalpel techniques, respectively). 20
Recommendation: NSV should be performed because it is associated with a significantly lower risk of postoperative complications (hematoma, pain, infection) than conventional vasectomy (Grade A-B).
# Vas occlusion technique
# Fascial interposition vs. no fascial interposition
In a randomized controlled trial of over 800 vasectomies, it was shown that the use of fascial interposition during vasectomy is associated with a significantly higher rate of azoospermia at three months than simple ligation and excision without fascial interposition (OR 0.42, 95% CI 0.26-0.70); however, fascial interposition may increase the complication rate of vasectomy. 25
# Mucosal cautery
In a comparative (case-control) study, cautery of the vas was associated with a lower risk of failure (defined as >100 000 sperm in the ejaculate) than fascial interposition (1% vs. 4.9%, OR 4.8, 95% CI 1.6-14.3). 3
# Recommendation: Mucosal cautery and/or fascial interposition (with vas ligation and excision
) should be performed during vasectomy, as these techniques are associated with the lowest failure rates (Grade B). Nonetheless, surgeons may opt to use their preferred occlusion technique as long they obtain consistently low vasectomy failure rates.
# Postoperative counselling
After the vasectomy has been performed, men should be instructed about proper wound and scrotal care and shortterm physical limitations. Men should be told how to collect the semen sample (completeness, type of container) and reminded of the importance of submitting the sample to the laboratory in a timely fashion (within 30-60 minutes after producing the sample). They should also be told that semen samples should be collected after an abstinence period of two or more days and no more than seven days, and maintained at body temperature before delivery to the laboratory. A list of local laboratories that perform proper postvasectomy semen analysis should be given to the patient. The men must be reminded to use other contraceptive measures until post-vasectomy semen testing has confirmed absence of motile sperm.
# Contraceptive efficacy of vasectomy
The early failure rate of vasectomy (presence of motile sperm in the ejaculate at 3-6 months post-vasectomy) is in the range of 0.2-5% and has been linked to surgeon experience and the technique. 25 Both technical failure (e.g., missed vas deferens) and early re-canalization of the vas deferens have been proposed as plausible explanations for early vasectomy failure.
Late vasectomy failure has been reported to be in the range of 0.04-0.08% (approximately 1/2000 cases) and is defined as the presence of motile spermatozoa in the ejaculate after documented azoospermia in two post-vasectomy semen analyses. 26,27 In most cases, late failure is first identified as a pregnancy and later confirmed by semen analysis (documenting presence of motile spermatozoa).
The reappearance of sperm (often immotile) after documented azoospermia three months post-vasectomy may be much higher than 1/2000 according to the reported identification of spermatozoa in nearly 10% of ejaculates from men undergoing semen assessment prior to vasectomy reversal. 28 It is unlikely that the reappearance (or persistence) of immotile sperm years after vasectomy is of clinical significance, as this has not been associated with documented pregnancies. 29,30
# Post-vasectomy semen testing
The post-vasectomy semen analysis should be performed on fresh (unprocessed) semen and on the centrifuged semen to confirm the absence of low numbers of motile sperm. The laboratory should give an estimation of sperm concentration or numbers of spermatozoa observed per high power field (×400 magnification). It is important to recognize that compliance with post-vasectomy semen testing is a significant issue, with up to 30% of men failing to submit a single sample. 32,33 Figure 1 depicts a proposed algorithm for post-vasectomy testing protocol.
# One vs. two post-vasectomy samples
Surveys have shown significant variability in the post-vasectomy testing protocols. 34 Most agree that a single semen analysis showing azoospermia is sufficient to deem the vasectomy effective. 31,35 Moreover, a single semen analysis showing rare non-motile sperm (<100 000 non-motile sperm/ml) is also sufficient to deem the vasectomy effective, assuming the analysis is performed by an experienced, reputable lab.
In a study of 5233 vasectomies, Alderman reported that the risk of conversion from azoospermia or rare non-motile sperm to greater numbers of sperm is very rare (approximately 0.1% of cases) and is more commonly followed by conversion to azoospermia. 36 Similarly, Barone et al estimated that the predictive value of a single semen analysis with rare non-motile sperm for vasectomy success is 99.7%. 37 A second semen analysis should be requested in men with greater numbers of non-motile sperm (>100 000 non-motile sperm/ml) and/ or any number of motile sperm on the first semen analysis. Some clinicians may prefer to request two semen samples at the onset, as this may reduce the number of post-vasectomy counselling sessions (e.g., phone calls or office visits); however, this may also decrease the overall compliance. 33 Recommendation: A single semen sample showing azoospermia or rare non-motile sperm (100 000/ml) or any number of motile sperm on the first semen analysis (Grade C).
# Timing of post-vasectomy testing
Although most studies suggest that post-vasectomy testing be conducted at three months after vasectomy, the issue remains debatable, with some studies suggesting earlier examinations and others proposing later examinations. 33,38,39 The difficulty in establishing a set time point for semen testing stems largely from the variable success of the vasectomy occlusion techniques. 25 Azoospermia is achieved much later with the ligation (and excision) compared to the cautery or fascial interposition techniques. 25,38,40 The argument in favor of waiting at least three months is that this will reduce the number of false-positive samples and minimize the need for repeat laboratory assessment and counselling. 39 Recommendation: Post-vasectomy testing should be conducted at three months after vasectomy (Grade C). CUA BPR: Vasectomy
# Interpreting and communicating results
Azoospermia or rare immotile sperm (<100 000 per/ml) as an indication of successful vasectomy Contraceptive measures may be abandoned after men have produced one azoospermic sample or one semen sample with rare (<100 000/ml) immotile spermatozoa. It is the physician's responsibility (not the laboratory's) to communicate these results to the patient and measures should be taken to ensure that patients are not lost to followup. Physicians must also remind couples about the risk of late failure (approximately 1/2000) despite azoospermia or rare immotile sperm on initial testing.
It is estimated that approximately 20-40% of samples have rare non-motile sperm at three months post-vasectomy, with a lower percentage having non-motile sperm at six months .32,39 When there is doubt regarding the analysis, physicians may want to contact the laboratory and confirm that there was no reporting error (i.e., that the sample was incorrectly labeled as "non-motile"). The literature has suggested that the risk of pregnancy occurring from these nonmotile sperm is small -perhaps no more than the risk of late pregnancy after two azoospermic semen samples because of spontaneous re-canalization. 29,30 Similarly, rare non-motile sperm can appear in the ejaculate one or more years after vasectomy with no increased risk of failure (pregnancy or motile sperm). Therefore, repeat semen testing in men with rare non-motile sperm is unnecessary because pregnancy is very unlikely to occur in this setting.
Motile sperm or large numbers of immotile sperm as a measure of failure If any motile sperm or substantial numbers of immotile spermatozoa (>100 000 sperm/ml) are detected, the physician must inform the patient to continue the use of other contraceptive measures and request that a repeat semen analysis be performed. A repeat vasectomy is indicated when there is persistence of motile sperm or large numbers of nonmotile sperm in the ejaculate. No long-term studies have evaluated the risk of pregnancy in this setting.
Recommendation: Persistence of any number of motile sperm or >100 000 sperm/ml on two semen samples is an indication of vasectomy failure (Grade C).
# Summary
Vasectomy is a safe and effective method of birth control. The NSV technique is associated with a lower risk of early postoperative complications and the use of mucosal cautery or fascial interposition will reduce the risk of contraceptive failure. Post-vasectomy testing should consist of analysis of one or two semen samples at approximately three months after vasectomy. The laboratory should examine a freshly produced seminal fluid specimen by direct microscopy and if no sperm are seen, the centrifuged sample should be examined for the presence of motile and non-motile spermatozoa. Other contraceptive measures may be abandoned after the production of one azoospermic ejaculate or one ejaculate with <100 000 immotile spermatozoa. Couples must be counselled (both pre-and postoperatively) about the risks of early and late failure.
Competing interests: Dr. Zini holds investments in YAD Tech. The remaining authors do not report any competing personal or financial interests related to this work.
Prior to publication, this guideline was reviewed by the CUA Guidelines Committee and the CUA Board of Directors.
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The following is an update of the 2016 Canadian Urological Association vasectomy guideline. The changes introduced are relatively minor, and include: -Clarified text on the optimal vasectomy occlusion technique, with a statement added about the surgeon being able to choose his/her preferred technique so long as outcomes are good. -Clarification of the recommendations on the number of post-vasectomy semen analyses.# Introduction
Vasectomy is a safe and effective method of birth control. Although it is a simple elective procedure, vasectomy is associated with potential minor and major complications. The early failure rate of vasectomy (presence of motile sperm in the ejaculate at 3-6 months post-vasectomy) is in the range of 0.2-5% and the late failure rate is in the range of 0.04-0.08%. The no-scalpel vasectomy technique is associated with a lower risk of early postoperative complications and the use of cautery or fascial interposition will reduce the risk of contraceptive failure. As such, detailed preoperative counselling and careful assessment of the post-vasectomy ejaculate (for presence of sperm) is imperative. Failure to provide and document adequate information and counselling to patients may lead to litigation.
The focus of this guideline is the management of men presenting for vasectomy. Specifically, the topics covered include preoperative counselling, vasectomy efficacy and complications, technical aspects of vasectomy, post-vasectomy semen testing, and interpretation-communication of post-vasectomy semen results. By performing an extensive literature review, we have generated an evidence-based consensus on the management of these men and have provided a recommendation grade based on the level of evidence (Table 1). The objective of this guideline is to help standardize the treatment of men presenting for vasectomy.
# Preoperative counselling
The procedure should be described during the initial consultation. Men must be informed about wound care and the potential for early complications: infection (0.2-1.5%), bleeding or hematoma (4-20%), and primary (early) surgical failure (0.2-5%) with motile sperm in the ejaculate at 3-6 months post-vasectomy. [1][2][3][4] Men should also be made aware of late complications: chronic scrotal pain (1-14%) and delayed vasectomy failure after azoospermia at four months (0.05-1%). 1,5,6 Complications, such as bleeding and testicular pain, can often be managed medically but infrequently (<0.1%) these conditions may require a surgical intervention. 7,8 Exceptionally, surgical management of these complications may lead to testicular atrophy or an orchiectomy. Such information should be discussed verbally, and an information pamphlet should also be provided. The patient must be told that the vasectomy should be viewed as a permanent form of contraception with a high probability of reversibility. 9 Preoperative sperm banking and postoperative vasectomy reversal and sperm retrieval (for subsequent in vitro fertilization) can be discussed if patients are concerned about the permanent nature of the procedure.
Patients can be reassured that the data do not demonstrate a clear association between vasectomy and prostate cancer. 10 No other late complications have been associated with vasectomy (e.g., vascular disease, hypertension, testicular cancer) and, as such, these need not be discussed unless the patient inquires.
Most men are potentially fertile shortly after vasectomy. Moreover, in cases of early re-canalization or technical failure (e.g., missed vas deferens), men will remain fertile. Therefore, couples must be reminded about the rate of primary (early) surgical failure (0.2-5%) and instructed to use 4 A re-do vasectomy is recommended if motile spermatozoa continue to be present in the ejaculate six months after the procedure. Although the relationship between this finding (motile spermatozoa in the ejaculate at six months postoperatively) and subsequent pregnancy has not been established, pregnancies have been attributed to unprotected intercourse during the immediate post-vasectomy period. 11 While it is good practice to allow patients time for further reflection on their decision to undergo vasectomy, reconsider alternative contraceptive methods, and seek additional opinions from other healthcare providers, some patients may be fully ready to undergo vasectomy at the end of the initial consultation. In fact, it is logical to assume that many men in Canada seeking vasectomy have obtained information on the procedure from various sources, including the media, internet, friends/family, and/or other healthcare providers. Currently, there is no good data in the literature suggesting that providing a "cool-down" period after initial encounter of vasectomy counselling correlates to better surgical outcomes or better patient satisfaction. Thus, in the absence of valid medical reasons, such as time required to discontinue certain medications (e.g., anticoagulation) or recovery from temporary change of health status (e.g., acute infection), vasectomy may be performed (in most patients) shortly after the initial consultation.
With regards to the age limit of vasectomy, any man with the legal capacity to provide informed consent (this may vary from province to province) may undergo vasectomy. Studies in the U.S. indicate that it is rare for men below the age of 25 to choose vasectomy as a form of contraception. 12,13 An earlier study indicates that men who undergo vasectomy in their 20s have a 12.5 times greater likelihood of subsequently seeking vasectomy reversal. 14 Although data are lacking for men in their 20s seeking vasectomy, it is prudent to offer more time to these men (to reflect on their decision) prior to performing the surgery. Furthermore, when counselling about vasectomy in young patients, particularly minors and patients with an unclear level of understanding of or motivation to undergo vasectomy, surgeons should be prepared to offer consultations for psychosocial and ethical assessment prior to performing the surgery. Special consideration should be given when performing vasectomy in men with a clinical varicocele or with prior varicocelectomy. It has been estimated that varicoceles are found in 15% of the general male population, with a higher prevalence in men with primary or secondary infertility. Men who undergo surgical varicocelectomy for repair of a clinical varicocele may be left with only the deferential veins as the sole testicular venous return. In addition, during varicocelectomy, it is also possible to damage the testicular artery(ies), leaving the deferential artery as the principal arterial supply to the testis. Thus, when a vasectomy is performed in men who have undergone or may undergo varicocelectomy in the future, it is strongly advisable to isolate the vas deferens carefully and completely exclude the associated deferential arteries and veins to avoid potential injury to the deferential vasculature and minimize the risk of ipsilateral testicular injury. 15
# Vasectomy technique (access and occlusion)
The technique of vasectomy has undergone significant modifications over the years. Furthermore, the equipment, materials, and methods of anesthesia have also evolved over the years. Though experienced surgeons may prefer their own approach for vasectomies, it is advisable for surgeons to obtain regular continuing medical education focusing on various issues surrounding vasectomy, from surgical techniques to new studies in the latest peer-reviewed journals and clinical guidelines.
Local anesthesia is sufficient for most patients undergoing a vasectomy; however, anxious patients or those with complicating factors, such as a previous orchidopexy or other scrotal surgery, may require sedation or a general anesthetic. There is controversy regarding the benefit of topical anesthetic before injection of local anesthetic; 16,17 however, a small, 27-32-gauge needle is thought to be beneficial. Pneumatic injectors have not shown a clear benefit, 18,19 but may be suitable for patents with a needle phobia. The use of buffered xylocaine has not been studied in vasectomy patients.
# Isolation of the vas deferens
# Conventional vs. no scalpel vasectomy
The two most common surgical techniques for accessing the vas during vasectomy are the traditional incisional method and the no-scalpel vasectomy (NSV) technique. The conventional incisional technique involves the use of a scalpel to make one or two incisions in the scrotal skin to access the vas deferens; the NSV technique uses a sharp, forceps-like instrument to puncture the skin to access the vas deferens.
A Cochrane review of two randomized controlled trials found that compared to the standard incision technique, the NSV approach is associated with a significantly lower risk of postoperative hematoma (odds ratio [OR] 0.20, 95% [20][21][22] The Cochrane review also found that NSV is a faster procedure than the standard incision technique; however, there was no significant difference in the effectiveness (azoospermic or absence of motile sperm) between the two procedures (1.6% vs. 1.8% early failure rate for the NSV and the conventional scalpel techniques, respectively). 20
Recommendation: NSV should be performed because it is associated with a significantly lower risk of postoperative complications (hematoma, pain, infection) than conventional vasectomy (Grade A-B).
# Vas occlusion technique
# Fascial interposition vs. no fascial interposition
In a randomized controlled trial of over 800 vasectomies, it was shown that the use of fascial interposition during vasectomy is associated with a significantly higher rate of azoospermia at three months than simple ligation and excision without fascial interposition (OR 0.42, 95% CI 0.26-0.70); [22][23][24] however, fascial interposition may increase the complication rate of vasectomy. 25
# Mucosal cautery
In a comparative (case-control) study, cautery of the vas was associated with a lower risk of failure (defined as >100 000 sperm in the ejaculate) than fascial interposition (1% vs. 4.9%, OR 4.8, 95% CI 1.6-14.3). 3
# Recommendation: Mucosal cautery and/or fascial interposition (with vas ligation and excision
) should be performed during vasectomy, as these techniques are associated with the lowest failure rates (Grade B). Nonetheless, surgeons may opt to use their preferred occlusion technique as long they obtain consistently low vasectomy failure rates.
# Postoperative counselling
After the vasectomy has been performed, men should be instructed about proper wound and scrotal care and shortterm physical limitations. Men should be told how to collect the semen sample (completeness, type of container) and reminded of the importance of submitting the sample to the laboratory in a timely fashion (within 30-60 minutes after producing the sample). They should also be told that semen samples should be collected after an abstinence period of two or more days and no more than seven days, and maintained at body temperature before delivery to the laboratory. A list of local laboratories that perform proper postvasectomy semen analysis should be given to the patient. The men must be reminded to use other contraceptive measures until post-vasectomy semen testing has confirmed absence of motile sperm.
# Contraceptive efficacy of vasectomy
The early failure rate of vasectomy (presence of motile sperm in the ejaculate at 3-6 months post-vasectomy) is in the range of 0.2-5% and has been linked to surgeon experience and the technique. 25 Both technical failure (e.g., missed vas deferens) and early re-canalization of the vas deferens have been proposed as plausible explanations for early vasectomy failure.
Late vasectomy failure has been reported to be in the range of 0.04-0.08% (approximately 1/2000 cases) and is defined as the presence of motile spermatozoa in the ejaculate after documented azoospermia in two post-vasectomy semen analyses. 26,27 In most cases, late failure is first identified as a pregnancy and later confirmed by semen analysis (documenting presence of motile spermatozoa).
The reappearance of sperm (often immotile) after documented azoospermia three months post-vasectomy may be much higher than 1/2000 according to the reported identification of spermatozoa in nearly 10% of ejaculates from men undergoing semen assessment prior to vasectomy reversal. 28 It is unlikely that the reappearance (or persistence) of immotile sperm years after vasectomy is of clinical significance, as this has not been associated with documented pregnancies. 29,30
# Post-vasectomy semen testing
The post-vasectomy semen analysis should be performed on fresh (unprocessed) semen and on the centrifuged semen to confirm the absence of low numbers of motile sperm. The laboratory should give an estimation of sperm concentration or numbers of spermatozoa observed per high power field (×400 magnification). [29][30][31] It is important to recognize that compliance with post-vasectomy semen testing is a significant issue, with up to 30% of men failing to submit a single sample. 32,33 Figure 1 depicts a proposed algorithm for post-vasectomy testing protocol.
# One vs. two post-vasectomy samples
Surveys have shown significant variability in the post-vasectomy testing protocols. 34 Most agree that a single semen analysis showing azoospermia is sufficient to deem the vasectomy effective. 31,35 Moreover, a single semen analysis showing rare non-motile sperm (<100 000 non-motile sperm/ml) is also sufficient to deem the vasectomy effective, assuming the analysis is performed by an experienced, reputable lab.
In a study of 5233 vasectomies, Alderman reported that the risk of conversion from azoospermia or rare non-motile sperm to greater numbers of sperm is very rare (approximately 0.1% of cases) and is more commonly followed by conversion to azoospermia. 36 Similarly, Barone et al estimated that the predictive value of a single semen analysis with rare non-motile sperm for vasectomy success is 99.7%. 37 A second semen analysis should be requested in men with greater numbers of non-motile sperm (>100 000 non-motile sperm/ml) and/ or any number of motile sperm on the first semen analysis. Some clinicians may prefer to request two semen samples at the onset, as this may reduce the number of post-vasectomy counselling sessions (e.g., phone calls or office visits); however, this may also decrease the overall compliance. 33 Recommendation: A single semen sample showing azoospermia or rare non-motile sperm (<100 000 non-motile sperm/ml) is sufficient to deem the vasectomy effective. A second semen analysis should be requested in men with a greater number of non-motile sperm (>100 000/ml) or any number of motile sperm on the first semen analysis (Grade C).
# Timing of post-vasectomy testing
Although most studies suggest that post-vasectomy testing be conducted at three months after vasectomy, the issue remains debatable, with some studies suggesting earlier examinations and others proposing later examinations. 33,38,39 The difficulty in establishing a set time point for semen testing stems largely from the variable success of the vasectomy occlusion techniques. 25 Azoospermia is achieved much later with the ligation (and excision) compared to the cautery or fascial interposition techniques. 25,38,40 The argument in favor of waiting at least three months is that this will reduce the number of false-positive samples and minimize the need for repeat laboratory assessment and counselling. 39 Recommendation: Post-vasectomy testing should be conducted at three months after vasectomy (Grade C). CUA BPR: Vasectomy
# Interpreting and communicating results
Azoospermia or rare immotile sperm (<100 000 per/ml) as an indication of successful vasectomy Contraceptive measures may be abandoned after men have produced one azoospermic sample or one semen sample with rare (<100 000/ml) immotile spermatozoa. It is the physician's responsibility (not the laboratory's) to communicate these results to the patient and measures should be taken to ensure that patients are not lost to followup. Physicians must also remind couples about the risk of late failure (approximately 1/2000) despite azoospermia or rare immotile sperm on initial testing.
It is estimated that approximately 20-40% of samples have rare non-motile sperm at three months post-vasectomy, with a lower percentage having non-motile sperm at six months .32,39 When there is doubt regarding the analysis, physicians may want to contact the laboratory and confirm that there was no reporting error (i.e., that the sample was incorrectly labeled as "non-motile"). The literature has suggested that the risk of pregnancy occurring from these nonmotile sperm is small -perhaps no more than the risk of late pregnancy after two azoospermic semen samples because of spontaneous re-canalization. 29,30 Similarly, rare non-motile sperm can appear in the ejaculate one or more years after vasectomy with no increased risk of failure (pregnancy or motile sperm). Therefore, repeat semen testing in men with rare non-motile sperm is unnecessary because pregnancy is very unlikely to occur in this setting.
Motile sperm or large numbers of immotile sperm as a measure of failure If any motile sperm or substantial numbers of immotile spermatozoa (>100 000 sperm/ml) are detected, the physician must inform the patient to continue the use of other contraceptive measures and request that a repeat semen analysis be performed. A repeat vasectomy is indicated when there is persistence of motile sperm or large numbers of nonmotile sperm in the ejaculate. No long-term studies have evaluated the risk of pregnancy in this setting.
Recommendation: Persistence of any number of motile sperm or >100 000 sperm/ml on two semen samples is an indication of vasectomy failure (Grade C).
# Summary
Vasectomy is a safe and effective method of birth control. The NSV technique is associated with a lower risk of early postoperative complications and the use of mucosal cautery or fascial interposition will reduce the risk of contraceptive failure. Post-vasectomy testing should consist of analysis of one or two semen samples at approximately three months after vasectomy. The laboratory should examine a freshly produced seminal fluid specimen by direct microscopy and if no sperm are seen, the centrifuged sample should be examined for the presence of motile and non-motile spermatozoa. Other contraceptive measures may be abandoned after the production of one azoospermic ejaculate or one ejaculate with <100 000 immotile spermatozoa. Couples must be counselled (both pre-and postoperatively) about the risks of early and late failure.
Competing interests: Dr. Zini holds investments in YAD Tech. The remaining authors do not report any competing personal or financial interests related to this work.
Prior to publication, this guideline was reviewed by the CUA Guidelines Committee and the CUA Board of Directors.
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To provide practical information on the optimal utilization of prasugrel in clinical practice.Prasugrel is an irreversible inhibitor of platelet activation and aggregation through the binding of its active metabolite to the P2Y12 adenosine diphosphate (ADP) receptor on platelets.# INDICATION:
Prasugrel, co-administered with acetylsalicylic acid (ASA), is indicated for the secondary prevention of ischemic cardiac events in patients with an acute coronary syndrome (ACS) (i.e. unstable angina, ST elevation myocardial infarction or non-ST elevation MI) who are managed with percutaneous coronary intervention (PCI). This indication is based on the findings of a large phase 3 randomized controlled trial that demonstrated a statistically significant 2.2% absolute risk reduction (ARR) with prasugrel on the combined outcome rate of cardiovascular death, non-fatal MI, and non-fatal stroke (driven mostly by non-fatal MI) compared with clopidogrel, in patients presenting with ACS managed by PCI (number needed to treat = 46). MI and stent thrombosis were also significantly reduced (ARR 2.3%; NNT = 43 and ARR 1.3%; NNT = 77, respectively). The benefit of prasugrel has been demonstrated only in patients with ACS undergoing PCI. There was no benefit for prasugrel over clopidogrel in ASA-treated patients who were managed medically following non-ST elevation ACS.
Evidence directly comparing the efficacy and safety of ticagrelor and prasugrel in patients undergoing PCI is mixed. Smaller studies have reported similar outcomes, but a moderately sized (n= 4018), randomized, open-label comparison between prasugrel and ticagrelor in patients hospitalized with ACS intended to receive a planned invasive evaluation suggested improved outcomes with prasugrel. The ARR at one year for the composite of MI, stroke and CV death was 2.4% in patients treated with prasugrel, and there was no difference in the risk of major bleeding compared to ticagrelor.
# DOSING:
In patients with ACS, a loading dose of 60 mg should be administered at the time of PCI followed by a maintenance dose of 10 mg daily. Prasugrel is not recommended in patients weighing 75 years due to increased risk of bleeding. Prasugrel 5mg daily, however, was evaluated in patients >75 years in a secondary analysis of a study in medically managed ACS patients and was shown to have similar bleeding rates to that seen with clopidogrel. However, there is currently no approved indication for a 5 mg daily dosing in Canada and the available 10 mg pill is not scored to permit accurate dose reduction.
Patients taking prasugrel should also take ASA 81 mg daily, unless specifically contraindicated. Absorption is not affected by food intake and no dosing adjustment is required for patients with chronic renal disease or patients with mild to moderate hepatic impairment. There do not appear to be any significant pharmacokinetic drug interactions with prasugrel. Duration of therapy is typically one year, but this may vary by clinical factors.
# ADVERSE EFFECTS:
As with all antiplatelet agents, prasugrel increases the risk of major bleeding including intracerebral hemorrhage. In a 1-year randomized trial of 13,608 ACS patients undergoing PCI, major bleeding unrelated to coronary artery bypass graft (CABG) surgery occurred in 2.4% of subjects randomized to prasugrel, a significant absolute increase of 0.6% compared with clopidogrel (number needed to harm = 167). Major bleeding related to CABG occurred in 13.4% of prasugrel patients, a significant absolute increase of 10.2% (NNH=10) versus clopidogrel. Fatal bleeding, although rare, was also significantly increased compared with clopidogrel (0.4% vs 0.1%; NNH = 333). Although intracranial hemorrhage was not increased overall, patients with a history of stroke or transient ischemic attack (TIA) were at a significantly greater risk. Major bleeding was also increased, and the net clinical benefit to prasugrel therapy was lost in patients age >75 years or with a body weight <60 kg.
# PERIPROCEDURAL MANAGEMENT:
The periprocedural use of antiplatelet agents may increase the risk of bleeding and transfusion requirements associated with surgery and other invasive procedures. However, discontinuation of dual antiplatelet therapy within 12 months of stent implantation is associated with an increased risk of major adverse cardiovascular events and stent thrombosis. For this reason, procedures associated with significant bleeding risk should be delayed beyond 1 year if possible, and, if not possible, done with consideration of the patient remaining on therapy. If prasugrel can be stopped safely, it should be discontinued 7 days prior to surgery. In general, consultation with a specialist is advised before discontinuing prasugrel in patients with a coronary stent. In patients undergoing a minor procedure (e.g. dental, skin, cataract, arthrocentesis), discontinuation is not necessary. See Clinical Guide Perioperative Management of Antiplatelet Therapy.
# SPECIAL CONSIDERATIONS:
Due to increased risk of fatal and intracranial bleeding, prasugrel should be avoided in patients with a previous history of stroke or TIA. Prasugrel should not be prescribed to patients with severe liver disease. There are no adequate and well-controlled studies of this drug in pregnant women; therefore, prasugrel should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. A study in rats showed that prasugrel metabolites are excreted in the animals' milk. There are no clinical studies in lactating women and it is not known whether this drug is excreted in human milk. Prasugrel use while breastfeeding is generally not recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Acetylsalicylic Acid (ASA) - Clopidogrel (Plavix®) - Perioperative Management of Antiplatelet Therapy - Ticagrelor (Brilinta®)
# Date of Version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
|
To provide practical information on the optimal utilization of prasugrel in clinical practice.Prasugrel is an irreversible inhibitor of platelet activation and aggregation through the binding of its active metabolite to the P2Y12 adenosine diphosphate (ADP) receptor on platelets.# INDICATION:
Prasugrel, co-administered with acetylsalicylic acid (ASA), is indicated for the secondary prevention of ischemic cardiac events in patients with an acute coronary syndrome (ACS) (i.e. unstable angina, ST elevation myocardial infarction [MI] or non-ST elevation MI) who are managed with percutaneous coronary intervention (PCI). This indication is based on the findings of a large phase 3 randomized controlled trial that demonstrated a statistically significant 2.2% absolute risk reduction (ARR) with prasugrel on the combined outcome rate of cardiovascular death, non-fatal MI, and non-fatal stroke (driven mostly by non-fatal MI) compared with clopidogrel, in patients presenting with ACS managed by PCI (number needed to treat [NNT] = 46). MI and stent thrombosis were also significantly reduced (ARR 2.3%; NNT = 43 and ARR 1.3%; NNT = 77, respectively). The benefit of prasugrel has been demonstrated only in patients with ACS undergoing PCI. There was no benefit for prasugrel over clopidogrel in ASA-treated patients who were managed medically following non-ST elevation ACS.
Evidence directly comparing the efficacy and safety of ticagrelor and prasugrel in patients undergoing PCI is mixed. Smaller studies have reported similar outcomes, but a moderately sized (n= 4018), randomized, open-label comparison between prasugrel and ticagrelor in patients hospitalized with ACS intended to receive a planned invasive evaluation suggested improved outcomes with prasugrel. The ARR at one year for the composite of MI, stroke and CV death was 2.4% in patients treated with prasugrel, and there was no difference in the risk of major bleeding compared to ticagrelor.
# DOSING:
In patients with ACS, a loading dose of 60 mg should be administered at the time of PCI followed by a maintenance dose of 10 mg daily. Prasugrel is not recommended in patients weighing <60 kg or age >75 years due to increased risk of bleeding. Prasugrel 5mg daily, however, was evaluated in patients >75 years in a secondary analysis of a study in medically managed ACS patients and was shown to have similar bleeding rates to that seen with clopidogrel. However, there is currently no approved indication for a 5 mg daily dosing in Canada and the available 10 mg pill is not scored to permit accurate dose reduction.
Patients taking prasugrel should also take ASA 81 mg daily, unless specifically contraindicated. Absorption is not affected by food intake and no dosing adjustment is required for patients with chronic renal disease or patients with mild to moderate hepatic impairment. There do not appear to be any significant pharmacokinetic drug interactions with prasugrel. Duration of therapy is typically one year, but this may vary by clinical factors.
# ADVERSE EFFECTS:
As with all antiplatelet agents, prasugrel increases the risk of major bleeding including intracerebral hemorrhage. In a 1-year randomized trial of 13,608 ACS patients undergoing PCI, major bleeding unrelated to coronary artery bypass graft (CABG) surgery occurred in 2.4% of subjects randomized to prasugrel, a significant absolute increase of 0.6% compared with clopidogrel (number needed to harm [NNH] = 167). Major bleeding related to CABG occurred in 13.4% of prasugrel patients, a significant absolute increase of 10.2% (NNH=10) versus clopidogrel. Fatal bleeding, although rare, was also significantly increased compared with clopidogrel (0.4% vs 0.1%; NNH = 333). Although intracranial hemorrhage was not increased overall, patients with a history of stroke or transient ischemic attack (TIA) were at a significantly greater risk. Major bleeding was also increased, and the net clinical benefit to prasugrel therapy was lost in patients age >75 years or with a body weight <60 kg.
# PERIPROCEDURAL MANAGEMENT:
The periprocedural use of antiplatelet agents may increase the risk of bleeding and transfusion requirements associated with surgery and other invasive procedures. However, discontinuation of dual antiplatelet therapy within 12 months of stent implantation is associated with an increased risk of major adverse cardiovascular events and stent thrombosis. For this reason, procedures associated with significant bleeding risk should be delayed beyond 1 year if possible, and, if not possible, done with consideration of the patient remaining on therapy. If prasugrel can be stopped safely, it should be discontinued 7 days prior to surgery. In general, consultation with a specialist is advised before discontinuing prasugrel in patients with a coronary stent. In patients undergoing a minor procedure (e.g. dental, skin, cataract, arthrocentesis), discontinuation is not necessary. See Clinical Guide Perioperative Management of Antiplatelet Therapy.
# SPECIAL CONSIDERATIONS:
Due to increased risk of fatal and intracranial bleeding, prasugrel should be avoided in patients with a previous history of stroke or TIA. Prasugrel should not be prescribed to patients with severe liver disease. There are no adequate and well-controlled studies of this drug in pregnant women; therefore, prasugrel should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. A study in rats showed that prasugrel metabolites are excreted in the animals' milk. There are no clinical studies in lactating women and it is not known whether this drug is excreted in human milk. Prasugrel use while breastfeeding is generally not recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Acetylsalicylic Acid (ASA) • Clopidogrel (Plavix®) • Perioperative Management of Antiplatelet Therapy • Ticagrelor (Brilinta®)
# Date of Version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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d5a957ec4571b2d3fc26ad0a8056c8b7596028ec
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cma
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None
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The primary purpose of this statement is to improve neuroprognostication after devastating brain injury (DBI), with a secondary benefit of potential organ and tissue donation.Adult patients with DBI who have had initiation of resuscitation measures, including intubation and mechanical ventilation.Clinical decision-making regarding initiation of resuscitation measures after DBI.# INTRODUCTION
Devastating brain injury is defined as a neurological injury (trauma, subarachnoid hemorrhage, stroke, hypoxic injury, etc.) that is assessed as an immediate threat to life or incompatible with good functional recovery and where early limitation or withdrawal of therapy is being considered. 1,2 The outcomes for patients who present in the emergency department (ED) with DBI are often death or, in some cases, survival with extremely limited capacity. Consequently, many physicians consider admission to the intensive care unit (ICU) inappropriate as it is not only futile and challenging in the face of scarce ICU resources, but also a burden on patients and families by offering prolongation of what may be an inevitably poor outcome.
However, the management of DBI in the ED is evolving. Accurate prognostication in the early stages of DBI cases can be difficult, and rigorous, evidence-based prognostication strategies in patients with DBI are limited. Clinician variability in the withdrawal of life-sustaining treatments impacts patient outcomes. A recent multicentre retrospective cohort study of patients with severe DBI in Canadian level-one trauma centres identified significant variation in mortality across centres. Mortality rates were significantly impacted by varying approaches to withdrawal of life-sustaining measures (WLSM), highlighting deficiencies of early prognostic strategies in trauma. 3 In-hospital mortality after intracerebral hemorrhage is significantly influenced by the variability in the rate at which treating hospitals use do-not-resuscitate orders, even after adjusting for case mix. 4 To improve the quality of decision-making to better inform whether the patient can survive and recover, transfer to the ICU for a period of physiological support and observation is recommended. 1,2 The optimal period for observation to establish greater confidence and accuracy in prognostication following DBI is not well established. The Neurocritical Care Society 1 recommends a 72-hour observation period, during which physiological support can prevent unwarranted deterioration and allow sufficient opportunity for prognostic evaluation, care planning, and a more definitive determination of prognosis based on repeated examinations over time. The United Kingdom (Faculty of Intensive Care Medicine, Intensive Care Society, Neuroanaesthesia and Critical Care Society, Royal College of Emergency Medicine, Society of British Neurological Surgeons) recommends that the length of the observation period be based on a combination of clinical judgement, changes in neurological function, the degree of support required to maintain physiological stability, and communication with the patient's family to determine patient preferences. 2 Though death may be the most likely outcome in many of these cases, a period of observation will further ensure the accuracy of this prognosis and avoid what may be an inappropriate limitation in care. 5 The primary aim is to improve the ability to distinguish patients who may have the capacity to recover and survive. In addition, it allows for a timely referral to the provincial organ donation organization, ensuring that patients and their families are given sufficient opportunity to consider organ and tissue donation. A recent systematic review 6 of ED deaths revealed that a substantial proportion (46.2-84%) of potential organ donors was missed due to a failure to refer for consideration of organ donation, in part, due to incorrect assumptions regarding eligibility criteria and failure of the healthcare team to refer for consideration of donation. In Ontario, over the 2017-2018 to 2018-2019 fiscal years, 33 (19%) of 178 patients who died in the ED and were not referred to the organ donation organization had organ donation potential (unpublished data, Trillium Gift of Life Network, 2019).
A potential organ donor is someone who has a very high chance of death but in whom active care continues or suitability for donation has not yet been established. In those cases where continued physiological support will have no benefit for prognostication or neurological outcome, physicians should refer patients to their provincial organ donation organization prior to WLSM. In accordance with the Potential Organ Donor Identification and System Accountability guideline, 7 patients who meet the following criteria should be considered potential organ donors and referred to the organ donation organization:
- Ventilated (invasive or non-invasive) 2. Condition with a grave prognosis in which death is imminent
# Consideration of WLSM
# POSITION STATEMENT
To ensure that the management of DBI includes an observation period for optimized neuro-prognostication and that families are given the opportunity to consider organ donation as part of quality end-of-life care, the following high-level concepts are supported:
- Early prognostication in devastating brain injury has known limitations and can be inaccurate. A sufficient period of observation and physiological support increases the opportunity for patient survival/recovery.
- WLSM in DBI cases should be decided after observation of clinical evolution in an ICU setting in order to optimize patient outcomes. Exceptions to this would include, but are not limited to, the following case scenarios:
- It is clearly outlined that ongoing care is not consistent with the patient's previously expressed wishes (either documented or supported by available substitute decision-maker)
- Physiological futilityinability to maintain cardiorespiratory stability function due to extent of injuries or illness severity
- Concurrent comorbidities that are considered inappropriate for ICU admission in the absence of a DBI 3. Although a critical care setting with neurosurgical capacity is preferred when indicated and feasible, for patients without surgical indications, these aims could be achieved in any critical care environment.
- Where patient survival/recovery is not possible, it provides an important opportunity to consider organ donation.
- Identification and timely referral of potential organ donors in the ED as part of end-of-life care can save and enhance lives through organ and tissue donation.
- Physiological support should be maintained until the following:
- The patient receives an appropriate period of observation for neuro-prognostication based on clinical circumstances
- A decision for WLSM has been made or the patient meets neurological criteria for death determination
- The patient has been referred to the organ donation organization
- A donation conversation has been facilitated, where appropriate 7. This strategy has the potential to increase the number of survivors from DBI and fulfils the opportunity to save lives through organ and tissue donation.
Competing interests: Dr. Healey reports personal fees from Trillium Gift of Life Network, outside the submitted work. Dr. Shemie is the medical advisor for deceased organ donation for Canadian Blood Services.
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The primary purpose of this statement is to improve neuroprognostication after devastating brain injury (DBI), with a secondary benefit of potential organ and tissue donation.Adult patients with DBI who have had initiation of resuscitation measures, including intubation and mechanical ventilation.Clinical decision-making regarding initiation of resuscitation measures after DBI.# INTRODUCTION
Devastating brain injury is defined as a neurological injury (trauma, subarachnoid hemorrhage, stroke, hypoxic injury, etc.) that is assessed as an immediate threat to life or incompatible with good functional recovery and where early limitation or withdrawal of therapy is being considered. 1,2 The outcomes for patients who present in the emergency department (ED) with DBI are often death or, in some cases, survival with extremely limited capacity. Consequently, many physicians consider admission to the intensive care unit (ICU) inappropriate as it is not only futile and challenging in the face of scarce ICU resources, but also a burden on patients and families by offering prolongation of what may be an inevitably poor outcome.
However, the management of DBI in the ED is evolving. Accurate prognostication in the early stages of DBI cases can be difficult, and rigorous, evidence-based prognostication strategies in patients with DBI are limited. Clinician variability in the withdrawal of life-sustaining treatments impacts patient outcomes. A recent multicentre retrospective cohort study of patients with severe DBI in Canadian level-one trauma centres identified significant variation in mortality across centres. Mortality rates were significantly impacted by varying approaches to withdrawal of life-sustaining measures (WLSM), highlighting deficiencies of early prognostic strategies in trauma. 3 In-hospital mortality after intracerebral hemorrhage is significantly influenced by the variability in the rate at which treating hospitals use do-not-resuscitate orders, even after adjusting for case mix. 4 To improve the quality of decision-making to better inform whether the patient can survive and recover, transfer to the ICU for a period of physiological support and observation is recommended. 1,2 The optimal period for observation to establish greater confidence and accuracy in prognostication following DBI is not well established. The Neurocritical Care Society 1 recommends a 72-hour observation period, during which physiological support can prevent unwarranted deterioration and allow sufficient opportunity for prognostic evaluation, care planning, and a more definitive determination of prognosis based on repeated examinations over time. The United Kingdom (Faculty of Intensive Care Medicine, Intensive Care Society, Neuroanaesthesia and Critical Care Society, Royal College of Emergency Medicine, Society of British Neurological Surgeons) recommends that the length of the observation period be based on a combination of clinical judgement, changes in neurological function, the degree of support required to maintain physiological stability, and communication with the patient's family to determine patient preferences. 2 Though death may be the most likely outcome in many of these cases, a period of observation will further ensure the accuracy of this prognosis and avoid what may be an inappropriate limitation in care. 5 The primary aim is to improve the ability to distinguish patients who may have the capacity to recover and survive. In addition, it allows for a timely referral to the provincial organ donation organization, ensuring that patients and their families are given sufficient opportunity to consider organ and tissue donation. A recent systematic review 6 of ED deaths revealed that a substantial proportion (46.2-84%) of potential organ donors was missed due to a failure to refer for consideration of organ donation, in part, due to incorrect assumptions regarding eligibility criteria and failure of the healthcare team to refer for consideration of donation. In Ontario, over the 2017-2018 to 2018-2019 fiscal years, 33 (19%) of 178 patients who died in the ED and were not referred to the organ donation organization had organ donation potential (unpublished data, Trillium Gift of Life Network, 2019).
A potential organ donor is someone who has a very high chance of death but in whom active care continues or suitability for donation has not yet been established. In those cases where continued physiological support will have no benefit for prognostication or neurological outcome, physicians should refer patients to their provincial organ donation organization prior to WLSM. In accordance with the Potential Organ Donor Identification and System Accountability guideline, 7 patients who meet the following criteria should be considered potential organ donors and referred to the organ donation organization:
1. Ventilated (invasive or non-invasive) 2. Condition with a grave prognosis in which death is imminent
# Consideration of WLSM
# POSITION STATEMENT
To ensure that the management of DBI includes an observation period for optimized neuro-prognostication and that families are given the opportunity to consider organ donation as part of quality end-of-life care, the following high-level concepts are supported:
1. Early prognostication in devastating brain injury has known limitations and can be inaccurate. A sufficient period of observation and physiological support increases the opportunity for patient survival/recovery.
2. WLSM in DBI cases should be decided after observation of clinical evolution in an ICU setting in order to optimize patient outcomes. Exceptions to this would include, but are not limited to, the following case scenarios:
• It is clearly outlined that ongoing care is not consistent with the patient's previously expressed wishes (either documented or supported by available substitute decision-maker)
• Physiological futilityinability to maintain cardiorespiratory stability function due to extent of injuries or illness severity
• Concurrent comorbidities that are considered inappropriate for ICU admission in the absence of a DBI 3. Although a critical care setting with neurosurgical capacity is preferred when indicated and feasible, for patients without surgical indications, these aims could be achieved in any critical care environment.
4. Where patient survival/recovery is not possible, it provides an important opportunity to consider organ donation.
5. Identification and timely referral of potential organ donors in the ED as part of end-of-life care can save and enhance lives through organ and tissue donation.
6. Physiological support should be maintained until the following:
• The patient receives an appropriate period of observation for neuro-prognostication based on clinical circumstances
• A decision for WLSM has been made or the patient meets neurological criteria for death determination
• The patient has been referred to the organ donation organization
• A donation conversation has been facilitated, where appropriate 7. This strategy has the potential to increase the number of survivors from DBI and fulfils the opportunity to save lives through organ and tissue donation.
#
Competing interests: Dr. Healey reports personal fees from Trillium Gift of Life Network, outside the submitted work. Dr. Shemie is the medical advisor for deceased organ donation for Canadian Blood Services.
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c8369476dbcc32ea3732275715922c39fadf5bee
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cma
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This represents an update to the "Sleep Clinic/Laboratory Testing" section of our original CTS position statement (April 16, 2020) 1 . This position statement aims to provide rapid guidance to sleep practitioners and other health care providers for management of these patients during the COVID-19 pandemic. This document was based on the consensus of the authors, many of whom are members of the SDB Assembly of the Canadian Thoracic Society. The recommendations are informed by a very limited body of evidence. These recommendations are subject to change as information regarding COVID-19 and its effects are further understood. We plan to update this guidance as new information becomes available, and recommend periodically checking the Canadian Thoracic Society website () for updates.# Sleep Clinic/Laboratory Testing Overview
In many regions in Canada, there is partial resumption of societal and medical activities that were put on hold during the early stages of the pandemic. Currently, there is a need to enable access to sleep services to maintain health, balanced against the need to reduce community transmission and to protect staff. There was general consensus that sleep apnea testing should be restarted. However, local practices and policies may differ depending on the extent of community spread, prevalence of disease, availability of COVID-19 testing, and provincial/ facility guidelines. We recognize the diverse circumstances of different jurisdictions across Canada and between health care facilities. Guidance from the Public Health Agency of Canada, local/provincial public health or infection control units regarding health care facility capacity to re-open and recommended public health measures should supersede this document. Facility specific re-opening plans should include consultation with a multi-disciplinary team of all relevant stakeholders.
At this time, testing should be limited to urgent/semiurgent patients (as per locally applicable criteria) who do not have suspected/confirmed COVID-19, with rigorous screening, and measures to protect staff with personal protective equipment (PPE). The extent of the testing required (i.e., home sleep apnea testing (HSAT) vs. diagnostic polysomnography (PSG) vs. positive airway pressure (PAP) titration) should be determined in an individual patient by balancing the risk of delayed therapy (including PAP) with the potential risk of COVID-19 to staff.
The extent of PPE required by staff may differ regionally depending on local/provincial risk assessment/infection control recommendations. PAP titration is higher risk as an aerosol generating medical procedure (AGMP) than face-to-face clinical interactions like HSAT teaching, PSG setup or clinic visits. If adequate PPE cannot be sourced, PPE training is unavailable, or technicians lack the ability to use PPE appropriately, testing should not be restarted.
Children may have a higher rate of mildly symptomatic/asymptomatic COVID-19 disease. This fact should be considered in the screening process (e.g., mandating COVID-19 testing prior to in-laboratory studies 2 , for example).
# In-Person Visits
For urgent/semiurgent patients in whom virtual visits are inadequate, in-person visits should be resumed. Screening for COVID-19 should be performed for all patients within 72 hours of the scheduled test. The type of screening should be consistent with practices according to local infection control. At minimum, this should include screening based on a questionnaire (e.g., symptoms, COVID-19 risk factors such as exposure or travel), but could also include COVID testing and/or temperature check. Patients who screen positive should not be seen.
A COVID-19 screening questionnaire such as the one developed by Vancouver Coastal Health can be used or contact local public health offices for screening tools.
# Level 3/4 Studies (HSAT):
- Prior to HSAT, patients should be screened for COVID-19 within 72 hours of the scheduled test; the type of screening should be consistent with practices according to local/provincial infection control. At minimum, this should include screening based on a questionnaire, but could also include COVID-19 testing and/or temperature check. Patients who screen positive for COVID-19 should not undergo sleep study testing.
- Home testing should preferably be done with fully disposable equipment. However, if this is not feasible, then proper cleaning of the non-disposable components (e.g., monitor) should be instituted according to local/provincial infection control guidelines. Appropriate PPE should be used for all staff (e.g., surgical mask) during patient contact and cleaning of equipment. Nasal cannulas should have a manufacturer-approved filter. There is currently little data about if/how long virus may survive within the devices (which might not be easily cleaned). Timing and handling of the reuse of nondisposable components of the devices should be directed by infection control and consultation with the manufacturers.
# Diagnostic In-Laboratory PSG, Multiple Sleep Latency Test (MSLT), Maintenance of Wakefulness Test (MWT):
- Prior to any of these procedures, patients should be screened for COVID-19 within 72 hours of the scheduled test; the type of screening should be consistent with practices according to local/provincial infection control and local capacity. At minimum, this should include screening based on a questionnaire, but could also include COVID testing and/or temperature check. Patients who screen positive for COVID-19 should not undergo sleep testing.
- Patients who have tested positive for COVID-19 should NOT be permitted in the sleep laboratory until symptoms have resolved, and/or two consecutive COVID-19 PCR swabs collected ≥24 hours apart that are negative. 3 Viral shedding can occur after 10 days, therefore, resolution of symptoms and a minimum period of three weeks after symptom onset is recommended when negative tests cannot be obtained. 4,5 Those with pending COVID-19 test results should not undergo sleep testing until COVID-19 can be ruled out.
- These procedures require close proximity between technicians and patients. Proper PPE for all staff and cleaning precautions for the physical space and equipment should be instituted in all cases. We recognize that different regions and provinces may have varying infection control recommendations in place due to differences in prevalence rates, access to testing, screening procedures, etc. Except in extenuating circumstances (or in the case of pediatric patients), patients should attend the sleep test alone, measures should be undertaken to assure adequate physical distancing between patients, and consideration should be given for patients wearing a mask for close interactions with staff or in common areas (e.g., hallways) where there may be interaction with other patients. For pediatric PSGs, attendance should be limited to one caregiver who does not require PAP themselves during the night.
- Staff with symptoms should not report to work as per local occupational health policies. Staff and patients should follow appropriate hand hygiene measures.
# PAP Titration Polysomnogram (PAP PSG):
- There are potential additional risks of aerosol generation with PAP titration studies. As such, the decision to restart these studies must be consistent with local/provincial infection control guidelines
- Prior to PAP PSG, patients should be screened for COVID-19 within 72 hours of the scheduled test and upon entrance into the clinic or hospital on the day of testing; the type of screening should be consistent with practices according to local infection control and local capacity. However, the greater risks associated with PAP should be recognized, as PAP devices aerosolize droplets. At a minimum, this should include screening based on a questionnaire, but could also include COVID-19 testing and/or temperature check if locally feasible. Patients who screen positive for COVID-19 should not undergo sleep testing. Except in extenuating circumstances, patients should attend the sleep test alone.
- Proper PPE for all staff and cleaning precautions for the physical space and equipment should be instituted in all cases. Based on the available evidence 6 and to err on the side of caution, during peak pandemic and post peak pandemic phases, fit-tested N95 masks (or equivalent), face shields, gowns, and protection appropriate for AGMP should be employed by all staff.
- Patients and staff should follow appropriate hand hygiene measures.
- Staff should be educated and trained on correct donning and doffing technique for PPE.
- Cleaning should include wiping down of all surfaces contacted by patients and/or staff with antiviral sanitizer , cleaning of the mask with a viricidal wipe, and cleaning of the hose with sterilizing solution (e.g., sodium hypochlorite solution of 0.1% or 1000 ppm).
- Studies should be done in a private room. Sufficient time between appointments should be scheduled to allow time for aerosols to dissipate and for cleaning. Time between patients should consider the number of air exchanges for the testing room (determined by each facility) to ensure 99.9 % removal of airborne microorganisms. See CDC guidance for time required per air exchange rate. 7
- These measures may not be necessary in the post pandemic phase, when community spread is minimal. In addition, local/provincial public health or infection control recommended measures should supersede this document.
# PAP Prescriptions:
- New PAP prescriptions should be limited, and delayed if it is safe to do so. The best option is the sale of new machines/masks (e.g. auto-titrating devices, remote titration), preferably sent by mail or courier rather than picked up in person.
Please also see the following sites for additional resources for patients and practitioners:
|
This represents an update to the "Sleep Clinic/Laboratory Testing" section of our original CTS position statement (April 16, 2020) 1 . This position statement aims to provide rapid guidance to sleep practitioners and other health care providers for management of these patients during the COVID-19 pandemic. This document was based on the consensus of the authors, many of whom are members of the SDB Assembly of the Canadian Thoracic Society. The recommendations are informed by a very limited body of evidence. These recommendations are subject to change as information regarding COVID-19 and its effects are further understood. We plan to update this guidance as new information becomes available, and recommend periodically checking the Canadian Thoracic Society website (https://cts-sct.ca/covid-19) for updates.# Sleep Clinic/Laboratory Testing Overview
In many regions in Canada, there is partial resumption of societal and medical activities that were put on hold during the early stages of the pandemic. Currently, there is a need to enable access to sleep services to maintain health, balanced against the need to reduce community transmission and to protect staff. There was general consensus that sleep apnea testing should be restarted. However, local practices and policies may differ depending on the extent of community spread, prevalence of disease, availability of COVID-19 testing, and provincial/ facility guidelines. We recognize the diverse circumstances of different jurisdictions across Canada and between health care facilities. Guidance from the Public Health Agency of Canada, local/provincial public health or infection control units regarding health care facility capacity to re-open and recommended public health measures should supersede this document. Facility specific re-opening plans should include consultation with a multi-disciplinary team of all relevant stakeholders.
At this time, testing should be limited to urgent/semiurgent patients (as per locally applicable criteria) who do not have suspected/confirmed COVID-19, with rigorous screening, and measures to protect staff with personal protective equipment (PPE). The extent of the testing required (i.e., home sleep apnea testing (HSAT) vs. diagnostic polysomnography (PSG) vs. positive airway pressure (PAP) titration) should be determined in an individual patient by balancing the risk of delayed therapy (including PAP) with the potential risk of COVID-19 to staff.
The extent of PPE required by staff may differ regionally depending on local/provincial risk assessment/infection control recommendations. PAP titration is higher risk as an aerosol generating medical procedure (AGMP) than face-to-face clinical interactions like HSAT teaching, PSG setup or clinic visits. If adequate PPE cannot be sourced, PPE training is unavailable, or technicians lack the ability to use PPE appropriately, testing should not be restarted.
Children may have a higher rate of mildly symptomatic/asymptomatic COVID-19 disease. This fact should be considered in the screening process (e.g., mandating COVID-19 testing prior to in-laboratory studies 2 , for example).
# In-Person Visits
For urgent/semiurgent patients in whom virtual visits are inadequate, in-person visits should be resumed. Screening for COVID-19 should be performed for all patients within 72 hours of the scheduled test. The type of screening should be consistent with practices according to local infection control. At minimum, this should include screening based on a questionnaire (e.g., symptoms, COVID-19 risk factors such as exposure or travel), but could also include COVID testing and/or temperature check. Patients who screen positive should not be seen.
A COVID-19 screening questionnaire such as the one developed by Vancouver Coastal Health can be used or contact local public health offices for screening tools.
# Level 3/4 Studies (HSAT):
• Prior to HSAT, patients should be screened for COVID-19 within 72 hours of the scheduled test; the type of screening should be consistent with practices according to local/provincial infection control. At minimum, this should include screening based on a questionnaire, but could also include COVID-19 testing and/or temperature check. Patients who screen positive for COVID-19 should not undergo sleep study testing.
• Home testing should preferably be done with fully disposable equipment. However, if this is not feasible, then proper cleaning of the non-disposable components (e.g., monitor) should be instituted according to local/provincial infection control guidelines. Appropriate PPE should be used for all staff (e.g., surgical mask) during patient contact and cleaning of equipment. Nasal cannulas should have a manufacturer-approved filter. There is currently little data about if/how long virus may survive within the devices (which might not be easily cleaned). Timing and handling of the reuse of nondisposable components of the devices should be directed by infection control and consultation with the manufacturers.
# Diagnostic In-Laboratory PSG, Multiple Sleep Latency Test (MSLT), Maintenance of Wakefulness Test (MWT):
• Prior to any of these procedures, patients should be screened for COVID-19 within 72 hours of the scheduled test; the type of screening should be consistent with practices according to local/provincial infection control and local capacity. At minimum, this should include screening based on a questionnaire, but could also include COVID testing and/or temperature check. Patients who screen positive for COVID-19 should not undergo sleep testing.
• Patients who have tested positive for COVID-19 should NOT be permitted in the sleep laboratory until symptoms have resolved, and/or two consecutive COVID-19 PCR swabs collected ≥24 hours apart that are negative. 3 Viral shedding can occur after 10 days, therefore, resolution of symptoms and a minimum period of three weeks after symptom onset is recommended when negative tests cannot be obtained. 4,5 Those with pending COVID-19 test results should not undergo sleep testing until COVID-19 can be ruled out.
• These procedures require close proximity between technicians and patients. Proper PPE for all staff and cleaning precautions for the physical space and equipment should be instituted in all cases. We recognize that different regions and provinces may have varying infection control recommendations in place due to differences in prevalence rates, access to testing, screening procedures, etc. Except in extenuating circumstances (or in the case of pediatric patients), patients should attend the sleep test alone, measures should be undertaken to assure adequate physical distancing between patients, and consideration should be given for patients wearing a mask for close interactions with staff or in common areas (e.g., hallways) where there may be interaction with other patients. For pediatric PSGs, attendance should be limited to one caregiver who does not require PAP themselves during the night.
• Staff with symptoms should not report to work as per local occupational health policies. Staff and patients should follow appropriate hand hygiene measures.
# PAP Titration Polysomnogram (PAP PSG):
• There are potential additional risks of aerosol generation with PAP titration studies. As such, the decision to restart these studies must be consistent with local/provincial infection control guidelines
• Prior to PAP PSG, patients should be screened for COVID-19 within 72 hours of the scheduled test and upon entrance into the clinic or hospital on the day of testing; the type of screening should be consistent with practices according to local infection control and local capacity. However, the greater risks associated with PAP should be recognized, as PAP devices aerosolize droplets. At a minimum, this should include screening based on a questionnaire, but could also include COVID-19 testing and/or temperature check if locally feasible. Patients who screen positive for COVID-19 should not undergo sleep testing. Except in extenuating circumstances, patients should attend the sleep test alone.
• Proper PPE for all staff and cleaning precautions for the physical space and equipment should be instituted in all cases. Based on the available evidence 6 and to err on the side of caution, during peak pandemic and post peak pandemic phases, fit-tested N95 masks (or equivalent), face shields, gowns, and protection appropriate for AGMP should be employed by all staff.
• Patients and staff should follow appropriate hand hygiene measures.
• Staff should be educated and trained on correct donning and doffing technique for PPE.
• Cleaning should include wiping down of all surfaces contacted by patients and/or staff with antiviral sanitizer , cleaning of the mask with a viricidal wipe, and cleaning of the hose with sterilizing solution (e.g., sodium hypochlorite solution of 0.1% or 1000 ppm).
• Studies should be done in a private room. Sufficient time between appointments should be scheduled to allow time for aerosols to dissipate and for cleaning. Time between patients should consider the number of air exchanges for the testing room (determined by each facility) to ensure 99.9 % removal of airborne microorganisms. See CDC guidance for time required per air exchange rate. 7
• These measures may not be necessary in the post pandemic phase, when community spread is minimal. In addition, local/provincial public health or infection control recommended measures should supersede this document.
# PAP Prescriptions:
• New PAP prescriptions should be limited, and delayed if it is safe to do so. The best option is the sale of new machines/masks (e.g. auto-titrating devices, remote titration), preferably sent by mail or courier rather than picked up in person.
Please also see the following sites for additional resources for patients and practitioners:
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82a039ac9cee9c3bf3be3e7703bc4c0d0ba56867
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cma
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None
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As we progress toward an endemic phase of the COVID-19 pandemic, there is a need to re-evaluate which pandemic precautions should be maintained for performance of pulmonary function tests (PFT). Specifically, how should risk be mitigated for patients and health care workers as the dynamics of viral transmission evolve over time. This third update of the Resumption of PFTs in the era of COVID-19 presents the current evidence to support performance of PFT in dedicated laboratories and in primary care settings across Canada.
Throughout the pandemic, health care workers have been at increased risk of exposure to SARS-CoV-2. 1,2 Conversely, within Canada, there have been no reported cases of SARS-CoV-2 transmission in a PFT laboratory. This likely reflects the cautious approach applied by most PFT laboratories and that performing PFTs has been mainly limited to well ventilated spaces with high air exchange rates (AERs).
With nearly ∼75% of the Canadian population now fully vaccinated against SARS-CoV-2, 3 the risk of COVID-19 in healthcare settings, 4,5 as well as in the general population, is reduced but not eliminated. Vaccination is most effective at reducing severe illness and death, not virus transmission, and the duration of protection is uncertain. Community spread of SARS-CoV-2 continues in Canada as does uncertainty with respect to future risk as novel variants of concern emerge. Mandates for vaccination of health care workers vary across the country, and a large proportion of the population is still only partially vaccinated or unvaccinated (including children). Furthermore, there are patients (and health care workers) who remain at high risk of COVID-19 despite being fully vaccinated. The perception of risk varies between individuals, and those who attend PFTs need to feel safe and reassured that the level of risk in a PFT laboratory is low and that precautions are being taken to keep them safe.
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#
As we progress toward an endemic phase of the COVID-19 pandemic, there is a need to re-evaluate which pandemic precautions should be maintained for performance of pulmonary function tests (PFT). Specifically, how should risk be mitigated for patients and health care workers as the dynamics of viral transmission evolve over time. This third update of the Resumption of PFTs in the era of COVID-19 presents the current evidence to support performance of PFT in dedicated laboratories and in primary care settings across Canada.
Throughout the pandemic, health care workers have been at increased risk of exposure to SARS-CoV-2. 1,2 Conversely, within Canada, there have been no reported cases of SARS-CoV-2 transmission in a PFT laboratory. This likely reflects the cautious approach applied by most PFT laboratories and that performing PFTs has been mainly limited to well ventilated spaces with high air exchange rates (AERs).
With nearly ∼75% of the Canadian population now fully vaccinated against SARS-CoV-2, 3 the risk of COVID-19 in healthcare settings, 4,5 as well as in the general population, is reduced but not eliminated. Vaccination is most effective at reducing severe illness and death, not virus transmission, and the duration of protection is uncertain. Community spread of SARS-CoV-2 continues in Canada as does uncertainty with respect to future risk as novel variants of concern emerge. Mandates for vaccination of health care workers vary across the country, and a large proportion of the population is still only partially vaccinated or unvaccinated (including children). Furthermore, there are patients (and health care workers) who remain at high risk of COVID-19 despite being fully vaccinated. The perception of risk varies between individuals, and those who attend PFTs need to feel safe and reassured that the level of risk in a PFT laboratory is low and that precautions are being taken to keep them safe.
Acknowledging that the level of risk of COVID-19 in Canada still varies depending on regional and individual circumstances, this update emphasizes the hierarchy of controls that can help to reduce the risk of SARS-CoV-2 transmission in the PFT laboratory as well as when testing is performed in primary care settings. It is likely that COVID-19 will become an endemic pathogen; therefore, PFT laboratory protocols should be flexible such that they can be modified depending on the local level of transmission, vaccination rates or characteristics of any new variants of concern. 6,7 Clear communication of local transmission rates and COVID-19 protocols is imperative to effectively implement necessary precautions. We emphasize ventilation as a key factor to reduce risk and recommend individual risk mitigation alongside the other controls such as screening and judicious use of appropriate personal protective equipment (PPE).
# Ventilation
The opinion of multiple expert panels and reviews, including the Public Health Agency of Canada, 8 has concluded that SARS-CoV-2, and other respiratory viruses, can be transmitted by small aerosols (≤5 µm), warranting airborne precautions. 9,10 The Public Health Agency of Canada and the U.S. Centers for Disease Control and Prevention (CDC) 11,12 both advise for improved ventilation to reduce the risk of transmission. The American Society of Heating, Refrigerating and Air-Conditioning Engineers recommends a minimum of 6 AER per hour. 13 Within the context of performing PFTs, aerosol precautions are relevant regardless of whether PFTs are classified as aerosol generating medical procedures (AGMPs) or not. 14,15 Several studies have recently measured the aerosols generated during PFTs. There is some evidence that the actual PFT maneuver (with inline filter) does not produce more aerosols than breathing/speaking, 16,17 whereas other studies demonstrate PFTs do generate a greater number of aerosols than tidal breathing and speaking. 18,19 Importantly, these studies confirm that coughing produces more aerosols than tidal breathing. Since approximately 50% of people will cough during/after a PFT, 20 the likelihood that aerosols are generated in a PFT laboratory is high. Therefore, the risk posed by PFTs occurs in the period immediately during and after a maneuver when the unmasked patient may cough. A suggested mitigation strategy made by the British Thoracic Society, alongside ventilation, screening and appropriate PPE, is to ask patients who are able to, to immediately replace their masks and to cough directly into their mask/tissue. 21 Maintaining adequate ventilation is an effective way to reduce aerosol transmission of SARS-CoV-2. [9][10][11][12] The use of HEPA filters may further reduce the risk of viral transmission. This precaution is especially relevant when PFTs are conducted in the primary care setting or independent laboratory settings, when AER are not known or when adequate ventilation cannot be assured. Where possible, laboratory staff should consult with building engineers and local infection prevention and control to determine appropriate protocols and policies to ensure adequate ventilation. AER should be re-checked whenever there are significant changes to ventilation systems. These measures are not only relevant to reduce transmission of SARS-CoV-2 but may also help to reduce the transmission of other pathogens. 9 The ventilation efficiency within each facility should be used to determine adequate time between tests. 22,23 Laboratories should have the AER measured by building engineering or can use portable CO 2 monitors to provide an estimate of ventilation efficiency. [24][25][26] The tables provided by the CDC for both AER and ambient CO 2 can be used as a guide to determine local policies. 25 Physical distance between the technician and patient should be maintained as much as possible. Many institutions and businesses have installed plexiglass to provide a physical barrier between individuals. This barrier primarily helps to prevent transmission from droplets; however, given the increased risk of aerosol transmission, plexiglass barriers may be insufficient to prevent transmission and may actually impair effective room ventilation. Previous safeguards such as the use of disposable bacterial/viral filters to prevent inter-patient transmission must continue to be employed. 27
# Assessing and mitigating risk
The level of risk may differ for each patient and health care professional, depending on the community, facility, technologist and patient factors. Risk mitigation strategies at the individual level are encouraged (see Government of Canada -Table 1: Risk assessment and mitigation considerations by risk factor). 28 Vaccination status, rates of local community transmission and individual risk factors should all be considered to mitigate risk. Patient vaccination status will likely be a major determinant of the level of risk; however, the logistics of coordinating tests around individual vaccination status makes this an unreasonable solution. Relying on bacterial/viral filters alone while conducting PFTs has the potential to increase risk for the health care professional conducting the test and subsequent patients attending the PFT laboratory. The use of surgical masks is the minimum level of protection required in this setting. With the ongoing uncertainty around SARS-CoV-2 transmission and variants of concerns, the use of N95 masks is still warranted in most circumstances when aerosols are generated.
In situations where there is an increased level or risk to either patient or the health care professional, individual point of care risk assessment should be conducted. If the level of risk is high, extra precautions such as leaving extra time between patients (or testing at end of day), testing in an isolated space (negative pressure room, or room with a higher AER) and/or the use of a higher level of PPE are recommended. 27 Personal protective equipment PPE is a critical part of infection prevention and control; however, PPE should be considered the last line of defense within a broader "hierarchy of controls" framework. Since SARS-CoV-2 is likely transmitted by small aerosol particles, we continue to recommend that fit-tested N95 respirators be worn by health care professionals conducting PFTs. Given that there are no longer PPE shortages in Canada, there should be no barriers to accessing appropriate PPE, as needed.
There is limited evidence directly comparing N95 to surgical masks to prevent transmission of SARS-CoV-2. [29][30][31] A recent meta-analysis of 6 studies concluded there is insufficient data to definitively determine superiority of 1 type of mask. 29 Furthermore, most studies compare N95 and surgical masks for protection against influenza and were not specific to SARS-CoV-2. A single center study found FFP3 (N95 equivalent) masks provided 30-100% protection against SARS-CoV-2 acquisition on COVID-19 wards. 32 Conversely, an in-vitro study found that for low-risk settings, surgical masks and N95s provided similar protection. 33 In the majority of cases, where both health care workers and the patient are vaccinated and community transmission of SARS-CoV-2 is low, gown, glove, face shield and properly worn surgical masks should be sufficient to protect both the PFT technologist and patient. 33 Aerosol precautions, including N95 masks, must be taken when mandated by local authorities, or in communities with community spread of SARS-CoV-2 transmission. All health care workers should be permitted to make individual point of care risk assessments and ought to be provided appropriate PPE (including N95 respirators and eye protection) if the perceived level of risk is high. For some PFTs, nebulized treatments such as methacholine challenges, and CPET without a filter in-situ should be considered high risk procedures and aerosol precautions (such as N95 masks and longer intervals between tests) should be taken irrespective of vaccination status or level of community virus transmission.
# Screening and testing
For the duration of the pandemic, screening protocols prior to an appointment, at entry into a facility and in the PFT laboratory have been in place. However, we note that these screening protocols are not effective as a large proportion of transmission occurs in asymptomatic individuals. Symptomatic and COVID-19 positive patients have arrived for PFT appointments, despite screening protocols. Furthermore, COVID-19 symptoms have changed with each variant making it more challenging to effectively conduct screening. The requirement for patients to have a negative PCR COVID-19 test prior to their PFT appointment may be an unnecessary barrier to people who require pulmonary function testing. Nonetheless, screening for acute respiratory symptoms, documenting vaccination status and individual level of risk (i.e., immune-compromised patients) is important and could be included on PFT requisitions to help mitigate risk.
# Prioritization and testing backlogs
As many laboratories continue to experience high volumes of testing backlogs, patients should continue to be prioritized such that those with urgent or immediate need for PFTs are tested promptly. 34 Medical directors of PFT laboratories will continue to play an important role in helping to prioritize patients and to liaise with referring physicians to better understand the urgency of individual cases.
Should Canada experience additional waves of SARS-CoV-2 infections, or other emerging pathogens, it will again be necessary to carefully prioritize patients for PFTs. The current backlog of PFTs presents an opportunity to advocate, at all levels of government, for the need for expanded access to PFT laboratories for objective diagnosis of lung disease, to evaluate severity and for disease control.
# Learner participation
Competence in performing and/or interpreting PFTs is a requirement for training of health care professionals working in PFT laboratories. It is, therefore, important that learners who require opportunities to refine their competencies relating to PFTs can safely do so in a supervised testing environment.
In the early stages of the pandemic, learner access to PFT laboratories was limited as educational programs and their clinical partners aimed to protect the learners, PFT laboratory staff, and patients and to conserve PPE. As pulmonary function testing resume, questions about learner access to labs may occur.
The decision to permit learners to perform PFTs requires consideration of the perceived risk to the learner, laboratory staff and patients and the educational needs of the learner. Educational programs should ensure competency in infection control practices prior to sending learners to a clinical environment. With respect to performing PFTs, appropriate infection control practices will be based on the local context (eg, community transmission rates, local vaccination rates and site environmental controls) as outlined in this document. Learners in the PFT laboratory must have access to and be properly fitted for appropriate PPE and adhere to infection control practices.
# Conclusions
As we approach an endemic phase of the COVID-19 pandemic, there will be ongoing risks imposed by the SARS-CoV-2 virus. A return to pre-pandemic infection control practices in PFT testing will not provide acceptable risk mitigation, and it remains important to ensure ongoing adherence to the recommended hierarchy of controls, most notably appropriate room ventilation with adequate AER. Adaptations to PFT laboratory protocols due to the COVID-19 pandemic present an opportunity to update PFT laboratory protocols moving forward to provide ongoing risk mitigation for transmission of the SARS-CoV-2 virus and other emerging pathogens.
# Disclosure statement
The authorship group declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy. A summary of individual member conflict of interest statements are posted on the CTS website.
# Funding
The author(s) reported there is no funding associated with the work featured in this article.
# ORCID
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cccfda33339826f78885967a2e06c650ae51724e
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cma
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# Introduction
Sarcomas are often large, deep-seated masses that may occur in locations that are poorly accessible to biopsy. This document outlines recommendations by the AHS Provincial Sarcoma Tumor Team comprised of individuals from the departments of surgery, radiation oncology, pathology, radiology and medical oncology. It is our goal to ensure that potential sarcomas are biopsied and submitted in the proper manner (without compromise in management) in order to provide adequate material for diagnosis and/or molecular testing. This will result in optimized treatment and decrease incidence of re-biopsy due to insufficient tissue.
# Guideline Questions
- What is the optimal procedure for biopsy of possible sarcomas?
# Search Strategy
This guideline was created using an informal literature search.
# Target Population
The following recommendations apply to adult patients who require biopsy for possible sarcomas.
# Recommendations
We strongly encourage physicians seeing patients suspected of having sarcomas or having patients recently diagnosed with sarcomas to contact a member of the Provincial Sarcoma Tumor Team in order to enable proper evaluation and work-up of patients. This will ensure that they are given the best surgical options and treatment available.
# SPECIMENS:
Biopsy specimens may be of the following types:
- Core needle biopsies -usually under diagnostic imaging guidance and often performed by radiologists. Creates minimal tissue damage and allows for flexibility in future surgical planning. This method of biopsy can occasionally leave some sarcomas unclassified and may underestimate grade, but is nevertheless the preferred biopsy method.
- Excisional biopsies -recommended only for small superficial lesions (above fascia).
Incisions should not be oriented in the transverse plane, as this results in more extensive surgery if margins are found to be inadequate.
- Incisional biopsies -usually only performed after discussion with multidisciplinary sarcoma team and often only by surgical oncologist. Allows for triage of material for molecular testing and improves sampling.
If a gastrointestinal stromal tumor (GIST) is suspected clinically, please refer to Provincial GIST guidelines: ()
# SUBMISSION OF SPECIMENS FOR PATHOLOGIC EXAMINATION:
- Core needle biopsies: Ideally, four-five (4-5) cores of tumor should be submitted, with the cores submitted as follows:
- Option 1: 4 -5 cores submitted in a formalin-filled container.
- Option 2: 1 of the 5 cores may be submitted fresh, on saline-soaked gauze, and immediately transported to the laboratory (for freezing/research purposes, if proper consent forms completed), remaining cores divided in 2 formalin-filled containers as above. The frozen tissue can potentially be used for diagnostic purposes if needed i.e. if the cores submitted in formalin are non-diagnostic.
If uncertain as to which biopsy approach should be used, please contact surgical oncologist.
The size of needle used should be the largest gauge possible that can safely be used in a given patient/clinical situation. Ideally, 14 gauge is preferred .
The needle used should enter the same skin puncture site and is then passed in different directions though the mass, ensuring diverse sampling of different regions of tumor. For retroperitoneal masses, a retroperitoneal approach is preferred to avoid tumor seeding. The anatomic approach for the biopsy should be chosen in anticipation of future surgery.
- Incisional/excisional biopsies: submission of part of the tissue fresh/in saline (optional). This allows tissue to either be frozen for research purposes, provided there are proper consent forms completed.
# Frozen section:
If sarcoma is mentioned in the differential diagnosis, submission of the specimen as per #2 is recommended.
# Fine needle aspiration biopsy (FNAB):
Although a potentially valuable biopsy method to document recurrent or metastatic soft tissue tumors, we recommend core needle biopsy (or incisional biopsy if a lesion is easily accessible) in the initial workup of an unknown soft tissue mass. If core biopsy is being performed, FNA is not required, and should not be performed.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Sarcoma Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, radiologist, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2020.
# Levels of Evidence
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# Introduction
Sarcomas are often large, deep-seated masses that may occur in locations that are poorly accessible to biopsy. This document outlines recommendations by the AHS Provincial Sarcoma Tumor Team comprised of individuals from the departments of surgery, radiation oncology, pathology, radiology and medical oncology. It is our goal to ensure that potential sarcomas are biopsied and submitted in the proper manner (without compromise in management) in order to provide adequate material for diagnosis and/or molecular testing. This will result in optimized treatment and decrease incidence of re-biopsy due to insufficient tissue.
# Guideline Questions
1. What is the optimal procedure for biopsy of possible sarcomas?
# Search Strategy
This guideline was created using an informal literature search.
# Target Population
The following recommendations apply to adult patients who require biopsy for possible sarcomas.
# Recommendations
We strongly encourage physicians seeing patients suspected of having sarcomas or having patients recently diagnosed with sarcomas to contact a member of the Provincial Sarcoma Tumor Team in order to enable proper evaluation and work-up of patients. This will ensure that they are given the best surgical options and treatment available.
# SPECIMENS:
Biopsy specimens may be of the following types:
1. Core needle biopsies -usually under diagnostic imaging guidance and often performed by radiologists. Creates minimal tissue damage and allows for flexibility in future surgical planning. This method of biopsy can occasionally leave some sarcomas unclassified and may underestimate grade, but is nevertheless the preferred biopsy method.
2. Excisional biopsies -recommended only for small superficial lesions (above fascia).
Incisions should not be oriented in the transverse plane, as this results in more extensive surgery if margins are found to be inadequate.
3. Incisional biopsies -usually only performed after discussion with multidisciplinary sarcoma team and often only by surgical oncologist. Allows for triage of material for molecular testing and improves sampling.
If a gastrointestinal stromal tumor (GIST) is suspected clinically, please refer to Provincial GIST guidelines: (http://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancerguide-sar002-gist.pdf)
# SUBMISSION OF SPECIMENS FOR PATHOLOGIC EXAMINATION:
1. Core needle biopsies: Ideally, four-five (4-5) cores of tumor should be submitted, with the cores submitted as follows:
• Option 1: 4 -5 cores submitted in a formalin-filled container.
• Option 2: 1 of the 5 cores may be submitted fresh, on saline-soaked gauze, and immediately transported to the laboratory (for freezing/research purposes, if proper consent forms completed), remaining cores divided in 2 formalin-filled containers as above. The frozen tissue can potentially be used for diagnostic purposes if needed i.e. if the cores submitted in formalin are non-diagnostic.
If uncertain as to which biopsy approach should be used, please contact surgical oncologist.
The size of needle used should be the largest gauge possible that can safely be used in a given patient/clinical situation. Ideally, 14 gauge is preferred [See Appendix A].
The needle used should enter the same skin puncture site and is then passed in different directions though the mass, ensuring diverse sampling of different regions of tumor. For retroperitoneal masses, a retroperitoneal approach is preferred to avoid tumor seeding. The anatomic approach for the biopsy should be chosen in anticipation of future surgery.
2. Incisional/excisional biopsies: submission of part of the tissue fresh/in saline (optional). This allows tissue to either be frozen for research purposes, provided there are proper consent forms completed.
# Frozen section:
If sarcoma is mentioned in the differential diagnosis, submission of the specimen as per #2 is recommended.
# Fine needle aspiration biopsy (FNAB):
Although a potentially valuable biopsy method to document recurrent or metastatic soft tissue tumors, we recommend core needle biopsy (or incisional biopsy if a lesion is easily accessible) in the initial workup of an unknown soft tissue mass. If core biopsy is being performed, FNA is not required, and should not be performed.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Sarcoma Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, radiologist, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2020.
# Levels of Evidence
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial Sarcoma Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2020) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/.
The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of CancerControl Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerControl Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Carolyn O'Hara has nothing to disclose.
Derek Tilley has nothing to disclose.
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e7509ccd0d8873cd204afc31602c0e8bb2803c42
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To review the frequency and clinical relevance of and diagnostic testing for factor V Leiden and prothrombin gene mutation G20210A. - To review recommendations for management of affected individuals.Thrombophilias are a group of inherited conditions associated with an increased risk of developing venous thromboembolism (VTE). A point mutation (G1691A) in the gene that codes for clotting factor V produces an abnormal factor V protein known as factor V Leiden (FVL). FVL is the most common inherited thrombophilia with an approximate incidence of 5% to 8% in the heterozygous form in Caucasians. The functional consequence of this mutation is impaired inactivation of factor V (also known as "activated protein C resistance"), resulting in increased thrombin generation. The second most frequent thrombophilia is a single nucleotide substitution (G20210A) in the promoter region of the gene for the clotting factor II (prothrombin). This prothrombin gene mutation (PGM) results in an increase in the concentration of prothrombin. The approximate incidence of heterozygous PGM is 1-4% in Caucasians. Homozygous FVL, homozygous PGM, and compound heterozygotes (heterozygous for both FVL and PGM) are rare and affect less than 1% of the population. These mutations are inherited in an autosomal dominant fashion. First degree relatives of heterozygous carriers of FVL or PGM have a 50% chance of also being carriers of the mutation.# RISK OF THROMBOSIS WITH FVL AND PGM:
Heterozygous FVL is present in approximately 20% of unselected, symptomatic VTE patients and in up to 40% of patients with a strong family history of VTE. In their heterozygous forms, FVL or PGM are associated with a modest increase in VTE risk and are not considered to significantly increase the risk of recurrent VTE. However, patients with homozygous FVL or PGM and patients with compound heterozygous FVL and PGM have a much greater risk of VTE and are at increased risk of recurrence.
Although most individuals who are heterozygous for FVL or PGM will not develop VTE over their lifetime, the overall VTE risk is compounded by increasing age, oral contraceptive (OCP) use, menopausal hormone therapy, pregnancy, and other VTE risk factors. Despite the thrombotic risk associated with these mutations, affected individuals have a normal life expectancy.
To understand and counsel patients on the risk of VTE associated with hormonal therapies or genetic risk factors, we advise discussing risk in the form of absolute risk of VTE per year. The incidence of VTE in women of child-bearing age who are not taking oral contraceptives is approximately 1 in 10,000 per year. The baseline risk of VTE those on combined oral contraceptive pill increases to 4 in 10,000 per year. In those with a first degree relative with a history of VTE the risk doubles to 8 in 10,000 per year even in the absence of identifiable thrombophilia. The presence of both heterozygous factor V Leiden and use of combined oral contraceptive pills increases the risk of thrombosis to 35-40/10,000 per year, generously approximated at <1 in 200 per year, or a 0.5% risk of VTE per year.
Increased risk of arterial thrombosis in this population has not been clearly established. Limited and weak data suggest that FVL and PGM might be associated with a slightly increased risk of arterial stroke, particularly in young adults; however, the clinical significance of this finding is not clear.
# RISK OF PREGNANCY COMPLICATIONS WITH FVL AND PGM
Available data suggests that women who are heterozygous for FVL or PGM are not at significantly increased risk of placental complications in pregnancy, including pregnancy loss, small-for-gestationalage, pre-eclampsia, or placental abruption.
# DIAGNOSIS AND SCREENING:
The presence of FVL or PGM can be detected by DNA testing using a routine blood sample. Additionally, the presence of FVL can be screened for using the Activated Protein C Resistance ratio, a functional screening test. No functional test exists to detect the presence of PGM. The practice of widespread thrombophilia testing is not effective at reducing adverse outcomes and rarely influences clinical decision-making; thus thrombophilia testing is not recommended as a screening procedure.
The advantages and disadvantages of testing should be discussed with the patient and testing should be reserved for those in whom results will influence clinical decision-making, for example, FVL or PGM testing may be indicated in asymptomatic women with a first-degree relative with known FVL or PGM and a history of VTE who are pregnant/contemplating pregnancy or considering hormonal contraceptive use, if the result would change the decision to use VTE prophylaxis or a contraceptive associated with an increased thrombotic risk. A positive test result may produce unnecessary anxiety for the patient and their family, may affect their eligibility for insurance, could lead to inappropriate denial of effective contraception, and may result in unnecessary anticoagulant use during periods of perceived risk.
Screening for FVL and PGM in women with a history of pregnancy complications and in patients with a history of arterial vascular disease are not recommended.
# TREATMENT OF VTE:
The therapeutic options and duration of VTE treatment are generally not affected if FVL or PGM are present. Published data on the use of DOACs in patients with homozygous FVL or PGM are limited. There is little, if any, difference in the risk of VTE recurrence, when anticoagulation is stopped, between those with FVL or PGM in the heterozygous form and the general population.
# PREVENTION OF VTE:
Individuals with FVL or PGM should receive appropriate thromboprophylaxis during periods of increased VTE risk. Women who are heterozygous for FVL or PGM do not warrant routine thromboprophylaxis during pregnancy unless they have previously experienced VTE. Postpartum prophylaxis is not recommended in asymptomatic women with heterozygous FVL or PGM.
Antepartum and postpartum thromboprophylaxis is usually suggested in pregnant women who are homozygous for FVL or PGM or compound heterozygous for FVL and PGM.
OCP and menopausal hormone therapy use in carriers of FVL or PGM is associated with a further increase in VTE risk; therefore, the risk-benefit of OCP or menopausal hormone therapy use should be carefully discussed. In asymptomatic female carriers of FVL or PGM with no other VTE risk factors (such as a personal history of thrombosis) who cannot tolerate reliable, alternative forms of contraception, combined oral contraceptives containing estrogen can be considered on a case by case basis. It would require a careful discussion of risks and benefits and a consideration of the values and preferences of the patient.
# PEDIATRICS:
Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism and those with confirmed or suspected thrombophilias. When this is not possible, a combination of a neonatologist/pediatrician and a pediatric hematologist or an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Deep Vein Thrombosis (DVT): Treatment
# Date of Version: 14Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To review the frequency and clinical relevance of and diagnostic testing for factor V Leiden and prothrombin gene mutation G20210A. • To review recommendations for management of affected individuals.Thrombophilias are a group of inherited conditions associated with an increased risk of developing venous thromboembolism (VTE). A point mutation (G1691A) in the gene that codes for clotting factor V produces an abnormal factor V protein known as factor V Leiden (FVL). FVL is the most common inherited thrombophilia with an approximate incidence of 5% to 8% in the heterozygous form in Caucasians. The functional consequence of this mutation is impaired inactivation of factor V (also known as "activated protein C resistance"), resulting in increased thrombin generation. The second most frequent thrombophilia is a single nucleotide substitution (G20210A) in the promoter region of the gene for the clotting factor II (prothrombin). This prothrombin gene mutation (PGM) results in an increase in the concentration of prothrombin. The approximate incidence of heterozygous PGM is 1-4% in Caucasians. Homozygous FVL, homozygous PGM, and compound heterozygotes (heterozygous for both FVL and PGM) are rare and affect less than 1% of the population. These mutations are inherited in an autosomal dominant fashion. First degree relatives of heterozygous carriers of FVL or PGM have a 50% chance of also being carriers of the mutation.# RISK OF THROMBOSIS WITH FVL AND PGM:
Heterozygous FVL is present in approximately 20% of unselected, symptomatic VTE patients and in up to 40% of patients with a strong family history of VTE. In their heterozygous forms, FVL or PGM are associated with a modest increase in VTE risk and are not considered to significantly increase the risk of recurrent VTE. However, patients with homozygous FVL or PGM and patients with compound heterozygous FVL and PGM have a much greater risk of VTE and are at increased risk of recurrence.
Although most individuals who are heterozygous for FVL or PGM will not develop VTE over their lifetime, the overall VTE risk is compounded by increasing age, oral contraceptive (OCP) use, menopausal hormone therapy, pregnancy, and other VTE risk factors. Despite the thrombotic risk associated with these mutations, affected individuals have a normal life expectancy.
To understand and counsel patients on the risk of VTE associated with hormonal therapies or genetic risk factors, we advise discussing risk in the form of absolute risk of VTE per year. The incidence of VTE in women of child-bearing age who are not taking oral contraceptives is approximately 1 in 10,000 per year. The baseline risk of VTE those on combined oral contraceptive pill increases to 4 in 10,000 per year. In those with a first degree relative with a history of VTE the risk doubles to 8 in 10,000 per year even in the absence of identifiable thrombophilia. The presence of both heterozygous factor V Leiden and use of combined oral contraceptive pills increases the risk of thrombosis to 35-40/10,000 per year, generously approximated at <1 in 200 per year, or a 0.5% risk of VTE per year.
Increased risk of arterial thrombosis in this population has not been clearly established. Limited and weak data suggest that FVL and PGM might be associated with a slightly increased risk of arterial stroke, particularly in young adults; however, the clinical significance of this finding is not clear.
# RISK OF PREGNANCY COMPLICATIONS WITH FVL AND PGM
Available data suggests that women who are heterozygous for FVL or PGM are not at significantly increased risk of placental complications in pregnancy, including pregnancy loss, small-for-gestationalage, pre-eclampsia, or placental abruption.
# DIAGNOSIS AND SCREENING:
The presence of FVL or PGM can be detected by DNA testing using a routine blood sample. Additionally, the presence of FVL can be screened for using the Activated Protein C Resistance ratio, a functional screening test. No functional test exists to detect the presence of PGM. The practice of widespread thrombophilia testing is not effective at reducing adverse outcomes and rarely influences clinical decision-making; thus thrombophilia testing is not recommended as a screening procedure.
The advantages and disadvantages of testing should be discussed with the patient and testing should be reserved for those in whom results will influence clinical decision-making, for example, FVL or PGM testing may be indicated in asymptomatic women with a first-degree relative with known FVL or PGM and a history of VTE who are pregnant/contemplating pregnancy or considering hormonal contraceptive use, if the result would change the decision to use VTE prophylaxis or a contraceptive associated with an increased thrombotic risk. A positive test result may produce unnecessary anxiety for the patient and their family, may affect their eligibility for insurance, could lead to inappropriate denial of effective contraception, and may result in unnecessary anticoagulant use during periods of perceived risk.
Screening for FVL and PGM in women with a history of pregnancy complications and in patients with a history of arterial vascular disease are not recommended.
# TREATMENT OF VTE:
The therapeutic options and duration of VTE treatment are generally not affected if FVL or PGM are present. Published data on the use of DOACs in patients with homozygous FVL or PGM are limited. There is little, if any, difference in the risk of VTE recurrence, when anticoagulation is stopped, between those with FVL or PGM in the heterozygous form and the general population.
# PREVENTION OF VTE:
Individuals with FVL or PGM should receive appropriate thromboprophylaxis during periods of increased VTE risk. Women who are heterozygous for FVL or PGM do not warrant routine thromboprophylaxis during pregnancy unless they have previously experienced VTE. Postpartum prophylaxis is not recommended in asymptomatic women with heterozygous FVL or PGM.
Antepartum and postpartum thromboprophylaxis is usually suggested in pregnant women who are homozygous for FVL or PGM or compound heterozygous for FVL and PGM.
OCP and menopausal hormone therapy use in carriers of FVL or PGM is associated with a further increase in VTE risk; therefore, the risk-benefit of OCP or menopausal hormone therapy use should be carefully discussed. In asymptomatic female carriers of FVL or PGM with no other VTE risk factors (such as a personal history of thrombosis) who cannot tolerate reliable, alternative forms of contraception, combined oral contraceptives containing estrogen can be considered on a case by case basis. It would require a careful discussion of risks and benefits and a consideration of the values and preferences of the patient.
# PEDIATRICS:
Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with thromboembolism and those with confirmed or suspected thrombophilias. When this is not possible, a combination of a neonatologist/pediatrician and a pediatric hematologist or an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Deep Vein Thrombosis (DVT): Treatment
# Date of Version: 14Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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- Medical exemption updates regarding myocarditis and pericarditis based on updated NACI statement This guidance provides basic information only.# Background
This document is intended to assist physicians/specialists and nurse practitioners in evaluating contraindications or precautions to COVID-19 vaccination that may warrant a medical exemption. A contraindication is a situation where a vaccine should not be given as the risks outweigh any potential therapeutic benefit. A precaution is a condition that may increase the risk of an adverse event following immunization (AEFI) or compromise the ability of the vaccine to produce an immune response, which may result in deferral of immunization; however, there may be circumstances where the benefits of vaccination outweigh the potential risks from vaccination associated with the condition or where reduced immunogenicity still benefits immunocompromised individuals (Canadian Immunization Guide). In general, there are very few actual contraindications to Health Canada authorized COVID-19 vaccines that would qualify as medical exemptions and most individuals can receive COVID-19 vaccines. Only individuals with contraindications to mRNA and viral vector vaccines qualify for medical exemption. This document is based on recommendations from Canada's National Advisory Committee on Immunization (NACI) and expert clinician advice, prepared in consultation with Public Health Ontario and several specialist physicians with expertise in AEFIs.
As the context and evidence on COVID-19 vaccines evolves, this guidance will be updated and individuals with medical exemptions should be periodically re-evaluated by their nurse practitioner/physician/specialist as emerging evidence and new vaccine products become available.
# Reasons for Medical Exemption
Individuals who have experienced serious adverse events following COVID-19 immunization and those with certain medical conditions that may affect their immune response to immunization should be referred to an appropriate physician or nurse practitioner based on their adverse event/medical condition for further assessment. This should include a detailed patient history, assessment of the adverse event/medical condition and investigations/diagnosis, individualized riskbenefit analysis, and recommendations/options for future immunization. For serious or rare AEFIs, individuals should be thoroughly investigated to determine if the event can be attributed to an alternative etiology. Referral and specialist consultation support for physicians and nurse practitioners is available through Ontario's eConsult Service, OTN Hub, and the Special Immunization Clinic (SIC) Network. In many instances, safe administration of subsequent doses of COVID-19 vaccine is possible under the management of an appropriate physician or nurse practitioner. True medical exemptions are expected to be infrequent and should be supported by expert consultation.
Tables 1-4: Summary of conditions and/or adverse events following immunization (AEFI) that may qualify for a medical exemption to COVID-19 vaccination 1 As per NACI if the diagnosis with myocarditis is remote and they are no longer followed clinically by a medical professional for cardiac issues, they should receive an mRNA COVID-19 vaccine.
# Condition/AEFI Management
Myocarditis prior to initiating an mRNA COVID-19 vaccine series
# Contraindications to Initiating an AstraZeneca or Janssen COVID-19
# Vaccine Series Condition/AEFI Management
History of capillary leak syndrome (CLS)
- Series should be completed with an mRNA vaccine.
- Qualifies for medical exemption if:
- Individual has medical exemption to completing their vaccine series with an mRNA vaccine.
# History of cerebral venous sinus thrombosis (CVST) with thrombocytopenia
- Series should be completed with an mRNA vaccine.
- Qualifies for medical exemption if:
- Individual has medical exemption to completing their vaccine series with an mRNA vaccine.
# History of heparin-induced thrombocytopenia (HIT)
- Series should be completed with an mRNA vaccine.
- Qualifies for medical exemption if:
- Individual has medical exemption to completing their vaccine series with an mRNA vaccine.
# History of major venous and/or arterial thrombosis with thrombocytopenia
- Series should be completed with an mRNA vaccine.
- Qualifies for medical exemption if:
- Individual has medical exemption to completing their vaccine series with an mRNA vaccine.
# Adverse Events
# Other Condition/AEFI Management
Actively receiving monoclonal antibody therapy OR convalescent plasma therapy for the treatment or prevention of COVID-19
- Qualifies for time-limited medical exemption while they are actively receiving therapy.
# History of Myocarditis prior to initiating an mRNA COVID-19 vaccine series
Individuals who have a history of myocarditis unrelated to mRNA COVID-19 vaccination should consult their clinical team for individual considerations and recommendations. Individuals previously diagnosed with myocarditis, whose diagnosis is considered remote and are no longer followed clinically by a medical professional for cardiac issues should receive the vaccine. This guidance is issued by the National Advisory Committee on Immunization (NACI). A medical exemption may be issued only if discussion has occurred with an appropriate physician or nurse practitioner regarding potential options for immunization with an mRNA COVID-19 vaccine or alternative, and the physician or nurse practitioner has determined that the individual cannot receive any COVID-19 vaccine.
# History of severe allergic reaction or anaphylaxis to any component of a COVID-19 vaccine
Individuals with a confirmed severe, immediate (≤4h following exposure) allergy (e.g., anaphylaxis) to a component of a specific COVID-19 vaccine or its container (e.g., PEG), are recommended to consult with an appropriate physician or nurse practitioner before receiving the specific COVID-19 vaccine. Individuals who are allergic to tromethamine (found in the Moderna COVID-19 vaccine and pediatric Pfizer-BioNTech COVID-19 vaccine) should be offered the Pfizer-BioNTech COVID-19 vaccine if 12 years or age or older, which does not contain this excipient. Individuals who are allergic to polysorbates (found in viral vector vaccines), should be offered an mRNA vaccine. A medical exemption may be issued only if discussion has occurred with the appropriate physician or nurse practitioner on options for immunization with the COVID-19 vaccine, including a risk-benefit analysis for the individual, and the physician or nurse practitioner has determined that the individual cannot receive any COVID-19 vaccine.
For a comprehensive list of components in the vaccine and packaging, please consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database.
# Contraindications to Initiating an AstraZeneca or Janssen COVID-19
Vaccine Series
# History of capillary leak syndrome (CLS)
Individuals who have experienced episodes of capillary leak syndrome (CLS) should not receive the AstraZeneca or Janssen COVID-19 vaccine. Very rare cases of capillary leak syndrome (CLS) have been reported following immunization with the AstraZeneca COVID-19 vaccine. This is a contraindication to receiving the AstraZeneca or Janssen COVID-19 vaccine. An authorized COVID-19 vaccine using a different platform (i.e., mRNA) should be offered for immunization. A medical exemption may be issued only if an mRNA COVID-19 vaccine is contraindicated for the individual.
# History of cerebral venous sinus thrombosis (CVST) with thrombocytopenia
Individuals who have experienced a previous CVST with thrombocytopenia should not receive the AstraZeneca or Janssen COVID-19 vaccine. This is a contraindication to receiving the AstraZeneca or Janssen COVID-19 vaccine. An authorized COVID-19 vaccine using a different platform (i.e., mRNA) should be offered for immunization. A medical exemption may be issued only if an mRNA COVID-19 vaccine is contraindicated for the individual.
# History of heparin-induced thrombocytopenia (HIT)
Individuals who have experienced a HIT should not receive the AstraZeneca or Janssen COVID-19 vaccine. This is a contraindication to receiving the AstraZeneca or Janssen COVID-19 vaccine. An authorized COVID-19 vaccine using a different platform (i.e., mRNA) should be offered for immunization. A medical exemption may be issued only if mRNA COVID-19 vaccine is contraindicated for the individual.
# History of major venous and/or arterial thrombosis with thrombocytopenia following any vaccine
Individuals who have experienced major venous and/or arterial thrombosis with thrombocytopenia following vaccination with any vaccine should not receive the AstraZeneca or Janssen COVID-19 vaccine. This is a contraindication based on recommendations issued by Ontario's Vaccine Clinical Advisory Group on Immunization. An authorized COVID-19 vaccine using a different platform (i.e., mRNA) should be offered for immunization. A medical exemption may be issued only if an mRNA COVID-19 vaccine is contraindicated for the individual.
# Adverse Events Following Immunization (AEFI) with COVID-19 vaccine Thrombosis with thrombocytopenia syndrome (TTS)/VITT following AstraZeneca or Janssen COVID-19 vaccine
Individuals who have experienced a major venous or arterial thrombosis with thrombocytopenia following vaccination with AstraZeneca or Janssen COVID-19 vaccine are contraindicated to receiving the AstraZeneca or Janssen vaccine. An authorized COVID-19 vaccine using a different platform (i.e. mRNA) should be offered for subsequent immunization. A medical exemption may be issued only if they have a medical exemption to completing their series with an mRNA COVID-19 vaccine.
# Myocarditis/Pericarditis following mRNA COVID-19 vaccination
A medical exemption may be issued if myocarditis/pericarditis was diagnosed after medical evaluation (e.g., ER physician, relevant specialist). In most circumstances, and as a precautionary measure until more information is available, individuals with a diagnosed episode of myocarditis/pericarditis within 6 weeks of receipt of a previous dose of an mRNA COVID-19 vaccine should defer further doses of the vaccine. This includes any person who had an abnormal cardiac investigation including electrocardiogram (ECG), elevated troponins, echocardiogram or cardiac MRI after a dose of an mRNA vaccine. This is a precaution based on recommendations issued by the National Advisory Committee on Immunization (NACI). NACI, Public Health Ontario (PHO), and the Ontario Ministry of Health (MOH) are following this closely and will update this recommendation as more evidence becomes available.
In situations where there is uncertainty regarding myocarditis diagnosis, discussion should occur with an appropriate physician or nurse practitioner on potential options for (re)immunization with the same or alternative COVID-19 vaccine, including a riskbenefit analysis for the individual. The individual qualifies for a medical exemption if the physician or nurse practitioner has determined that the individual is unable to receive any COVID-19 vaccine. Those with a history compatible with pericarditis and who either had no cardiac workup or had normal cardiac investigations, can be re(immunized) once they are symptom free and at least 90 days has passed since vaccination. Some people with confirmed myocarditis and/or pericarditis may choose to receive another dose of vaccine after discussing the risks and benefits with their healthcare provider. Individuals can be revaccinated once they are symptom free and at least 90 days has passed since vaccination. If another dose of vaccine is offered, they should be offered the Pfizer-BioNTech 30 mcg vaccine due to the lower reported rate of myocarditis and/or pericarditis following the Pfizer-BioNTech 30mcg vaccine compared to the Moderna 100 mcg vaccine. Informed consent should include discussion about the unknown risk of recurrence of myocarditis and/or pericarditis following receipt of additional doses of Pfizer-BioNTech COVID-19 vaccine in individuals with a history of confirmed myocarditis and/or pericarditis after a previous dose of mRNA COVID-19 vaccine, as well as the need to seek immediate medical assessment and care should symptoms develop.
# Severe Allergic Reaction or Anaphylaxis following a COVID-19 vaccine
In individuals with a history of a severe, immediate (≤4h following vaccination) allergic reaction (e.g., anaphylaxis) after previous administration of an mRNA COVID-19 vaccine, re-vaccination (i.e. administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. The risk of a severe immediate allergic reaction after re-immunization appears to be low and no long-term morbidity has been associated with re-vaccination.
- Consultation with an allergist may be sought prior to re-vaccination.
- If re-vaccinated, vaccine administration should be done in a controlled setting with expertise and equipment to manage allergic reactions. Individuals should be observed for at least 30 minutes after re-vaccination. For example, a longer period of observation is warranted for individuals exhibiting any symptom suggestive of an evolving AEFI at the end of the 30 minute observation period.
For those with a previous history of allergy to an mRNA vaccine, re-vaccination with an mRNA vaccine is preferred over a viral vector vaccine due to the better effectiveness and immunogenicity of mRNA vaccines and the possible adverse effects specifically associated with viral vector vaccines (e.g., Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT), capillary leak syndrome (CLS), and Guillain-Barré Syndrome (GBS)).
In individuals with a history of a severe, immediate (≤4h following vaccination) allergic reaction (e.g., anaphylaxis) after previous administration of a viral vector COVID-19 vaccine, re-vaccination may be offered with an mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. If re-vaccinated, individuals should be observed for at least 30 minutes after re-vaccination.
A medical exemption may be issued if discussion has occurred with an appropriate physician or nurse practitioner on potential options for (re)immunization with the same or alternative COVID-19 vaccine, including a risk-benefit analysis for the individual, and the physician or nurse practitioner has determined that the individual cannot receive any COVID-19 vaccine with the currently available mitigation strategies.
# Other allergies
Individuals with other types of non-severe allergies can receive COVID-19 vaccines as outlined in the MOH's Vaccination Recommendations for Special Populations. These allergies do not on their own constitute the grounds for a medical exemption. For more information on the management of individuals with allergies, please see the MOH's Vaccination Recommendations for Special Populations.
# Serious Adverse Event Following COVID-19 Immunization (AEFI)
Individuals who experience a serious adverse event following immunization (AEFI) (e.g., hospitalization, persistent or significant disability/incapacity) with a COVID-19 vaccine should be medically assessed by an appropriate physician or nurse practitioner, and the event should be reported to their local public health unit (PHU). This may include clinical syndromes such as Guillain-Barré Syndrome (GBS). The Health Protection and Promotion Act (HPPA) mandates reporting of AEFIs by healthcare providers who administer immunizations (e.g., registered nurses, nurse practitioners, pharmacists, and physicians).
AEFI reports received by PHUs are investigated, assessed, and documented according to provincial surveillance guidelines, as required by the Ontario Public Health Standards (OPHS). For serious AEFIs, this includes referral to an appropriate physician or nurse practitioner for diagnosis/management and expert assessment for recommendation for subsequent immunization (e.g., the Special Immunization Clinic (SIC) Network, immunologist, etc.). This assessment will include a detailed assessment of the adverse event including investigations and diagnosis, and assessment for alternative etiology for the event. Discussion with the patient should then consider the event and the personal and epidemiological context (in terms of risk of COVID-19 infection) for the patient, and the risks and benefits regarding recommendations/options for immunization. The individual qualifies for a medical exemption if the appropriate physician or nurse practitioner (e.g., immunologist, SIC network, Medical Officer of Health, etc.) determines that the individual is unable to receive any COVID-19 vaccine after the event has been medically evaluated AND a discussion has occurred on the individual's risks and benefits of potential options for immunization with the same or alternative COVID-19 vaccine.
There are very few serious AEFIs that would result in a medical exemption to COVID-19 vaccination.
# Other
Actively receiving monoclonal antibody or convalescent plasma therapy for the treatment or prevention of COVID-19 disease Individuals who are actively receiving monoclonal antibody or convalescent plasma therapy for the treatment or prevention of COVID-19 disease should not receive a COVID-19 vaccine (NACI). This is a time-limited (temporary) precaution. COVID-19 vaccines may be administered to these individuals once therapy is discontinued, with the timing of administration and potential for immune interference evaluated on a case-by-case basis by an appropriate physician or nurse practitioner. A medical exemption may be issued only if the individual is actively receiving therapy.
# Actively receiving or recently completed immunosuppressing therapy anticipated to significantly blunt vaccine response
Individuals who are actively receiving or recently completed an immunosuppressive therapy listed in the table below may be advised by their physician or nurse practitioner to defer COVID-19 vaccination to a later point to optimize immune response to the COVID-19 vaccine and minimize delays in management of their underlying condition. This is a time-limited (temporary) precaution. The recommended maximum deferral duration following completion of specific therapies is listed in the table below.
COVID-19 vaccines may be administered to these individuals once therapy is discontinued, with timing of administration evaluated on a case-by-case basis by an appropriate physician or nurse practitioner. Discussion with the patient should then consider their medical condition and the personal and epidemiological context (in terms of risk of COVID-19 infection) for the patient, and the risks and benefits regarding timing and recommendations/options for immunization. A time-limited medical exemption may be issued only if the appropriate physician or nurse practitioner has recommended that the individual defer COVID-19 vaccination to a later point to optimize their immune response.
|
• Medical exemption updates regarding myocarditis and pericarditis based on updated NACI statement This guidance provides basic information only.# Background
This document is intended to assist physicians/specialists and nurse practitioners in evaluating contraindications or precautions to COVID-19 vaccination that may warrant a medical exemption. A contraindication is a situation where a vaccine should not be given as the risks outweigh any potential therapeutic benefit. A precaution is a condition that may increase the risk of an adverse event following immunization (AEFI) or compromise the ability of the vaccine to produce an immune response, which may result in deferral of immunization; however, there may be circumstances where the benefits of vaccination outweigh the potential risks from vaccination associated with the condition or where reduced immunogenicity still benefits immunocompromised individuals (Canadian Immunization Guide). In general, there are very few actual contraindications to Health Canada authorized COVID-19 vaccines that would qualify as medical exemptions and most individuals can receive COVID-19 vaccines. Only individuals with contraindications to mRNA and viral vector vaccines qualify for medical exemption. This document is based on recommendations from Canada's National Advisory Committee on Immunization (NACI) and expert clinician advice, prepared in consultation with Public Health Ontario and several specialist physicians with expertise in AEFIs.
As the context and evidence on COVID-19 vaccines evolves, this guidance will be updated and individuals with medical exemptions should be periodically re-evaluated by their nurse practitioner/physician/specialist as emerging evidence and new vaccine products become available.
# Reasons for Medical Exemption
Individuals who have experienced serious adverse events following COVID-19 immunization and those with certain medical conditions that may affect their immune response to immunization should be referred to an appropriate physician or nurse practitioner based on their adverse event/medical condition for further assessment. This should include a detailed patient history, assessment of the adverse event/medical condition and investigations/diagnosis, individualized riskbenefit analysis, and recommendations/options for future immunization. For serious or rare AEFIs, individuals should be thoroughly investigated to determine if the event can be attributed to an alternative etiology. Referral and specialist consultation support for physicians and nurse practitioners is available through Ontario's eConsult Service, OTN Hub, and the Special Immunization Clinic (SIC) Network. In many instances, safe administration of subsequent doses of COVID-19 vaccine is possible under the management of an appropriate physician or nurse practitioner. True medical exemptions are expected to be infrequent and should be supported by expert consultation.
Tables 1-4: Summary of conditions and/or adverse events following immunization (AEFI) that may qualify for a medical exemption to COVID-19 vaccination 1 As per NACI if the diagnosis with myocarditis is remote and they are no longer followed clinically by a medical professional for cardiac issues, they should receive an mRNA COVID-19 vaccine.
# Condition/AEFI Management
Myocarditis prior to initiating an mRNA COVID-19 vaccine series
# Contraindications to Initiating an AstraZeneca or Janssen COVID-19
# Vaccine Series Condition/AEFI Management
History of capillary leak syndrome (CLS)
• Series should be completed with an mRNA vaccine.
• Qualifies for medical exemption if:
o Individual has medical exemption to completing their vaccine series with an mRNA vaccine.
# History of cerebral venous sinus thrombosis (CVST) with thrombocytopenia
• Series should be completed with an mRNA vaccine.
• Qualifies for medical exemption if:
o Individual has medical exemption to completing their vaccine series with an mRNA vaccine.
# History of heparin-induced thrombocytopenia (HIT)
• Series should be completed with an mRNA vaccine.
• Qualifies for medical exemption if:
o Individual has medical exemption to completing their vaccine series with an mRNA vaccine.
# History of major venous and/or arterial thrombosis with thrombocytopenia
• Series should be completed with an mRNA vaccine.
• Qualifies for medical exemption if:
o Individual has medical exemption to completing their vaccine series with an mRNA vaccine.
# Adverse Events
# Other Condition/AEFI Management
Actively receiving monoclonal antibody therapy OR convalescent plasma therapy for the treatment or prevention of COVID-19
• Qualifies for time-limited medical exemption while they are actively receiving therapy.
# History of Myocarditis prior to initiating an mRNA COVID-19 vaccine series
Individuals who have a history of myocarditis unrelated to mRNA COVID-19 vaccination should consult their clinical team for individual considerations and recommendations. Individuals previously diagnosed with myocarditis, whose diagnosis is considered remote and are no longer followed clinically by a medical professional for cardiac issues should receive the vaccine. This guidance is issued by the National Advisory Committee on Immunization (NACI). A medical exemption may be issued only if discussion has occurred with an appropriate physician or nurse practitioner regarding potential options for immunization with an mRNA COVID-19 vaccine or alternative, and the physician or nurse practitioner has determined that the individual cannot receive any COVID-19 vaccine.
# History of severe allergic reaction or anaphylaxis to any component of a COVID-19 vaccine
Individuals with a confirmed severe, immediate (≤4h following exposure) allergy (e.g., anaphylaxis) to a component of a specific COVID-19 vaccine or its container (e.g., PEG), are recommended to consult with an appropriate physician or nurse practitioner before receiving the specific COVID-19 vaccine. Individuals who are allergic to tromethamine (found in the Moderna COVID-19 vaccine and pediatric Pfizer-BioNTech COVID-19 vaccine) should be offered the Pfizer-BioNTech COVID-19 vaccine if 12 years or age or older, which does not contain this excipient. Individuals who are allergic to polysorbates (found in viral vector vaccines), should be offered an mRNA vaccine. A medical exemption may be issued only if discussion has occurred with the appropriate physician or nurse practitioner on options for immunization with the COVID-19 vaccine, including a risk-benefit analysis for the individual, and the physician or nurse practitioner has determined that the individual cannot receive any COVID-19 vaccine.
For a comprehensive list of components in the vaccine and packaging, please consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database.
# Contraindications to Initiating an AstraZeneca or Janssen COVID-19
Vaccine Series
# History of capillary leak syndrome (CLS)
Individuals who have experienced episodes of capillary leak syndrome (CLS) should not receive the AstraZeneca or Janssen COVID-19 vaccine. Very rare cases of capillary leak syndrome (CLS) have been reported following immunization with the AstraZeneca COVID-19 vaccine. This is a contraindication to receiving the AstraZeneca or Janssen COVID-19 vaccine. An authorized COVID-19 vaccine using a different platform (i.e., mRNA) should be offered for immunization. A medical exemption may be issued only if an mRNA COVID-19 vaccine is contraindicated for the individual.
# History of cerebral venous sinus thrombosis (CVST) with thrombocytopenia
Individuals who have experienced a previous CVST with thrombocytopenia should not receive the AstraZeneca or Janssen COVID-19 vaccine. This is a contraindication to receiving the AstraZeneca or Janssen COVID-19 vaccine. An authorized COVID-19 vaccine using a different platform (i.e., mRNA) should be offered for immunization. A medical exemption may be issued only if an mRNA COVID-19 vaccine is contraindicated for the individual.
# History of heparin-induced thrombocytopenia (HIT)
Individuals who have experienced a HIT should not receive the AstraZeneca or Janssen COVID-19 vaccine. This is a contraindication to receiving the AstraZeneca or Janssen COVID-19 vaccine. An authorized COVID-19 vaccine using a different platform (i.e., mRNA) should be offered for immunization. A medical exemption may be issued only if mRNA COVID-19 vaccine is contraindicated for the individual.
# History of major venous and/or arterial thrombosis with thrombocytopenia following any vaccine
Individuals who have experienced major venous and/or arterial thrombosis with thrombocytopenia following vaccination with any vaccine should not receive the AstraZeneca or Janssen COVID-19 vaccine. This is a contraindication based on recommendations issued by Ontario's Vaccine Clinical Advisory Group on Immunization. An authorized COVID-19 vaccine using a different platform (i.e., mRNA) should be offered for immunization. A medical exemption may be issued only if an mRNA COVID-19 vaccine is contraindicated for the individual.
# Adverse Events Following Immunization (AEFI) with COVID-19 vaccine Thrombosis with thrombocytopenia syndrome (TTS)/VITT following AstraZeneca or Janssen COVID-19 vaccine
Individuals who have experienced a major venous or arterial thrombosis with thrombocytopenia following vaccination with AstraZeneca or Janssen COVID-19 vaccine are contraindicated to receiving the AstraZeneca or Janssen vaccine. An authorized COVID-19 vaccine using a different platform (i.e. mRNA) should be offered for subsequent immunization. A medical exemption may be issued only if they have a medical exemption to completing their series with an mRNA COVID-19 vaccine.
# Myocarditis/Pericarditis following mRNA COVID-19 vaccination
A medical exemption may be issued if myocarditis/pericarditis was diagnosed after medical evaluation (e.g., ER physician, relevant specialist). In most circumstances, and as a precautionary measure until more information is available, individuals with a diagnosed episode of myocarditis/pericarditis within 6 weeks of receipt of a previous dose of an mRNA COVID-19 vaccine should defer further doses of the vaccine. This includes any person who had an abnormal cardiac investigation including electrocardiogram (ECG), elevated troponins, echocardiogram or cardiac MRI after a dose of an mRNA vaccine. This is a precaution based on recommendations issued by the National Advisory Committee on Immunization (NACI). NACI, Public Health Ontario (PHO), and the Ontario Ministry of Health (MOH) are following this closely and will update this recommendation as more evidence becomes available.
In situations where there is uncertainty regarding myocarditis diagnosis, discussion should occur with an appropriate physician or nurse practitioner on potential options for (re)immunization with the same or alternative COVID-19 vaccine, including a riskbenefit analysis for the individual. The individual qualifies for a medical exemption if the physician or nurse practitioner has determined that the individual is unable to receive any COVID-19 vaccine. Those with a history compatible with pericarditis and who either had no cardiac workup or had normal cardiac investigations, can be re(immunized) once they are symptom free and at least 90 days has passed since vaccination. Some people with confirmed myocarditis and/or pericarditis may choose to receive another dose of vaccine after discussing the risks and benefits with their healthcare provider. Individuals can be revaccinated once they are symptom free and at least 90 days has passed since vaccination. If another dose of vaccine is offered, they should be offered the Pfizer-BioNTech 30 mcg vaccine due to the lower reported rate of myocarditis and/or pericarditis following the Pfizer-BioNTech 30mcg vaccine compared to the Moderna 100 mcg vaccine. Informed consent should include discussion about the unknown risk of recurrence of myocarditis and/or pericarditis following receipt of additional doses of Pfizer-BioNTech COVID-19 vaccine in individuals with a history of confirmed myocarditis and/or pericarditis after a previous dose of mRNA COVID-19 vaccine, as well as the need to seek immediate medical assessment and care should symptoms develop.
# Severe Allergic Reaction or Anaphylaxis following a COVID-19 vaccine
In individuals with a history of a severe, immediate (≤4h following vaccination) allergic reaction (e.g., anaphylaxis) after previous administration of an mRNA COVID-19 vaccine, re-vaccination (i.e. administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. The risk of a severe immediate allergic reaction after re-immunization appears to be low and no long-term morbidity has been associated with re-vaccination.
• Consultation with an allergist may be sought prior to re-vaccination.
• If re-vaccinated, vaccine administration should be done in a controlled setting with expertise and equipment to manage allergic reactions. Individuals should be observed for at least 30 minutes after re-vaccination. For example, a longer period of observation is warranted for individuals exhibiting any symptom suggestive of an evolving AEFI at the end of the 30 minute observation period.
For those with a previous history of allergy to an mRNA vaccine, re-vaccination with an mRNA vaccine is preferred over a viral vector vaccine due to the better effectiveness and immunogenicity of mRNA vaccines and the possible adverse effects specifically associated with viral vector vaccines (e.g., Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT), capillary leak syndrome (CLS), and Guillain-Barré Syndrome (GBS)).
In individuals with a history of a severe, immediate (≤4h following vaccination) allergic reaction (e.g., anaphylaxis) after previous administration of a viral vector COVID-19 vaccine, re-vaccination may be offered with an mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. If re-vaccinated, individuals should be observed for at least 30 minutes after re-vaccination.
A medical exemption may be issued if discussion has occurred with an appropriate physician or nurse practitioner on potential options for (re)immunization with the same or alternative COVID-19 vaccine, including a risk-benefit analysis for the individual, and the physician or nurse practitioner has determined that the individual cannot receive any COVID-19 vaccine with the currently available mitigation strategies.
# Other allergies
Individuals with other types of non-severe allergies can receive COVID-19 vaccines as outlined in the MOH's Vaccination Recommendations for Special Populations. These allergies do not on their own constitute the grounds for a medical exemption. For more information on the management of individuals with allergies, please see the MOH's Vaccination Recommendations for Special Populations.
# Serious Adverse Event Following COVID-19 Immunization (AEFI)
Individuals who experience a serious adverse event following immunization (AEFI) (e.g., hospitalization, persistent or significant disability/incapacity) with a COVID-19 vaccine should be medically assessed by an appropriate physician or nurse practitioner, and the event should be reported to their local public health unit (PHU). This may include clinical syndromes such as Guillain-Barré Syndrome (GBS). The Health Protection and Promotion Act (HPPA) mandates reporting of AEFIs by healthcare providers who administer immunizations (e.g., registered nurses, nurse practitioners, pharmacists, and physicians).
AEFI reports received by PHUs are investigated, assessed, and documented according to provincial surveillance guidelines, as required by the Ontario Public Health Standards (OPHS). For serious AEFIs, this includes referral to an appropriate physician or nurse practitioner for diagnosis/management and expert assessment for recommendation for subsequent immunization (e.g., the Special Immunization Clinic (SIC) Network, immunologist, etc.). This assessment will include a detailed assessment of the adverse event including investigations and diagnosis, and assessment for alternative etiology for the event. Discussion with the patient should then consider the event and the personal and epidemiological context (in terms of risk of COVID-19 infection) for the patient, and the risks and benefits regarding recommendations/options for immunization. The individual qualifies for a medical exemption if the appropriate physician or nurse practitioner (e.g., immunologist, SIC network, Medical Officer of Health, etc.) determines that the individual is unable to receive any COVID-19 vaccine after the event has been medically evaluated AND a discussion has occurred on the individual's risks and benefits of potential options for immunization with the same or alternative COVID-19 vaccine.
There are very few serious AEFIs that would result in a medical exemption to COVID-19 vaccination.
# Other
Actively receiving monoclonal antibody or convalescent plasma therapy for the treatment or prevention of COVID-19 disease Individuals who are actively receiving monoclonal antibody or convalescent plasma therapy for the treatment or prevention of COVID-19 disease should not receive a COVID-19 vaccine (NACI). This is a time-limited (temporary) precaution. COVID-19 vaccines may be administered to these individuals once therapy is discontinued, with the timing of administration and potential for immune interference evaluated on a case-by-case basis by an appropriate physician or nurse practitioner. A medical exemption may be issued only if the individual is actively receiving therapy.
# Actively receiving or recently completed immunosuppressing therapy anticipated to significantly blunt vaccine response
Individuals who are actively receiving or recently completed an immunosuppressive therapy listed in the table below may be advised by their physician or nurse practitioner to defer COVID-19 vaccination to a later point to optimize immune response to the COVID-19 vaccine and minimize delays in management of their underlying condition. This is a time-limited (temporary) precaution. The recommended maximum deferral duration following completion of specific therapies is listed in the table below.
COVID-19 vaccines may be administered to these individuals once therapy is discontinued, with timing of administration evaluated on a case-by-case basis by an appropriate physician or nurse practitioner. Discussion with the patient should then consider their medical condition and the personal and epidemiological context (in terms of risk of COVID-19 infection) for the patient, and the risks and benefits regarding timing and recommendations/options for immunization. A time-limited medical exemption may be issued only if the appropriate physician or nurse practitioner has recommended that the individual defer COVID-19 vaccination to a later point to optimize their immune response.
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How should the various types of acute infusion-related adverse events be managed? 7. How should patients experiencing an acute infusion-related adverse events be followed-up?The PubMed and EMBASE database were searched for relevant studies, guidelines and consensus documents published up to May 2019. The specific search strategy, search terms, and search results, are presented in Appendix A, and evidence tables are available upon request. Online resources from oncology-based health organizations and guideline developers were also systematically searched, and relevant guidelines from the following organizations were considered in the development of our recommendations: Cancer Care Ontario (CCO), The Comité de l'évoltion des pratiques en oncologie (CEPO), and the European Society for Medical Oncology (ESMO).# Background
Many chemotherapy drugs and monoclonal antibodies are reported to cause acute infusion-related allergic and allergic-like reactions in cancer patients. These reactions range from mild cutaneous appearances (e.g. pruritus and hives) to life-threatening anaphylaxis with hypotension, oxygen desaturation and cardiovascular collapse, and death. 1 Acute infusion-related adverse events vary based on the type of drug used, as well as the duration, frequency of infusion and prior exposure to the drug. 2 Understanding the pathophysiology of these acute infusion-related adverse events and the terminology used to describe them is confusing. The traditional classification relies on the clinical presentation of typical symptoms and their timing, and include: 3 - type I (IgE mediated reactions) - type II (antibody mediated cytotoxicity reactions) - type III (immune complex-mediated reactions)
- type IV (delayed reactions)
The traditional classification, however, does not encompass the current spectrum of reactions and symptoms occurring in cancer patients. 1,4,5 Some of the reactions have no known underlying mechanism, others have a known mechanism which is not part of the traditional classification, while some drugs induce mixed reactions with two or more proposed mechanisms. 1 Regardless of the underlying mechanism, acute infusion-related adverse events to chemotherapy drugs and monoclonal antibodies are unexpected, can be severe, and can prevent the use of first-line therapies which has the potential to negatively impact patient's survival and quality of life. 1 To facilitate prompt identification and management of these reactions, a shared understanding of the terminology, incidence, characteristics, and management approaches is required between healthcare professionals.
# Guideline Questions
As it pertains to chemotherapy drugs and monoclonal antibodies: 1. How are acute infusion-related adverse events defined? 2. What are the risk factors for acute infusion-related adverse events? 3. What is the incidence of acute infusion-related adverse events? 4. What are the characteristics (signs, symptoms, timing, and grading) of acute infusion-related adverse events? 5. What is unique about acute infusion-related adverse events with the following drugs classes: a. Platinum derivatives? b. Anthracyclines? c. Taxanes? d. Monoclonal antibodies?
# Target Population
The recommendations presented in this guideline apply to adult patients over the age of 18 who are receiving chemotherapy and/or monoclonal antibodies. Different principles may apply to pediatric patients.
# Guideline Development Notes
Acute infusion-related adverse events associated with chemotherapy drugs and monoclonal antibodies is difficult to evaluate through prospective randomized studies because of the unexpected nature of these reactions. 6 The available published data is largely drug-specific, and while reported as secondary outcomes or included in safety analysis from randomized controlled trials, the data is primarily derived from single-center cohort, retrospective, or case reports.
We chose to provide high-level recommendations about the identification and management of infusion-related adverse events in this guideline and refer clinicians to the drug table in Appendix B for specific details about individual chemotherapy drugs and monoclonal antibodies. The information presented in Appendix B was largely identified in Lexicomp (specific drug or drug class) using a combination of search terms, including infusion reaction, infusion-related reaction, anaphylaxis, cytokine release, and hypersensitivity. For some drugs, additional new information was added from Cancer Care Ontario's Cancer Medication Infusion Reactions Drug Table. 7 Acute infusion-related adverse associated with supportive drugs used during cancer treatment (e.g. sargramostim) are beyond the scope of this guideline.
For recommendations about the management of acute infusion-related adverse events following treatment with immune effectors cells, please refer to Alberta Health Services' Alberta Bone Marrow and Blood Cell Transplant Program: Standard Practice Manual. 8 Recommendations
# Acute Infusion-Related Adverse Events Terminology
Several terms are used to describe acute infusion-related adverse events to chemotherapy and monoclonal antibodies, including drug hypersensitivity reactions, infusion-related reactions, cytokine release syndrome and anaphylaxis. We recommend using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to help standardize the definitions of some of these terms. 9 The CTCAE is a commonly used system of nomenclature for classifying adverse events and their associated severity in cancer clinical trials. 10 - Drug hypersensitivity reactions (HSR) are the adverse effects of pharmaceutical formulations (including active drugs and excipients) that clinically resemble allergic reactions. 11 - Infusion-related reaction (IRR) is a disorder characterized by adverse reaction to the infusion of pharmacological or biological substances. 9 An IRR may occur during administration (intravenous/subcutaneous) or sometime after on the first day of drug administration. 12 - Cytokine release syndrome (CRS) is a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines. 9 CRS is a specific type of nonantibody-mediated infusion reaction (often referred to as anaphylactoid reactions) that is associated with monoclonal antibodies and T-cell-directed therapies. 13 - Anaphylaxis is a disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, anaphylaxis presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death. 9
# Risk Factors for Acute Infusion-Related Adverse Events
There are no well-established risk factors to identify who may experience an acute infusion-related adverse events. Low-level evidence has identified some drug-related, treatment regimen-related, and patient-related risk factors, which are summarized in Table 1.
# Incidence of Acute Infusion-Related Adverse Events
Capturing the incidence of acute infusion-related adverse events, drugs involved, management, treatment, and outcomes has been possible only through volunteer registries. 31,32 Thus, it can be expected that the incidence of acute infusion-related adverse events with chemotherapy drugs and monoclonal antibodies is often different depending on the source of evidence. To assist healthcare professionals with risk recognition we chose Lexicomp as our source of evidence and allocated individual chemotherapy drugs and monoclonal antibodies into one of three categories based on arbitrarily selected ranges: 26-30, 33-60
- High potential (≥30%): blinatumomab, daratumumab, obinutuzumab (1 st infusion), paclitaxel (conventional), rituximab (decreases with subsequent infusions)
- Moderate potential (<30% to ≥10%): asparaginase (E. coli), carboplatin, cetuximab, cisplatin, daunorubicin (liposomal), docetaxel, nivolumab, obinutuzumab (2 nd infusion), pertuzumab, ramucirumab, trastuzumab
- Low potential (<10%): alemtuzumab, atezolizumab, bevacizumab, bleomycin, brentuimab vedotin, cabazitaxel, daunorubicin (conventional), doxorubicin (conventional), doxorubicin (liposomal), epirubicin, etoposide, idarubicin, inotuzumab ozogamicin, ipilimumab, obitutuzumab (≥ 3 rd infusion), oxaliplatin, paclitaxel (protein bound), panitumumab, pembrolizumab, While most chemotherapy drugs and monoclonal antibodies have an anaphylactic incidence rate of less than 1%, they are reported as the third leading cause of fatal drug-induced anaphylaxis. 61
# Characteristics of Acute Infusion-Related Adverse Events
Signs and symptoms. Common signs and symptoms of acute infusion-related adverse events include:
- Cutaneous e.g. rash, flushing, urticaria, pruritus Acute infusion-related adverse events to taxanes and monoclonal antibodies usually occur during the first or second infusion versus platinum compounds where they typically occur after multiple cycles. 24, For example, in retrospective reviews, reactions to oxaliplatin occurred at a median of 7 to 9 cycles as reported in Lexicomp (see Appendix B).
Grading. The CTCAE differentiates Grades 1 through 5 for acute infusion-related adverse events with unique clinical descriptions of severity for each (see Table 3). 9 These grades should be used to guide diagnosis and management decisions associated with acute infusion-related adverse events caused by chemotherapy drugs and monoclonal antibodies.
# Unique Characteristics of Acute Infusion-Related Adverse Events by Main Drug Class
Anthracyclines (Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Valrubicin) 73 - Reactions usually occur immediately.
- Reactions appear to be immunologically mediated. However, in the case of liposomal formulations, complement activation may be an important factor. - Systemic hypersensitivity and anaphylaxis are rarely reported. 74 - Reactions are thought to be mainly caused by type I IgE-mediated or type IV T-cell-mediated hypersensitivity although nonimmune mechanisms may also play a role. - Most reactions to platinum derivatives occur after multiple infusions.
# Platinum derivatives (Carboplatin, Cisplatin, Oxaliplatin)
- Reactions usually occur during or shortly after the infusion.
- The chance of hypersensitivity reactions is increased when platinum derivatives are given in combination with other chemotherapy. - Cross-sensitivity may occur between the platinum derivatives.
- There is insufficient evidence that routine premedication with antihistamines, H2 blockers, and corticosteroids are effective in preventing hypersensitivity reactions to platinum salts. 75 - Special considerations:
- Corticosteroids and H1-receptor antagonists ± H2-receptor antagonists may reduce infusion-related reaction rates for some patients receiving carboplatin (e.g. gynecological patients with a platinum-free interval >12 months or a history of drug allergy who are receiving carboplatin starting from the 7 th cycle) but no optimal premedication regimen has been established. 7
Taxanes (Cabazitaxel, Docetaxel, Paclitaxel) 76 - Hypersensitivity reactions are similar in nature between the taxanes and may include shortness of breath, itching, hypotension, back pain and erythematous rashes. Rarely, bronchospasm and death have occurred. - Most hypersensitivity reactions are understood to be non-IgE-mediated. It is likely that allergic reactions can be attributed, at least in some instances to the vehicle (e.g. Cremophor EL, polysorbate 80) - Most hypersensitivity reactions occur with the first or second dose.
- Cross-reactivity may exist between the taxanes.
- Special considerations:
- Evidence indicates that premedications can be discontinued in patients who have completed two cycles of paclitaxel without a documented infusion-related reaction. 72 o If the patient has reacted, or subsequently reacts, premedications should be given on every cycle
Monoclonal Antibodies 77 - Most reactions are mild and non-life-threatening.
- Anaphylaxis is uncommon but has been reported with rituximab trastuzumab and cetuximab.
- Infusion-related reaction are typically immediate and occur during the initial few minutes of the first or second infusion. - Reactions may occur after the first exposure or after many exposures, but in general, the risk of an infusion-related reaction decreases following each treatment. - Most reactions appear to be due to antibody-antigen reactions prompting cytokine release.
- Information about cross-reactivity is lacking.
# Biosimilars
- Biosimilars are currently available for bevacizumab, trastuzumab, and rituximab.
- For a drug to be called a biosimilar, the manufacturer must provide Health Canada with information to show that the biosimilar is highly similar to the reference biologic drug, and that there are no clinically meaningful differences in terms of safety and efficacy. 78 Therefore, clinicians should expect to see the same rate of acute infusion-related adverse events in biosimilars that they would expect to see in the biologic drug. - Despite reported safety profiles and similar rates of adverse events, clinicians should be vigilant when switching patients who have already been treated with an originator drug.
# Management of Acute Infusion-Related Adverse Events
# Preparation
- All healthcare professionals should be trained to understand the risk and recognize the signs and symptoms of an acute infusion-related adverse events.
- Before chemotherapy drugs and monoclonal antibodies are administered, all patients should be asked about their medical history and history of acute infusion-related adverse events. 6
- An updated organizational protocol for the management of acute infusion-related adverse events should be accessible.
- Emergency equipment and medications should be available for immediate use in case of serious, life threatening infusion-related adverse events.
# Use of Premedication
- Premedication can be used to help prevent and/or reduce the severity of acute infusion-related adverse events, although it is less effective in preventing anaphylaxis. 79 - For certain drugs that are associated with a high incidence of acute infusion-related adverse events, prophylaxis with one or more of the following is reported in the literature:
- H1 antihistamine (diphenhydramine)
- Glucocorticoid (dexamethasone, hydrocortisone, methylprednisolone) o H2 antihistamine (ranitidine, cimetidine, famotidine)
- Antipyretic (acetaminophen)
- Leukotriene receptor antagonist (montelukast)
- Specific prophylactic regimens that are recommended for individual drugs can be found in Appendix B. Note that these regimens are derived using empirical evidence rather than through randomized trials. 79
Observation 6
- Premedication does not exclude the possibility of an acute infusion-related adverse events.
- Patients should be observed closely during and after their infusion for acute infusion-related adverse events.
- Patients should be educated on a drug's potential to cause an acute infusion-related adverse event and notify healthcare providers promptly about any signs and symptoms.
- Recommended observation periods for certain drugs that are associated with a high incidence of acute infusion-related adverse events can be found in Appendix B.
# General Treatment Recommendations (for more retailed recommendations see Appendix B)
Acute infusion-related adverse events require a rapid response from healthcare professionals. Management of the event is based on the severity of presenting symptoms, but also symptoms as the reaction is monitored and progresses (worsens/resolves). Because acute infusion reactions often unfold and change quickly, grading using CTCAE to document the severity of the reaction, should be reserved until after the reaction has resolved and all of the required treatment for the reaction has been administered. We recommend differentiating treatment as follows:
Mild to moderate reactions (no features suggestive of anaphylaxis). If the reaction is mild or moderate without features suggestive of anaphylaxis, interrupt or slow the rate of infusion (generally by 50%) and manage symptoms as appropriate. Upon symptom resolution, restart at reduced rate or slowly increase infusion from 50% as tolerated by the patient. Assess vitals, body systems for symptoms of further reaction, and level of consciousness often.
Severe reactions: If the reaction is severe, interrupt therapy and assess for features of anaphylaxis. If the patient fulfills any of the criteria for anaphylaxis (Table 2) refer to Alberta Health Services' policy for Anaphylaxis Management: Administration of Intramuscular Epinephrine. 63 If vital symptoms were affected, permanently discontinue therapy.
If anaphylaxis criteria are not met (i.e. vital signs were not affected), manage symptoms as appropriate. Upon symptom resolution, the infusion may be reinitiated at no more than 50% of the rate at which the reaction occurred. If no further infusion-related symptoms occur, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Assess vitals and level of consciousness often.
Note: Some drugs should be discontinued immediately if a severe infusion-related adverse event, including:
- Alemtuzumab - Atezolizumab - Cetuximab - Pembrolizumab - Ramucirumab
Diagnostic tools. Serum, plasma, and urine obtained during or shortly after an acute infusion-related adverse events can support the clinical diagnosis of anaphylaxis. While assays for mediators released during anaphylaxis such as tryptase (serum/plasma) and histamine (plasma, urine) are commercially available, they are not routinely recommended in practice because these tests are not universally available, not performed in real time (i.e. emergency situations), and normal levels do not exclude the possibility of anaphylaxis. 6,80,81 Re-start/Re-challenge: 6 No re-start/rechallenge should be undertaken for patients with suspected or confirmed anaphylaxis. The severity and nature of the acute infusion-related adverse event will determine the decision to restart the treatment once symptoms have been managed (usually at a reduced infusion rate), or to re-challenge (re-expose the patient to the treatment) at a later date (usually with a reduced infusion rate and additional premedications).
Desensitization: Desensitization protocols are potentially dangerous procedures and should only be performed by experienced individuals in an area with immediate access to emergency drugs and equipment 79,82 Successful desensitization has been reported using the following drugs:
- Carboplatin 66, 69, 71, 83-87
- Etoposide 88, 89
- Oxaliplatin - Pegaspargase 94
- Trastuzumab 83,95 - Infliximab 96
- Rituximab 71 We discourage the use of desensitization protocols unless performed by allergists, or oncologists who have experience with desensitization protocols. 79
# Acute Infusion-Related Adverse Event Follow-up 6
Following an acute infusion-related adverse event, healthcare professionals should attempt to establish, based on the suspect drug and the characteristics of the event, the steps that could be taken to prevent future episodes. This information, including confirmation that a reaction occurred, should be communicated to patients and family members once any medication affecting cognitive function has worn off.
For drugs that are restarted/rechallenged, patients should be observation for lengths of time that are based on the severity of the reaction and proximity to an emergency facility, with prolonged observation times or hospital admission for patients with severe or refractory symptoms.
If an acute infusion-related adverse event causes significant anxiety and distress for patients who require further treatment, an open discussion about the potential benefits of continuing with the drug and the risk of recurring acute infusion-related adverse events is recommended. Psychological intervention should be provided to alleviate symptoms of anxiety and distress related to a potential infusion-related adverse event with chemotherapy drugs or monoclonal antibodies.
- Gadducci A, Tana R, Teti G, Zanca G, Fanucchi A, Genazzani AR. Analysis of the pattern of hypersensitivity reactions in patients receiving carboplatin retreatment for recurrent ovarian cancer. - Overall incidence of reactions: 1-44%
- Anaphylaxis: <1% (post-marketing, and/or case reports)
# Onset
- Most reactions to platinum derivatives occur after multiple infusions, typically with 7 th -10 th exposure, although reactions may occur after initial infusion
- Reactions usually occur during or shortly after infusion; however, some reports of delayed reactions occurring hrs. later - Anaphylactic-like reactions may occur within mins. of administration
# Risk factors
- Previous exposure to platinum therapy, platinum-free interval >12 months, history of other systemic reactions, cumulative carboplatin dose, past drug allergies, disease severity, histological type, and malignant ascites, patients sensitized to oxaliplatin
- Chance of HSR increased when platinum derivatives given in combination with other chemotherapy and with multiple infusions
# Mechanism
- Exact mechanism of platinum reactions unknown; reactions thought to be mainly caused by type I IgE-mediated or type IV T-cell-mediated hypersensitivity although nonimmune mechanisms may also play a role
# Symptoms
- Mild to moderate reactions consisting of itching or erythema alone, on palms and soles, or facial flushing - Rash, abdominal cramps, facial edema, hypotension, bronchospasm, chest pain, tachycardia, systemic anaphylaxis
# Cross-reactivity
- Cross-sensitivity may occur between platinum derivatives. Substitution of one platinum derivative has been done successfully in some instances, but it has also been unsuccessful and fatal in others
# Pre-medication
- Insufficient evidence that routine pre-medications reduce IRR rates - Based on low level evidence, corticosteroids and H1 antagonists ± H2 antagonists may reduce IRR rates for some patients (e.g. gynecological patients with PFI >12 months or history of drug allergy who are receiving carboplatin starting from 7 th cycle) but no optimal pre-medication regimen established
# Extended infusion
- Insufficient evidence that routine prophylaxis with extended infusion reduces IRR rates
# Management
- Mild to moderate HSRs: range of different treatment strategies have been used, including lowering infusion rate and use of pre-medication with corticosteroids and H2 antagonists
- Patients reacting to carboplatin may be able to tolerate oxaliplatin or cisplatin
# Re-challenge
- Successful re-challenges to platinum derivatives have occurred using pre-medication with steroids, antihistamines and various desensitization techniques
- May consider adding montelukast ± acetylsalicylic acid. Up to 50% of patients can experience recurrent reactions during re-challenge despite using pre-medications (e.g. corticosteroid and H1/H2 antagonist)
- Following carboplatin reactions, a dose escalation desensitization technique has been used to successfully treat patients with either cisplatin or carboplatin
- Decision to continue therapy with platinum drug after reaction using desensitization or substitution of another platinum derivative should be done carefully and only if benefits outweigh risks - HSR: 6-21%
- Anaphylactic shock: <1% (post-marketing, and/or case reports)
# Onset
- Most HSRs occur with 1 st or 2 nd dose
# Mechanism
- Most HSRs thought to be non-IgE-mediated
# Symptoms
- Minor reactions including flushing or localized skin reactions may occur - Severe HSRs, characterized by generalized rash/erythema, hypotension, bronchospasms, or rare anaphylaxis may occur (may be fatal; has occurred in patients receiving 3-day corticosteroid pre-medication)
- Dyspnea, urticaria, chest or back pain, tachycardia
# Cross-reactivity
- Cross-reactivity may exist between taxanes - Nab-paclitaxel has been well-tolerated in patients with previous histories of taxane HSRs
# Pre-medication
- Pre-medication with oral corticosteroids recommended to decrease incidence and severity of HSRs o Dexamethasone 16 mg/day (8 mg twice daily) orally for 3 days, starting day before docetaxel administration. Dexamethasone 10-20 mg IV can be given if patient forgot to take oral doses o For prostate cancer, when prednisone part of antineoplastic regimen, dexamethasone 8 mg orally administered at 12 hrs., 3 hrs., and 1 hr. prior to docetaxel o Do not discontinue dexamethasone, even in absence of IRR, due to benefits on other adverse effects (e.g. pain and edema)
# Management
- Do not administer to patients with severe hypersensitivity to docetaxel or polysorbate 80 - Observe for hypersensitivity, especially with first 2 infusions - HSRs require immediate discontinuation and administration of appropriate therapy - Patients with history of HSR to paclitaxel may develop hypersensitivity to docetaxel; may be severe or fatal (including anaphylaxis); monitor patients with paclitaxel hypersensitivity closely during initiation of docetaxel Ranitidine 50 mg IV OR famotidine 20 mg IV 30-60 mins. pre-infusion *Oral and IV dexamethasone both effective at reducing overall IRR rates. Some evidence suggests that oral dexamethasone may be more effective for reducing severe reactions; however, adverse effects and compliance remain a concern
# Pre-medication for weekly paclitaxel
To be given 30-60 mins. prior to paclitaxel infusion:
- Patients may be able to undergo rapid drug desensitization to remain on first-line therapy - Do not re-challenge after severe HSRs
# Other considerations
- Consider discontinuing pre-medications if there was no IRR in 1 st 2 doses - Extended infusion not recommended as primary prophylaxis to reduce IRRs - Insufficient evidence to recommend addition of hydrocortisone 100 mg IV to existing standard pre-medication regimen
# Management
- IRR hypotension, bradycardia, and/or hypertension may occur; frequent monitoring of vital signs recommended, especially during 1 st hr. of infusion - Minor HSRs (flushing, skin reactions, dyspnea, hypotension, or tachycardia) do not require interruption of treatment - If severe hypersensitivity occurs, stop infusion and do not re-challenge
# Re-challenge
Patients may be able to undergo rapid drug desensitization to remain on first-line therapy
# Pre-medication
- Administer 1-3 hrs. prior to each infusion. If dexamethasone is the background regimen-specific corticosteroid, the dexamethasone treatment dose will serve as the corticosteroid pre-medication on daratumumab infusion days. Additional background regimen-specific corticosteroids (e.g. prednisone) should NOT be administered on daratumumab infusion days when patients receive dexamethasone (or equivalent) as a premedication.
Corticosteroid:
- Monotherapy: Methylprednisolone 100 mg IV or equivalent intermediate-or long-acting corticosteroid; following the second infusion, the dose may be decreased (e.g. methylprednisolone 60 mg or equivalent) o Combination therapy: Dexamethasone 20 mg (or equivalent) prior to each daratumumab infusion; administer IV prior to the first infusion; oral administration may be considered prior to subsequent infusions plus - Antipyretic: Oral: Acetaminophen 650 to 1,000 mg plus - Antihistamine: IV or Oral: Diphenhydramine 25 to 50 mg or equivalent
The following pre-medication regimen has also been reported: o First infusion: Acetaminophen 325 mg orally, diphenhydramine 25 mg orally or IV, dexamethasone 20 mg IV, montelukast 10 mg orally, and famotidine 20 mg IV. o Subsequent infusions: Acetaminophen 325 mg orally, diphenhydramine 25 mg IV, and dexamethasone 20 mg IV
# Post-medication
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How should the various types of acute infusion-related adverse events be managed? 7. How should patients experiencing an acute infusion-related adverse events be followed-up?The PubMed and EMBASE database were searched for relevant studies, guidelines and consensus documents published up to May 2019. The specific search strategy, search terms, and search results, are presented in Appendix A, and evidence tables are available upon request. Online resources from oncology-based health organizations and guideline developers were also systematically searched, and relevant guidelines from the following organizations were considered in the development of our recommendations: Cancer Care Ontario (CCO), The Comité de l'évoltion des pratiques en oncologie (CEPO), and the European Society for Medical Oncology (ESMO).# Background
Many chemotherapy drugs and monoclonal antibodies are reported to cause acute infusion-related allergic and allergic-like reactions in cancer patients. These reactions range from mild cutaneous appearances (e.g. pruritus and hives) to life-threatening anaphylaxis with hypotension, oxygen desaturation and cardiovascular collapse, and death. 1 Acute infusion-related adverse events vary based on the type of drug used, as well as the duration, frequency of infusion and prior exposure to the drug. 2 Understanding the pathophysiology of these acute infusion-related adverse events and the terminology used to describe them is confusing. The traditional classification relies on the clinical presentation of typical symptoms and their timing, and include: 3 • type I (IgE mediated reactions) • type II (antibody mediated cytotoxicity reactions) • type III (immune complex-mediated reactions)
• type IV (delayed reactions)
The traditional classification, however, does not encompass the current spectrum of reactions and symptoms occurring in cancer patients. 1,4,5 Some of the reactions have no known underlying mechanism, others have a known mechanism which is not part of the traditional classification, while some drugs induce mixed reactions with two or more proposed mechanisms. 1 Regardless of the underlying mechanism, acute infusion-related adverse events to chemotherapy drugs and monoclonal antibodies are unexpected, can be severe, and can prevent the use of first-line therapies which has the potential to negatively impact patient's survival and quality of life. 1 To facilitate prompt identification and management of these reactions, a shared understanding of the terminology, incidence, characteristics, and management approaches is required between healthcare professionals.
# Guideline Questions
As it pertains to chemotherapy drugs and monoclonal antibodies: 1. How are acute infusion-related adverse events defined? 2. What are the risk factors for acute infusion-related adverse events? 3. What is the incidence of acute infusion-related adverse events? 4. What are the characteristics (signs, symptoms, timing, and grading) of acute infusion-related adverse events? 5. What is unique about acute infusion-related adverse events with the following drugs classes: a. Platinum derivatives? b. Anthracyclines? c. Taxanes? d. Monoclonal antibodies?
# Target Population
The recommendations presented in this guideline apply to adult patients over the age of 18 who are receiving chemotherapy and/or monoclonal antibodies. Different principles may apply to pediatric patients.
# Guideline Development Notes
Acute infusion-related adverse events associated with chemotherapy drugs and monoclonal antibodies is difficult to evaluate through prospective randomized studies because of the unexpected nature of these reactions. 6 The available published data is largely drug-specific, and while reported as secondary outcomes or included in safety analysis from randomized controlled trials, the data is primarily derived from single-center cohort, retrospective, or case reports.
We chose to provide high-level recommendations about the identification and management of infusion-related adverse events in this guideline and refer clinicians to the drug table in Appendix B for specific details about individual chemotherapy drugs and monoclonal antibodies. The information presented in Appendix B was largely identified in Lexicomp (specific drug or drug class) using a combination of search terms, including infusion reaction, infusion-related reaction, anaphylaxis, cytokine release, and hypersensitivity. For some drugs, additional new information was added from Cancer Care Ontario's Cancer Medication Infusion Reactions Drug Table. 7 Acute infusion-related adverse associated with supportive drugs used during cancer treatment (e.g. sargramostim) are beyond the scope of this guideline.
For recommendations about the management of acute infusion-related adverse events following treatment with immune effectors cells, please refer to Alberta Health Services' Alberta Bone Marrow and Blood Cell Transplant Program: Standard Practice Manual. 8 Recommendations
# Acute Infusion-Related Adverse Events Terminology
Several terms are used to describe acute infusion-related adverse events to chemotherapy and monoclonal antibodies, including drug hypersensitivity reactions, infusion-related reactions, cytokine release syndrome and anaphylaxis. We recommend using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to help standardize the definitions of some of these terms. 9 The CTCAE is a commonly used system of nomenclature for classifying adverse events and their associated severity in cancer clinical trials. 10 • Drug hypersensitivity reactions (HSR) are the adverse effects of pharmaceutical formulations (including active drugs and excipients) that clinically resemble allergic reactions. 11 • Infusion-related reaction (IRR) is a disorder characterized by adverse reaction to the infusion of pharmacological or biological substances. 9 An IRR may occur during administration (intravenous/subcutaneous) or sometime after on the first day of drug administration. 12 • Cytokine release syndrome (CRS) is a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines. 9 CRS is a specific type of nonantibody-mediated infusion reaction (often referred to as anaphylactoid reactions) that is associated with monoclonal antibodies and T-cell-directed therapies. 13 • Anaphylaxis is a disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, anaphylaxis presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death. 9
# Risk Factors for Acute Infusion-Related Adverse Events
There are no well-established risk factors to identify who may experience an acute infusion-related adverse events. Low-level evidence has identified some drug-related, treatment regimen-related, and patient-related risk factors, which are summarized in Table 1. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]
# Incidence of Acute Infusion-Related Adverse Events
Capturing the incidence of acute infusion-related adverse events, drugs involved, management, treatment, and outcomes has been possible only through volunteer registries. 31,32 Thus, it can be expected that the incidence of acute infusion-related adverse events with chemotherapy drugs and monoclonal antibodies is often different depending on the source of evidence. To assist healthcare professionals with risk recognition we chose Lexicomp as our source of evidence and allocated individual chemotherapy drugs and monoclonal antibodies into one of three categories based on arbitrarily selected ranges: 26-30, 33-60
• High potential (≥30%): blinatumomab, daratumumab, obinutuzumab (1 st infusion), paclitaxel (conventional), rituximab (decreases with subsequent infusions)
• Moderate potential (<30% to ≥10%): asparaginase (E. coli), carboplatin, cetuximab, cisplatin, daunorubicin (liposomal), docetaxel, nivolumab, obinutuzumab (2 nd infusion), pertuzumab, ramucirumab, trastuzumab
• Low potential (<10%): alemtuzumab, atezolizumab, bevacizumab, bleomycin, brentuimab vedotin, cabazitaxel, daunorubicin (conventional), doxorubicin (conventional), doxorubicin (liposomal), epirubicin, etoposide, idarubicin, inotuzumab ozogamicin, ipilimumab, obitutuzumab (≥ 3 rd infusion), oxaliplatin, paclitaxel (protein bound), panitumumab, pembrolizumab, While most chemotherapy drugs and monoclonal antibodies have an anaphylactic incidence rate of less than 1%, they are reported as the third leading cause of fatal drug-induced anaphylaxis. 61
# Characteristics of Acute Infusion-Related Adverse Events
Signs and symptoms. Common signs and symptoms of acute infusion-related adverse events include:
• Cutaneous e.g. rash, flushing, urticaria, pruritus Acute infusion-related adverse events to taxanes and monoclonal antibodies usually occur during the first or second infusion [65][66][67][68] versus platinum compounds where they typically occur after multiple cycles. 24, [69][70][71] For example, in retrospective reviews, reactions to oxaliplatin occurred at a median of 7 to 9 cycles as reported in Lexicomp (see Appendix B).
Grading. The CTCAE differentiates Grades 1 through 5 for acute infusion-related adverse events with unique clinical descriptions of severity for each (see Table 3). 9 These grades should be used to guide diagnosis and management decisions associated with acute infusion-related adverse events caused by chemotherapy drugs and monoclonal antibodies.
# Unique Characteristics of Acute Infusion-Related Adverse Events by Main Drug Class
Anthracyclines (Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Valrubicin) 73 • Reactions usually occur immediately.
• Reactions appear to be immunologically mediated. However, in the case of liposomal formulations, complement activation may be an important factor. • Systemic hypersensitivity and anaphylaxis are rarely reported. 74 • Reactions are thought to be mainly caused by type I IgE-mediated or type IV T-cell-mediated hypersensitivity although nonimmune mechanisms may also play a role. • Most reactions to platinum derivatives occur after multiple infusions.
# Platinum derivatives (Carboplatin, Cisplatin, Oxaliplatin)
• Reactions usually occur during or shortly after the infusion.
• The chance of hypersensitivity reactions is increased when platinum derivatives are given in combination with other chemotherapy. • Cross-sensitivity may occur between the platinum derivatives.
• There is insufficient evidence that routine premedication with antihistamines, H2 blockers, and corticosteroids are effective in preventing hypersensitivity reactions to platinum salts. 75 • Special considerations:
o Corticosteroids and H1-receptor antagonists ± H2-receptor antagonists may reduce infusion-related reaction rates for some patients receiving carboplatin (e.g. gynecological patients with a platinum-free interval >12 months or a history of drug allergy who are receiving carboplatin starting from the 7 th cycle) but no optimal premedication regimen has been established. 7
Taxanes (Cabazitaxel, Docetaxel, Paclitaxel) 76 • Hypersensitivity reactions are similar in nature between the taxanes and may include shortness of breath, itching, hypotension, back pain and erythematous rashes. Rarely, bronchospasm and death have occurred. • Most hypersensitivity reactions are understood to be non-IgE-mediated. It is likely that allergic reactions can be attributed, at least in some instances to the vehicle (e.g. Cremophor EL, polysorbate 80) • Most hypersensitivity reactions occur with the first or second dose.
• Cross-reactivity may exist between the taxanes.
• Special considerations:
o Evidence indicates that premedications can be discontinued in patients who have completed two cycles of paclitaxel without a documented infusion-related reaction. 72 o If the patient has reacted, or subsequently reacts, premedications should be given on every cycle
Monoclonal Antibodies 77 • Most reactions are mild and non-life-threatening.
• Anaphylaxis is uncommon but has been reported with rituximab trastuzumab and cetuximab.
• Infusion-related reaction are typically immediate and occur during the initial few minutes of the first or second infusion. • Reactions may occur after the first exposure or after many exposures, but in general, the risk of an infusion-related reaction decreases following each treatment. • Most reactions appear to be due to antibody-antigen reactions prompting cytokine release.
• Information about cross-reactivity is lacking.
# Biosimilars
• Biosimilars are currently available for bevacizumab, trastuzumab, and rituximab.
• For a drug to be called a biosimilar, the manufacturer must provide Health Canada with information to show that the biosimilar is highly similar to the reference biologic drug, and that there are no clinically meaningful differences in terms of safety and efficacy. 78 Therefore, clinicians should expect to see the same rate of acute infusion-related adverse events in biosimilars that they would expect to see in the biologic drug. • Despite reported safety profiles and similar rates of adverse events, clinicians should be vigilant when switching patients who have already been treated with an originator drug.
# Management of Acute Infusion-Related Adverse Events
# Preparation
• All healthcare professionals should be trained to understand the risk and recognize the signs and symptoms of an acute infusion-related adverse events.
• Before chemotherapy drugs and monoclonal antibodies are administered, all patients should be asked about their medical history and history of acute infusion-related adverse events. 6
• An updated organizational protocol for the management of acute infusion-related adverse events should be accessible.
• Emergency equipment and medications should be available for immediate use in case of serious, life threatening infusion-related adverse events.
# Use of Premedication
• Premedication can be used to help prevent and/or reduce the severity of acute infusion-related adverse events, although it is less effective in preventing anaphylaxis. 79 • For certain drugs that are associated with a high incidence of acute infusion-related adverse events, prophylaxis with one or more of the following is reported in the literature:
o H1 antihistamine (diphenhydramine)
o Glucocorticoid (dexamethasone, hydrocortisone, methylprednisolone) o H2 antihistamine (ranitidine, cimetidine, famotidine)
o Antipyretic (acetaminophen)
o Leukotriene receptor antagonist (montelukast)
• Specific prophylactic regimens that are recommended for individual drugs can be found in Appendix B. Note that these regimens are derived using empirical evidence rather than through randomized trials. 79
Observation 6
• Premedication does not exclude the possibility of an acute infusion-related adverse events.
• Patients should be observed closely during and after their infusion for acute infusion-related adverse events.
• Patients should be educated on a drug's potential to cause an acute infusion-related adverse event and notify healthcare providers promptly about any signs and symptoms.
• Recommended observation periods for certain drugs that are associated with a high incidence of acute infusion-related adverse events can be found in Appendix B.
# General Treatment Recommendations (for more retailed recommendations see Appendix B)
Acute infusion-related adverse events require a rapid response from healthcare professionals. Management of the event is based on the severity of presenting symptoms, but also symptoms as the reaction is monitored and progresses (worsens/resolves). Because acute infusion reactions often unfold and change quickly, grading using CTCAE to document the severity of the reaction, should be reserved until after the reaction has resolved and all of the required treatment for the reaction has been administered. We recommend differentiating treatment as follows:
Mild to moderate reactions (no features suggestive of anaphylaxis). If the reaction is mild or moderate without features suggestive of anaphylaxis, interrupt or slow the rate of infusion (generally by 50%) and manage symptoms as appropriate. Upon symptom resolution, restart at reduced rate or slowly increase infusion from 50% as tolerated by the patient. Assess vitals, body systems for symptoms of further reaction, and level of consciousness often.
Severe reactions: If the reaction is severe, interrupt therapy and assess for features of anaphylaxis. If the patient fulfills any of the criteria for anaphylaxis (Table 2) refer to Alberta Health Services' policy for Anaphylaxis Management: Administration of Intramuscular Epinephrine. 63 If vital symptoms were affected, permanently discontinue therapy.
If anaphylaxis criteria are not met (i.e. vital signs were not affected), manage symptoms as appropriate. Upon symptom resolution, the infusion may be reinitiated at no more than 50% of the rate at which the reaction occurred. If no further infusion-related symptoms occur, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Assess vitals and level of consciousness often.
Note: Some drugs should be discontinued immediately if a severe infusion-related adverse event, including:
• Alemtuzumab • Atezolizumab • Cetuximab • Pembrolizumab • Ramucirumab
Diagnostic tools. Serum, plasma, and urine obtained during or shortly after an acute infusion-related adverse events can support the clinical diagnosis of anaphylaxis. While assays for mediators released during anaphylaxis such as tryptase (serum/plasma) and histamine (plasma, urine) are commercially available, they are not routinely recommended in practice because these tests are not universally available, not performed in real time (i.e. emergency situations), and normal levels do not exclude the possibility of anaphylaxis. 6,80,81 Re-start/Re-challenge: 6 No re-start/rechallenge should be undertaken for patients with suspected or confirmed anaphylaxis. The severity and nature of the acute infusion-related adverse event will determine the decision to restart the treatment once symptoms have been managed (usually at a reduced infusion rate), or to re-challenge (re-expose the patient to the treatment) at a later date (usually with a reduced infusion rate and additional premedications).
Desensitization: Desensitization protocols are potentially dangerous procedures and should only be performed by experienced individuals in an area with immediate access to emergency drugs and equipment 79,82 Successful desensitization has been reported using the following drugs:
• Carboplatin 66, 69, 71, 83-87
• Etoposide 88, 89
• Oxaliplatin [90][91][92][93] • Pegaspargase 94
• Trastuzumab 83,95 • Infliximab 96
• Rituximab 71 We discourage the use of desensitization protocols unless performed by allergists, or oncologists who have experience with desensitization protocols. 79
# Acute Infusion-Related Adverse Event Follow-up 6
Following an acute infusion-related adverse event, healthcare professionals should attempt to establish, based on the suspect drug and the characteristics of the event, the steps that could be taken to prevent future episodes. This information, including confirmation that a reaction occurred, should be communicated to patients and family members once any medication affecting cognitive function has worn off.
For drugs that are restarted/rechallenged, patients should be observation for lengths of time that are based on the severity of the reaction and proximity to an emergency facility, with prolonged observation times or hospital admission for patients with severe or refractory symptoms.
If an acute infusion-related adverse event causes significant anxiety and distress for patients who require further treatment, an open discussion about the potential benefits of continuing with the drug and the risk of recurring acute infusion-related adverse events is recommended. Psychological intervention should be provided to alleviate symptoms of anxiety and distress related to a potential infusion-related adverse event with chemotherapy drugs or monoclonal antibodies.
17. Gadducci A, Tana R, Teti G, Zanca G, Fanucchi A, Genazzani AR. Analysis of the pattern of hypersensitivity reactions in patients receiving carboplatin retreatment for recurrent ovarian cancer. • Overall incidence of reactions: 1-44%
• Anaphylaxis: <1% (post-marketing, and/or case reports)
# Onset
• Most reactions to platinum derivatives occur after multiple infusions, typically with 7 th -10 th exposure, although reactions may occur after initial infusion
• Reactions usually occur during or shortly after infusion; however, some reports of delayed reactions occurring hrs. later • Anaphylactic-like reactions may occur within mins. of administration
# Risk factors
• Previous exposure to platinum therapy, platinum-free interval >12 months, history of other systemic reactions, cumulative carboplatin dose, past drug allergies, disease severity, histological type, and malignant ascites, patients sensitized to oxaliplatin
• Chance of HSR increased when platinum derivatives given in combination with other chemotherapy and with multiple infusions
# Mechanism
• Exact mechanism of platinum reactions unknown; reactions thought to be mainly caused by type I IgE-mediated or type IV T-cell-mediated hypersensitivity although nonimmune mechanisms may also play a role
# Symptoms
• Mild to moderate reactions consisting of itching or erythema alone, on palms and soles, or facial flushing • Rash, abdominal cramps, facial edema, hypotension, bronchospasm, chest pain, tachycardia, systemic anaphylaxis
# Cross-reactivity
• Cross-sensitivity may occur between platinum derivatives. Substitution of one platinum derivative has been done successfully in some instances, but it has also been unsuccessful and fatal in others
# Pre-medication
• Insufficient evidence that routine pre-medications reduce IRR rates • Based on low level evidence, corticosteroids and H1 antagonists ± H2 antagonists may reduce IRR rates for some patients (e.g. gynecological patients with PFI >12 months or history of drug allergy who are receiving carboplatin starting from 7 th cycle) but no optimal pre-medication regimen established
# Extended infusion
• Insufficient evidence that routine prophylaxis with extended infusion reduces IRR rates
# Management
• Mild to moderate HSRs: range of different treatment strategies have been used, including lowering infusion rate and use of pre-medication with corticosteroids and H2 antagonists
• Patients reacting to carboplatin may be able to tolerate oxaliplatin or cisplatin
# Re-challenge
• Successful re-challenges to platinum derivatives have occurred using pre-medication with steroids, antihistamines and various desensitization techniques
• May consider adding montelukast ± acetylsalicylic acid. Up to 50% of patients can experience recurrent reactions during re-challenge despite using pre-medications (e.g. corticosteroid and H1/H2 antagonist)
• Following carboplatin reactions, a dose escalation desensitization technique has been used to successfully treat patients with either cisplatin or carboplatin
• Decision to continue therapy with platinum drug after reaction using desensitization or substitution of another platinum derivative should be done carefully and only if benefits outweigh risks • HSR: 6-21%
• Anaphylactic shock: <1% (post-marketing, and/or case reports)
# Onset
• Most HSRs occur with 1 st or 2 nd dose
# Mechanism
• Most HSRs thought to be non-IgE-mediated
# Symptoms
• Minor reactions including flushing or localized skin reactions may occur • Severe HSRs, characterized by generalized rash/erythema, hypotension, bronchospasms, or rare anaphylaxis may occur (may be fatal; has occurred in patients receiving 3-day corticosteroid pre-medication)
• Dyspnea, urticaria, chest or back pain, tachycardia
# Cross-reactivity
• Cross-reactivity may exist between taxanes • Nab-paclitaxel has been well-tolerated in patients with previous histories of taxane HSRs
# Pre-medication
• Pre-medication with oral corticosteroids recommended to decrease incidence and severity of HSRs o Dexamethasone 16 mg/day (8 mg twice daily) orally for 3 days, starting day before docetaxel administration. Dexamethasone 10-20 mg IV can be given if patient forgot to take oral doses o For prostate cancer, when prednisone part of antineoplastic regimen, dexamethasone 8 mg orally administered at 12 hrs., 3 hrs., and 1 hr. prior to docetaxel o Do not discontinue dexamethasone, even in absence of IRR, due to benefits on other adverse effects (e.g. pain and edema)
# Management
• Do not administer to patients with severe hypersensitivity to docetaxel or polysorbate 80 • Observe for hypersensitivity, especially with first 2 infusions • HSRs require immediate discontinuation and administration of appropriate therapy • Patients with history of HSR to paclitaxel may develop hypersensitivity to docetaxel; may be severe or fatal (including anaphylaxis); monitor patients with paclitaxel hypersensitivity closely during initiation of docetaxel Ranitidine 50 mg IV OR famotidine 20 mg IV 30-60 mins. pre-infusion *Oral and IV dexamethasone both effective at reducing overall IRR rates. Some evidence suggests that oral dexamethasone may be more effective for reducing severe reactions; however, adverse effects and compliance remain a concern
# Pre-medication for weekly paclitaxel
To be given 30-60 mins. prior to paclitaxel infusion:
• Patients may be able to undergo rapid drug desensitization to remain on first-line therapy • Do not re-challenge after severe HSRs
# Other considerations
• Consider discontinuing pre-medications if there was no IRR in 1 st 2 doses • Extended infusion not recommended as primary prophylaxis to reduce IRRs • Insufficient evidence to recommend addition of hydrocortisone 100 mg IV to existing standard pre-medication regimen
# Management
• IRR hypotension, bradycardia, and/or hypertension may occur; frequent monitoring of vital signs recommended, especially during 1 st hr. of infusion • Minor HSRs (flushing, skin reactions, dyspnea, hypotension, or tachycardia) do not require interruption of treatment • If severe hypersensitivity occurs, stop infusion and do not re-challenge
# Re-challenge •
Patients may be able to undergo rapid drug desensitization to remain on first-line therapy
# Pre-medication
• Administer 1-3 hrs. prior to each infusion. If dexamethasone is the background regimen-specific corticosteroid, the dexamethasone treatment dose will serve as the corticosteroid pre-medication on daratumumab infusion days. Additional background regimen-specific corticosteroids (e.g. prednisone) should NOT be administered on daratumumab infusion days when patients receive dexamethasone (or equivalent) as a premedication.
# •
Corticosteroid:
# 16
o Monotherapy: Methylprednisolone 100 mg IV or equivalent intermediate-or long-acting corticosteroid; following the second infusion, the dose may be decreased (e.g. methylprednisolone 60 mg [IV or oral] or equivalent) o Combination therapy: Dexamethasone 20 mg (or equivalent) prior to each daratumumab infusion; administer IV prior to the first infusion; oral administration may be considered prior to subsequent infusions plus • Antipyretic: Oral: Acetaminophen 650 to 1,000 mg plus • Antihistamine: IV or Oral: Diphenhydramine 25 to 50 mg or equivalent •
The following pre-medication regimen has also been reported: o First infusion: Acetaminophen 325 mg orally, diphenhydramine 25 mg orally or IV, dexamethasone 20 mg IV, montelukast 10 mg orally, and famotidine 20 mg IV. o Subsequent infusions: Acetaminophen 325 mg orally, diphenhydramine 25 mg IV, and dexamethasone 20 mg IV
# Post-medication
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c30597234d92d13f3b7f7496ed1244e09e9111fc
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Note: It is the policy of the Canadian Psychiatric Association to review each position paper, policy statement and clinical practice guideline every five years after publication or last review. Any such document that has been published more than five years ago and does not explicitly state it has been reviewed and retained as an official document of the CPA, either with revisions or as originally published, should be considered as a historical reference document only.#
This position statement provides a brief background of the opioid crisis in Canada, summarizing the current evidence, followed by the Canadian Psychiatric Association's recommendations. In this statement, the term "opioid" refers to all compounds that bind to opioid receptors, including:
Natural opiates (derivatives of the opium poppy such as morphine and codeine).
Semisynthetic opioids (synthesized from naturally occurring opiates such as heroin from morphine; oxycodone and buprenorphine from thebaine). Synthetic opioids (compounds formed through a chemical process such as methadone, fentanyl, and carfentanyl).
"Narcotic" is the legal term used for opioids and certain other substances. It should not be used in the clinical setting.
Since ancient times, opioids have been widely used for a variety of medicinal purposes. In addition to their medicinal benefits, opioids have a long history of recreational use due to their euphoric effects. Societal ills related to their abuse have been part of the landscape for millennia.
Ever since opioids entered the sphere of medical therapeutics in the 1800s, an uneasy tension has existed between the medicinal benefits of these drugs and their potential for abuse and addiction. 1 Indeed, only 25 years after the hypodermic needle was invented and used to inject morphine to relieve pain (in 1853), the first accurate and comprehensive monograph on opiate addiction was written by the pioneering addiction psychiatrist Eduardo Levinstein (in 1878). 2 Throughout their history as therapeutic agents, erroneous claims that opioids had low abuse liability contributed to enthusiastic overprescribing for a wide variety of ailments and underrecognition of the harms associated with their indiscriminate use. 3 In parallel with medicinal use of these substances, the illegal market also flourished.
At different points in ancient and modern history, governments and international organizations have intervened to limit the licit and illicit use of these potent agents. 1,4 For example, Canada was one of the first countries to ban opium for personal, nonmedicinal use with the introduction of the Opium Act in 1908 (which predated the well-known U.S. Harrison Narcotic Tax Act of 1914) in an effort to stem the use of opium among the populace. 5 More recently in April 2016, British Columbia's provincial health officer declared a public health emergency in response to the rise in drug overdoses and deaths, and in November 2016, the federal government issued a "Joint Statement of Action" to address the opioid crisis, outlining the combined response of over 30 partner organizations to address this crisis.
Although opioids constitute an established part of modern medical treatment (primarily for the management of pain, as adjunct medications in anaesthesia, and as replacement therapy for the management of opioid use disorder), the prescription of these drugs rose dramatically in the last 25 years. In the past two decades, there has again been growing worldwide concern about opioid use and related deaths and harms. 6 This has stemmed from three interrelated problems:
The liberal prescribing of opioids for the management of chronic noncancer pain, at times leading to iatrogenic opioid dependence.
A substantial increase in the prevalence of nonmedical use of prescription opioids, 7 through diversion and misuse.
A larger and more diversified illicit opioid market with newly emerging powerful fentanyl-related substances. 8 Currently in this country, opioid-related morbidity and mortality is impacting every province and territory and shows little sign of abating. 9,10 Opioids were responsible for 3,987 deaths in Canada in 2017, over 1,000 more than the previous year. 11 Every day in 2017, an average of 17 Canadians were hospitalized due to opioid poisoning, 12 which corresponds to a 53 per cent increase over the previous 10 years. The problem is particularly acute in western provinces and northern regions where the harms due to opioid poisoning are over twice the national average. 10 Of particular concern are the rising rates of harm and deaths among Indigenous populations, seniors, and youth in Canada. Overall, opioid users who overdose are three to four times more likely to have a comorbid mental disorder (excluding other substance use disorders) compared to matched individuals with no overdose. 16 This is not surprising, given the overlapping mechanisms of substance use disorders and other mental disorders as well as the frequent convergence of signs and symptoms of these conditions. 17,18 This highlights the importance of assessment for psychiatric comorbidity in patients with opioid use disorder in order to identify individuals at substantially elevated mortality risk and to enable a personalized approach to their care.
While the opioid crisis has affected every part of the country, there are clear differences in death rates and the substances involved across provinces and territories. 12 In western provinces and northern regions, this crisis is especially associated with synthetic opioids such as fentanyl, whereas in Atlantic Canada, the issue is mainly with misuse of prescription drugs. 19,20 This suggests that a "one-size-fits-all" approach to addressing the opioid crisis will not be effective and that psychiatrists must be aware of local issues and be prepared to respond to local needs. For example, in areas where overprescribing is substantially contributing to the opioid crisis, psychiatrists may be called upon to assist with advising about appropriate prescribing in patients with concurrent disorders, including mental health conditions and chronic pain. In areas where illicit market is very prevalent, psychiatrists may be well positioned to advocate for supervised consumption sites and provide support for the development of drug courts and other diversionary models to assist in the management of opioid users who run into trouble with the law.
More broadly, psychiatrists should support the development of robust, evidence-based strategies for identifying, preventing, treating, and reducing the harms of opioid dependence and the comorbidities. Psychiatrists must have the knowledge base and clinical training to be able to recognize risk factors for addiction during general assessment and consultation, keeping in mind that most Canadian illicit opioid users are polysubstance users, 21 contributing to morbidity and mortality. At all times, psychiatrists should be aware of the potential risk of prescribing benzodiazepines and other sedating medications in patients who are also taking opioids. Wherever possible, integrated treatment models that address underlying mental health issues that may contribute to or exacerbate substance use disorder should be employed. Throughout Canada, psychiatrists should continue to work collaboratively with addiction medicine specialists and public health officials to enhance access to mental health care and harm reduction strategies, particularly in Indigenous and underserved, rural and remote communities.
Patients with chronic noncancer pain may benefit from an interdisciplinary model of care to allow care providers to address the multiple components of the patient's pain experience. 22,23 Such patients often have comorbid mental health and addiction issues. Psychiatrists should educate themselves about the comorbidities associated with the treatment of chronic noncancer pain and be prepared to work in a collaborative fashion with other care providers, including primary care. For those psychiatrists who already treat chronic noncancer pain and are considering use of an opioid, national guidelines 24 that outline the appropriate prescription of opioids should be followed, while at the same time ensuring that patients who have comorbid mental health conditions are not excluded from appropriate pain management. Multidisciplinary pain management programs should include mental health staff, including psychiatrists, to encourage the adoption of a multimodal approach to the management of chronic noncancer pain. This will require the collaboration across several medical specialties, including anaesthesia, addiction medicine and psychiatry.
In future, the principles of integrated treatment approaches for these complex conditions should be inculcated into residency training programs across the country. Pain Medicine is a medical subspecialty recognized by the Royal College of Physicians and Surgeons of Canada that is concerned with the prevention, evaluation, diagnosis, treatment and rehabilitation of patients with acute and chronic pain associated with cancer and noncancer diagnoses. The Canadian Psychiatric Association encourages resident psychiatrists with an interest in pain management to pursue training in this subspecialty following their specialist psychiatric training.
Given that incautious opioid prescribing practices may have contributed to the current opioid crisis and that commercial influences may affect prescribing patterns, it is imperative that psychiatrists exercise prudent clinical judgment in prescribing and be guided by evidence and treatment guidelines established independently of commercial influence. 25 Cessation of all industry-initiated marketing to physicians regarding opioid prescribing should be considered as a priority for policymakers.
Finally, psychiatrists have a critical role to play in the stigma-free diagnosis and management of opioids use disorder and comorbid mental disorders and should be actively involved in their dual management, particularly for complex cases. Reversing the trajectory of the current opioid crisis requires psychiatrists to lead the discussion in reducing the stigma associated with the diagnosis and treatment of these disorders, to ensure that they are addressed as chronic illnesses, not moral failings.
|
Note: It is the policy of the Canadian Psychiatric Association to review each position paper, policy statement and clinical practice guideline every five years after publication or last review. Any such document that has been published more than five years ago and does not explicitly state it has been reviewed and retained as an official document of the CPA, either with revisions or as originally published, should be considered as a historical reference document only.#
This position statement provides a brief background of the opioid crisis in Canada, summarizing the current evidence, followed by the Canadian Psychiatric Association's recommendations. In this statement, the term "opioid" refers to all compounds that bind to opioid receptors, including:
Natural opiates (derivatives of the opium poppy such as morphine and codeine).
Semisynthetic opioids (synthesized from naturally occurring opiates such as heroin from morphine; oxycodone and buprenorphine from thebaine). Synthetic opioids (compounds formed through a chemical process such as methadone, fentanyl, and carfentanyl).
"Narcotic" is the legal term used for opioids and certain other substances. It should not be used in the clinical setting.
Since ancient times, opioids have been widely used for a variety of medicinal purposes. In addition to their medicinal benefits, opioids have a long history of recreational use due to their euphoric effects. Societal ills related to their abuse have been part of the landscape for millennia.
Ever since opioids entered the sphere of medical therapeutics in the 1800s, an uneasy tension has existed between the medicinal benefits of these drugs and their potential for abuse and addiction. 1 Indeed, only 25 years after the hypodermic needle was invented and used to inject morphine to relieve pain (in 1853), the first accurate and comprehensive monograph on opiate addiction was written by the pioneering addiction psychiatrist Eduardo Levinstein (in 1878). 2 Throughout their history as therapeutic agents, erroneous claims that opioids had low abuse liability contributed to enthusiastic overprescribing for a wide variety of ailments and underrecognition of the harms associated with their indiscriminate use. 3 In parallel with medicinal use of these substances, the illegal market also flourished.
At different points in ancient and modern history, governments and international organizations have intervened to limit the licit and illicit use of these potent agents. 1,4 For example, Canada was one of the first countries to ban opium for personal, nonmedicinal use with the introduction of the Opium Act in 1908 (which predated the well-known U.S. Harrison Narcotic Tax Act of 1914) in an effort to stem the use of opium among the populace. 5 More recently in April 2016, British Columbia's provincial health officer declared a public health emergency in response to the rise in drug overdoses and deaths, and in November 2016, the federal government issued a "Joint Statement of Action" to address the opioid crisis, outlining the combined response of over 30 partner organizations to address this crisis.
Although opioids constitute an established part of modern medical treatment (primarily for the management of pain, as adjunct medications in anaesthesia, and as replacement therapy for the management of opioid use disorder), the prescription of these drugs rose dramatically in the last 25 years. In the past two decades, there has again been growing worldwide concern about opioid use and related deaths and harms. 6 This has stemmed from three interrelated problems:
The liberal prescribing of opioids for the management of chronic noncancer pain, at times leading to iatrogenic opioid dependence.
A substantial increase in the prevalence of nonmedical use of prescription opioids, 7 through diversion and misuse.
A larger and more diversified illicit opioid market with newly emerging powerful fentanyl-related substances. 8 Currently in this country, opioid-related morbidity and mortality is impacting every province and territory and shows little sign of abating. 9,10 Opioids were responsible for 3,987 deaths in Canada in 2017, over 1,000 more than the previous year. 11 Every day in 2017, an average of 17 Canadians were hospitalized due to opioid poisoning, 12 which corresponds to a 53 per cent increase over the previous 10 years. The problem is particularly acute in western provinces and northern regions where the harms due to opioid poisoning are over twice the national average. 10 Of particular concern are the rising rates of harm and deaths among Indigenous populations, seniors, and youth in Canada. [13][14][15] Overall, opioid users who overdose are three to four times more likely to have a comorbid mental disorder (excluding other substance use disorders) compared to matched individuals with no overdose. 16 This is not surprising, given the overlapping mechanisms of substance use disorders and other mental disorders as well as the frequent convergence of signs and symptoms of these conditions. 17,18 This highlights the importance of assessment for psychiatric comorbidity in patients with opioid use disorder in order to identify individuals at substantially elevated mortality risk and to enable a personalized approach to their care.
While the opioid crisis has affected every part of the country, there are clear differences in death rates and the substances involved across provinces and territories. 12 In western provinces and northern regions, this crisis is especially associated with synthetic opioids such as fentanyl, whereas in Atlantic Canada, the issue is mainly with misuse of prescription drugs. 19,20 This suggests that a "one-size-fits-all" approach to addressing the opioid crisis will not be effective and that psychiatrists must be aware of local issues and be prepared to respond to local needs. For example, in areas where overprescribing is substantially contributing to the opioid crisis, psychiatrists may be called upon to assist with advising about appropriate prescribing in patients with concurrent disorders, including mental health conditions and chronic pain. In areas where illicit market is very prevalent, psychiatrists may be well positioned to advocate for supervised consumption sites and provide support for the development of drug courts and other diversionary models to assist in the management of opioid users who run into trouble with the law.
More broadly, psychiatrists should support the development of robust, evidence-based strategies for identifying, preventing, treating, and reducing the harms of opioid dependence and the comorbidities. Psychiatrists must have the knowledge base and clinical training to be able to recognize risk factors for addiction during general assessment and consultation, keeping in mind that most Canadian illicit opioid users are polysubstance users, 21 contributing to morbidity and mortality. At all times, psychiatrists should be aware of the potential risk of prescribing benzodiazepines and other sedating medications in patients who are also taking opioids. Wherever possible, integrated treatment models that address underlying mental health issues that may contribute to or exacerbate substance use disorder should be employed. Throughout Canada, psychiatrists should continue to work collaboratively with addiction medicine specialists and public health officials to enhance access to mental health care and harm reduction strategies, particularly in Indigenous and underserved, rural and remote communities.
Patients with chronic noncancer pain may benefit from an interdisciplinary model of care to allow care providers to address the multiple components of the patient's pain experience. 22,23 Such patients often have comorbid mental health and addiction issues. Psychiatrists should educate themselves about the comorbidities associated with the treatment of chronic noncancer pain and be prepared to work in a collaborative fashion with other care providers, including primary care. For those psychiatrists who already treat chronic noncancer pain and are considering use of an opioid, national guidelines 24 that outline the appropriate prescription of opioids should be followed, while at the same time ensuring that patients who have comorbid mental health conditions are not excluded from appropriate pain management. Multidisciplinary pain management programs should include mental health staff, including psychiatrists, to encourage the adoption of a multimodal approach to the management of chronic noncancer pain. This will require the collaboration across several medical specialties, including anaesthesia, addiction medicine and psychiatry.
In future, the principles of integrated treatment approaches for these complex conditions should be inculcated into residency training programs across the country. Pain Medicine is a medical subspecialty recognized by the Royal College of Physicians and Surgeons of Canada that is concerned with the prevention, evaluation, diagnosis, treatment and rehabilitation of patients with acute and chronic pain associated with cancer and noncancer diagnoses. The Canadian Psychiatric Association encourages resident psychiatrists with an interest in pain management to pursue training in this subspecialty following their specialist psychiatric training.
Given that incautious opioid prescribing practices may have contributed to the current opioid crisis and that commercial influences may affect prescribing patterns, it is imperative that psychiatrists exercise prudent clinical judgment in prescribing and be guided by evidence and treatment guidelines established independently of commercial influence. 25 Cessation of all industry-initiated marketing to physicians regarding opioid prescribing should be considered as a priority for policymakers.
Finally, psychiatrists have a critical role to play in the stigma-free diagnosis and management of opioids use disorder and comorbid mental disorders and should be actively involved in their dual management, particularly for complex cases. Reversing the trajectory of the current opioid crisis requires psychiatrists to lead the discussion in reducing the stigma associated with the diagnosis and treatment of these disorders, to ensure that they are addressed as chronic illnesses, not moral failings.
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efa2400cdac3c3034db94e240f7e0e738ef19231
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cma
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None
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Individuals with severe opioid use disorder who inject opioids and have not adequately benefited from oral opioid agonist treatment face substantial risks, including premature death, nonfatal overdose, blood-borne infectious diseases, violence and arrest. - Individuals with severe opioid use disorder who inject opioids may not benefit adequately from oral opioid agonist treatment medications, for a variety of reasons.# I
n 2018, at least 4460 Canadians died from an opioid overdose, of which 94% were determined to be unintentional (accidental) overdoses. This represents a 9% increase in overdose deaths from 2017 and a 48% increase from 2016. 1 The recent emergence of street fentanyl, carfentanil and other highly potent synthetic opioids increasingly cut into heroin and other street drugs is a pressing public health concern that has contributed substantially to the overdose emergency. Contamination of street drugs is ongoing and progressive, with new agents such as benzodiazepine analogs being found in substances sold as opioids. 2 Fentanyl and other synthetic analogs were implicated in 73% of opioid-related deaths in Canada in 2018, compared with 67% in 2017 and 50% in 2016. 1 Although pan-Canadian opioid-related deaths were not tracked before 2016, at least 655 fentanyl-related deaths occurred between 2009 and 2014, 3 compared with an estimated 3256 deaths involving fentanyl or fentanyl analogs in 2018 alone. 1 Opioid agonist treatment has proven to be the most effective approach to reducing all-cause mortality in individuals with opioid use disorder 4 and harms associated with illicit opioid use, including morbidity and mortality. However, individuals with severe opioid use disorder who inject opioids may not adequately benefit from oral opioid agonist treatment medications for a variety of reasons, including cravings that persist despite optimal opioid agonist treatment dosing; inability to reach a thera peutic dose; or intolerable adverse effects or contraindications. Individuals who are unable to achieve stabilization or cessation of illicit opioids from first-line medications, or whose circumstances and risks otherwise indicate that they may benefit from injectable opioid agonist treatment, like other individuals using illicit opioids, face substantial risks, including premature death, nonfatal overdose, blood-borne infectious diseases (e.g., HIV and hepatitis C), violence and arrest. 10,11 Meta-analyses have shown that, among individuals who are refractory to treatment with methadone, supervised injectable diacetylmorphine is beneficial in terms of reducing illicit opioid use, premature treatment discontinuation (or "treatment dropout"), criminal activity, incarceration and mortality, as well as improving overall health and social functioning, quality of life and stability. In response to regulatory barriers limiting the provision of diacetylmorphine for the treatment of opioid use disorder in Canada, the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) trial compared injectable hydromorphone to injectable diacetylmorphine and found that both medications, delivered in identical conditions, showed positive outcomes such as high retention rates and reduction of street opioid use (from daily to a few days per month) and illegal activities. 14 Thus, in jurisdictions where diacetylmorphine is currently not available, or for patients in whom it is contraindicated or unsuccessful, hydromorphone may provide an effective, licensed alternative. 14
# GUIDELINE
# VULNERABLE POPULATIONS CPD
Injectable opioid agonist treatment for opioid use disorder: a national clinical guideline
- This guideline recommends that injectable opioid agonist treatment be considered for individuals with severe, treatmentrefractory opioid use disorder and ongoing illicit (nonmedical or illegal or both) injection opioid use.
- For patients who are determined to be likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone are acceptable treatment options.
- Injectable opioid agonist treatment should be provided as an open-ended treatment, with decisions to transition away from injectable opioid agonist treatment made collaboratively with the patient.
This clinical guideline provides 3 key recommendations focused on defining the patient population that should be considered for injectable opioid agonist treatment and outlining considerations for medication selection and length of treatment. Additionally, this document contains expert opinion on clinical care approaches, including eligibility, titration and missed doses.
# Scope
This guideline was created to provide Canadian health professionals with clinical recommendations and guidance for the treatment of severe opioid use disorder with injectable opioid agonist treatment. These recommendations are relevant for the clinical management of severe opioid use disorder in adults who inject opioids and have continued to experience substantial health or social consequences related to their opioid use disorder, despite past experience with oral opioid agonist treatment at appropriate dosages, previous attempts on opioid agonist treatment without being able to achieve a therapeutic dose, or other circumstances and risks that indicate the patient may benefit from injectable opioid agonist treatment. Individuals who are not appropriate candidates for injectable opioid agonist treatment should be treated according to Management of Opioid Use Disorders: A National Clinical Practice Guideline 18 developed by the Canadian Research Initiative in Substance Misuse (CRISM).
# Methods
# Composition of the guideline committee
The CRISM National Injectable Opioid Agonist Treatment Steering Committee, funded by CRISM, a research network funded by the Canadian Institutes of Health Research, was assembled to coordinate activities to prepare the guideline, which included recruiting the guideline review committee. Representation was sought from each of the 4 CRISM nodes (British Columbia, Prairies, Ontario and Quebec-Atlantic) for the steering committee. The steering committee (N.F, B.L.F., M-E.G., M.T., J.T., K. M., M.P.) included representation from British Columbia, Alberta, Ontario and Quebec; each member had relevant expertise, including in prescribing, research and service planning of injectable opioid agonist treatment.
The steering committee decided to create 2 complementary documents: a clinical guideline and an operational guidance document. To that end, the steering committee assembled the National Injectable Opioid Agonist Treatment Clinical Guideline Review Committee and the National Injectable Opioid Agonist Treatment Operational Guidance Review Committee for the operational guidance document.
Each member of the steering committee was invited to nominate relevant experts from their own province and across the country. As guideline review committee members accepted the invitation to join, they were encouraged to nominate additional members to ensure a diverse guideline review committee that represented a range of experience and expertise. Final committee composition was determined by consensus of the guideline review committee co-chairs (N.F. and C.S.). The guideline review committee was composed of 30 individuals, including the 2 cochairs, and physicians, nurses and nurse practitioners, pharmacists, people with lived experience, researchers, treatment providers and front-line staff. A full list of the guideline review committee is available in Appendix 1, available at www.cmaj.ca/lookup/suppl/ doi:10.1503/cmaj.190344/-/DC1.
# Guideline development
The guideline review committee co-chairs (N.F. and C.S.) and medical writer (J.R.), on behalf of CRISM, used a structured literature review approach to develop the recommendations. We used relevant search terms and structured search strategies to search PubMed, the Cochrane Library databases, and reference lists (up to Aug. 1, 2018) using a hierarchical approach (J.R.), whereby meta-analyses and systematic reviews were given the most weight, followed by individual randomized controlled trials (RCTs), quasi-experimental studies, observational studies and, lastly, expert opinion.
The medical writer manually reviewed titles, abstracts and full text of identified citations; selected evidence for inclusion; and compiled narrative evidence reviews, including costeffectiveness data, for the co-chairs and the guideline review panel. The medical writer also conducted grey literature searches for any other existing guidelines on injectable opioid agonist treatment, and engaged international researchers and other experts in the field to determine whether injectable opioid agonist treatment guidelines exist anywhere in the world. Although some individual clinics have various protocols and manuals, this process helped us to ascertain that the British Columbia Centre on Substance Use's 2017 provincial guidance document for injectable opioid agonist treatment 19 is the only clinical guidance document in existence, to date. The medical writer brought any questions or uncertainties in the literature search, evidence review and synthesis processes to the co-chairs for clarity and consensus. A detailed description of the methods used to compile evidence summaries for each recommendation, including search terms, can be found in Appendix 2, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.190344/-/DC1.
# Development of recommendations
The guideline review committee co-chairs in conjunction with the medical writer developed key questions and developed and graded draft recommendations (Box 1), using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool through an iterative consensus process. This guideline also contains clinical guidance that is distinct from the recommendations, which were formally categorized using the GRADE system. The rest of the guidance in this guideline can be understood as clinical guidance informed by the existing literature, expert opinion and clinical expertise, and reached by consensus of the experts on the guideline review committee.
# Review of recommendations
The review process consisted of 2 rounds of revisions of the draft guideline recommendations and evidence review by the guideline review committee. The medical writer and committee co-chairs consolidated guideline revisions as needed to address committee feedback. Differences in opinion or interpretation with regard to the guideline recommendations or the evidence review were resolved through facilitated discussions by the guideline review committee through teleconference or direct communication. A final decision was reached for all cases, without the need for arbitration.
All 30 guideline review committee members participated in multiple rounds of review and revision of the draft and granted final approval of the guideline contents and clinical recommendations.
# External review process
This guideline was reviewed by the National Injectable Opioid Agonist Treatment Operational Guidance Review Committee, which was responsible for the development of its partner document. After this review, 10 international experts, individuals with lived experience of opioid use disorder, and 1 family member affected by opioid use disorder reviewed and provided input on the final draft. These external reviewers provided input on the clinical guidance, not on the 3 key recommendations.
After external review, the guideline review committee reviewed the entire guideline a final time and signed off on it, after which the guideline review committee co-chairs did the same (a more detailed explanation of the development of recommendations is available in Appendix 2).
# Schedule and process for updates
In line with Appraisal of Guidelines for Research & Evaluation (AGREE) II criteria, 24 every 2 years, a structured literature search from the last date update will be conducted, and the guideline review committee will be reconvened to determine which updates from research evidence and expert consensus should be added.
# Box 1: GRADE approach and interpretation of grading
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rating quality of evidence starts with a simplified categorization of study types (meta-analyses and randomized controlled trials (RCTs), quasi-experimental studies, observational studies and expert opinion), accompanied by initial estimated levels of confidence (high, moderate, low or very low) in the estimate of a treatment effect. The rating scheme allows for factors that would raise or lower a level of confidence. Factors that would lower confidence in evidence include risk of bias, inconsistency across the RCTs, indirectness and publication bias; factors that would increase confidence include large effect size and an observed dose-response effect. The final quality ratings are reflective of the confidence in the estimated effect in context of bias and limitations that have been identified, as described below:
- High: We are very confident that the true effect lies close to that of the estimate of the effect.
- Moderate: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
- Low: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
- Very low: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
The GRADE approach uses a binary system to classify strength of recommendations as either strong or weak -also known as "conditional." For this guideline, "conditional" was used rather than "weak." It is important to note that, although quality of evidence is an important factor when classifying strength of recommendations, "strong" or "conditional" in this case does not refer exclusively to the quality of evidence underlying a given recommendation. Except for cost and resource allocation, the recommended GRADE factors to classify strength of recommendations were considered:
- Balance between desirable and undesirable effects: The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a weak recommendation is warranted.
- Quality of evidence: The higher the quality of evidence, the higher the likelihood that a strong recommendation is warranted.
- Values and preferences: The more values and preferences vary, or the greater the uncertainty in values and preferences, the higher the likelihood that a conditional recommendation is warranted.
# Interpretation of strength of recommendations
Examples of how a strong versus conditional recommendation could be interpreted by selected audience or user groups are listed below.
# A strong recommendation indicates the following:
- For patients: Most people in your situation would want the recommended course of action and only a small proportion would not; you should request discussion with your care provider if the intervention is not offered.
- For clinicians: Most patients should receive the recommended course of action. As an example, in this scenario, an algorithm or decision-making tool would not be necessary -the benefits of the recommended course of action would clearly outweigh any advantages of alternative interventions.
- For health care administrators: The recommendation can be adopted as a policy in most situations.
# A conditional recommendation indicates the following:
- For patients: Most people in your situation would want the recommended course of action, but many would not.
- For clinicians: You should recognize that different choices will be appropriate for different patients and that you must help each patient to arrive at a management decision consistent with her or his values and preferences. In this scenario, an algorithm or decision-making tool would be advantageous to determine the best course of action.
- For health care administrators: Policy-making will require substantial debate and involvement of many stakeholders.
# Management of competing interests
This guideline was entirely funded through the CRISM network, which in turn is funded by the Canadian Institutes of Health Research, and without pharmaceutical industry support. Competing interests were assessed using the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts in Guidelines. 25 No current or ongoing direct competing interests were disclosed by the 30 members of the clinical subcommittee on screening for participation in the review committee. Twenty-one individuals disclosed special interests in relation to the guideline content, pertaining to specific expertise or clinical experience or both, involvement with provincial programs and committees for opioid agonist treatment or injectable opioid agonist treatment, or research interests and publications. No individual reported that their clinical revenue would be influenced by the guideline recommendations. Upon review by the committee co-chairs, none of the potential direct or indirect conflicts of interest or bias disclosed by committee members were deemed to be of sufficient relevance or weight to warrant the members' exclusion from the committee.
# Recommendations
The 3 key recommendations are based on the existing literature on injectable opioid agonist treatment, including 2 systematic reviews and meta-analyses. The rest of the guidance in this guideline can be understood as clinical guidance informed by the existing literature and reached by consensus of the experts on the guideline review committee. A list of the recommendations is shown in Table 1, and a summary of the clinical guidance is shown in Table 2. The complete guideline is available in Appendix 1 and includes additional commentary on each of the 3 key clinical recommendations, as well as clinical guidance.
# Injectable opioid agonist treatment
Injectable opioid agonist treatment should be considered for individuals with severe, treatment-refractory opioid use disorder and ongoing illicit injection opioid use (quality of evidence: moderate; strength of recommendation: conditional).
The accompanying full guideline in Appendix 1 provides additional guidance and tools for providing injectable opioid agonist treatment, including eligibility considerations, the preand postinjection evaluation tool (the Pasero Opioid Sedation Scale 26 ), titration protocols and missed-dose protocols.
# Evidence summary
Meta-analyses and systematic reviews of clinical trials involving patients with long-term, refractory heroin addiction have shown the efficacy of diacetylmorphine in comparison with methadone in terms of reducing illicit heroin use, criminal activity and involvement in sex work, as well as improving overall health and social functioning. 12,13 These meta-analyses include a 2011 Cochrane Review that found that supervised injection of diacetylmorphine, paired with flexible doses of methadone, was superior to oral methadone alone in retaining treatment-refractory patients in treatment (4 RCTs; n = 1388, relative risk 1.44, 95% confidence interval 1.19 to 1.75) 12 and a 2015 systematic review and meta-analysis that found supervised injectable heroin treatment to be superior to methadone in treating treatment-refractory opioid use disorder (4 RCTs; n = 1377, RR 1.37, 95% CI 1.03 to 1.83). 13 Both systematic reviews also reported greater reductions in illicit drug use (both heroin and other illicit substances), but owing to heterogeneity in reporting, these were reported narratively rather than included in the meta-analyses.
The SALOME trial compared diacetylmorphine to injectable hydromorphone in a population of patients (n = 202) with longterm, treatment-refractory opioid use disorder. Both perprotocol (PP) and intention-to-treat (ITT) analyses found that injectable hydromorphone was not inferior to injectable diacetylmorphine for long-term injection street opioid users not currently benefiting from oral opioid agonist treatment, in terms of retention rates (≥ 92% PP; ≥ 77% ITT) and reduction of any street opioid use (-0.15, 90% CI -2.09 to 1.76) PP; -0.85, 90% CI -2.97 to 1.25, ITT) and illegal activities (-1.06, 95% CI -3.46 to 1.14, PP; -0.98, 95% CI -3.11 to 1.04, ITT). 14 Per-protocol analysis also found noninferiority for reduction in street heroin use (-1.44, 90% CI -3.22 to 0.27). Thus, in jurisdictions in which diacetylmorphine is currently not available, or for patients in whom it is contraindicated or unsuccessful, hydromorphone provides an effective, licensed alternative. 14 The quality of evidence is rated moderate to reflect a moderate confidence in the effect estimate. This is owing to the low number of trials and the possibility (although low) that a single study with results strongly in favour of oral opioid agonist treatment could substantially alter the effect size in the direction of no effect. This recommendation is rated as conditional given that although there are many patients who would choose injectable opioid agonist treatment, there will be some who would find the attendance requirements onerous or otherwise not have their needs met by injectable opioid agonist treatment.
# Medication selection
For patients who are determined to be likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone are acceptable treatment options (quality of evidence: low; strength of recommendation: strong).
The accompanying full guideline in Appendix 1 provides additional guidance on medication selection, preparation and dispensation.
# Evidence summary
As outlined above, 2 systematic reviews support the recommendation of diacetylmorphine for the treatment of severe opioid use disorder. 12,13 Both PP and ITT analysis in the SALOME trial found that injectable hydromorphone was not inferior to injectable diacetylmorphine for long-term injection street opioid users not currently benefiting from oral opioid agonist treatment, in terms of retention rates (≥ 92% PP; ≥ 77% ITT) and reduction of any street opioid use (-0.15, 90% CI
# Quality of evidence
# Strength of recommendation
# Injectable opioid agonist treatment
Injectable opioid agonist treatment should be considered for individuals with severe, treatment-refractory opioid use disorder and ongoing illicit injection opioid use.
# Moderate Conditional
# Medication selection
For patients who are determined to be likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone are acceptable treatment options.
# Eligibility
Guideline recommendations for eligibility should be considered in concert with clinical judgment and precautions.
# Titration process
The titration protocol should be followed.
# Pre-intake assessment
This must be performed by a qualified health professional or other trained staff member supervised by a health professional to ensure the patient is not intoxicated or in any other contraindicated acute clinical condition.
# Administration of injectable medications
- Generally, up to 3 visits per day are recommended.
- Individuals should self-administer under supervision of a qualified health professional.
- Patients may inject intravenously, intramuscularly or subcutaneously.
- Intravenous injection is recommended in upper extremities only. Lower extremity injection should be discussed and risks identified for those who cannot find an appropriate site in their upper extremities or who otherwise prefer intravenous injection in their legs or feet.
- Intramuscular sites should be identified by a qualified health professional and rotated according to established practice standards.
# Postintake assessment
This must be performed by a qualified health professional or other trained staff member supervised by a health professional to ensure safety and attend to dose intolerance or other adverse event.
Co-prescription of oral opioid agonist treatment Co-prescription of slow-release oral morphine or methadone should be considered, to prevent withdrawal and cravings between injectable opioid agonist treatment doses, particularly overnight.
# Missed doses
The missed-doses protocol should be consulted.
Ongoing substance use Ongoing substance use while on injectable opioid agonist treatment may be an indication to intensify treatment, which may include increasing dosage, transferring to a more intensive model of care, or increasing psychosocial and other supports. The substance-specific guidance should be consulted.
# Stabilization
Stabilization will be patient specific, depending on each patient's circumstances and needs and how these change over time. Patients' DSM-5 diagnoses, physical and mental health comorbidities, and social determinants of health (e.g., poverty, homelessness) should be identified at baseline and tracked over time. Stabilization includes:
- Clinical stabilization, which includes -2.09 to 1.76, PP; -0.85, 90% CI -2.97 to 1.25, ITT) and illegal activities (-1.06, 95% CI -3.46 to 1.14, PP; -0.98, 95% CI -3.11 to 1.04, ITT). 14 Per-protocol analysis also found noninferiority for reduction in street heroin use (-1.44, 90% CI -3.22 to 0.27). 14 Although diacetylmorphine has substantially more evidence supporting its efficacy in treating opioid use disorder, it may pose an increased risk of adverse events (e.g., histamine reactions, seizures and overdose) compared with injectable hydromorphone. 14,27 Hydromorphone was associated with a significantly lower risk of both adverse events (0.60, 95% CI 0.39 to 0.90) and serious adverse events (0.21, 95% CI 0.06 to 0.69) compared with diacetylmorphine. 14 For these reasons, either medication can be considered a reasonable choice, based on availability, patient choice and prescriber judgment.
The quality of evidence is rated low owing to the discrepancy in evidence supporting each medication, with 2 systematic reviews supporting the use of diacetylmorphine, and only a single study supporting the use of hydromorphone. The recommendation is rated as strong based on expert consensus, substantial clinical experience in British Columbia, reduced risk of adverse events for hydromorphone compared with diacetylmorphine, and the lack of regulatory and supply barriers affecting access to hydromorphone.
# Treatment end date
Injectable opioid agonist treatment should be provided as an open-ended treatment, with decisions to transition to oral opioid agonist treatment made collaboratively with the patient (quality of evidence: low; strength of recommendation: strong).
The accompanying full guideline in Appendix 1 provides additional guidance on continuing care and treatment transitions, including considerations for transitioning off injectable opioid agonist treatment, short-term transition to oral treatment for travel and continuity of care.
# Evidence summary
A loss of treatment benefit when prescription diacetylmorphine treatment was discontinued at a predetermined end date has been found in 2 post-RCT observational cohorts. 28,29 Both of these studies found an increase in street heroin use after end of treatment, to levels comparable with that of the control group. One study found a rapid deterioration in 82% (94/115) of responders in the diacetylmorphine group 2 months after treatment discontinuation, with mean scores on the constituent scales of the multidomain outcome index returning to pretreatment levels, 29 while the other showed a significant increase of street heroin use in the diacetylmorphine group 3 months after treatment discontinuation (p = 0.005, mean number of days of heroin use in past month = 8 days at 12 months, mean = 14 days at 15 months). 28 Another study compared individuals who voluntarily transitioned from injectable diacetylmorphine to oral methadone before the completion of an RCT against those who were involuntarily transitioned at the end of the 12-month trial, and found that the mean prior 30 days of illicit heroin use was higher in the involuntary group than in the voluntary group at 24 months (adjusted mean difference -5.58, 95% CI -11.62 to 0.47) and treatment retention was significantly lower (adjusted odds ratio 5.55, 95% CI 1.11 to 27.81). 30 The quality of evidence is rated low owing to the low number of studies evaluating the impact of predetermined treatment end dates. This recommendation was rated strong despite the low quality of evidence, owing to the risk associated with fentanyl-contaminated illicit opioid use and its alignment with a recommendation from the World Health Organization that opioid agonist treatment be provided as an open-ended treatment. 31
# Implementation
Policy-makers and program planners in each province will have to determine the model or models of care most appropriate for each setting. Considerations will include the number of patients who would benefit from injectable opioid agonist treatment, the infrastructure and services already in place, available funding and staffing requirements. The National Injectable Opioid Agonist Treatment for Opioid Use Disorder -Operational Guidance document provides (available at -guideline/) in-depth guidance on planning, implementation, operation and evaluation of injectable opioid agonist treatment programs and is intended to guide the development of new injectable opioid agonist treatment programs across the country. With the release and dissemination of a national clinical guideline and operational guidance document, the primary barrier to treatment will be funding. Thus, jurisdictions will need to ensure adequate funding in order to expand access to injectable opioid agonist treatment across the country.
As with the clinical guideline, every 2 years a structured literature search from the last update will be conducted to inform the operational guidance document and the guidance committee will be reconvened to determine which updates from research evidence and expert consensus should be added.
# Other guidelines
Three main guidelines on the treatment of opioid use disorder were published in the past decade, 1 by the American Society of Addiction Medicine, 32 1 by the World Health Organization, 33 and 1 by CRISM (the same group funding and leading this guideline). 18 In 2017, the BC Centre on Substance Use released a provincial guidance document for injectable opioid agonist treatment. 19 However, this guideline -a clinical guideline for injectable opioid agonist treatment for opioid use disorder -is the first of its kind in the world, to our knowledge. Although earlier guidelines present evidence and guidance on the use of (oral) opioid agonist treatment, the 2017 BC provincial guidance document and this clinical guideline are the first to provide clinical guidance for injectable opioid agonist treatment for severe opioid use disorder. This guideline also provides more in-depth guidance, including 3 key clinical recommendations using the GRADE approach, on managing ongoing substance use, comprehensive guidance on patient-centred care and guidance on treatment transitions for patients in hospital or correctional facilities. Additionally, this guideline is national in scope.
# Gaps in knowledge
Although treatment with diacetylmorphine is a standard of care in several countries, 34 some gaps in knowledge remain. Because of restrictions on accessing diacetylmorphine in Canada, hydromorphone has been used to expand access to injectable opioid agonist treatment, based on a 2016 noninferiority study. 14 Additional research is required to identify whether certain patients benefit more from hydromorphone or diacetylmorphine, and expanded access to diacetylmorphine across Canada is needed.
To date, published evidence on injectable opioid agonist treatment in special populations is limited. Published evidence on the feasibility and safety of injectable opioid agonist treatment during pregnancy is limited to 2 European case reports, both of which attribute positive pregnancy outcomes to the continuation of treatment with diacetylmorphine in the case of women with severe opioid use disorder and multiple comorbidities. 35,36 In addition, no research has been conducted that specifically looks at injectable opioid agonist treatment in youth.
Most clinical trials evaluating injectable opioid agonist treatment have restricted participation to individuals who have previously undergone oral opioid agonist treatment; thus, the evidence base can be understood as being supportive of injectable opioid agonist treatment for the treatment of patients who have not benefited from oral opioid agonist treatment. However, clinical practice in British Columbia has shifted to broader eligibility considerations, which are aligned with the expanded eligibility considerations presented in the full guideline (Appendix 1). These expanded eligibility considerations should be evaluated.
Finally, for individuals who have stabilized on injectable opioid agonist treatment and wish to transition to a less intensive approach, more research is needed to determine optimal approaches to transitioning to other treatments.
# Conclusion
Individuals with severe opioid use disorder who inject opioids may not adequately benefit from oral opioid agonist treatment medications, for a variety of reasons. This guideline provides a framework for how to build a clinical practice of injectable opioid agonist treatment and recommends that this treatment should be considered for individuals with severe, treatmentrefractory opioid use disorder and ongoing illicit injection opioid use. For those individuals determined likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone should be considered appropriate treatments. Finally, injectable opioid agonist treatment should be provided as an open-ended treatment, with decisions to transition to oral opioid agonist treatment made collaboratively with the patient.
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Individuals with severe opioid use disorder who inject opioids and have not adequately benefited from oral opioid agonist treatment face substantial risks, including premature death, nonfatal overdose, blood-borne infectious diseases, violence and arrest. • Individuals with severe opioid use disorder who inject opioids may not benefit adequately from oral opioid agonist treatment medications, for a variety of reasons.# I
n 2018, at least 4460 Canadians died from an opioid overdose, of which 94% were determined to be unintentional (accidental) overdoses. This represents a 9% increase in overdose deaths from 2017 and a 48% increase from 2016. 1 The recent emergence of street fentanyl, carfentanil and other highly potent synthetic opioids increasingly cut into heroin and other street drugs is a pressing public health concern that has contributed substantially to the overdose emergency. Contamination of street drugs is ongoing and progressive, with new agents such as benzodiazepine analogs being found in substances sold as opioids. 2 Fentanyl and other synthetic analogs were implicated in 73% of opioid-related deaths in Canada in 2018, compared with 67% in 2017 and 50% in 2016. 1 Although pan-Canadian opioid-related deaths were not tracked before 2016, at least 655 fentanyl-related deaths occurred between 2009 and 2014, 3 compared with an estimated 3256 deaths involving fentanyl or fentanyl analogs in 2018 alone. 1 Opioid agonist treatment has proven to be the most effective approach to reducing all-cause mortality in individuals with opioid use disorder 4 and harms associated with illicit opioid use, including morbidity and mortality. [5][6][7][8][9] However, individuals with severe opioid use disorder who inject opioids may not adequately benefit from oral opioid agonist treatment medications for a variety of reasons, including cravings that persist despite optimal opioid agonist treatment dosing; inability to reach a thera peutic dose; or intolerable adverse effects or contraindications. Individuals who are unable to achieve stabilization or cessation of illicit opioids from first-line medications, or whose circumstances and risks otherwise indicate that they may benefit from injectable opioid agonist treatment, like other individuals using illicit opioids, face substantial risks, including premature death, nonfatal overdose, blood-borne infectious diseases (e.g., HIV and hepatitis C), violence and arrest. 10,11 Meta-analyses have shown that, among individuals who are refractory to treatment with methadone, supervised injectable diacetylmorphine is beneficial in terms of reducing illicit opioid use, premature treatment discontinuation (or "treatment dropout"), criminal activity, incarceration and mortality, as well as improving overall health and social functioning, quality of life and stability. [12][13][14][15][16][17] In response to regulatory barriers limiting the provision of diacetylmorphine for the treatment of opioid use disorder in Canada, the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) trial compared injectable hydromorphone to injectable diacetylmorphine and found that both medications, delivered in identical conditions, showed positive outcomes such as high retention rates and reduction of street opioid use (from daily to a few days per month) and illegal activities. 14 Thus, in jurisdictions where diacetylmorphine is currently not available, or for patients in whom it is contraindicated or unsuccessful, hydromorphone may provide an effective, licensed alternative. 14
# GUIDELINE
# VULNERABLE POPULATIONS CPD
Injectable opioid agonist treatment for opioid use disorder: a national clinical guideline
• This guideline recommends that injectable opioid agonist treatment be considered for individuals with severe, treatmentrefractory opioid use disorder and ongoing illicit (nonmedical or illegal or both) injection opioid use.
• For patients who are determined to be likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone are acceptable treatment options.
• Injectable opioid agonist treatment should be provided as an open-ended treatment, with decisions to transition away from injectable opioid agonist treatment made collaboratively with the patient.
This clinical guideline provides 3 key recommendations focused on defining the patient population that should be considered for injectable opioid agonist treatment and outlining considerations for medication selection and length of treatment. Additionally, this document contains expert opinion on clinical care approaches, including eligibility, titration and missed doses.
# Scope
This guideline was created to provide Canadian health professionals with clinical recommendations and guidance for the treatment of severe opioid use disorder with injectable opioid agonist treatment. These recommendations are relevant for the clinical management of severe opioid use disorder in adults who inject opioids and have continued to experience substantial health or social consequences related to their opioid use disorder, despite past experience with oral opioid agonist treatment at appropriate dosages, previous attempts on opioid agonist treatment without being able to achieve a therapeutic dose, or other circumstances and risks that indicate the patient may benefit from injectable opioid agonist treatment. Individuals who are not appropriate candidates for injectable opioid agonist treatment should be treated according to Management of Opioid Use Disorders: A National Clinical Practice Guideline 18 developed by the Canadian Research Initiative in Substance Misuse (CRISM).
# Methods
# Composition of the guideline committee
The CRISM National Injectable Opioid Agonist Treatment Steering Committee, funded by CRISM, a research network funded by the Canadian Institutes of Health Research, was assembled to coordinate activities to prepare the guideline, which included recruiting the guideline review committee. Representation was sought from each of the 4 CRISM nodes (British Columbia, Prairies, Ontario and Quebec-Atlantic) for the steering committee. The steering committee (N.F, B.L.F., M-E.G., M.T., J.T., K. M., M.P.) included representation from British Columbia, Alberta, Ontario and Quebec; each member had relevant expertise, including in prescribing, research and service planning of injectable opioid agonist treatment.
The steering committee decided to create 2 complementary documents: a clinical guideline and an operational guidance document. To that end, the steering committee assembled the National Injectable Opioid Agonist Treatment Clinical Guideline Review Committee and the National Injectable Opioid Agonist Treatment Operational Guidance Review Committee for the operational guidance document.
Each member of the steering committee was invited to nominate relevant experts from their own province and across the country. As guideline review committee members accepted the invitation to join, they were encouraged to nominate additional members to ensure a diverse guideline review committee that represented a range of experience and expertise. Final committee composition was determined by consensus of the guideline review committee co-chairs (N.F. and C.S.). The guideline review committee was composed of 30 individuals, including the 2 cochairs, and physicians, nurses and nurse practitioners, pharmacists, people with lived experience, researchers, treatment providers and front-line staff. A full list of the guideline review committee is available in Appendix 1, available at www.cmaj.ca/lookup/suppl/ doi:10.1503/cmaj.190344/-/DC1.
# Guideline development
The guideline review committee co-chairs (N.F. and C.S.) and medical writer (J.R.), on behalf of CRISM, used a structured literature review approach to develop the recommendations. We used relevant search terms and structured search strategies to search PubMed, the Cochrane Library databases, and reference lists (up to Aug. 1, 2018) using a hierarchical approach (J.R.), whereby meta-analyses and systematic reviews were given the most weight, followed by individual randomized controlled trials (RCTs), quasi-experimental studies, observational studies and, lastly, expert opinion.
The medical writer manually reviewed titles, abstracts and full text of identified citations; selected evidence for inclusion; and compiled narrative evidence reviews, including costeffectiveness data, for the co-chairs and the guideline review panel. The medical writer also conducted grey literature searches for any other existing guidelines on injectable opioid agonist treatment, and engaged international researchers and other experts in the field to determine whether injectable opioid agonist treatment guidelines exist anywhere in the world. Although some individual clinics have various protocols and manuals, this process helped us to ascertain that the British Columbia Centre on Substance Use's 2017 provincial guidance document for injectable opioid agonist treatment 19 is the only clinical guidance document in existence, to date. The medical writer brought any questions or uncertainties in the literature search, evidence review and synthesis processes to the co-chairs for clarity and consensus. A detailed description of the methods used to compile evidence summaries for each recommendation, including search terms, can be found in Appendix 2, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.190344/-/DC1.
# Development of recommendations
The guideline review committee co-chairs in conjunction with the medical writer developed key questions and developed and graded draft recommendations (Box 1), using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool [20][21][22][23] through an iterative consensus process. This guideline also contains clinical guidance that is distinct from the recommendations, which were formally categorized using the GRADE system. The rest of the guidance in this guideline can be understood as clinical guidance informed by the existing literature, expert opinion and clinical expertise, and reached by consensus of the experts on the guideline review committee.
# Review of recommendations
The review process consisted of 2 rounds of revisions of the draft guideline recommendations and evidence review by the guideline review committee. The medical writer and committee co-chairs consolidated guideline revisions as needed to address committee feedback. Differences in opinion or interpretation with regard to the guideline recommendations or the evidence review were resolved through facilitated discussions by the guideline review committee through teleconference or direct communication. A final decision was reached for all cases, without the need for arbitration.
All 30 guideline review committee members participated in multiple rounds of review and revision of the draft and granted final approval of the guideline contents and clinical recommendations.
# External review process
This guideline was reviewed by the National Injectable Opioid Agonist Treatment Operational Guidance Review Committee, which was responsible for the development of its partner document. After this review, 10 international experts, individuals with lived experience of opioid use disorder, and 1 family member affected by opioid use disorder reviewed and provided input on the final draft. These external reviewers provided input on the clinical guidance, not on the 3 key recommendations.
After external review, the guideline review committee reviewed the entire guideline a final time and signed off on it, after which the guideline review committee co-chairs did the same (a more detailed explanation of the development of recommendations is available in Appendix 2).
# Schedule and process for updates
In line with Appraisal of Guidelines for Research & Evaluation (AGREE) II criteria, 24 every 2 years, a structured literature search from the last date update will be conducted, and the guideline review committee will be reconvened to determine which updates from research evidence and expert consensus should be added.
# Box 1: GRADE approach and interpretation of grading
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [20][21][22][23] to rating quality of evidence starts with a simplified categorization of study types (meta-analyses and randomized controlled trials (RCTs), quasi-experimental studies, observational studies and expert opinion), accompanied by initial estimated levels of confidence (high, moderate, low or very low) in the estimate of a treatment effect. The rating scheme allows for factors that would raise or lower a level of confidence. Factors that would lower confidence in evidence include risk of bias, inconsistency across the RCTs, indirectness and publication bias; factors that would increase confidence include large effect size and an observed dose-response effect. The final quality ratings are reflective of the confidence in the estimated effect in context of bias and limitations that have been identified, as described below:
• High: We are very confident that the true effect lies close to that of the estimate of the effect.
• Moderate: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
• Low: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
• Very low: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
The GRADE approach uses a binary system to classify strength of recommendations as either strong or weak -also known as "conditional." For this guideline, "conditional" was used rather than "weak." It is important to note that, although quality of evidence is an important factor when classifying strength of recommendations, "strong" or "conditional" in this case does not refer exclusively to the quality of evidence underlying a given recommendation. Except for cost and resource allocation, the recommended GRADE factors to classify strength of recommendations were considered:
• Balance between desirable and undesirable effects: The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a weak recommendation is warranted.
• Quality of evidence: The higher the quality of evidence, the higher the likelihood that a strong recommendation is warranted.
• Values and preferences: The more values and preferences vary, or the greater the uncertainty in values and preferences, the higher the likelihood that a conditional recommendation is warranted.
# Interpretation of strength of recommendations
Examples of how a strong versus conditional recommendation could be interpreted by selected audience or user groups are listed below.
# A strong recommendation indicates the following:
• For patients: Most people in your situation would want the recommended course of action and only a small proportion would not; you should request discussion with your care provider if the intervention is not offered.
• For clinicians: Most patients should receive the recommended course of action. As an example, in this scenario, an algorithm or decision-making tool would not be necessary -the benefits of the recommended course of action would clearly outweigh any advantages of alternative interventions.
• For health care administrators: The recommendation can be adopted as a policy in most situations.
# A conditional recommendation indicates the following:
• For patients: Most people in your situation would want the recommended course of action, but many would not.
• For clinicians: You should recognize that different choices will be appropriate for different patients and that you must help each patient to arrive at a management decision consistent with her or his values and preferences. In this scenario, an algorithm or decision-making tool would be advantageous to determine the best course of action.
• For health care administrators: Policy-making will require substantial debate and involvement of many stakeholders.
# Management of competing interests
This guideline was entirely funded through the CRISM network, which in turn is funded by the Canadian Institutes of Health Research, and without pharmaceutical industry support. Competing interests were assessed using the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts in Guidelines. 25 No current or ongoing direct competing interests were disclosed by the 30 members of the clinical subcommittee on screening for participation in the review committee. Twenty-one individuals disclosed special interests in relation to the guideline content, pertaining to specific expertise or clinical experience or both, involvement with provincial programs and committees for opioid agonist treatment or injectable opioid agonist treatment, or research interests and publications. No individual reported that their clinical revenue would be influenced by the guideline recommendations. Upon review by the committee co-chairs, none of the potential direct or indirect conflicts of interest or bias disclosed by committee members were deemed to be of sufficient relevance or weight to warrant the members' exclusion from the committee.
# Recommendations
The 3 key recommendations are based on the existing literature on injectable opioid agonist treatment, including 2 systematic reviews and meta-analyses. The rest of the guidance in this guideline can be understood as clinical guidance informed by the existing literature and reached by consensus of the experts on the guideline review committee. A list of the recommendations is shown in Table 1, and a summary of the clinical guidance is shown in Table 2. The complete guideline is available in Appendix 1 and includes additional commentary on each of the 3 key clinical recommendations, as well as clinical guidance.
# Injectable opioid agonist treatment
Injectable opioid agonist treatment should be considered for individuals with severe, treatment-refractory opioid use disorder and ongoing illicit injection opioid use (quality of evidence: moderate; strength of recommendation: conditional).
The accompanying full guideline in Appendix 1 provides additional guidance and tools for providing injectable opioid agonist treatment, including eligibility considerations, the preand postinjection evaluation tool (the Pasero Opioid Sedation Scale 26 ), titration protocols and missed-dose protocols.
# Evidence summary
Meta-analyses and systematic reviews of clinical trials involving patients with long-term, refractory heroin addiction have shown the efficacy of diacetylmorphine in comparison with methadone in terms of reducing illicit heroin use, criminal activity and involvement in sex work, as well as improving overall health and social functioning. 12,13 These meta-analyses include a 2011 Cochrane Review that found that supervised injection of diacetylmorphine, paired with flexible doses of methadone, was superior to oral methadone alone in retaining treatment-refractory patients in treatment (4 RCTs; n = 1388, relative risk [RR] 1.44, 95% confidence interval [CI] 1.19 to 1.75) 12 and a 2015 systematic review and meta-analysis that found supervised injectable heroin treatment to be superior to methadone in treating treatment-refractory opioid use disorder (4 RCTs; n = 1377, RR 1.37, 95% CI 1.03 to 1.83). 13 Both systematic reviews also reported greater reductions in illicit drug use (both heroin and other illicit substances), but owing to heterogeneity in reporting, these were reported narratively rather than included in the meta-analyses.
The SALOME trial compared diacetylmorphine to injectable hydromorphone in a population of patients (n = 202) with longterm, treatment-refractory opioid use disorder. Both perprotocol (PP) and intention-to-treat (ITT) analyses found that injectable hydromorphone was not inferior to injectable diacetylmorphine for long-term injection street opioid users not currently benefiting from oral opioid agonist treatment, in terms of retention rates (≥ 92% PP; ≥ 77% ITT) and reduction of any street opioid use (-0.15, 90% CI -2.09 to 1.76) PP; -0.85, 90% CI -2.97 to 1.25, ITT) and illegal activities (-1.06, 95% CI -3.46 to 1.14, PP; -0.98, 95% CI -3.11 to 1.04, ITT). 14 Per-protocol analysis also found noninferiority for reduction in street heroin use (-1.44, 90% CI -3.22 to 0.27). Thus, in jurisdictions in which diacetylmorphine is currently not available, or for patients in whom it is contraindicated or unsuccessful, hydromorphone provides an effective, licensed alternative. 14 The quality of evidence is rated moderate to reflect a moderate confidence in the effect estimate. This is owing to the low number of trials and the possibility (although low) that a single study with results strongly in favour of oral opioid agonist treatment could substantially alter the effect size in the direction of no effect. This recommendation is rated as conditional given that although there are many patients who would choose injectable opioid agonist treatment, there will be some who would find the attendance requirements onerous or otherwise not have their needs met by injectable opioid agonist treatment.
# Medication selection
For patients who are determined to be likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone are acceptable treatment options (quality of evidence: low; strength of recommendation: strong).
The accompanying full guideline in Appendix 1 provides additional guidance on medication selection, preparation and dispensation.
# Evidence summary
As outlined above, 2 systematic reviews support the recommendation of diacetylmorphine for the treatment of severe opioid use disorder. 12,13 Both PP and ITT analysis in the SALOME trial found that injectable hydromorphone was not inferior to injectable diacetylmorphine for long-term injection street opioid users not currently benefiting from oral opioid agonist treatment, in terms of retention rates (≥ 92% PP; ≥ 77% ITT) and reduction of any street opioid use (-0.15, 90% CI
# Quality of evidence
# Strength of recommendation
# Injectable opioid agonist treatment
Injectable opioid agonist treatment should be considered for individuals with severe, treatment-refractory opioid use disorder and ongoing illicit injection opioid use.
# Moderate Conditional
# Medication selection
For patients who are determined to be likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone are acceptable treatment options.
# Eligibility
Guideline recommendations for eligibility should be considered in concert with clinical judgment and precautions.
# Titration process
The titration protocol should be followed.
# Pre-intake assessment
This must be performed by a qualified health professional or other trained staff member supervised by a health professional to ensure the patient is not intoxicated or in any other contraindicated acute clinical condition.
# Administration of injectable medications
• Generally, up to 3 visits per day are recommended.
• Individuals should self-administer under supervision of a qualified health professional.
• Patients may inject intravenously, intramuscularly or subcutaneously.
• Intravenous injection is recommended in upper extremities only. Lower extremity injection should be discussed and risks identified for those who cannot find an appropriate site in their upper extremities or who otherwise prefer intravenous injection in their legs or feet.
• Intramuscular sites should be identified by a qualified health professional and rotated according to established practice standards.
# Postintake assessment
This must be performed by a qualified health professional or other trained staff member supervised by a health professional to ensure safety and attend to dose intolerance or other adverse event.
Co-prescription of oral opioid agonist treatment Co-prescription of slow-release oral morphine or methadone should be considered, to prevent withdrawal and cravings between injectable opioid agonist treatment doses, particularly overnight.
# Missed doses
The missed-doses protocol should be consulted.
Ongoing substance use Ongoing substance use while on injectable opioid agonist treatment may be an indication to intensify treatment, which may include increasing dosage, transferring to a more intensive model of care, or increasing psychosocial and other supports. The substance-specific guidance should be consulted.
# Stabilization
Stabilization will be patient specific, depending on each patient's circumstances and needs and how these change over time. Patients' DSM-5 diagnoses, physical and mental health comorbidities, and social determinants of health (e.g., poverty, homelessness) should be identified at baseline and tracked over time. Stabilization includes:
• Clinical stabilization, which includes -2.09 to 1.76, PP; -0.85, 90% CI -2.97 to 1.25, ITT) and illegal activities (-1.06, 95% CI -3.46 to 1.14, PP; -0.98, 95% CI -3.11 to 1.04, ITT). 14 Per-protocol analysis also found noninferiority for reduction in street heroin use (-1.44, 90% CI -3.22 to 0.27). 14 Although diacetylmorphine has substantially more evidence supporting its efficacy in treating opioid use disorder, it may pose an increased risk of adverse events (e.g., histamine reactions, seizures and overdose) compared with injectable hydromorphone. 14,27 Hydromorphone was associated with a significantly lower risk of both adverse events (0.60, 95% CI 0.39 to 0.90) and serious adverse events (0.21, 95% CI 0.06 to 0.69) compared with diacetylmorphine. 14 For these reasons, either medication can be considered a reasonable choice, based on availability, patient choice and prescriber judgment.
The quality of evidence is rated low owing to the discrepancy in evidence supporting each medication, with 2 systematic reviews supporting the use of diacetylmorphine, and only a single study supporting the use of hydromorphone. The recommendation is rated as strong based on expert consensus, substantial clinical experience in British Columbia, reduced risk of adverse events for hydromorphone compared with diacetylmorphine, and the lack of regulatory and supply barriers affecting access to hydromorphone.
# Treatment end date
Injectable opioid agonist treatment should be provided as an open-ended treatment, with decisions to transition to oral opioid agonist treatment made collaboratively with the patient (quality of evidence: low; strength of recommendation: strong).
The accompanying full guideline in Appendix 1 provides additional guidance on continuing care and treatment transitions, including considerations for transitioning off injectable opioid agonist treatment, short-term transition to oral treatment for travel and continuity of care.
# Evidence summary
A loss of treatment benefit when prescription diacetylmorphine treatment was discontinued at a predetermined end date has been found in 2 post-RCT observational cohorts. 28,29 Both of these studies found an increase in street heroin use after end of treatment, to levels comparable with that of the control group. One study found a rapid deterioration in 82% (94/115) of responders in the diacetylmorphine group 2 months after treatment discontinuation, with mean scores on the constituent scales of the multidomain outcome index returning to pretreatment levels, 29 while the other showed a significant increase of street heroin use in the diacetylmorphine group 3 months after treatment discontinuation (p = 0.005, mean number of days of heroin use in past month = 8 days at 12 months, mean = 14 days at 15 months). 28 Another study compared individuals who voluntarily transitioned from injectable diacetylmorphine to oral methadone before the completion of an RCT against those who were involuntarily transitioned at the end of the 12-month trial, and found that the mean prior 30 days of illicit heroin use was higher in the involuntary group than in the voluntary group at 24 months (adjusted mean difference -5.58, 95% CI -11.62 to 0.47) and treatment retention was significantly lower (adjusted odds ratio 5.55, 95% CI 1.11 to 27.81). 30 The quality of evidence is rated low owing to the low number of studies evaluating the impact of predetermined treatment end dates. This recommendation was rated strong despite the low quality of evidence, owing to the risk associated with fentanyl-contaminated illicit opioid use and its alignment with a recommendation from the World Health Organization that opioid agonist treatment be provided as an open-ended treatment. 31
# Implementation
Policy-makers and program planners in each province will have to determine the model or models of care most appropriate for each setting. Considerations will include the number of patients who would benefit from injectable opioid agonist treatment, the infrastructure and services already in place, available funding and staffing requirements. The National Injectable Opioid Agonist Treatment for Opioid Use Disorder -Operational Guidance document provides (available at https://crism.ca/projects/ioat -guideline/) in-depth guidance on planning, implementation, operation and evaluation of injectable opioid agonist treatment programs and is intended to guide the development of new injectable opioid agonist treatment programs across the country. With the release and dissemination of a national clinical guideline and operational guidance document, the primary barrier to treatment will be funding. Thus, jurisdictions will need to ensure adequate funding in order to expand access to injectable opioid agonist treatment across the country.
As with the clinical guideline, every 2 years a structured literature search from the last update will be conducted to inform the operational guidance document and the guidance committee will be reconvened to determine which updates from research evidence and expert consensus should be added.
# Other guidelines
Three main guidelines on the treatment of opioid use disorder were published in the past decade, 1 by the American Society of Addiction Medicine, 32 1 by the World Health Organization, 33 and 1 by CRISM (the same group funding and leading this guideline). 18 In 2017, the BC Centre on Substance Use released a provincial guidance document for injectable opioid agonist treatment. 19 However, this guideline -a clinical guideline for injectable opioid agonist treatment for opioid use disorder -is the first of its kind in the world, to our knowledge. Although earlier guidelines present evidence and guidance on the use of (oral) opioid agonist treatment, the 2017 BC provincial guidance document and this clinical guideline are the first to provide clinical guidance for injectable opioid agonist treatment for severe opioid use disorder. This guideline also provides more in-depth guidance, including 3 key clinical recommendations using the GRADE approach, on managing ongoing substance use, comprehensive guidance on patient-centred care and guidance on treatment transitions for patients in hospital or correctional facilities. Additionally, this guideline is national in scope.
# Gaps in knowledge
Although treatment with diacetylmorphine is a standard of care in several countries, 34 some gaps in knowledge remain. Because of restrictions on accessing diacetylmorphine in Canada, hydromorphone has been used to expand access to injectable opioid agonist treatment, based on a 2016 noninferiority study. 14 Additional research is required to identify whether certain patients benefit more from hydromorphone or diacetylmorphine, and expanded access to diacetylmorphine across Canada is needed.
To date, published evidence on injectable opioid agonist treatment in special populations is limited. Published evidence on the feasibility and safety of injectable opioid agonist treatment during pregnancy is limited to 2 European case reports, both of which attribute positive pregnancy outcomes to the continuation of treatment with diacetylmorphine in the case of women with severe opioid use disorder and multiple comorbidities. 35,36 In addition, no research has been conducted that specifically looks at injectable opioid agonist treatment in youth.
Most clinical trials evaluating injectable opioid agonist treatment have restricted participation to individuals who have previously undergone oral opioid agonist treatment; thus, the evidence base can be understood as being supportive of injectable opioid agonist treatment for the treatment of patients who have not benefited from oral opioid agonist treatment. However, clinical practice in British Columbia has shifted to broader eligibility considerations, which are aligned with the expanded eligibility considerations presented in the full guideline (Appendix 1). These expanded eligibility considerations should be evaluated.
Finally, for individuals who have stabilized on injectable opioid agonist treatment and wish to transition to a less intensive approach, more research is needed to determine optimal approaches to transitioning to other treatments.
# Conclusion
Individuals with severe opioid use disorder who inject opioids may not adequately benefit from oral opioid agonist treatment medications, for a variety of reasons. This guideline provides a framework for how to build a clinical practice of injectable opioid agonist treatment and recommends that this treatment should be considered for individuals with severe, treatmentrefractory opioid use disorder and ongoing illicit injection opioid use. For those individuals determined likely to benefit from injectable opioid agonist treatment, both diacetylmorphine and hydromorphone should be considered appropriate treatments. Finally, injectable opioid agonist treatment should be provided as an open-ended treatment, with decisions to transition to oral opioid agonist treatment made collaboratively with the patient.
# Acknowledgements:
The authors thank all committee members for their involvement as experts and reviewers, as well as Emily Wagner, Erin Eydt, Steffanie Fisher, Chiarine Hsu, Kevin Hollett, Cheyenne Johnson, Nirupa Goel and Shirley Wong. The authors also thank Evan Wood, Jurgen Rehm and other CRISM principal investigators and staff. Furthermore, the authors highlight the contributions of members of the committee with lived experience of opioid use disorder and thank them for sharing their insight, experience and expertise.
#
Competing interests: Marie-Ève Goyer reports receiving an honorarium and training from Gilead Sciences, outside of the submitted work. Bernard Le Foll reports receiving grants from Pfizer and Brainsway, Bioprojet, Alkermes, Canopy and the American Chemical Society, as well as nonfinancial support from Aurora, outside the submitted work. Josey Ross is employed by the BC Centre on Substance Use, the British Columbia node of the Canadian Research Initiative in Substance Misuse (CRISM). Christy Sutherland is employed by the BC Centre on Substance Use and is also the medical director of PHS Community Services Society, which provides injectable opioid agonist treatment. Michael Trew works for Alberta Health Services; the development of injectable opioid agonist treament clinics in Alberta have been partially funded through specific grants from the Alberta Ministry of Health for this work. Nadia Fairbairn reports receiving personal fees from British Columbia Centre on Substance Use, during the conduct of the study. No other competing interests were declared. This article has been peer reviewed.
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This guideline provides recommendations for the diagnosis, investigation and management of iron deficiency in patients of all ages.- Use a case-finding approach to identify individuals at risk of iron deficiency and iron deficiency anemia (Table 1). There is no indication for population-based general screening. - Determine the cause of iron deficiency. Consider age and clinical presentation when investigating for cause. - Iron deficiency by itself causes symptoms for patients, even in the absence of anemia, and warrants investigation and treatment. - Ferritin is the test of choice for the diagnosis of iron deficiency. - Ferritin values occur on a continuum. The suggested cut-offs are estimated ranges that should be interpreted using clinical judgment based on the patient's age, gender, risk profile (Table 1) and symptoms. - Serum iron, iron binding capacity, and transferrin saturation/fraction saturation are not routinely useful for investigating iron deficiency anemia. - Take a nutrition history and provide dietary education to address dietary risk factors. - Caregivers of infants and toddlers should receive guidance to prevent excessive cow's milk intake. - Prescribe oral iron supplements as first line therapy for iron deficiency. One preparation is not preferred over another; patient tolerance should be the guide. Anemia should correct in 2-4 months. Continue oral iron for 4-6 months after anemia corrects to replenish iron stores. - Consider prescribing IV iron when there is inadequate response to oral iron, intolerance to oral iron therapy, or ongoing blood loss.Iron deficiency: insufficient total body iron stores, caused by increased requirements, decreased intake, increased loss, and/or decreased absorption 1 (see Table 1). Anemia: low hemoglobin level, most frequently defined as a hemoglobin value over two standard deviations below the genderand age-adjusted mean. 1 A hemoglobin value below the local, lab-specific lower reference interval indicates anemia. Iron deficiency anemia (IDA): anemia due to insufficient body iron stores 1 . The following laboratory findings are typical for IDA: microcytic anemia, hypochromia, and decreased ferritin. IDA may be normocytic if anemia is mild or in early iron deficiency. 2# Identification of Patients at Risk for Iron Deficiency and Iron Deficiency Anemia
Screening of the general population for iron deficiency is not recommended. 3 Use a case-finding approach to identify patients at risk of iron deficiency and iron deficiency anemia (Table 1).
Common risk profiles, by age, include:
- Infants and toddlers (refer to page 7)
- Adolescents and adults: endurance athletes, regular blood donors, disordered eating - Pre-menopausal women: especially those with menorrhagia, vegetarian diet - All adults age >65 - All ages: low socioeconomic status, lack of balanced diet, inadequate nutritional intake Table 1: Common causes of and risk factors for iron deficiency and IDA in adults Note: Please refer to Iron Deficiency in Children and Iron Deficiency in Obstetrics on pages 7-8 for causes and risk factors in children, pregnancy and the perinatal period.
# Increased Requirements Decreased Intake
- Pregnancy (2nd/3rd trimester)
- Lactation - Rapid growth spurts (infants, children, adolescents)
- Low socioeconomic status - Vegetarian or vegan diet - Lack of balanced diet or poor intake - Eating disorder - Alcohol use disorder - Age > 65 4 - Recent immigration from developing regions with lower access to iron-rich foods, higher rates of infectious disease, and higher rates of multiparity 5 , especially Southeast Asia, Africa 6
Increased Loss Decreased Absorption
# Signs and Symptoms in Adults
Even in the absence of anemia, isolated iron deficiency causes symptoms and warrants investigation and treatment. Early stage iron deficiency can exist without overt anemia, but with other non-hematological symptoms 7 due to deficiency of ironcontaining cellular enzymes and unsaturated myoglobin. Some patients may be asymptomatic. - Children (ug/L) < 12 diagnostic of iron deficiency 12-20 possible iron deficiency
Ferritin values occur on a continuum; cut-offs are suggested and clinical interpretation is required:
- The likelihood of iron deficiency increases with lower ferritin concentrations, including those that overlap with the normal reference interval. The normal reference interval is derived from healthy outpatients without signs of iron deficiency or chronic illness. - In adults, iron deficiency is unlikely if ferritin >30 ug/L (or >70-100 in a patient with chronic inflammatory disease, 13 or >50 in the elderly 2 ) - Ferritin is an acute phase reactant and may be unreliable in patients with chronic disease, active inflammation, or malignancy. Testing ferritin is not recommended during acute infection or hospitalization. - Non-hematologic symptoms can occur when the serum ferritin is in the low normal range (< 30 ug/L)
# Hematology Profile (CBC)
- Hemoglobin value is required to assess severity of anemia - May suggest iron deficiency - Not diagnostic test of choice for iron deficiency
The following findings CBC and peripheral smear findings are highly suggestive of iron deficiency: - hypochromia (low mean corpuscular hemoglobin concentration (MCHC))
# - microcytosis (low mean corpuscular volume (MCV))
Patients with microcytic anemia should not be given iron supplements until iron deficiency is confirmed by testing ferritin. Low MCV in the setting of normal ferritin may indicate hemoglobinopathies such as thalassemia especially in high risk ethnic groups. Long term iron therapy is harmful for these patients.
# Refer to Appendix C: Algorithm for Investigation of Iron Deficiency in Non-Anemic Adults.
- Iron therapy may improve restless legs syndrome severity and restlessness. Iron supplementation is recommended if serum ferritin is ≤ 75 ug/L. 8,9 Additional tests for the diagnosis of iron deficiency in patients with chronic disease, inflammation or malignancy Anemia of chronic disease (ACD) may co-exist with an element of true iron deficiency. However, ferritin values may be falsely elevated in chronic disease as ferritin is an acute phase reactant. In this specific situation, ordering a fasting serum iron and transferrin saturation may be helpful to diagnose iron deficiency that may be missed by solely relying on ferritin. A typical iron deficiency profile for such patients (e.g. those with inflammatory bowel disease) is:
- low serum iron, - low or normal transferrin (i.e. total iron binding capacity), and - fasting transferrin saturation below 20%.
The clinical approach for such patients is the same as for iron deficiency in otherwise well patients (investigate for cause, supplement with iron and refer as appropriate). Patients with a true iron deficiency which co-exists with anemia of chronic disease will respond to a diagnostic trial of iron supplementation.
Guidance for the investigation and management of iron deficiency in the setting of specific chronic diseases is provided:
- Chronic Kidney Disease (CKD): Kidney Disease: Improving Global Outcomes (KDIGO) guidelines 14 recommend including CBC, absolute reticulocyte count, serum ferritin and TSAT as well as other tests (vitamin B12) in the initial evaluation of anemia in patients with CKD and anemia. Note that ferritin levels in patients with CKD may be elevated due to inflammation, and so many not accurately reflect iron status and need for supplementation. TSAT <24% is the current recommended threshold to confirm iron deficiency. In patients with CKD, if iron deficiency and other nutritional deficiencies are rectified, and anemia persists, consider erythropoiesis stimulating agents, which would require specialist referral.
- Heart Failure: Canadian Cardiovascular Society guidelines 15 recommend consideration of IV iron therapy for heart failure patients with all of the following: ejection fraction ≤40%, serum ferritin < 100 mg/L or between 100-299 mg/L, and TSAT <20%. If ferritin is unexpectedly elevated, in a patient without chronic disease, active inflammation, or malignancy, C-reactive protein (CRP) can help support the diagnosis of an inflammatory process. Refer to the BC Guideline: C-Reactive Protein and Erythrocyte Sedimentation Rate Testing for information on the use of CRP.
# Investigation of the Etiology of Iron Deficiency
Once iron deficiency/IDA is diagnosed, the etiology must be identified. Clinical evaluation of the cause of iron deficiency is important. It should be based upon a directed history, symptom review and physical examination.
# Directed history should include:
- nutrition and physical activity history - pregnancy status and number of pregnancies - history of blood loss, including GI bleeding, hematuria, menorrhagia, and blood donation - GI symptoms including changes in bowel habits, abdominal pain, dyspepsia, and unexplained weight loss - family history including colorectal cancer 16 Menorrhagia is the most frequent cause of iron deficiency among pre-menopausal women. Consider referral to gynecologist for management of heavy menses and/or consider bleeding disorder, e.g. von Willebrand disease screening.
Testing for malabsorption is recommended if small bowel disease is clinically suspected, or if oral iron supplementation results in inadequate response despite compliance.
Iron deficiency/IDA in adult men and post-menopausal women and in pre-menopausal women without menorrhagia is more likely to have a serious underlying cause of blood loss including malignancy. 16 Consider upper/lower endoscopy.
# Investigation of overt and occult GI and GU bleeding
Primary care providers are encouraged to consult with colleagues including local gastroenterology services or the RACE line to obtain rapid advice and avoid unnecessary travel and wait times.
# FIT and FOBT Testing
FIT and FOBT testing are not indicated for investigation of overt GI bleeding and are not needed for patients being referred. Given the risk of false negatives, FIT and FOBT testing should not be used to rule out GI bleeding.
# Overt GI bleeding
Overt GI bleeding that is otherwise unexplained, new, or out of pattern requires GI evaluation. Consider referral for GI evaluation.
BC colon cancer screening guidelines recommend that patients with signs or symptoms of colon cancer (e.g. unexplained GI bleeding, unexplained iron deficiency anemia) proceed directly to specialist referral for possible endoscopic investigation. 17,18 If any doubt remains about whether to refer for GI investigations, referral is strongly encouraged due to the potentially severe consequences of delayed identification of colorectal cancer. Age-specific risk for colon and rectal cancer is elevated among those born circa 1990 compared to older cohorts. 19
# Overt GU bleeding
Consider referral to urologist for further work-up, especially for gross painless hematuria.
# Unexplained iron deficiency/IDA
Adult males, post-menopausal females and pre-menopausal females with unexplained iron deficiency/IDA should receive:
- referral for GI investigations (upper/lower endoscopy)
- screening for GU bleeding with urinalysis - screening for celiac disease
# Management
The objective of treatment is to replenish iron stores: normalize hemoglobin levels and ferritin. 16 Target normal ferritin >100 µg/L.
Iron replacement therapy should begin as soon as iron deficiency is detected, whether or not anemia is also present.
The exception is: patients with microcytic anemia should not be given iron supplements until iron deficiency is confirmed by testing ferritin. Low MCV in the setting of normal ferritin may indicate hemoglobinopathies such as thalassemia. Long term iron therapy is harmful for these patients.
Individualize disease-specific management depending on underlying cause. 20 Even when there is an apparently obvious cause the etiology may be multifactorial.
# Dietary iron intake
To help prevent iron deficiency, encourage all individuals to consume a diet with sufficient iron. This may include establishing individualized iron intake goals according to recommended daily intake based on sex, age, pregnancy status, and diet. Refer to Associated Documents for recommended daily intake values, and foods high in iron. Consider dietitian referral. Patients can also call 8-1-1 to speak to a dietitian.
# Treatment with Oral Iron
Oral iron replacement is almost always preferred to intravenous (IV) therapy. Refer to Appendix A: Oral Iron Formulations and Adult Doses for a list of commonly used oral iron preparations, doses, and costs.
Advise patients that iron can be toxic to children and should always be safely stored.
Oral iron intolerance is very common:
- Oral iron preparations may cause nausea, vomiting, dyspepsia, constipation, diarrhea or dark stools.
- Strategies to minimize these effects include: 21 o start at a lower dose and increase gradually after 4 to 5 days (to reach target dose in a few weeks) o give divided doses o give the lowest effective dose o take supplements with meals (note: iron absorption is enhanced when supplements are taken on an empty stomach; however, tolerance and adherence may be improved when iron is taken with meals) o try a different iron preparation o try alternative dosing schedules such as every other day dosing 22 (resolution of symptoms and replenishment of iron stores may take longer)
Iron absorption can be decreased by various medications and supplements such as multivitamins, calcium, or antacid tablets.
Space administration by at least 2 hours apart. Avoid taking iron supplements with tea, coffee or milk.
Iron absorption from iron salts can be enhanced by taking them on an empty stomach (at least 1 hour before or 2 hours after eating), or with 600-1200 mg vitamin C. This does not apply to other types of iron preparations such as polysaccharides or polypeptides whose absorption is not affected by food.
Monitoring Response to Oral Iron 1. The frequency of subsequent monitoring depends upon the severity of the anemia, the underlying cause of the iron deficiency, and the clinical impact on the patient. Reassess patients with moderate to severe anemia by testing CBC as early as 2-4 weeks. Hemoglobin should increase by 10-20 g/L by 4 weeks. It may take up to 6 months to replenish iron stores. 2. Hemoglobin will correct within 2 to 4 months if appropriate iron dosages are taken as prescribed and underlying cause of iron deficiency is corrected. 3. Continue iron therapy an additional 4 to 6 months (adults) after correction of anemia to replenish the iron stores. 23 Ferritin should be re-checked 3 to 6 months after normalization of hemoglobin in anemic patients, or after initiation of iron supplementation in non-anemic patients. Target normal ferritin >100 µg/L. 4. If ferritin and hemoglobin are not responding as anticipated, consider adherence, ongoing bleeding, malabsorption, or alternate diagnosis. 5. If the patient's clinical status is compromised by moderate to severe anemia, consider blood transfusion. Once the patient is stable, iron replacement can commence.
# IV Iron Therapy
IV iron should not be considered a routine treatment. Access to IV iron and the processes to order it depend on local availability and protocols. Refer to Appendix B: Intravenous Iron Formulations and Adult Doses for a list of commonly used parenteral iron formulations and doses.
Intravenous therapy may be initiated when there is:
- complete or partial failure of oral iron therapy trial (in compliant patients)
- intolerance to oral iron therapy - inadequate iron absorption - continued blood loss - urgent surgery in an iron-deficient patient/pre-operative indication - chronic kidney disease, including dialysis patients 24 Maximum hemoglobin response to IV iron usually occurs within 2 to 3 weeks of the last dose.
# Intramuscular (IM) Therapy
IM iron therapy is not generally recommended because risks include unpredictable absorption, anaphylaxis, and local complications (e.g., pain, permanent staining of the skin, sarcoma formation). 25 IM iron therapy may be appropriate in certain contexts and clinical judgment is required.
# Iron supplementation: ongoing care
Once anemia has corrected and iron stores have normalized, a low maintenance dose may be prescribed if there is an ongoing need for additional iron (e.g., menorrhagia, rapid growth, regular blood donation, vegetarian diet). Consider similar supplementation for patients who have iron deficiency but not anemia. Ensure adequate dietary intake is established and maintained (refer to Associated Documents and consider dietitian referral; patients can also call 8-1-1 for dietitian services).
# Iron Deficiency and IDA in Infants, Children and Adolescents
Iron deficiency and IDA in children are associated with motor and cognitive deficits which may be irreversible. 26
# Common causes and risk factors
- All ages: Increased requirements due to growth, low socioeconomic status, lack of balanced diet, (including ethnic groups with low iron high fibre/phytates diet e.g., Asians), celiac disease, bleeding from any source, e.g., frequent nosebleeds, GI diseases including short gut syndrome, cow's milk protein colitis - Infants 750 mL/day, bottle use beyond 12-15 months, picky eating (insufficient intake or diversity of solid food), obesity 27 - Adolescents: menorrhagia, disordered eating, vegetarian diet (refer to Vegetarian and Vegan Diets on page 9), extreme physical exercise/endurance athletes, low body weight
# Signs and symptoms
- Some patients may be asymptomatic - All ages: tiredness, restless legs, inattention, poor school performance, irritability/depression, growth retardation, unexplained cognitive and intellectual impairment, breath-holding spells, developmental delay, pica/pagophagia - Infants: poor feeding, lethargy, failure to thrive, cardiomegaly, tachypnea - Adolescents: presyncope, syncope, headache, irritability, fatigue, exercise intolerance, restless legs
# Diagnosis
- Serum ferritin is the diagnostic test of choice for iron deficiency. The ferritin cut-offs for children are different from the ferritin cut-offs for adults. Refer to - Take a thorough dietary history: o Infants < 6 months: should consume breastmilk or formula. Animal milk (cow, goat, etc.) should not be consumed before 9-12 months. 29 o Infants 6-9 months: first foods should be iron-rich foods, offered at least twice a day. 29 o Infants 0-12 months who are not exclusively receiving breastmilk and are at risk of iron deficiency may benefit from formula with higher iron levels. o Toddlers 12-24 months should not consume more than 750 mL per day of cow's milk 30 because its volume can displace other iron rich foods. o Refer to BC Pediatric Nutrition Guidelines for more information on children age six months to six years. 29 o Refer to Associated Documents for age and sex-specific recommended daily iron intake and a list of iron-rich foods.
# Treatment
- Advise patients that iron can be toxic to children and should always be safely stored.
- Provide dietary counselling. Dietitian referral is recommended. Patients and caregivers can also call a dietitian at 8-1-1.
Refer to Associated Documents on page 11 for recommended dietary intake and a list of foods high in heme and non-heme iron. - Recommend infants and toddlers with iron deficiency begin treatment with liquid oral iron salts. Refer to Appendix B: Liquid Iron Formulations and Pediatric Doses for recommended treatment doses, strengths and bottle sizes of liquid iron products for use in children, and guidance on tolerability. - Blood transfusion is very rarely required for iron deficiency anemia in children because onset of anemia is gradual allowing for physiologic compensation and the response to iron supplementation is prompt. Judicious transfusion is indicated for very severe anemia in the setting of hemodynamic compromise/severe signs of anemia requiring emergent correction.
In this case, transfused blood should be administered in small aliquots of 5 mL/kg over 4 hours with close monitoring, for prevention of fluid overload/cardiac failure.
# Monitoring response
- Refer to adult Monitoring Response section for guidance.
- If hemoglobin is correcting by 4 weeks, continue oral iron and check CBC and ferritin at three months.
# Iron Deficiency and Obstetrics
There is an increase in iron requirement (about 1000 mg total) during pregnancy, parturition and lactation. 31,32 Iron is essential for normal fetal development. It is important to prevent iron deficiency in the fetus by preventing iron deficiency in pregnant women. 33 Assess risk of iron deficiency among women planning pregnancy, especially women in high-risk groups (Table 1).
# Iron supplementation for non-anemic pregnant women
Most pregnant women need to take a supplement to get enough iron. 34 An increase in iron consumption by about 15-30 mg elemental iron/day is recommended for non-anemic women, an amount readily met by most prenatal vitamin formulations. Health Canada recommends that pregnant women take a daily multivitamin that includes B12, 0.4mg of folic acid, and 16-20 mg of iron. 34 IDA in pregnant women IDA is the most frequent form of anemia in pregnant women. Refer to Appendix A: Oral Iron Formulations and Adult Doses. Anemia in pregnancy is defined as: - 1st trimester: hemoglobin < 110 g/L - 2nd and 3rd trimester: hemoglobin < 105 g/L Treatment with oral iron has been recommended when ferritin is less than 30 ug/L. Refer to Treatment with Oral Iron on page 6 for strategies to improve tolerance and compliance. Hemoglobin increase after two weeks indicates empirical confirmation of the diagnosis and response to treatment. 38 Ferritin decreases by approximately 50% in all pregnant women by the second trimester. This is a functional decrease that does not indicate iron deficiency.
If necessary, intravenous iron is considered to be safe for the second and third trimester (refer to Appendix B: Intravenous Iron Formulations and Adult Doses). 33
# Iron Deficiency in the Elderly
Anemia in the elderly is a common clinical finding, often multifactorial, and has significant impact on quality of life, functional decline, and mortality. Treatment of iron deficiency and its underlying cause(s) may improve outcomes. Iron deficiency is the second most common cause of anemia after anemia of chronic disease (the reverse is true for younger patients).
The diagnosis of absolute iron deficiency is challenging in the elderly. 39 Serum ferritin below 50 ug/L should be investigated for iron deficiency in the elderly 2 though cut-offs between 30 and 100 mg/L have been proposed. 39 Serum ferritin levels may also be increased by comorbidity.
Investigation of anemia in the elderly is recommended if the life expectancy is more than a year. 40 An individualised approach is recommended, recognizing the risks of invasive investigations and surgeries to elderly patients with increasing frailty and multimorbidity. 41 Replacement options for elderly patients are similar to the options for younger patients. If standard dosing is not tolerated, low dose iron therapy (15 mg elemental iron per day, or 30 mg every other day) is an effective treatment in octogenarians, with significantly reduced adverse effects (refer to Appendix A: Oral Iron Formulations and Adult Doses). Note: iron stores take longer to replete with lower iron doses. Refer to Treatment with Oral Iron on page 6 for strategies to improve tolerance and compliance. IV iron may also be considered in appropriate clinical situations as reviewed above (refer to Appendix B: Intravenous Iron Formulations and Adult Doses).
# Vegetarian and Vegan Diets
Well-balanced vegetarian and vegan diets can provide sufficient iron intake for children, adolescents 45 and adults. Vegetarians require 1.8 times higher iron intake than non-vegetarians because non-heme iron is not absorbed as well as heme iron. 46 If uncertain, consider referral to a registered dietitian.
Refer to Resources section for information on getting enough dietary iron and choosing iron-rich foods, including patient handouts. Patients in BC can also phone a dietitian at 8-1-1.
# Indications for specialist referral
|
This guideline provides recommendations for the diagnosis, investigation and management of iron deficiency in patients of all ages.• Use a case-finding approach to identify individuals at risk of iron deficiency and iron deficiency anemia (Table 1). There is no indication for population-based general screening. • Determine the cause of iron deficiency. Consider age and clinical presentation when investigating for cause. • Iron deficiency by itself causes symptoms for patients, even in the absence of anemia, and warrants investigation and treatment. • Ferritin is the test of choice for the diagnosis of iron deficiency. • Ferritin values occur on a continuum. The suggested cut-offs are estimated ranges that should be interpreted using clinical judgment based on the patient's age, gender, risk profile (Table 1) and symptoms. • Serum iron, iron binding capacity, and transferrin saturation/fraction saturation are not routinely useful for investigating iron deficiency anemia. • Take a nutrition history and provide dietary education to address dietary risk factors. • Caregivers of infants and toddlers should receive guidance to prevent excessive cow's milk intake. • Prescribe oral iron supplements as first line therapy for iron deficiency. One preparation is not preferred over another; patient tolerance should be the guide. Anemia should correct in 2-4 months. Continue oral iron for 4-6 months after anemia corrects to replenish iron stores. • Consider prescribing IV iron when there is inadequate response to oral iron, intolerance to oral iron therapy, or ongoing blood loss.Iron deficiency: insufficient total body iron stores, caused by increased requirements, decreased intake, increased loss, and/or decreased absorption 1 (see Table 1). Anemia: low hemoglobin level, most frequently defined as a hemoglobin value over two standard deviations below the genderand age-adjusted mean. 1 A hemoglobin value below the local, lab-specific lower reference interval indicates anemia. Iron deficiency anemia (IDA): anemia due to insufficient body iron stores 1 . The following laboratory findings are typical for IDA: microcytic anemia, hypochromia, and decreased ferritin. IDA may be normocytic if anemia is mild or in early iron deficiency. 2# Identification of Patients at Risk for Iron Deficiency and Iron Deficiency Anemia
Screening of the general population for iron deficiency is not recommended. 3 Use a case-finding approach to identify patients at risk of iron deficiency and iron deficiency anemia (Table 1).
Common risk profiles, by age, include:
• Infants and toddlers (refer to page 7)
• Adolescents and adults: endurance athletes, regular blood donors, disordered eating • Pre-menopausal women: especially those with menorrhagia, vegetarian diet • All adults age >65 • All ages: low socioeconomic status, lack of balanced diet, inadequate nutritional intake Table 1: Common causes of and risk factors for iron deficiency and IDA in adults Note: Please refer to Iron Deficiency in Children and Iron Deficiency in Obstetrics on pages 7-8 for causes and risk factors in children, pregnancy and the perinatal period.
# Increased Requirements Decreased Intake
• Pregnancy (2nd/3rd trimester)
• Lactation • Rapid growth spurts (infants, children, adolescents)
• Low socioeconomic status • Vegetarian or vegan diet • Lack of balanced diet or poor intake • Eating disorder • Alcohol use disorder • Age > 65 4 • Recent immigration from developing regions with lower access to iron-rich foods, higher rates of infectious disease, and higher rates of multiparity 5 , especially Southeast Asia, Africa 6
Increased Loss Decreased Absorption
# Signs and Symptoms in Adults
Even in the absence of anemia, isolated iron deficiency causes symptoms and warrants investigation and treatment. Early stage iron deficiency can exist without overt anemia, but with other non-hematological symptoms 7 due to deficiency of ironcontaining cellular enzymes and unsaturated myoglobin. Some patients may be asymptomatic. • Children (ug/L) < 12 diagnostic of iron deficiency 12-20 possible iron deficiency
Ferritin values occur on a continuum; cut-offs are suggested and clinical interpretation is required:
• The likelihood of iron deficiency increases with lower ferritin concentrations, including those that overlap with the normal reference interval. The normal reference interval is derived from healthy outpatients without signs of iron deficiency or chronic illness. • In adults, iron deficiency is unlikely if ferritin >30 ug/L (or >70-100 in a patient with chronic inflammatory disease, 13 or >50 in the elderly 2 ) • Ferritin is an acute phase reactant and may be unreliable in patients with chronic disease, active inflammation, or malignancy. Testing ferritin is not recommended during acute infection or hospitalization. • Non-hematologic symptoms can occur when the serum ferritin is in the low normal range (< 30 ug/L)
# Hematology Profile (CBC)
• Hemoglobin value is required to assess severity of anemia • May suggest iron deficiency • Not diagnostic test of choice for iron deficiency
The following findings CBC and peripheral smear findings are highly suggestive of iron deficiency: • hypochromia (low mean corpuscular hemoglobin concentration (MCHC))
# • microcytosis (low mean corpuscular volume (MCV))
Patients with microcytic anemia should not be given iron supplements until iron deficiency is confirmed by testing ferritin. Low MCV in the setting of normal ferritin may indicate hemoglobinopathies such as thalassemia especially in high risk ethnic groups. Long term iron therapy is harmful for these patients.
# Refer to Appendix C: Algorithm for Investigation of Iron Deficiency in Non-Anemic Adults.
* Iron therapy may improve restless legs syndrome severity and restlessness. Iron supplementation is recommended if serum ferritin is ≤ 75 ug/L. 8,9 Additional tests for the diagnosis of iron deficiency in patients with chronic disease, inflammation or malignancy Anemia of chronic disease (ACD) may co-exist with an element of true iron deficiency. However, ferritin values may be falsely elevated in chronic disease as ferritin is an acute phase reactant. In this specific situation, ordering a fasting serum iron and transferrin saturation may be helpful to diagnose iron deficiency that may be missed by solely relying on ferritin. A typical iron deficiency profile for such patients (e.g. those with inflammatory bowel disease) is:
• low serum iron, • low or normal transferrin (i.e. total iron binding capacity), and • fasting transferrin saturation below 20%.
The clinical approach for such patients is the same as for iron deficiency in otherwise well patients (investigate for cause, supplement with iron and refer as appropriate). Patients with a true iron deficiency which co-exists with anemia of chronic disease will respond to a diagnostic trial of iron supplementation.
Guidance for the investigation and management of iron deficiency in the setting of specific chronic diseases is provided:
• Chronic Kidney Disease (CKD): Kidney Disease: Improving Global Outcomes (KDIGO) guidelines 14 recommend including CBC, absolute reticulocyte count, serum ferritin and TSAT as well as other tests (vitamin B12) in the initial evaluation of anemia in patients with CKD and anemia. Note that ferritin levels in patients with CKD may be elevated due to inflammation, and so many not accurately reflect iron status and need for supplementation. TSAT <24% is the current recommended threshold to confirm iron deficiency. In patients with CKD, if iron deficiency and other nutritional deficiencies are rectified, and anemia persists, consider erythropoiesis stimulating agents, which would require specialist referral.
• Heart Failure: Canadian Cardiovascular Society guidelines 15 recommend consideration of IV iron therapy for heart failure patients with all of the following: ejection fraction ≤40%, serum ferritin < 100 mg/L or between 100-299 mg/L, and TSAT <20%. If ferritin is unexpectedly elevated, in a patient without chronic disease, active inflammation, or malignancy, C-reactive protein (CRP) can help support the diagnosis of an inflammatory process. Refer to the BC Guideline: C-Reactive Protein and Erythrocyte Sedimentation Rate Testing for information on the use of CRP.
# Investigation of the Etiology of Iron Deficiency
Once iron deficiency/IDA is diagnosed, the etiology must be identified. Clinical evaluation of the cause of iron deficiency is important. It should be based upon a directed history, symptom review and physical examination.
# Directed history should include:
• nutrition and physical activity history • pregnancy status and number of pregnancies • history of blood loss, including GI bleeding, hematuria, menorrhagia, and blood donation • GI symptoms including changes in bowel habits, abdominal pain, dyspepsia, and unexplained weight loss • family history including colorectal cancer 16 Menorrhagia is the most frequent cause of iron deficiency among pre-menopausal women. Consider referral to gynecologist for management of heavy menses and/or consider bleeding disorder, e.g. von Willebrand disease screening.
Testing for malabsorption is recommended if small bowel disease is clinically suspected, or if oral iron supplementation results in inadequate response despite compliance.
Iron deficiency/IDA in adult men and post-menopausal women and in pre-menopausal women without menorrhagia is more likely to have a serious underlying cause of blood loss including malignancy. 16 Consider upper/lower endoscopy.
# Investigation of overt and occult GI and GU bleeding
Primary care providers are encouraged to consult with colleagues including local gastroenterology services or the RACE line to obtain rapid advice and avoid unnecessary travel and wait times.
# FIT and FOBT Testing
FIT and FOBT testing are not indicated for investigation of overt GI bleeding and are not needed for patients being referred. Given the risk of false negatives, FIT and FOBT testing should not be used to rule out GI bleeding.
# Overt GI bleeding
Overt GI bleeding that is otherwise unexplained, new, or out of pattern requires GI evaluation. Consider referral for GI evaluation.
BC colon cancer screening guidelines recommend that patients with signs or symptoms of colon cancer (e.g. unexplained GI bleeding, unexplained iron deficiency anemia) proceed directly to specialist referral for possible endoscopic investigation. 17,18 If any doubt remains about whether to refer for GI investigations, referral is strongly encouraged due to the potentially severe consequences of delayed identification of colorectal cancer. Age-specific risk for colon and rectal cancer is elevated among those born circa 1990 compared to older cohorts. 19
# Overt GU bleeding
Consider referral to urologist for further work-up, especially for gross painless hematuria.
# Unexplained iron deficiency/IDA
Adult males, post-menopausal females and pre-menopausal females with unexplained iron deficiency/IDA should receive:
• referral for GI investigations (upper/lower endoscopy)
• screening for GU bleeding with urinalysis • screening for celiac disease
# Management
The objective of treatment is to replenish iron stores: normalize hemoglobin levels and ferritin. 16 Target normal ferritin >100 µg/L.
Iron replacement therapy should begin as soon as iron deficiency is detected, whether or not anemia is also present.
The exception is: patients with microcytic anemia should not be given iron supplements until iron deficiency is confirmed by testing ferritin. Low MCV in the setting of normal ferritin may indicate hemoglobinopathies such as thalassemia. Long term iron therapy is harmful for these patients.
Individualize disease-specific management depending on underlying cause. 20 Even when there is an apparently obvious cause the etiology may be multifactorial.
# Dietary iron intake
To help prevent iron deficiency, encourage all individuals to consume a diet with sufficient iron. This may include establishing individualized iron intake goals according to recommended daily intake based on sex, age, pregnancy status, and diet. Refer to Associated Documents for recommended daily intake values, and foods high in iron. Consider dietitian referral. Patients can also call 8-1-1 to speak to a dietitian.
# Treatment with Oral Iron
Oral iron replacement is almost always preferred to intravenous (IV) therapy. Refer to Appendix A: Oral Iron Formulations and Adult Doses for a list of commonly used oral iron preparations, doses, and costs.
Advise patients that iron can be toxic to children and should always be safely stored.
Oral iron intolerance is very common:
• Oral iron preparations may cause nausea, vomiting, dyspepsia, constipation, diarrhea or dark stools.
• Strategies to minimize these effects include: 21 o start at a lower dose and increase gradually after 4 to 5 days (to reach target dose in a few weeks) o give divided doses o give the lowest effective dose o take supplements with meals (note: iron absorption is enhanced when supplements are taken on an empty stomach; however, tolerance and adherence may be improved when iron is taken with meals) o try a different iron preparation o try alternative dosing schedules such as every other day dosing 22 (resolution of symptoms and replenishment of iron stores may take longer)
Iron absorption can be decreased by various medications and supplements such as multivitamins, calcium, or antacid tablets.
Space administration by at least 2 hours apart. Avoid taking iron supplements with tea, coffee or milk.
Iron absorption from iron salts can be enhanced by taking them on an empty stomach (at least 1 hour before or 2 hours after eating), or with 600-1200 mg vitamin C. This does not apply to other types of iron preparations such as polysaccharides or polypeptides whose absorption is not affected by food.
Monitoring Response to Oral Iron 1. The frequency of subsequent monitoring depends upon the severity of the anemia, the underlying cause of the iron deficiency, and the clinical impact on the patient. Reassess patients with moderate to severe anemia by testing CBC as early as 2-4 weeks. Hemoglobin should increase by 10-20 g/L by 4 weeks. It may take up to 6 months to replenish iron stores. 2. Hemoglobin will correct within 2 to 4 months if appropriate iron dosages are taken as prescribed and underlying cause of iron deficiency is corrected. 3. Continue iron therapy an additional 4 to 6 months (adults) after correction of anemia to replenish the iron stores. 23 Ferritin should be re-checked 3 to 6 months after normalization of hemoglobin in anemic patients, or after initiation of iron supplementation in non-anemic patients. Target normal ferritin >100 µg/L. 4. If ferritin and hemoglobin are not responding as anticipated, consider adherence, ongoing bleeding, malabsorption, or alternate diagnosis. 5. If the patient's clinical status is compromised by moderate to severe anemia, consider blood transfusion. Once the patient is stable, iron replacement can commence.
# IV Iron Therapy
IV iron should not be considered a routine treatment. Access to IV iron and the processes to order it depend on local availability and protocols. Refer to Appendix B: Intravenous Iron Formulations and Adult Doses for a list of commonly used parenteral iron formulations and doses.
Intravenous therapy may be initiated when there is:
• complete or partial failure of oral iron therapy trial (in compliant patients)
• intolerance to oral iron therapy • inadequate iron absorption • continued blood loss • urgent surgery in an iron-deficient patient/pre-operative indication • chronic kidney disease, including dialysis patients 24 Maximum hemoglobin response to IV iron usually occurs within 2 to 3 weeks of the last dose.
# Intramuscular (IM) Therapy
IM iron therapy is not generally recommended because risks include unpredictable absorption, anaphylaxis, and local complications (e.g., pain, permanent staining of the skin, sarcoma formation). 25 IM iron therapy may be appropriate in certain contexts and clinical judgment is required.
# Iron supplementation: ongoing care
Once anemia has corrected and iron stores have normalized, a low maintenance dose may be prescribed if there is an ongoing need for additional iron (e.g., menorrhagia, rapid growth, regular blood donation, vegetarian diet). Consider similar supplementation for patients who have iron deficiency but not anemia. Ensure adequate dietary intake is established and maintained (refer to Associated Documents and consider dietitian referral; patients can also call 8-1-1 for dietitian services).
# Iron Deficiency and IDA in Infants, Children and Adolescents
Iron deficiency and IDA in children are associated with motor and cognitive deficits which may be irreversible. 26
# Common causes and risk factors
• All ages: Increased requirements due to growth, low socioeconomic status, lack of balanced diet, (including ethnic groups with low iron high fibre/phytates diet e.g., Asians), celiac disease, bleeding from any source, e.g., frequent nosebleeds, GI diseases including short gut syndrome, cow's milk protein colitis • Infants < 6 months: maternal iron deficiency, prematurity/low birth weight (low blood volume at birth, phlebotomy), feeding inappropriate milk substitutes other than breastmilk or commercial infant formula, history of fetal-maternal hemorrhage, history of twin-twin transfusion • Toddlers (6-36 months): prematurity, exclusive breastfeeding beyond 6 months, cow's milk before 9 months, excessive cow's milk >750 mL/day, bottle use beyond 12-15 months, picky eating (insufficient intake or diversity of solid food), obesity 27 • Adolescents: menorrhagia, disordered eating, vegetarian diet (refer to Vegetarian and Vegan Diets on page 9), extreme physical exercise/endurance athletes, low body weight
# Signs and symptoms
• Some patients may be asymptomatic • All ages: tiredness, restless legs, inattention, poor school performance, irritability/depression, growth retardation, unexplained cognitive and intellectual impairment, breath-holding spells, developmental delay, pica/pagophagia • Infants: poor feeding, lethargy, failure to thrive, cardiomegaly, tachypnea • Adolescents: presyncope, syncope, headache, irritability, fatigue, exercise intolerance, restless legs
# Diagnosis
• Serum ferritin is the diagnostic test of choice for iron deficiency. The ferritin cut-offs for children are different from the ferritin cut-offs for adults. Refer to • Take a thorough dietary history: o Infants < 6 months: should consume breastmilk or formula. Animal milk (cow, goat, etc.) should not be consumed before 9-12 months. 29 o Infants 6-9 months: first foods should be iron-rich foods, offered at least twice a day. 29 o Infants 0-12 months who are not exclusively receiving breastmilk and are at risk of iron deficiency may benefit from formula with higher iron levels. o Toddlers 12-24 months should not consume more than 750 mL per day of cow's milk 30 because its volume can displace other iron rich foods. o Refer to BC Pediatric Nutrition Guidelines for more information on children age six months to six years. 29 o Refer to Associated Documents for age and sex-specific recommended daily iron intake and a list of iron-rich foods.
# Treatment
• Advise patients that iron can be toxic to children and should always be safely stored.
• Provide dietary counselling. Dietitian referral is recommended. Patients and caregivers can also call a dietitian at 8-1-1.
Refer to Associated Documents on page 11 for recommended dietary intake and a list of foods high in heme and non-heme iron. • Recommend infants and toddlers with iron deficiency begin treatment with liquid oral iron salts. Refer to Appendix B: Liquid Iron Formulations and Pediatric Doses for recommended treatment doses, strengths and bottle sizes of liquid iron products for use in children, and guidance on tolerability. • Blood transfusion is very rarely required for iron deficiency anemia in children because onset of anemia is gradual allowing for physiologic compensation and the response to iron supplementation is prompt. Judicious transfusion is indicated for very severe anemia in the setting of hemodynamic compromise/severe signs of anemia requiring emergent correction.
In this case, transfused blood should be administered in small aliquots of 5 mL/kg over 4 hours with close monitoring, for prevention of fluid overload/cardiac failure.
# Monitoring response
• Refer to adult Monitoring Response section for guidance.
• If hemoglobin is correcting by 4 weeks, continue oral iron and check CBC and ferritin at three months.
# Iron Deficiency and Obstetrics
There is an increase in iron requirement (about 1000 mg total) during pregnancy, parturition and lactation. 31,32 Iron is essential for normal fetal development. It is important to prevent iron deficiency in the fetus by preventing iron deficiency in pregnant women. 33 Assess risk of iron deficiency among women planning pregnancy, especially women in high-risk groups (Table 1).
# Iron supplementation for non-anemic pregnant women
Most pregnant women need to take a supplement to get enough iron. 34 An increase in iron consumption by about 15-30 mg elemental iron/day is recommended for non-anemic women, an amount readily met by most prenatal vitamin formulations. Health Canada recommends that pregnant women take a daily multivitamin that includes B12, 0.4mg of folic acid, and 16-20 mg of iron. 34 IDA in pregnant women IDA is the most frequent form of anemia in pregnant women. Refer to Appendix A: Oral Iron Formulations and Adult Doses. Anemia in pregnancy is defined as: [35][36][37] • 1st trimester: hemoglobin < 110 g/L • 2nd and 3rd trimester: hemoglobin < 105 g/L Treatment with oral iron has been recommended when ferritin is less than 30 ug/L. Refer to Treatment with Oral Iron on page 6 for strategies to improve tolerance and compliance. Hemoglobin increase after two weeks indicates empirical confirmation of the diagnosis and response to treatment. 38 Ferritin decreases by approximately 50% in all pregnant women by the second trimester. This is a functional decrease that does not indicate iron deficiency.
If necessary, intravenous iron is considered to be safe for the second and third trimester (refer to Appendix B: Intravenous Iron Formulations and Adult Doses). 33
# Iron Deficiency in the Elderly
Anemia in the elderly is a common clinical finding, often multifactorial, and has significant impact on quality of life, functional decline, and mortality. Treatment of iron deficiency and its underlying cause(s) may improve outcomes. Iron deficiency is the second most common cause of anemia after anemia of chronic disease (the reverse is true for younger patients).
The diagnosis of absolute iron deficiency is challenging in the elderly. 39 Serum ferritin below 50 ug/L should be investigated for iron deficiency in the elderly 2 though cut-offs between 30 and 100 mg/L have been proposed. 39 Serum ferritin levels may also be increased by comorbidity.
Investigation of anemia in the elderly is recommended if the life expectancy is more than a year. 40 An individualised approach is recommended, recognizing the risks of invasive investigations and surgeries to elderly patients with increasing frailty and multimorbidity. 41 Replacement options for elderly patients are similar to the options for younger patients. If standard dosing is not tolerated, low dose iron therapy (15 mg elemental iron per day, or 30 mg every other day) is an effective treatment in octogenarians, with significantly reduced adverse effects (refer to Appendix A: Oral Iron Formulations and Adult Doses). [42][43][44] Note: iron stores take longer to replete with lower iron doses. Refer to Treatment with Oral Iron on page 6 for strategies to improve tolerance and compliance. IV iron may also be considered in appropriate clinical situations as reviewed above (refer to Appendix B: Intravenous Iron Formulations and Adult Doses).
# Vegetarian and Vegan Diets
Well-balanced vegetarian and vegan diets can provide sufficient iron intake for children, adolescents 45 and adults. Vegetarians require 1.8 times higher iron intake than non-vegetarians because non-heme iron is not absorbed as well as heme iron. 46 If uncertain, consider referral to a registered dietitian.
Refer to Resources section for information on getting enough dietary iron and choosing iron-rich foods, including patient handouts. Patients in BC can also phone a dietitian at 8-1-1.
# Indications for specialist referral
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This guideline is based on scientific evidence current as of January 2019.
The guideline was developed by the Guidelines and Protocols Advisory Committee in collaboration with BC's Agency for Pathology and Laboratory Medicine, and adopted by the Medical Services Commission.
# Appendix A: Oral Iron Formulations and Adult Doses
This Appendix is a supplement to the BC Guideline Iron Deficiency -Investigation and Management.
One iron preparation is not preferred over another; patient tolerance should be the guide. While polysaccharide and polypeptide formulations can be taken with food to reduce GI side effects, they are more expensive than the iron salt formulations and are not a PharmaCare benefit. Remind patients that products are kept behind the counter in the pharmacy and to see a pharmacist to confirm the product.
Adverse GI reactions (nausea, vomiting, dyspepsia, constipation, diarrhea, and dark stools) are dependent on the dose of elemental iron. These adverse reactions are temporary and will likely disappear with continued treatment, with the exception of dark stools which can remain for the duration of therapy.
Therapeutic doses can range from 100 to 200 mg of elemental iron/day, 21,47 depending on severity of symptoms, ferritin levels, age of the patient, and GI side effects. If poor tolerability with oral iron, consider a lower dose, a different formulation or alternative dosing schedules (such as every other day dosing). 24 Resolution of symptoms and replenishment of iron stores may take longer. Abbreviations: BID twice daily; Fe elemental iron; GI gastrointestinal; IV intravenous; IM intramuscular; mg milligrams; mL milliliters; PO orally; TID three times daily. † Treatment with oral iron may take as long as six to eight weeks in order to fully ameliorate the anemia, and as long as six months to replenish iron stores. ‡ Estimated retail prices as of January 2019 based on the adult dose range. All prices are subject to change. In most situations, oral iron products are least expensive when purchased over the counter. However, PharmaCare benefits may reduce the cost to the patient when a prescription is provided. PharmaCare coverage is subject to the patient's plan rules, including any deductible requirement. Patients can discuss with their pharmacist for more information. § Iron absorption may be decreased by antacids or supplements containing aluminum, magnesium, calcium, zinc, proton pump inhibitors, and histamine2 receptor antagonists.
# Appendix B: Parenteral Iron Formulations and Adult Doses
This Appendix is a supplement to the BC Guideline Iron Deficiency -Investigation and Management. Manage known risk factors for iron deficiency (Table 1).
1. Manage known risk factors for iron deficiency (Table 1). 2. Investigate for additional causes (if not already established), including potential malignancy.
3. While investigating, provide iron supplementation* to treat symptoms and increase stores to protect against future losses (pregnancy, surgery).
Consider iron supplementation* primarily to increase stores to protect against future losses (pregnancy, surgery).
Ferritin >100 ug/L Normal iron stores. Clinical symptoms are not related to iron deficiency.
If ferritin is persistently ≥ 600 ug/L, consider test for iron overload.
Clinical symptoms and/or risk factors for iron deficiency. Refer to Table 1 for risk factors Measure serum ferritin.
# Guidelines & Protocols Advisory Committee
# Appendix D: Pediatric iron doses and liquid formulations
This Appendix is a supplement to the BC Guideline Iron Deficiency -Investigation and Management. Refer to page 7 for guidance on diagnosis, monitoring and treatment of iron deficiency and iron deficiency anemia in children.
• Advise patients that iron can be toxic to children and should always be safely stored.
• Provide dietary counselling. Dietitian referral is recommended. Patients and caregivers can call a dietitian at 8-1-1. Refer to Associated Documents for recommended dietary intake and a list of iron-rich foods.
• Recommend infants and toddlers with iron deficiency begin treatment with liquid oral iron.
• It is important to specify the strength (in mg elemental Fe/mL) in addition to dosing instructions (often in mL) to aid in selection of the intended product and prevent dosing errors. Remind patients that products are kept behind the counter in the pharmacy and to see a pharmacist to confirm the product. • Adverse GI reactions (nausea, vomiting, dyspepsia, constipation, diarrhea, and dark stools) are dependent on the dose of elemental iron. These adverse reactions are temporary and will likely disappear with continued treatment, with the exception of dark stools which can remain for the duration of therapy. If poor tolerability with oral iron, consider a lower dose, a different formulation or alternative dosing schedules (such as every other day dosing). 22 Resolution of symptoms and replenishment of iron stores may take longer.
# Recommended treatment doses of elemental iron for infants and toddlers 32
# Age group
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Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of Non-Hodgkin lymphoma in North America. While most patients often respond well to frontline treatment, there is a significant proportion of patients (30-40%) that will either be refractory to or relapse following frontline therapy. The standard of care for patients in the relapsed/refractory setting includes salvage therapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) for patients whose disease demonstrate chemosensitivity and who are fit and transplant eligible. However, there is a group of patients that do not demonstrate chemosensitivity to salvage therapy, are ineligible for ASCT, or relapse post-SCT. For this group of patients, there are variable treatment options which may differ across the Canadian provinces due to access and funding. In Canada, no unified national guideline exists for the treatment of relapsed/refractory DLBCL, and the provincial guidelines in existence vary. A national treatment guideline supported by Canadian hematologists is warranted to ensure that patients with relapsed/refractory DLBCL are treated according to best practice and have equitable access to best available care. A group of experts from across Canada have developed a national evidence-based treatment guideline to provide healthcare professionals with clear guidance on the management of relapsed or refractory DLBCL. Results of the current provincial guidelines in existence are presented with consensus recommendations based on available evidence.# Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma (NHL) and constitutes 30-40% of all Canadian NHL cases. DLBCL represents a heterogeneous group of aggressive B-cell malignancies that differ in prognosis, clinical and molecular features, and treatment options. Classifying patients by appropriate DLBCL subtype and accounting for additional risk factors are important in establishing the grade of aggressiveness of the lymphoma to determine prognosis. However, this is often difficult in practice and may not necessarily have implications on the treatment and management plan.
Due to the aggressiveness of DLBCL, rapid diagnosis and initiation of frontline treatment are essential. There are specific recommendations for frontline treatment for Canadian DLBCL patients based on high-risk molecular features, central nervous system disease, and risk factors 1 . Following treatment with the standard frontline therapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), approximately 30-50% of treated patients will suffer from relapse or refractory disease 2 . For these patients, the standard approach is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) for those who meet the eligibility criteria and have chemosensitive disease. In contrast, those who do not show chemosensitivity to salvage therapy are not transplant eligible. This group of patients, along with those who relapse following ASCT, are eligible for chimeric antigen receptor (CAR) T-cell therapy. However, provincial funding currently varies and some patients are required to travel out of province or country to access CAR-T therapy. For those that are not eligible for CAR-T therapy or fail treatment, there is no standard treatment approach and treatment will depend on access to clinical trials as well as patientrelated factors. Across Canada, several barriers could hinder the availability and timely access to therapies. Such factors can include provincial funding decisions, number and availability of hematologists or oncologists within the province to provide timely access, and number and location of treatment centers. These barriers can result in inequities and delays in treatment for DLBCL patients, especially in the relapse/refractory setting where experimental treatment options may only be available in certain provinces and at certain hospitals through clinical trials.
There are provincial guidelines in existence that distinguish optimal treatment approaches for DLBCL patients based on the presence of comorbid disease, DLBCL subtypes, and in some provinces IPI risk groups. However, guidelines are not universally available in all provinces and thus provinces may differ in their recommendations based on institutional considerations. There is currently no Canadian-wide guideline that provides a roadmap to the standardized management of DLBCL in the relapsed/refractory setting. This indicates a need for an evidence-based guideline. In collaboration with Lymphoma Canada, a group of Canadian DLBCL experts have developed a nationwide consensus-guideline based on the current best available evidence for the management of patients with relapsed/refractory DLBCL.
# GUIDELINE RECOMMENDATIONS
- Proposed high-dose chemotherapy and ASCT eligibility criteria; 2. Recommendation for patients ineligible for ASCT; 3. Recommendation for patients who do not respond to salvage chemotherapy; 4. Proposed chimeric antigen receptor (CAR) T-cell therapy eligibility criteria; 5. Recommendation for patients when CAR-T therapy is not feasible or for those who are ineligible for CAR-T therapy.
# Methodology
An initial web-based search was performed on all provincial cancer centers to identify whether DLBCL management guidelines are in existence. DLBCL provincial experts were contacted to verify guidelines and provide insight and input if a guideline could not be located. Once existing guidelines were collected, information was extracted and differentiated based on common treatment considerations. Following compilation of provincial and institutional guidelines, this information was reviewed by the nationally developed panel of Canadian DLBCL experts for the development of recommendations, incorporating important considerations for patients in the relapse/refractory setting. The National Comprehensive Cancer Network categories of evidence and consensus (Table 1) was used by the steering committee to grade the level of evidence and support for the recommendations for relapsed/refractory DLBCL patients 3 . Consensus was achieved based on the level of evidence and support for each recommendation.
A treatment algorithm was created based on these recommendations.
# CATEGORY 1
Based on the high-level evidence, there is uniform consensus that the intervention is appropriate.
# CATEGORY 2A
Based on the lower-level evidence, there is uniform consensus that the intervention is appropriate.
# CATEGORY 2B
Based on the lower-level evidence, there is consensus that the intervention is appropriate.
# CATEGORY 3
Based on any level of evidence, there is major disagreement that the intervention is appropriate.
An online search revealed existing DLBCL treatment and management guidelines in four provinces (British Columbia (BC), Alberta (AB), Ontario (ON), Nova Scotia (NS)). Three provinces (BC, AB, NS) had one guideline in existence, while one province (ON) had three DLBCL guidelines. Specialists from the remaining provinces (Saskatchewan (SK), Manitoba (MB), Quebec (QC), Newfoundland and Labrador (NF), New Brunswick (NB), Prince Edward Island (PEI)) and territories (Northwest Territories (NWT), Yukon (YK), Nunavut (NU)) were then contacted to confirm the existence of in-province/territory guidelines.
Physicians that did not have guidelines within their own province indicated they referred to BC Cancer (MB, PEI), Alberta Health Sciences (SK), Nova Scotia Cancer Care Program (PEI), Princess Margaret Cancer Centre (PMCC) and the National Comprehensive Cancer Network (NCCN) guidelines and adopted these guidelines to what is available locally and based on institutional regulations. Specific guidelines have not been uniformly adopted or endorsed, and feedback from specialists indicated an interest in the creation of a national DLBCL treatment guideline for both frontline and relapsed/refractory settings.
The information included in the existing provincial guidelines was reviewed for common themes to determine the methodology for data extraction and compilation to highlight similarities and differences. For relapsed/ refractory treatment, the common themes for treatment determination included transplant eligible vs. transplant ineligible and beyond second line treatment. The data from the existing guidelines was compiled according to these common themes as shown in Table 2.
GDP±R ➝ if CR/PR ➝ HDC + SCT GDP±R ➝ HDC- + in-vivo purge blood of tumour cells + ASCT *R-DICEP or R-MICE GDP±R ➝ if CR/PR ➝ HDC + SCT PET+ ➝ biopsy+ ➝ GDP±R ➝ if PR/CR ➝ HDC + SCT GDP±R ➝ if PR/CR➝ HDC- + ASCT - GDP, ICE, DHAP, ESHAP, EPOCH GDP±R ➝ if CR/PR ➝ HDC- + SCT - R-DHAP, R-ICE, R-mini-
# Relapsed/Refractory DLBCL Treatment
With the frontline immunochemotherapy regimen R-CHOP, more than 50% of advanced-stage de novo DLBCL patients are expected to be cured 4,5 . However, there are factors that can prevent this outcome. Between 30-50% of patients with DLBCL will be refractory to R-CHOP or will relapse after achieving a complete remission due to adverse prognostic factors 4,6,7 . Most relapses will occur within the subsequent 2-3 years after initial treatment. Patients that relapse early (within 12 months), or patients with refractory disease, will have a worse prognosis even with second line therapy 8 .
Salvage Therapy and High-Dose Chemotherapy Followed by ASCT Autologous stem cell transplantation (ASCT) is the standard treatment approach for DLBCL patients with chemosensitive disease that otherwise meet the eligibility criteria for this therapy. Certain criteria that could exclude patients from stem cell transplant include increasing age and comorbid health conditions. Older age (> 65 years) is not necessarily a contraindication to ASCT, and thus may be feasible in older more fit patients 9 . According to the stem cell transplant guidelines, ineligibility criteria for ASCT includes patients with poor performance status, active CNS involvement, and/or severe concomitant medical or psychiatric illness 10 .
Patients with HIV seropositivity may be considered for ASCT if well-controlled. Additional ineligibility criteria to assess organ function typically includes bilirubin level > 2xULN, creatinine level > 150 µmol/L, creatinine clearance < 50ml/min, low cardiac ejection fraction (< 50%), and a forced expiratory volume in one second < 50% and/or carbon monoxide diffusion test < 50% of predicted level; these values may differ according to provincial standards 11 .
Patients with primary refractory disease, which is typically defined as progression on therapy or within three months of treatment completion, are less likely to respond to salvage chemotherapy regimens and as a result will be less likely to benefit from ASCT. The landmark PARMA trial for establishing the role for ASCT over salvage chemotherapy alone showed an increase in event free survival (46% vs 12%) and 5-year overall survival (OS) (53% vs 32%) in the transplantation group over conventional therapy 12,13 .
Various studies have examined the use of different systemic treatment regimens prior to ASCT to maximize the response rate and OS. These regimens include R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) 14 , ICE (ifosfamide, carboplatin, etoposide) 15 , R-ICE (rituximab plus ICE) 16 , GDP (gemcitabine, dexamethasone, cisplatin) 17 and R-GEMOX (rituximab, gemcitabine, and oxaliplatin) 18,19 . Achieving better response to salvage chemotherapy is associated with better outcomes following ASCT, but no salvage regimen has been shown to be superior to another 20 .
The Canadian provincial guidelines and expert verification all report on stem cell transplant candidacy and salvage regimens in the relapsed/refractory setting for DLBCL patients. AB states the primary eligibility criteria for salvage chemotherapy followed by ASCT includes patients with good performance status.
Age, used in the past as a measurement of performance, has been removed completely from the criteria across provinces, now placing an emphasis on fitness and tolerability of the patient. If residual mass is FDG-avid post-systemic therapy, a biopsy is recommended (ON-PMH; BC), whereby a positive biopsy meets the criteria to proceed with salvage chemotherapy and ASCT. Most guidelines that recommend a specific regimen for high-dose salvage chemotherapy recommend gemcitabine + dexamethasone + cisplatin (GDP), with or without rituximab. GDP is the preferred regimen as it can be given on an outpatient basis and is less toxic than alternatives, with preservation of a better quality of life 17,21 . To maximize response to ASCT, it is recommended to include rituximab as part of the salvage chemotherapy regimen to in-vivo purge the blood of tumour cells. Certain provinces may currently, or in the past have been, required to consider the availability to use rituximab in combination with salvage chemotherapy with the intent to proceed to ASCT, as funding may only be provided after a certain amount of time has passed from frontline treatment with rituximab-based chemoimmunotherapy. Other provinces provide funding for rituximab combinations with all salvage regimens as required. The provinces have listed alternative regimen options in their guidelines such as DP+R (docetaxel, cisplatin, rituximab), R-DICEP (dose-intensive cyclophosphamide, etoposide, cisplatin, rituximab) or R-MICE (mitoxantrone, etoposide, and cytarabine, rituximab), R-DHAP, R-ICE, R-mini-BEAM (rituximab, carmustine, etoposide, cytarabine, melphalan), ESHAP (etoposide, cytarabine, cisplatin, methylprednisolone) and EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin).
In determining the response rate to ASCT, there are a few notable studies. The CORAL study, which examined the role for ASCT in the setting of early relapse following frontline treatment with R-CHOP, demonstrated similar response rates between the R-ICE and R-DHAP regimens 14 . Further, DLBCL patients with early rituximab failure were found to have a higher risk of disease relapse within the first year of transplantation 13 . With this information, this calls for a further need to understand the prognostic indicators that can identify r/r DLBCL patients that are unlikely to benefit from ASCT in order to investigate alternative therapies. One study reported that the presence of at least two of three risk factors (primary progressive disease, MYC rearrangement, intermediate-high NCCN-IPI) predicted a poor 2-year OS 22 .
# RECOMMENDATIONS
Based on high-level evidence, uniform consensus was achieved among the steering committee members on appropriate eligibility criteria for high-dose chemotherapy and ASCT: Based on high-level evidence, uniform consensus was achieved among the steering committee for the recommendation for stem cell transplant eligible chemosensitive patients to receive: salvage chemotherapy- followed by high-dose chemotherapy and autologous stem cell transplantation.
# Non-Stem Cell Candidates and Further Treatment Options
The prognosis of relapsed DLBCL patients who do not undergo high-dose therapy and ASCT is poor. Patients may either not meet the eligibility criteria to undergo ASCT, or not respond to salvage chemotherapy. Among patients who progress following frontline treatment, only 30-40% will respond to salvage chemotherapy and proceed with ASCT 5,14,17,23 . Even for those patients that respond to salvage chemotherapy and undergo ASCT, 50% are likely to relapse following transplantation 5,24,25 . The SCHOLAR-1 study among other similar studies, demonstrated that DLBCL patient's that are refractory to second-line therapy or relapse within < 12 months post-ASCT have poor outcomes 5,23,26,27,28 . In Canada, the standard approach for r/r DLBCL patients not responding to salvage chemotherapy or not eligible for ASCT is CAR T-cell therapy 20. Some provinces have funding and FACT (Foundation for the Accreditation of Cellular Therapy) accredited centers, and thus are able to administer manufactured CAR-T treatment locally. Other provinces will fund CAR-T therapy but will send their patients to receive treatment in other provinces or even to the United States. There are some provinces that also have new in-house CAR-T products available to patients through clinical trials. A list of current CAR T-cell therapies available to patients in Canada can be found in Supplementary Table 1.
Depending on the patient's health and fitness, treatment options for those that are ineligible for stem cell transplant, do not respond to salvage chemotherapy or relapse post-ASCT, include CAR T-cell therapy if appropriate, clinical trials, or palliative chemotherapy 10 or radiotherapy 29 . There are numerous chemotherapy options, but response rates are generally low and remission duration is short, however studies on the combination of these therapies are underway 30 . Polatuzumab vedotin, bendamustine and rituximab (Pola-BR) demonstrated improved PFS (7.5 vs 2.0 months), OS (12.4 vs 4.7 months), and time to first response and CR compared with bendamustine and rituximab 31,32,33 . This treatment provides a promising option for Canadians in this setting, as it is currently HC approved and recently obtained a positive CADTH recommendation for reimbursement. With high CR rates and prolonged disease control, Pola-BR is a beneficial stand-alone treatment and may even provide an important bridge in the future to consolidative therapies including SCT or CAR-T.
Another promising agent evaluated in combination with polatuzumab vedotin was obinituzumab, with a PFS and OS of 6.3 and 10.8 months respectively at median follow-up 34 . However, in comparison with Pola-BR, there was no indication of benefit of obinituzumab over rituximab in this setting 33 . Another therapy combination includes lenalidomide and tafasitamab, which demonstrated a modest ORR, with 43% having a CR, and is currently FDA approved and awaiting review by HC 35,36 . Neither of these regimens thus far are provincially funded, nor are their backbone therapies BR and lenalidomide, respectively. Other combination regimens are still in testing including ibrutinib, lenalidomide and rituximab, showing an ORR of 44% 37 . Chemotherapy options for fit patients can include R-ICE, RGemOx (rituximab, oxaliplatin, cytosine arabinoside, dexamethasone) 38 , and R-DHAX/rituximab, oxaliplatin, cytosine arabinoside, dexamethasone (ROAD) 39,40,41 . Palliative strategies can also be employed and should be simple to use, not require intravenous administration, and allow for outpatient administration 42 . Options tested but not all currently available in Canada include oral agents (prednisone, etoposide, procarbazine, cyclophosphamide) used alone or in combination (i.e. PEP-C) 42 , or intravenous therapy including GEPD (gemcitabine, etoposide, cisplatin, dexamethasone), DHAP, ESHAP, and EPIC (etoposide, prednisolone, ifosfamide, cisplatin) 43 .
Rarely, patients can have late relapses and may be eligible to receive curative intent therapy in the absence of transplant. Localized disease should be treated with combined modality therapy, while for advanced stage disease, combination chemotherapy may be appropriate especially with a low secondary IPI; this may be a curative approach in a minority of patients 12 . However, for the majority of transplant ineligible patients, as well as for those who have relapsed following transplant, the first consideration is eligibility for CAR-T treatment. For those that are ineligible for CAR-T, options are broad but may include further palliative chemotherapy or radiotherapy, or clinical trials. Clinical trials are the favoured approach if patients meet the eligibility criteria and are interested in participating. Although rare, patients with good performance status may be suitable for further combination chemotherapy including R-GDP, and less commonly R-ICE. For less fit patients, single agent chemotherapy may be used. Of note, these regimens can also be used as bridging therapy for CAR T-cell therapy. Other options for symptomatic management for this patient group at the time of palliation, or beyond second relapse, can include low dose daily oral chemotherapy with chlorambucil (0.1mg/kg/day) or etoposide (50 mg/day), prednisone, palliative regimen (cyclophosphamide/Celebrex or VP16/prednisone) or combination oral therapy (i.e. PEP-C), as detailed and endorsed by specific Canadian guidelines. This shows a high unmet need for reliable and effective treatment options for patients that are ASCT ineligible or progress following ASCT, where CAR-T may not be an option.
Four of the six Canadian guidelines available (AB, ON, NS, BC), more recent in their versions, present the option of CAR-T therapy for patient's ineligible for ASCT, have refractory disease post-frontline treatment and following two lines of therapy, or relapse following ASCT. However, CAR-T is employed across the country, even though provincial guidelines in existence may not have been recently updated with this information. For example, though CAR-T is available as a treatment option locally in Quebec, no provincially published treatment guideline is available stating this. CAR-T treatment provides a potentially curative approach in this patient population where cure was largely not possible. Results from the ZUMA-1 and JULIET trials were pivotal for understanding the role of CAR-T therapy in the setting of contraindications for ASCT or relapse following ASCT. With CAR-T, about 40% of patients achieved a CR and 12% achieved a PR 44 .
Though higher among the CR patients, at 12 months the rate of RFS was 65% 44 . Currently, CAR-T is approved in Canada for DLBCL patients that are disease refractory or have relapsed following two or more lines of therapy. If this option is not appropriate due to ineligibility criteria which can include decreased performance status, organ dysfunction (renal, cardiac, pulmonary) and active CNS disease, patients will typically be considered for clinical trials or palliative treatment options 45 . It is recommended that CAR-T is preferred over allo-SCT, and allo-SCT may be an option in some provinces if the patient relapses after CAR-T.
Bridging therapies are used if there is a concern for or evidence of progressive disease, causing symptoms or worsened clinical status. Therapies include single-agent treatment with cyclophosphamide, cytarabine, gemcitabine, GDP±R, DHAP±R, ICE±R, localized radiation therapy for bulky or symptomatic disease, steroids (dexamethasone or methylprednisolone), or GemOx±R 20 . *New options may become available in the palliation or clinical trial setting, such as Pola-BR.
# Relapse following/Refractory to Frontline Therapy
# Conclusion
Despite the progress in frontline therapy response rates for DLBCL patients, patients still experience disease relapses or are refractory to frontline treatment. The standard recommended therapy for this patient population is salvage therapy followed by high-dose chemotherapy and autologous stem cell transplantation. Though this treatment option does have a positive outcome in a large percentage of r/r DLBCL patients, there is still a group of patients that are ineligible for ASCT, are not responsive to salvage chemotherapy, or relapse post-ASCT. This patient group has a poor prognosis and is in need for effective treatment approaches. With CAR T-cell therapy being approved in Canada, this provides patients an encouraging prognosis.
The recommendation for patients in this group is to receive CAR-T, with bridging therapy if required. For patients that are not eligible for CAR-T or relapse post-CAR T-cell therapy, the recommendation includes palliative therapies and clinical trials. New options may become available in this setting once funded, such as Pola-BR. These are the recommendations issued by the national steering committee of leading hematologists and oncologists across Canada for patients with relapsed/refractory DLBCL.
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Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of Non-Hodgkin lymphoma in North America. While most patients often respond well to frontline treatment, there is a significant proportion of patients (30-40%) that will either be refractory to or relapse following frontline therapy. The standard of care for patients in the relapsed/refractory setting includes salvage therapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) for patients whose disease demonstrate chemosensitivity and who are fit and transplant eligible. However, there is a group of patients that do not demonstrate chemosensitivity to salvage therapy, are ineligible for ASCT, or relapse post-SCT. For this group of patients, there are variable treatment options which may differ across the Canadian provinces due to access and funding. In Canada, no unified national guideline exists for the treatment of relapsed/refractory DLBCL, and the provincial guidelines in existence vary. A national treatment guideline supported by Canadian hematologists is warranted to ensure that patients with relapsed/refractory DLBCL are treated according to best practice and have equitable access to best available care. A group of experts from across Canada have developed a national evidence-based treatment guideline to provide healthcare professionals with clear guidance on the management of relapsed or refractory DLBCL. Results of the current provincial guidelines in existence are presented with consensus recommendations based on available evidence.# Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma (NHL) and constitutes 30-40% of all Canadian NHL cases. DLBCL represents a heterogeneous group of aggressive B-cell malignancies that differ in prognosis, clinical and molecular features, and treatment options. Classifying patients by appropriate DLBCL subtype and accounting for additional risk factors are important in establishing the grade of aggressiveness of the lymphoma to determine prognosis. However, this is often difficult in practice and may not necessarily have implications on the treatment and management plan.
Due to the aggressiveness of DLBCL, rapid diagnosis and initiation of frontline treatment are essential. There are specific recommendations for frontline treatment for Canadian DLBCL patients based on high-risk molecular features, central nervous system disease, and risk factors 1 . Following treatment with the standard frontline therapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), approximately 30-50% of treated patients will suffer from relapse or refractory disease 2 . For these patients, the standard approach is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) for those who meet the eligibility criteria and have chemosensitive disease. In contrast, those who do not show chemosensitivity to salvage therapy are not transplant eligible. This group of patients, along with those who relapse following ASCT, are eligible for chimeric antigen receptor (CAR) T-cell therapy. However, provincial funding currently varies and some patients are required to travel out of province or country to access CAR-T therapy. For those that are not eligible for CAR-T therapy or fail treatment, there is no standard treatment approach and treatment will depend on access to clinical trials as well as patientrelated factors. Across Canada, several barriers could hinder the availability and timely access to therapies. Such factors can include provincial funding decisions, number and availability of hematologists or oncologists within the province to provide timely access, and number and location of treatment centers. These barriers can result in inequities and delays in treatment for DLBCL patients, especially in the relapse/refractory setting where experimental treatment options may only be available in certain provinces and at certain hospitals through clinical trials.
There are provincial guidelines in existence that distinguish optimal treatment approaches for DLBCL patients based on the presence of comorbid disease, DLBCL subtypes, and in some provinces IPI risk groups. However, guidelines are not universally available in all provinces and thus provinces may differ in their recommendations based on institutional considerations. There is currently no Canadian-wide guideline that provides a roadmap to the standardized management of DLBCL in the relapsed/refractory setting. This indicates a need for an evidence-based guideline. In collaboration with Lymphoma Canada, a group of Canadian DLBCL experts have developed a nationwide consensus-guideline based on the current best available evidence for the management of patients with relapsed/refractory DLBCL.
# GUIDELINE RECOMMENDATIONS
1. Proposed high-dose chemotherapy and ASCT eligibility criteria; 2. Recommendation for patients ineligible for ASCT; 3. Recommendation for patients who do not respond to salvage chemotherapy; 4. Proposed chimeric antigen receptor (CAR) T-cell therapy eligibility criteria; 5. Recommendation for patients when CAR-T therapy is not feasible or for those who are ineligible for CAR-T therapy.
# Methodology
An initial web-based search was performed on all provincial cancer centers to identify whether DLBCL management guidelines are in existence. DLBCL provincial experts were contacted to verify guidelines and provide insight and input if a guideline could not be located. Once existing guidelines were collected, information was extracted and differentiated based on common treatment considerations. Following compilation of provincial and institutional guidelines, this information was reviewed by the nationally developed panel of Canadian DLBCL experts for the development of recommendations, incorporating important considerations for patients in the relapse/refractory setting. The National Comprehensive Cancer Network categories of evidence and consensus (Table 1) was used by the steering committee to grade the level of evidence and support for the recommendations for relapsed/refractory DLBCL patients 3 . Consensus was achieved based on the level of evidence and support for each recommendation.
A treatment algorithm was created based on these recommendations.
# CATEGORY 1
Based on the high-level evidence, there is uniform consensus that the intervention is appropriate.
# CATEGORY 2A
Based on the lower-level evidence, there is uniform consensus that the intervention is appropriate.
# CATEGORY 2B
Based on the lower-level evidence, there is consensus that the intervention is appropriate.
# CATEGORY 3
Based on any level of evidence, there is major disagreement that the intervention is appropriate.
An online search revealed existing DLBCL treatment and management guidelines in four provinces (British Columbia (BC), Alberta (AB), Ontario (ON), Nova Scotia (NS)). Three provinces (BC, AB, NS) had one guideline in existence, while one province (ON) had three DLBCL guidelines. Specialists from the remaining provinces (Saskatchewan (SK), Manitoba (MB), Quebec (QC), Newfoundland and Labrador (NF), New Brunswick (NB), Prince Edward Island (PEI)) and territories (Northwest Territories (NWT), Yukon (YK), Nunavut (NU)) were then contacted to confirm the existence of in-province/territory guidelines.
Physicians that did not have guidelines within their own province indicated they referred to BC Cancer (MB, PEI), Alberta Health Sciences (SK), Nova Scotia Cancer Care Program (PEI), Princess Margaret Cancer Centre (PMCC) and the National Comprehensive Cancer Network (NCCN) guidelines and adopted these guidelines to what is available locally and based on institutional regulations. Specific guidelines have not been uniformly adopted or endorsed, and feedback from specialists indicated an interest in the creation of a national DLBCL treatment guideline for both frontline and relapsed/refractory settings.
The information included in the existing provincial guidelines was reviewed for common themes to determine the methodology for data extraction and compilation to highlight similarities and differences. For relapsed/ refractory treatment, the common themes for treatment determination included transplant eligible vs. transplant ineligible and beyond second line treatment. The data from the existing guidelines was compiled according to these common themes as shown in Table 2.
GDP±R ➝ if CR/PR ➝ HDC + SCT GDP±R ➝ HDC* + in-vivo purge blood of tumour cells + ASCT *R-DICEP or R-MICE GDP±R ➝ if CR/PR ➝ HDC + SCT PET+ ➝ biopsy+ ➝ GDP±R ➝ if PR/CR ➝ HDC + SCT GDP±R ➝ if PR/CR➝ HDC* + ASCT * GDP, ICE, DHAP, ESHAP, EPOCH GDP±R ➝ if CR/PR ➝ HDC* + SCT * R-DHAP, R-ICE, R-mini-
# Relapsed/Refractory DLBCL Treatment
With the frontline immunochemotherapy regimen R-CHOP, more than 50% of advanced-stage de novo DLBCL patients are expected to be cured 4,5 . However, there are factors that can prevent this outcome. Between 30-50% of patients with DLBCL will be refractory to R-CHOP or will relapse after achieving a complete remission due to adverse prognostic factors 4,6,7 . Most relapses will occur within the subsequent 2-3 years after initial treatment. Patients that relapse early (within 12 months), or patients with refractory disease, will have a worse prognosis even with second line therapy 8 .
Salvage Therapy and High-Dose Chemotherapy Followed by ASCT Autologous stem cell transplantation (ASCT) is the standard treatment approach for DLBCL patients with chemosensitive disease that otherwise meet the eligibility criteria for this therapy. Certain criteria that could exclude patients from stem cell transplant include increasing age and comorbid health conditions. Older age (> 65 years) is not necessarily a contraindication to ASCT, and thus may be feasible in older more fit patients 9 . According to the stem cell transplant guidelines, ineligibility criteria for ASCT includes patients with poor performance status, active CNS involvement, and/or severe concomitant medical or psychiatric illness 10 .
Patients with HIV seropositivity may be considered for ASCT if well-controlled. Additional ineligibility criteria to assess organ function typically includes bilirubin level > 2xULN, creatinine level > 150 µmol/L, creatinine clearance < 50ml/min, low cardiac ejection fraction (< 50%), and a forced expiratory volume in one second < 50% and/or carbon monoxide diffusion test < 50% of predicted level; these values may differ according to provincial standards 11 .
Patients with primary refractory disease, which is typically defined as progression on therapy or within three months of treatment completion, are less likely to respond to salvage chemotherapy regimens and as a result will be less likely to benefit from ASCT. The landmark PARMA trial for establishing the role for ASCT over salvage chemotherapy alone showed an increase in event free survival (46% vs 12%) and 5-year overall survival (OS) (53% vs 32%) in the transplantation group over conventional therapy 12,13 .
Various studies have examined the use of different systemic treatment regimens prior to ASCT to maximize the response rate and OS. These regimens include R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) 14 , ICE (ifosfamide, carboplatin, etoposide) 15 , R-ICE (rituximab plus ICE) 16 , GDP (gemcitabine, dexamethasone, cisplatin) 17 and R-GEMOX (rituximab, gemcitabine, and oxaliplatin) 18,19 . Achieving better response to salvage chemotherapy is associated with better outcomes following ASCT, but no salvage regimen has been shown to be superior to another 20 .
The Canadian provincial guidelines and expert verification all report on stem cell transplant candidacy and salvage regimens in the relapsed/refractory setting for DLBCL patients. AB states the primary eligibility criteria for salvage chemotherapy followed by ASCT includes patients with good performance status.
Age, used in the past as a measurement of performance, has been removed completely from the criteria across provinces, now placing an emphasis on fitness and tolerability of the patient. If residual mass is FDG-avid post-systemic therapy, a biopsy is recommended (ON-PMH; BC), whereby a positive biopsy meets the criteria to proceed with salvage chemotherapy and ASCT. Most guidelines that recommend a specific regimen for high-dose salvage chemotherapy recommend gemcitabine + dexamethasone + cisplatin (GDP), with or without rituximab. GDP is the preferred regimen as it can be given on an outpatient basis and is less toxic than alternatives, with preservation of a better quality of life 17,21 . To maximize response to ASCT, it is recommended to include rituximab as part of the salvage chemotherapy regimen to in-vivo purge the blood of tumour cells. Certain provinces may currently, or in the past have been, required to consider the availability to use rituximab in combination with salvage chemotherapy with the intent to proceed to ASCT, as funding may only be provided after a certain amount of time has passed from frontline treatment with rituximab-based chemoimmunotherapy. Other provinces provide funding for rituximab combinations with all salvage regimens as required. The provinces have listed alternative regimen options in their guidelines such as DP+R (docetaxel, cisplatin, rituximab), R-DICEP (dose-intensive cyclophosphamide, etoposide, cisplatin, rituximab) or R-MICE (mitoxantrone, etoposide, and cytarabine, rituximab), R-DHAP, R-ICE, R-mini-BEAM (rituximab, carmustine, etoposide, cytarabine, melphalan), ESHAP (etoposide, cytarabine, cisplatin, methylprednisolone) and EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin).
In determining the response rate to ASCT, there are a few notable studies. The CORAL study, which examined the role for ASCT in the setting of early relapse following frontline treatment with R-CHOP, demonstrated similar response rates between the R-ICE and R-DHAP regimens 14 . Further, DLBCL patients with early rituximab failure were found to have a higher risk of disease relapse within the first year of transplantation 13 . With this information, this calls for a further need to understand the prognostic indicators that can identify r/r DLBCL patients that are unlikely to benefit from ASCT in order to investigate alternative therapies. One study reported that the presence of at least two of three risk factors (primary progressive disease, MYC rearrangement, intermediate-high NCCN-IPI) predicted a poor 2-year OS 22 .
# RECOMMENDATIONS
Based on high-level evidence, uniform consensus was achieved among the steering committee members on appropriate eligibility criteria for high-dose chemotherapy and ASCT: Based on high-level evidence, uniform consensus was achieved among the steering committee for the recommendation for stem cell transplant eligible chemosensitive patients to receive: salvage chemotherapy* followed by high-dose chemotherapy and autologous stem cell transplantation.
# Non-Stem Cell Candidates and Further Treatment Options
The prognosis of relapsed DLBCL patients who do not undergo high-dose therapy and ASCT is poor. Patients may either not meet the eligibility criteria to undergo ASCT, or not respond to salvage chemotherapy. Among patients who progress following frontline treatment, only 30-40% will respond to salvage chemotherapy and proceed with ASCT 5,14,17,23 . Even for those patients that respond to salvage chemotherapy and undergo ASCT, 50% are likely to relapse following transplantation 5,24,25 . The SCHOLAR-1 study among other similar studies, demonstrated that DLBCL patient's that are refractory to second-line therapy or relapse within < 12 months post-ASCT have poor outcomes 5,23,26,27,28 . In Canada, the standard approach for r/r DLBCL patients not responding to salvage chemotherapy or not eligible for ASCT is CAR T-cell therapy 20. Some provinces have funding and FACT (Foundation for the Accreditation of Cellular Therapy) accredited centers, and thus are able to administer manufactured CAR-T treatment locally. Other provinces will fund CAR-T therapy but will send their patients to receive treatment in other provinces or even to the United States. There are some provinces that also have new in-house CAR-T products available to patients through clinical trials. A list of current CAR T-cell therapies available to patients in Canada can be found in Supplementary Table 1.
Depending on the patient's health and fitness, treatment options for those that are ineligible for stem cell transplant, do not respond to salvage chemotherapy or relapse post-ASCT, include CAR T-cell therapy if appropriate, clinical trials, or palliative chemotherapy 10 or radiotherapy 29 . There are numerous chemotherapy options, but response rates are generally low and remission duration is short, however studies on the combination of these therapies are underway 30 . Polatuzumab vedotin, bendamustine and rituximab (Pola-BR) demonstrated improved PFS (7.5 vs 2.0 months), OS (12.4 vs 4.7 months), and time to first response and CR compared with bendamustine and rituximab 31,32,33 . This treatment provides a promising option for Canadians in this setting, as it is currently HC approved and recently obtained a positive CADTH recommendation for reimbursement. With high CR rates and prolonged disease control, Pola-BR is a beneficial stand-alone treatment and may even provide an important bridge in the future to consolidative therapies including SCT or CAR-T.
Another promising agent evaluated in combination with polatuzumab vedotin was obinituzumab, with a PFS and OS of 6.3 and 10.8 months respectively at median follow-up 34 . However, in comparison with Pola-BR, there was no indication of benefit of obinituzumab over rituximab in this setting 33 . Another therapy combination includes lenalidomide and tafasitamab, which demonstrated a modest ORR, with 43% having a CR, and is currently FDA approved and awaiting review by HC 35,36 . Neither of these regimens thus far are provincially funded, nor are their backbone therapies BR and lenalidomide, respectively. Other combination regimens are still in testing including ibrutinib, lenalidomide and rituximab, showing an ORR of 44% 37 . Chemotherapy options for fit patients can include R-ICE, RGemOx (rituximab, oxaliplatin, cytosine arabinoside, dexamethasone) 38 , and R-DHAX/rituximab, oxaliplatin, cytosine arabinoside, dexamethasone (ROAD) 39,40,41 . Palliative strategies can also be employed and should be simple to use, not require intravenous administration, and allow for outpatient administration 42 . Options tested but not all currently available in Canada include oral agents (prednisone, etoposide, procarbazine, cyclophosphamide) used alone or in combination (i.e. PEP-C) 42 , or intravenous therapy including GEPD (gemcitabine, etoposide, cisplatin, dexamethasone), DHAP, ESHAP, and EPIC (etoposide, prednisolone, ifosfamide, cisplatin) 43 .
Rarely, patients can have late relapses and may be eligible to receive curative intent therapy in the absence of transplant. Localized disease should be treated with combined modality therapy, while for advanced stage disease, combination chemotherapy may be appropriate especially with a low secondary IPI; this may be a curative approach in a minority of patients 12 . However, for the majority of transplant ineligible patients, as well as for those who have relapsed following transplant, the first consideration is eligibility for CAR-T treatment. For those that are ineligible for CAR-T, options are broad but may include further palliative chemotherapy or radiotherapy, or clinical trials. Clinical trials are the favoured approach if patients meet the eligibility criteria and are interested in participating. Although rare, patients with good performance status may be suitable for further combination chemotherapy including R-GDP, and less commonly R-ICE. For less fit patients, single agent chemotherapy may be used. Of note, these regimens can also be used as bridging therapy for CAR T-cell therapy. Other options for symptomatic management for this patient group at the time of palliation, or beyond second relapse, can include low dose daily oral chemotherapy with chlorambucil (0.1mg/kg/day) or etoposide (50 mg/day), prednisone, palliative regimen (cyclophosphamide/Celebrex or VP16/prednisone) or combination oral therapy (i.e. PEP-C), as detailed and endorsed by specific Canadian guidelines. This shows a high unmet need for reliable and effective treatment options for patients that are ASCT ineligible or progress following ASCT, where CAR-T may not be an option.
Four of the six Canadian guidelines available (AB, ON, NS, BC), more recent in their versions, present the option of CAR-T therapy for patient's ineligible for ASCT, have refractory disease post-frontline treatment and following two lines of therapy, or relapse following ASCT. However, CAR-T is employed across the country, even though provincial guidelines in existence may not have been recently updated with this information. For example, though CAR-T is available as a treatment option locally in Quebec, no provincially published treatment guideline is available stating this. CAR-T treatment provides a potentially curative approach in this patient population where cure was largely not possible. Results from the ZUMA-1 and JULIET trials were pivotal for understanding the role of CAR-T therapy in the setting of contraindications for ASCT or relapse following ASCT. With CAR-T, about 40% of patients achieved a CR and 12% achieved a PR 44 .
Though higher among the CR patients, at 12 months the rate of RFS was 65% 44 . Currently, CAR-T is approved in Canada for DLBCL patients that are disease refractory or have relapsed following two or more lines of therapy. If this option is not appropriate due to ineligibility criteria which can include decreased performance status, organ dysfunction (renal, cardiac, pulmonary) and active CNS disease, patients will typically be considered for clinical trials or palliative treatment options 45 . It is recommended that CAR-T is preferred over allo-SCT, and allo-SCT may be an option in some provinces if the patient relapses after CAR-T.
Bridging therapies are used if there is a concern for or evidence of progressive disease, causing symptoms or worsened clinical status. Therapies include single-agent treatment with cyclophosphamide, cytarabine, gemcitabine, GDP±R, DHAP±R, ICE±R, localized radiation therapy for bulky or symptomatic disease, steroids (dexamethasone or methylprednisolone), or GemOx±R 20 . *New options may become available in the palliation or clinical trial setting, such as Pola-BR.
# Relapse following/Refractory to Frontline Therapy
# Conclusion
Despite the progress in frontline therapy response rates for DLBCL patients, patients still experience disease relapses or are refractory to frontline treatment. The standard recommended therapy for this patient population is salvage therapy followed by high-dose chemotherapy and autologous stem cell transplantation. Though this treatment option does have a positive outcome in a large percentage of r/r DLBCL patients, there is still a group of patients that are ineligible for ASCT, are not responsive to salvage chemotherapy, or relapse post-ASCT. This patient group has a poor prognosis and is in need for effective treatment approaches. With CAR T-cell therapy being approved in Canada, this provides patients an encouraging prognosis.
The recommendation for patients in this group is to receive CAR-T, with bridging therapy if required. For patients that are not eligible for CAR-T or relapse post-CAR T-cell therapy, the recommendation includes palliative therapies and clinical trials. New options may become available in this setting once funded, such as Pola-BR. These are the recommendations issued by the national steering committee of leading hematologists and oncologists across Canada for patients with relapsed/refractory DLBCL.
# Conflict of Interest Disclosures
The following represents disclosure information from the authors within the last two years related to the subject matter of this guideline. adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Februar y 2019
# RECOMMENDATIONS
Based on high-level evidence, uniform consensus was achieved among the steering committee for the recommendation for patients that are eligible for intensive therapy following failed salvage therapy or failed SCT to receive: CAR T-cell therapy.
Based on high-level evidence, uniform consensus was achieved among the steering committee for CAR-T eligibility criteria: • Recommendation for stem cell transplant eligible chemosensitive patients is to receive salvage chemotherapy* followed by high-dose chemotherapy and autologous stem cell transplantation.
-* Recommend GDP±R x3 cycles. R-ICE or R-DHAP may also be used with similar efficacy. R-DICEP also is an alternative. • Recommendation for relapsed/refractory patients ineligible for CAR-T is palliation therapy or treatment through clinical trials -New options may become available in this setting such as Pola-BR • Based on these recommendations, a treatment algorithm for relapsed/refractory DLBCL patients provides optimal treatment path(s) (Figure 1).
# YOU DON'T HAVE TO FACE LYMPHOMA ALONE.
Lymphoma Canada connects patients, their family and friends, medical professionals, researchers, volunteers and donors, to build a strong lymphoma community.
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Situation: Vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome (TTS), is a rare, idiosyncratic life-threatening condition that can arise after COVID-19 vaccination with AstraZeneca (AZ) or Johnson & Johnson/Janssen (JJ) vaccines (not reported with Pfizer or Moderna vaccines). This document with supplemental appendices has been developed through extensive consultation with BC medical experts and physician groups to improve awareness and to help guide screening, diagnosis and management of VITT/TTS. Background: VITT/TTS is a condition characterized by: 1) symptom onset 4 to 28 days after exposure to AZ or JJ vaccine; 2) platelet count less than 150 x 10 9 /L; and 3) thrombosis, especially in uncommon sites such as cerebral venous sinuses and abdominal veins (eg. portal vein), as well as arterial thrombosis. Mortality is estimated to be approximately 20%. VITT/TTS resembles heparin-induced thrombocytopenia (HIT) in its mechanism, and diagnosis requires the presence of anti-PF4/heparin antibodies. Similar to HIT, early diagnosis is essential because patients can deteriorate rapidly. Currently, the recommended treatment is empiric initiation of intravenous immunoglobulin (IVIG) and a non-heparin anticoagulant. Based on available data, the best estimate of the risk of VITT/TTS after vaccination with AZ or JJ vaccines is 1 in 100,000 doses. In BC, approximately 400,000 doses of the AZ and JJ vaccines are anticipated to be administered, but this number may increase as our vaccination campaign continues.In an effort to best protect British Columbians, BC medical experts have put together 4 documents for dissemination to all physicians and other healthcare providers involved in patient care post-vaccination.# Primary Care Outpatient Assessment
# Assess for Risk
- Risk of VITT/TTS is 1 in 100,000
- Only AstraZeneca and Johnson & Johnson (Janssen) vaccines have been associated with VITT/TTS
- Symptoms occur 4 -28 days after vaccine (peak period 6 -14 days)
- VITT/TTS can occur in all ages and both sexes, but is most commonly reported in younger women
- Patients with history of blood clots are not more likely to have VITT/TTS
# Assess for Clotting
- Have a high index of suspicion, ask about all of the following:
-persistent and severe headache
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Situation: Vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome (TTS), is a rare, idiosyncratic life-threatening condition that can arise after COVID-19 vaccination with AstraZeneca (AZ) or Johnson & Johnson/Janssen (JJ) vaccines (not reported with Pfizer or Moderna vaccines). This document with supplemental appendices has been developed through extensive consultation with BC medical experts and physician groups to improve awareness and to help guide screening, diagnosis and management of VITT/TTS. Background: VITT/TTS is a condition characterized by: 1) symptom onset 4 to 28 days after exposure to AZ or JJ vaccine; 2) platelet count less than 150 x 10 9 /L; and 3) thrombosis, especially in uncommon sites such as cerebral venous sinuses and abdominal veins (eg. portal vein), as well as arterial thrombosis. Mortality is estimated to be approximately 20%. VITT/TTS resembles heparin-induced thrombocytopenia (HIT) in its mechanism, and diagnosis requires the presence of anti-PF4/heparin antibodies. Similar to HIT, early diagnosis is essential because patients can deteriorate rapidly. Currently, the recommended treatment is empiric initiation of intravenous immunoglobulin (IVIG) and a non-heparin anticoagulant. Based on available data, the best estimate of the risk of VITT/TTS after vaccination with AZ or JJ vaccines is 1 in 100,000 doses. In BC, approximately 400,000 doses of the AZ and JJ vaccines are anticipated to be administered, but this number may increase as our vaccination campaign continues.In an effort to best protect British Columbians, BC medical experts have put together 4 documents for dissemination to all physicians and other healthcare providers involved in patient care post-vaccination.# Primary Care Outpatient Assessment
# Assess for Risk
• Risk of VITT/TTS is 1 in 100,000
• Only AstraZeneca and Johnson & Johnson (Janssen) vaccines have been associated with VITT/TTS
• Symptoms occur 4 -28 days after vaccine (peak period 6 -14 days)
• VITT/TTS can occur in all ages and both sexes, but is most commonly reported in younger women
• **Patients with history of blood clots are not more likely to have VITT/TTS
# Assess for Clotting
• Have a high index of suspicion, ask about all of the following:
•persistent and severe headache
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# 1) Recommendation
People living with HIV (PLWH) aged 5 years or older should be fully vaccinated for COVID-19, regardless of CD4 count provided that they do not have contraindications to the available age-appropriate vaccines (see below). Although the evidence was mixed in earlier studies, more recently, multiple large studies have indicated that PLWH are at increased risk of serious illness and death due to COVID-19 . To date, there appears to be no significant difference in the safety profile of the authorized COVID-19 vaccines in PLWH compared to the general population.
2) Current COVID-19 vaccine usage in BC a) Vaccine options authorized in Canada i) mRNA vaccines (Pfizer-BioNTech product: Comirnaty; or Moderna product: Spikevax). COVID-19 vaccine usage in Canada has shifted almost exclusively to one or another of the two mRNA vaccines due to both the higher level of protection against symptomatic infection or severe disease in addition to improved safety profiles compared to the viral vector vaccines . Both mRNA vaccines have been approved for adults and adolescents age 12 years and older , . For children, the Pfizer-BioNTech vaccine has been approved for those age 5-11 years and the Moderna vaccine at the pediatric dosage of 50 mcg (adult dosage is 100 mcg) has been approved as an alternative to the Pfizer-BioNTech vaccine for those age 6-11 years .
ii) Recombinant protein subunit vaccine (Novavax product: Nuvaxovid). This was approved for use in adults age 18 years and over by Health Canada on February 17 th 2022 , . The vaccine efficacy for protection against symptomatic COVID-19 illness was 89.7% (95% CI: 80.2-94.6%) in the clinical trial 2019nCoV-302 . However, these data were generated prior to the emergence of the delta and omicron variants.
iii) Viral vector vaccines (AstraZeneca product: ChAdOx1 nCOV-19, Vaxzevria; or Johnson & Johnson-Janssen product: Ad.COV2.S, Janssen COVID-19 vaccine) are approved for those age 18 years and over, using a 2-dose and 1-dose schedule, respectively . These products are only recommended for a primary series of COVID-19 vaccination if there are no specific contraindications to their use, and only when all other authorized COVID-19 vaccines are contraindicated . This NACI recommendation relates to the lower level of protection afforded by the viral vector vaccines in addition to the less favourable adverse effect profile, which includes rare but potentially serious adverse effects, as outlined below , . However, there is some preliminary evidence that the immune responses, as measured by peak antibody titres with the Janssen COVID-19 vaccine are initially lower than for mRNA vaccines but remain relatively stable over 8 months . Although there are no randomized controlled trials comparing different COVID-19 vaccines, a recent observational study suggested that the Janssen COVID-19 vaccine may provide more durable protection against breakthrough infections and hospitalizations .
# iv) Recombinant, plant-based virus-like particles (VLP) vaccine (Medicago product:
COVIFENZ). This vaccine contains purified, spike protein of SARS-CoV-2 expressed in virus-like particles produced by plant-based technology. In the phase 3 portion of the RCT Study 021, the vaccine efficacy was 71%. The vaccine was approved by Health Canada on February 24, 2022 for individuals 18-64 years of age .
b) Recommended primary vaccination series for COVID-19 (see Table ). The recommendations were updated by both the BCCDC and NACI . The recommendation is for a complete series with an mRNA COVID-19 vaccine for those who do not have a contraindication and are age-appropriate for the available vaccine. The Pfizer-BioNTech vaccine dosage for age 5 to 11 years with the pediatric formulation is 10 mcg; for age 12 years and older the dosage is 30 mcg. The Moderna vaccine dose for age 6 to 11 years is 50 mcg and for 12 years of age and over the dose is 100 mcg. The preference in the choice of mRNA vaccine is Moderna for age 30 years and older based upon indirect evidence of higher vaccine efficacy compared to the Pfizer-BioNTech vaccine . However, the preference for age 6 to 29 years is the Pfizer-BioNTech vaccine due to its lower incidence of myocarditis in this age group compared to the Moderna vaccine . The first and second vaccine doses should be spaced 8 weeks apart .
Those who are not able or willing to receive an mRNA COVID-19 vaccine should be offered the Novavax COVID-19 vaccine provided there is no contraindication. Although NACI has recommended that such individuals may alternatively be offered the recombinant VLP (Medicago) vaccine as a 2-dose primary vaccination series at least 21 days apart , to date this vaccine has not yet been recommended or stated as available in BC according to the BCCDC website. Those individuals who have contraindications to all other authorized COVID-19 vaccinations may be offered one of the viral vector vaccinations after informed consent. This should include discussion regarding the risks of rare but serious complications associated with these vaccines, specifically thrombosis and thrombocytopenia syndrome (TTS) and the need to seek immediate medical care should symptoms develop . The use of mixed 2-dose vaccine schedules (e.g., a viral vector vaccine followed by an mRNA vaccine) has been associated with similar high level of protection against COVID-19-related hospitalization which exceeded 90% when at least one dose was an mRNA vaccine . c) 3-dose primary vaccine series (see Table ). Multiple studies have demonstrated a suboptimal immune response to different 2-dose COVID-19 vaccine schedules in a substantial proportion of certain populations with immunocompromise or particular comorbidities , . In order to address this, the addition of a 3 rd dose to the primary vaccination series in transplant and hemodialysis patients has been associated with improved immune responses , . This is not considered to be a booster dose since the problem is the absence of a robust immune response to the first 2 doses rather than one of waning immunity. Given these findings, a 3 rd dose in the primary vaccine series is now being recommended for mRNA vaccines in moderately to severely immunocompromised adults and children, rather than the original 2-dose series . However, an additional dose has not been recommended in the primary vaccination series for either of the viral vector vaccines, unless alternative vaccines are contraindicated. Although the Moderna vaccine is considered to be an alternative for those age 6 to 29 years, it should be considered preferentially in immunocompromised children age 6-11 years given the evidence of higher seroconversion rates among immunocompromised Moderna vaccine recipients (versus Pfizer BioNtech recipients) and the much lower incidence of myocarditis in this younger age group in association with mRNA vaccination .
Among PLWH, this recommendation of a 3-dose primary vaccine series in British Columbia would apply to those with any of the following: a prior AIDS defining illness, or CD4 count 65 years; or perinatally acquired HIV infection . A recent study among PLWH with a median CD4 of count of 710 (IQR 525-935) cells/mm 3 and receiving antiretroviral therapy demonstrated similar humoral immune responses compared to controls, suggesting that a 3 rd vaccine dose in the primary series would not be necessary for most PLWH with viral load suppression and CD4 cell counts above 200 cells/mm 3 . ). i) Rationale. The first booster doses may be the 3 rd or 4 th dose depending upon whether the individual received a primary vaccination series of 2 or 3 doses. Decline in antibody titres and protection from COVID-19 disease have been demonstrated 6 months after completion of a 2-dose primary vaccine series using the initially recommended 21-day interval between doses for the Pfizer-BioNTech vaccine , , , . However, the protection has been restored with the use of a booster dose . Booster doses are now recommended at 6 months after completion of a primary COVID-19 vaccine series, with the booster being an mRNA COVID-19 vaccine even if the primary series was given with a viral vector vaccine. Similar or higher immune responses have been observed with heterologous versus homologous boosting regimens, which included the primary series and booster combinations using one or another of the two mRNA vaccines and the Janssen COVID-19 vaccine .
# d) COVID-19 booster dose recommendations (see Table
The priority for administration of such booster doses was initially targeting those who are at higher risk of severe disease due to COVID-19 (e.g., older age, immunocompromise, and comorbidities), but has since been broadened to include the general population of age 12 years and older by the BCCDC (see Table ). Booster doses are also recommended within 6 months after the last dose in pregnancy or breastfeeding and for any individual who has already received a three-dose primary vaccination series . The only group in the general population for whom a booster dose is not currently recommended is for children less than 12 years of age . A 4 th vaccine dose given within 6 months of the last dose is currently only being recommended as a booster dose in those who were eligible to receive a 3-dose primary immunization series, specifically the moderately to severely immunocompromised (as defined in Appendix A).
# Boosters in PLWH.
The waning of both humoral and cell-mediated immune response was recently demonstrated among PLWH receiving ART (87% had an HIV RNA <50 c/mL) at a median of 5 months following the second dose of either of the mRNA vaccines, particularly among those with CD4 counts <200 cells/mm 3 . The response to mRNA booster doses at a median of 142 days (132-156) after the second dose was recently evaluated among 216 PLWH receiving ART (93% had HIV RNA <50 c/ml) with a wide range of CD4 counts . A high response rate was observed and a CD4 count of <200 cells/mm 3 was not associated with a risk of failing to elicit a humoral or cell-mediated immune response . ii) Booster preference. The preference is for the Moderna vaccine for those 30 years of age or older due to higher neutralizing antibody titres and lower rates of breakthrough infection compared to the Pfizer-BioNTech vaccine , , . However, the rare adverse event of myocarditis, which has been observed predominantly in the age group of 12-29 years occurs more often with the Moderna compared to the Pfizer vaccine, making the latter the preference in this age group.
Second
iii) Booster alternative. An alternative booster vaccine option may be offered at >6 months after completion of a primary COVID-19 vaccine series to adults age 18 and above with the Novavax vaccine (Nuvaxovid) if they are not able or willing to receive an mRNA vaccine booster, provided that they have no contraindication (discretionary NACI recommendation) . Medicago Covifenz is not currently authorized for use as a booster dose in Canada .
# e) COVID-19 vaccinations for individuals with previous SARS-COV-2 infection and COVID-19 vaccination.
The risk of subsequent SARS-CoV-2 reinfection is significantly reduced by completing a COVID-19 vaccine schedule . Although the optimal time interval between COVID-19 infection and subsequent vaccination is uncertain, BCCDC has recommended that such individuals receive their next scheduled vaccination or booster any time after the resolution of COVID-19 symptoms and up to 3 months after having had a positive COVID-19 test result . However, the recent evidence that a longer interval between COVID-19 infection and vaccination is associated with improved antibody responses supports waiting for 2-3 months before vaccinating .
# f) Simultaneous administration of COVID-19 vaccines with other vaccinations.
Any of the currently authorized COVID-19 vaccinations may be given simultaneously or at any time before or after a non-COVID-19 vaccine, including either live or non-live vaccines (discretionary NACI recommendation) .
3) Vaccine-related adverse events. a) Very common and common adverse events are defined as those which occur in >10% and 1-9% of vaccine recipients, respectively. Local reactions with pain, redness, or swelling at the injection site typically resolve within a few days. Localized axillary lymphadenopathy with swelling or tenderness may also be encountered. Systemic adverse events may last a few days with fatigue, headache, muscle pain, chills, or joint pain. Among PLWH, transient HIV RNA viral blips have been detected within 1 month of SARS-CoV-2 vaccination in 8.9% of vaccinees who had been fully suppressed . Similar findings have been previously reported with influenza vaccination.
b) Rare and very rare adverse events. Rare and very rare adverse events occur in 0.01% to <0.1% and <0.01% (< 1:10,000) of vaccine recipients, respectively. Those adverse events which are very rare are unlikely to be identified in clinical trials, highlighting the importance of ongoing surveillance in the vaccinated population. i) mRNA vaccines.
Severe immediate allergic reactions (e.g., anaphylaxis) occur in approximately 2-10 cases per million doses of vaccine administered. The reactions typically occur within 15-30 minutes and when treated promptly within a supervised vaccine facility complete recovery is expected. So far there have been no fatalities or long-term morbidity associated with allergic reactions to mRNA vaccines reported in Canada . Myocarditis or pericarditis have been associated with both mRNA vaccines, but somewhat more frequently with the Moderna vaccine . This complication is usually noted within a week following vaccination, particularly the 2 nd dose. It also occurs mainly in males between the ages of 12-29 years and follows a mild clinical course with quick recovery in most individuals. The rates of myocarditis/pericarditis reported in Canada in association with the Moderna and Pfizer COVID-19 vaccines were 3.0 and 1.9 cases per 100,000 doses, respectively . In the Vaccine Adverse Event Reporting System (VAERS) in the US, among more than 190 million COVID-19 vaccine recipients, 1,626 cases of myocarditis were identified . Among those who developed myocarditis, the median age was 21 years (IQR 16-31 years) and the highest rate was observed in 16-17-year old males (105.9 per million doses). For men aged 18-24 years, the rates were 52.4 and 56.3 cases per million doses of the Pfizer and Moderna vaccines, respectively . Almost all of the cases (96%) were hospitalized, and 87% had resolution of presenting symptoms by the time of hospital discharge.
Bell's palsy. Very rare cases of Bell's palsy have been reported following vaccination with either of the mRNA vaccines .
# ii) Viral vector vaccines (AstraZeneca and Janssen COVID-19 vaccines). Thrombosis and thrombocytopenia syndrome (TTS)
. This is a very rare and serious adverse effect which may involve thrombosis in unusual locations (e.g., cerebral venous sinus thrombosis, splanchnic vein thrombosis or arterial thrombosis) associated with thrombocytopenia. A subgroup of TTS cases test positive for antibodies to platelet factor 4-polyanion complexes (anti-PF4) which is referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). TTS usually develops between 4-28 days following vaccination. The frequency of TTS with the AstraZeneca vaccine is between 1:26,000 and 1:100,000 doses. A lower incidence has been observed with the Janssen COVID-19 vaccine at 1:300,000 doses . The incidence of TTS is higher in women than men and higher in younger versus older adults. The case fatality rate is between 20-50% . Guillian-Barre syndrome (GBS). Both viral vector vaccines (but neither of the mRNA vaccines) have been associated with GBS . The onset has occurred between 6 hours and 25 days following vaccination among Canadian cases. Among those individuals with a prior history of GBS, there appears to be no clear indication that COVID-19 vaccination causes recurrent GBS. In a recent cohort study involving 702 patients with a prior history of GBS who received the Pfizer-BioNTech vaccine, there was only one individual identified as having a possible vaccine-related relapse of GBS . Systemic capillary leak syndrome. Very rare reports have described the development of this life-threatening immune disorder, which includes hypoalbuminemia, hypotension, and possibly shock with multi-organ failure. Almost all of the cases described in association with COVID-19 vaccination have involved one of the viral vector vaccines .
iii) Recombinant protein subunit vaccine (Novavax). The adverse events associated with this vaccine in the licensing clinical trial were local injection site reactions and systemic symptoms (e.g., headache, muscle pain, fatigue), as for the other vaccines. There were 7,020 subjects in the study who received the vaccine and the rate of serious adverse events was 0.5% for both the vaccine and placebo groups .
iv) Recombinant, plant-based virus-like particles vaccine (Medicago vaccine) . In the phase 3 clinical trial (study 021), there were 4,094 vaccine recipients in the safety subset analysis. Both local and systemic adverse reactions were more frequent in the vaccine group compared to placebo, but these were usually mild to moderate and resolved within a few days. Serious adverse events were observed in 0.4% and 0.3% of the vaccine and placebo groups, respectively. b) Precautions: i) Severe immediate allergic reactions such as anaphylaxis occur <4 hours following vaccination may related to a COVID-19 vaccine or a vaccine excipient. Such a reaction should prompt an allergy consultation with risk/benefit consideration prior to a further dose of an mRNA COVID-19 vaccine. Switching to a viral vector vaccine is not the preferred management. Such reactions are likely not IgE-mediated and have a low likelihood of recurrence after subsequent vaccine doses . Those who agree to receive a subsequent dosage of a COVID-19 vaccine, after informed consent and risk/benefit considerations have been discussed, should also have a longer post-vaccination observation time of 30 minutes instead of 15 minutes. Excipients which may be responsible for allergic reactions include: polyethylene glycol (PEG) (found in Pfizer-BioNTech vaccine), tromethamine (in Moderna vaccine), and polysorbates (present in viral vector vaccines) . Viral vector vaccines may also be associated with severe allergic reactions. Following such a reaction, any subsequent vaccination should be offered with an mRNA vaccine after informed consent and risk/benefit considerations have been discussed, including an extended 30-minute period of observation following the revaccination.
# 4) COVID-19 vaccine contraindications and precautions
ii) Immune thrombocytopenia (ITP). Individuals with ITP should not receive a viral vector vaccine and instead should be offered an mRNA vaccine. If an mRNA vaccine is contraindicated or inaccessible, then consider hematology assessment prior to vaccination in addition to platelet monitoring following vaccination.
iii) Thrombosis and thrombocytopenia syndrome (TTS). For those with a past history of TTS or unusual thrombosis, a viral vector vaccine should only be considered if other vaccines are contraindicated or inaccessible and after appropriate risk assessment. However, a previous history of cerebral venous sinus thrombosis (CVST) with thrombocytopenia unrelated to a viral vector and also those with previous heparininduced thrombocytopenia (HIT) unrelated to viral vector vaccine do not appear to be at increased risk of VITT after receiving a viral vector vaccine .
iv) Myocarditis and/or pericarditis following mRNA COVID-19 vaccinations. Myocarditis. Further doses of an mRNA COVID-19 vaccine should be deferred for people who developed myocarditis within 6 weeks of a previous dose of an mRNA vaccine (e.g., abnormal cardiac evaluation such as electrocardiogram, elevated troponins, echocardiogram or cardiac MRI) , . Pericarditis. Those with a history consistent with pericarditis and either no cardiac work up or normal cardiac investigations (i.e., no evidence of myocarditis) can receive a subsequent dose of an mRNA vaccination after they have been symptom-free for at least 90 days following the prior vaccination. Any subsequent dose of an mRNA vaccination in such patients should be with the Pfizer-BioNTech vaccine rather than Moderna, given the lower reported rate of myocarditis and/or pericarditis with the Pfizer product , .
Table
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# 1) Recommendation
People living with HIV (PLWH) aged 5 years or older should be fully vaccinated for COVID-19, regardless of CD4 count provided that they do not have contraindications to the available age-appropriate vaccines (see below). Although the evidence was mixed in earlier studies, more recently, multiple large studies have indicated that PLWH are at increased risk of serious illness and death due to COVID-19 [1][2][3][4][5][6]. To date, there appears to be no significant difference in the safety profile of the authorized COVID-19 vaccines in PLWH compared to the general population.
2) Current COVID-19 vaccine usage in BC a) Vaccine options authorized in Canada i) mRNA vaccines (Pfizer-BioNTech product: Comirnaty; or Moderna product: Spikevax). COVID-19 vaccine usage in Canada has shifted almost exclusively to one or another of the two mRNA vaccines due to both the higher level of protection against symptomatic infection or severe disease in addition to improved safety profiles compared to the viral vector vaccines [7][8][9]. Both mRNA vaccines have been approved for adults and adolescents age 12 years and older [10], [11]. For children, the Pfizer-BioNTech vaccine has been approved for those age 5-11 years [12, 13] and the Moderna vaccine at the pediatric dosage of 50 mcg (adult dosage is 100 mcg) has been approved as an alternative to the Pfizer-BioNTech vaccine for those age 6-11 years [14].
ii) Recombinant protein subunit vaccine (Novavax product: Nuvaxovid). This was approved for use in adults age 18 years and over by Health Canada on February 17 th 2022 [15], [16]. The vaccine efficacy for protection against symptomatic COVID-19 illness was 89.7% (95% CI: 80.2-94.6%) in the clinical trial 2019nCoV-302 [15]. However, these data were generated prior to the emergence of the delta and omicron variants.
iii) Viral vector vaccines (AstraZeneca product: ChAdOx1 nCOV-19, Vaxzevria; or Johnson & Johnson-Janssen product: Ad.COV2.S, Janssen COVID-19 vaccine) are approved for those age 18 years and over, using a 2-dose and 1-dose schedule, respectively [7]. These products are only recommended for a primary series of COVID-19 vaccination if there are no specific contraindications to their use, and only when all other authorized COVID-19 vaccines are contraindicated [7]. This NACI recommendation relates to the lower level of protection afforded by the viral vector vaccines in addition to the less favourable adverse effect profile, which includes rare but potentially serious adverse effects, as outlined below [8], [9]. However, there is some preliminary evidence that the immune responses, as measured by peak antibody titres with the Janssen COVID-19 vaccine are initially lower than for mRNA vaccines but remain relatively stable over 8 months [17]. Although there are no randomized controlled trials comparing different COVID-19 vaccines, a recent observational study suggested that the Janssen COVID-19 vaccine may provide more durable protection against breakthrough infections and hospitalizations [18].
# iv) Recombinant, plant-based virus-like particles (VLP) vaccine (Medicago product:
COVIFENZ). This vaccine contains purified, spike protein of SARS-CoV-2 expressed in virus-like particles produced by plant-based technology. In the phase 3 portion of the RCT Study 021, the vaccine efficacy was 71%. The vaccine was approved by Health Canada on February 24, 2022 for individuals 18-64 years of age [19].
b) Recommended primary vaccination series for COVID-19 (see Table [20]). The recommendations were updated by both the BCCDC and NACI [21]. The recommendation is for a complete series with an mRNA COVID-19 vaccine for those who do not have a contraindication and are age-appropriate for the available vaccine. The Pfizer-BioNTech vaccine dosage for age 5 to 11 years with the pediatric formulation is 10 mcg; for age 12 years and older the dosage is 30 mcg. The Moderna vaccine dose for age 6 to 11 years is 50 mcg and for 12 years of age and over the dose is 100 mcg. The preference in the choice of mRNA vaccine is Moderna for age 30 years and older based upon indirect evidence of higher vaccine efficacy compared to the Pfizer-BioNTech vaccine [7][14]. However, the preference for age 6 to 29 years is the Pfizer-BioNTech vaccine due to its lower incidence of myocarditis in this age group compared to the Moderna vaccine [7][14]. The first and second vaccine doses should be spaced 8 weeks apart [20][21].
Those who are not able or willing to receive an mRNA COVID-19 vaccine should be offered the Novavax COVID-19 vaccine provided there is no contraindication. Although NACI has recommended that such individuals may alternatively be offered the recombinant VLP (Medicago) vaccine as a 2-dose primary vaccination series at least 21 days apart [22], to date this vaccine has not yet been recommended or stated as available in BC according to the BCCDC website. Those individuals who have contraindications to all other authorized COVID-19 vaccinations may be offered one of the viral vector vaccinations after informed consent. This should include discussion regarding the risks of rare but serious complications associated with these vaccines, specifically thrombosis and thrombocytopenia syndrome (TTS) and the need to seek immediate medical care should symptoms develop [7]. The use of mixed 2-dose vaccine schedules (e.g., a viral vector vaccine followed by an mRNA vaccine) has been associated with similar high level of protection against COVID-19-related hospitalization which exceeded 90% when at least one dose was an mRNA vaccine [23]. c) 3-dose primary vaccine series (see Table [20]). Multiple studies have demonstrated a suboptimal immune response to different 2-dose COVID-19 vaccine schedules in a substantial proportion of certain populations with immunocompromise or particular comorbidities [24], [25]. In order to address this, the addition of a 3 rd dose to the primary vaccination series in transplant and hemodialysis patients has been associated with improved immune responses [25], [26]. This is not considered to be a booster dose since the problem is the absence of a robust immune response to the first 2 doses rather than one of waning immunity. Given these findings, a 3 rd dose in the primary vaccine series is now being recommended for mRNA vaccines in moderately to severely immunocompromised adults and children, rather than the original 2-dose series [21]. However, an additional dose has not been recommended in the primary vaccination series for either of the viral vector vaccines, unless alternative vaccines are contraindicated. Although the Moderna vaccine is considered to be an alternative for those age 6 to 29 years, it should be considered preferentially in immunocompromised children age 6-11 years given the evidence of higher seroconversion rates among immunocompromised Moderna vaccine recipients (versus Pfizer BioNtech recipients) and the much lower incidence of myocarditis in this younger age group in association with mRNA vaccination [14].
Among PLWH, this recommendation of a 3-dose primary vaccine series in British Columbia would apply to those with any of the following: a prior AIDS defining illness, or CD4 count <200/mm 3 , or CD4 fraction <15%; or detectable plasma viral load since January 2021; age >65 years; or perinatally acquired HIV infection [27]. A recent study among PLWH with a median CD4 of count of 710 (IQR 525-935) cells/mm 3 and receiving antiretroviral therapy demonstrated similar humoral immune responses compared to controls, suggesting that a 3 rd vaccine dose in the primary series would not be necessary for most PLWH with viral load suppression and CD4 cell counts above 200 cells/mm 3 [28]. [20]). i) Rationale. The first booster doses may be the 3 rd or 4 th dose depending upon whether the individual received a primary vaccination series of 2 or 3 doses. Decline in antibody titres and protection from COVID-19 disease have been demonstrated 6 months after completion of a 2-dose primary vaccine series using the initially recommended 21-day interval between doses for the Pfizer-BioNTech vaccine [29], [30], [31], [32]. However, the protection has been restored with the use of a booster dose [33]. Booster doses are now recommended at 6 months after completion of a primary COVID-19 vaccine series, with the booster being an mRNA COVID-19 vaccine even if the primary series was given with a viral vector vaccine. Similar or higher immune responses have been observed with heterologous versus homologous boosting regimens, which included the primary series and booster combinations using one or another of the two mRNA vaccines and the Janssen COVID-19 vaccine [34].
# d) COVID-19 booster dose recommendations (see Table
The priority for administration of such booster doses was initially targeting those who are at higher risk of severe disease due to COVID-19 (e.g., older age, immunocompromise, and comorbidities), but has since been broadened to include the general population of age 12 years and older by the BCCDC (see Table [20]). Booster doses are also recommended within 6 months after the last dose in pregnancy or breastfeeding and for any individual who has already received a three-dose primary vaccination series [21]. The only group in the general population for whom a booster dose is not currently recommended is for children less than 12 years of age [21]. A 4 th vaccine dose given within 6 months of the last dose is currently only being recommended as a booster dose in those who were eligible to receive a 3-dose primary immunization series, specifically the moderately to severely immunocompromised (as defined in Appendix A).
# Boosters in PLWH.
The waning of both humoral and cell-mediated immune response was recently demonstrated among PLWH receiving ART (87% had an HIV RNA <50 c/mL) at a median of 5 months following the second dose of either of the mRNA vaccines, particularly among those with CD4 counts <200 cells/mm 3 [35]. The response to mRNA booster doses at a median of 142 days (132-156) after the second dose was recently evaluated among 216 PLWH receiving ART (93% had HIV RNA <50 c/ml) with a wide range of CD4 counts [36]. A high response rate was observed and a CD4 count of <200 cells/mm 3 was not associated with a risk of failing to elicit a humoral or cell-mediated immune response [36]. ii) Booster preference. The preference is for the Moderna vaccine for those 30 years of age or older due to higher neutralizing antibody titres and lower rates of breakthrough infection compared to the Pfizer-BioNTech vaccine [38], [39], [40]. However, the rare adverse event of myocarditis, which has been observed predominantly in the age group of 12-29 years occurs more often with the Moderna compared to the Pfizer vaccine, making the latter the preference in this age group.
Second
iii) Booster alternative. An alternative booster vaccine option may be offered at >6 months after completion of a primary COVID-19 vaccine series to adults age 18 and above with the Novavax vaccine (Nuvaxovid) if they are not able or willing to receive an mRNA vaccine booster, provided that they have no contraindication (discretionary NACI recommendation) [16]. Medicago Covifenz is not currently authorized for use as a booster dose in Canada [22].
# e) COVID-19 vaccinations for individuals with previous SARS-COV-2 infection and COVID-19 vaccination.
The risk of subsequent SARS-CoV-2 reinfection is significantly reduced by completing a COVID-19 vaccine schedule [41]. Although the optimal time interval between COVID-19 infection and subsequent vaccination is uncertain, BCCDC has recommended that such individuals receive their next scheduled vaccination or booster any time after the resolution of COVID-19 symptoms and up to 3 months after having had a positive COVID-19 test result [42]. However, the recent evidence that a longer interval between COVID-19 infection and vaccination is associated with improved antibody responses supports waiting for 2-3 months before vaccinating [43][44].
# f) Simultaneous administration of COVID-19 vaccines with other vaccinations.
Any of the currently authorized COVID-19 vaccinations may be given simultaneously or at any time before or after a non-COVID-19 vaccine, including either live or non-live vaccines (discretionary NACI recommendation) [16].
3) Vaccine-related adverse events. a) Very common and common adverse events are defined as those which occur in >10% and 1-9% of vaccine recipients, respectively. Local reactions with pain, redness, or swelling at the injection site typically resolve within a few days. Localized axillary lymphadenopathy with swelling or tenderness may also be encountered. Systemic adverse events may last a few days with fatigue, headache, muscle pain, chills, or joint pain. Among PLWH, transient HIV RNA viral blips have been detected within 1 month of SARS-CoV-2 vaccination in 8.9% of vaccinees who had been fully suppressed [45]. Similar findings have been previously reported with influenza vaccination.
b) Rare and very rare adverse events. Rare and very rare adverse events occur in 0.01% to <0.1% and <0.01% (< 1:10,000) of vaccine recipients, respectively. Those adverse events which are very rare are unlikely to be identified in clinical trials, highlighting the importance of ongoing surveillance in the vaccinated population. i) mRNA vaccines.
Severe immediate allergic reactions (e.g., anaphylaxis) occur in approximately 2-10 cases per million doses of vaccine administered. The reactions typically occur within 15-30 minutes and when treated promptly within a supervised vaccine facility complete recovery is expected. So far there have been no fatalities or long-term morbidity associated with allergic reactions to mRNA vaccines reported in Canada [7]. Myocarditis or pericarditis have been associated with both mRNA vaccines, but somewhat more frequently with the Moderna vaccine [46]. This complication is usually noted within a week following vaccination, particularly the 2 nd dose. It also occurs mainly in males between the ages of 12-29 years and follows a mild clinical course with quick recovery in most individuals. The rates of myocarditis/pericarditis reported in Canada in association with the Moderna and Pfizer COVID-19 vaccines were 3.0 and 1.9 cases per 100,000 doses, respectively [47]. In the Vaccine Adverse Event Reporting System (VAERS) in the US, among more than 190 million COVID-19 vaccine recipients, 1,626 cases of myocarditis were identified [48] . Among those who developed myocarditis, the median age was 21 years (IQR 16-31 years) and the highest rate was observed in 16-17-year old males (105.9 per million doses). For men aged 18-24 years, the rates were 52.4 and 56.3 cases per million doses of the Pfizer and Moderna vaccines, respectively [48]. Almost all of the cases (96%) were hospitalized, and 87% had resolution of presenting symptoms by the time of hospital discharge.
Bell's palsy. Very rare cases of Bell's palsy have been reported following vaccination with either of the mRNA vaccines [47].
# ii) Viral vector vaccines (AstraZeneca and Janssen COVID-19 vaccines). Thrombosis and thrombocytopenia syndrome (TTS)
. This is a very rare and serious adverse effect which may involve thrombosis in unusual locations (e.g., cerebral venous sinus thrombosis, splanchnic vein thrombosis or arterial thrombosis) associated with thrombocytopenia. A subgroup of TTS cases test positive for antibodies to platelet factor 4-polyanion complexes (anti-PF4) [49] which is referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). TTS usually develops between 4-28 days following vaccination. The frequency of TTS with the AstraZeneca vaccine is between 1:26,000 and 1:100,000 doses. A lower incidence has been observed with the Janssen COVID-19 vaccine at 1:300,000 doses [7]. The incidence of TTS is higher in women than men and higher in younger versus older adults. The case fatality rate is between 20-50% [7]. Guillian-Barre syndrome (GBS). Both viral vector vaccines (but neither of the mRNA vaccines) have been associated with GBS [7]. The onset has occurred between 6 hours and 25 days following vaccination among Canadian cases. Among those individuals with a prior history of GBS, there appears to be no clear indication that COVID-19 vaccination causes recurrent GBS. In a recent cohort study involving 702 patients with a prior history of GBS who received the Pfizer-BioNTech vaccine, there was only one individual identified as having a possible vaccine-related relapse of GBS [50]. Systemic capillary leak syndrome. Very rare reports have described the development of this life-threatening immune disorder, which includes hypoalbuminemia, hypotension, and possibly shock with multi-organ failure. Almost all of the cases described in association with COVID-19 vaccination have involved one of the viral vector vaccines [51].
iii) Recombinant protein subunit vaccine (Novavax). The adverse events associated with this vaccine in the licensing clinical trial were local injection site reactions and systemic symptoms (e.g., headache, muscle pain, fatigue), as for the other vaccines. There were 7,020 subjects in the study who received the vaccine and the rate of serious adverse events was 0.5% for both the vaccine and placebo groups [15].
iv) Recombinant, plant-based virus-like particles vaccine (Medicago vaccine) [52]. In the phase 3 clinical trial (study 021), there were 4,094 vaccine recipients in the safety subset analysis. Both local and systemic adverse reactions were more frequent in the vaccine group compared to placebo, but these were usually mild to moderate and resolved within a few days. Serious adverse events were observed in 0.4% and 0.3% of the vaccine and placebo groups, respectively. b) Precautions: i) Severe immediate allergic reactions such as anaphylaxis occur <4 hours following vaccination may related to a COVID-19 vaccine or a vaccine excipient. Such a reaction should prompt an allergy consultation with risk/benefit consideration prior to a further dose of an mRNA COVID-19 vaccine. Switching to a viral vector vaccine is not the preferred management. Such reactions are likely not IgE-mediated and have a low likelihood of recurrence after subsequent vaccine doses [7]. Those who agree to receive a subsequent dosage of a COVID-19 vaccine, after informed consent and risk/benefit considerations have been discussed, should also have a longer post-vaccination observation time of 30 minutes instead of 15 minutes. Excipients which may be responsible for allergic reactions include: polyethylene glycol (PEG) (found in Pfizer-BioNTech vaccine), tromethamine (in Moderna vaccine), and polysorbates (present in viral vector vaccines) [7]. Viral vector vaccines may also be associated with severe allergic reactions. Following such a reaction, any subsequent vaccination should be offered with an mRNA vaccine after informed consent and risk/benefit considerations have been discussed, including an extended 30-minute period of observation following the revaccination.
# 4) COVID-19 vaccine contraindications and precautions
ii) Immune thrombocytopenia (ITP). Individuals with ITP should not receive a viral vector vaccine and instead should be offered an mRNA vaccine. If an mRNA vaccine is contraindicated or inaccessible, then consider hematology assessment prior to vaccination in addition to platelet monitoring following vaccination.
iii) Thrombosis and thrombocytopenia syndrome (TTS). For those with a past history of TTS or unusual thrombosis, a viral vector vaccine should only be considered if other vaccines are contraindicated or inaccessible and after appropriate risk assessment. However, a previous history of cerebral venous sinus thrombosis (CVST) with thrombocytopenia unrelated to a viral vector and also those with previous heparininduced thrombocytopenia (HIT) unrelated to viral vector vaccine do not appear to be at increased risk of VITT after receiving a viral vector vaccine [7].
iv) Myocarditis and/or pericarditis following mRNA COVID-19 vaccinations. Myocarditis. Further doses of an mRNA COVID-19 vaccine should be deferred for people who developed myocarditis within 6 weeks of a previous dose of an mRNA vaccine (e.g., abnormal cardiac evaluation such as electrocardiogram, elevated troponins, echocardiogram or cardiac MRI) [46], [48]. Pericarditis. Those with a history consistent with pericarditis and either no cardiac work up or normal cardiac investigations (i.e., no evidence of myocarditis) can receive a subsequent dose of an mRNA vaccination after they have been symptom-free for at least 90 days following the prior vaccination. Any subsequent dose of an mRNA vaccination in such patients should be with the Pfizer-BioNTech vaccine rather than Moderna, given the lower reported rate of myocarditis and/or pericarditis with the Pfizer product [46], [48].
Table [20]
#
[20]
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None
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46aa14452e53e6267767a768ad78c5a29363867a
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cma
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None
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To assist clinicians with the investigation and management of suspected and documented heparin-induced thrombocytopenia (HIT). - This table does not address special populations and circumstances such as children, pregnancy, percutaneous coronary interventions, cardiac surgery, vascular surgery, and renal replacement therapy. Apixaban and dabigatran have also been used to treat patients with HIT; however, there is very limited trial data# BACKGROUND:
HIT is a transient, immune-mediated adverse drug reaction in patients recently exposed to heparin that causes thrombocytopenia and often results in venous and/or arterial thrombosis. HIT occurs in up to 5% of patients receiving unfractionated heparin (UFH) for longer than 4 days and in <1% who receive low molecular weight heparin (LMWH). HIT is characterised by immunoglobulin G (IgG) antibodies that recognize an antigen complex of platelet factor 4 (PF4) bound to heparin. These antibodies trigger a highly prothrombotic state by causing intravascular platelet aggregation, intense platelet, monocyte and endothelial cell activation, and excessive thrombin generation.
# CLINICAL FEATURES:
HIT typically presents with a fall in platelet count with or without venous and/or arterial thrombosis.
- Thrombocytopenia: A platelet count fall >30% beginning 5-10 days after UFH or LMWH exposure, in the absence of other causes of thrombocytopenia, should be considered to be HIT, unless proven otherwise. A more rapid onset of platelet count fall (often within 24 hours of heparin exposure) can occur when there is a history of heparin exposure within the preceding 3 months. Bleeding is very infrequent. - Thrombosis: HIT is associated with a high risk (30-50%) of new venous or arterial thromboembolism. Thrombosis may be the presenting clinical manifestation of HIT or can occur during or shortly after the thrombocytopenia. - Other clinical manifestations of HIT: Less frequent manifestations include heparin-induced skin lesions, adrenal hemorrhagic infarction (secondary to adrenal vein thrombosis), transient global amnesia, and acute systemic reactions (e.g. chills, dyspnea, cardiac or respiratory arrest following IV heparin bolus).
# DIAGNOSIS:
The diagnosis of HIT is based on three criteria:
1) The patient is receiving or has had recent exposure to UFH or LMWH.
2) At least one clinical feature of the syndrome is present (significant fall in platelet count, new venous and/or arterial thrombosis). 3) There is laboratory evidence of HIT antibodies. 1 provide a rational approach to suspected HIT.
# Figure 1 and Table
# HIT ASSAYS:
Therapeutic decisions, including the cessation of UFH or LMWH and the administration of a HITsafe, alternative anticoagulant (see below), should not be delayed pending the results of laboratory testing if the clinical suspicion of HIT is not low. There are two main types of tests for HIT:
1) immunologic assays which detect antibodies to PF4/heparin complexes ("HIT antibodies"; e.g. enzyme-linked immunosorbent assay , particle gel immunoassay, latex particle agglutination assay), and; 2) functional assays (e.g. serotonin release assay , heparin-induced platelet aggregation ).
In most centres, only the immunologic assay results are available on an urgent basis.
Although both assay types are sensitive for HIT (>90%), false positives are common with the immunologic assays.
# 4TS SCORE:
Criteria for the 4Ts score, which is used to determine the likelihood that a patient has HIT, are outlined in Table 1. Given the high negative predictive value of the 4Ts score, laboratory testing for HIT is not always required for patients with low pre-test probability according to the 4Ts score, as long as all the elements of the score are known. Occasionally, there may be uncertainty about the score due to multiple missing platelet counts, unclear history of recent heparin exposure or concurrent potential causes of thrombocytopenia; in this case, testing for HIT should be done.
Since the majority of patients with a positive immunologic assay do not have HIT, and because of the long-term implications of a HIT diagnosis, obtaining a confirmatory functional assay should be considered in patients with an intermediate 4Ts score and/or ELISA optical density <2.0.
# MANAGEMENT:
Patients with HIT are best managed by, or in consultation with, a specialist experienced in managing HIT.
Each of the following points is important in the management of HIT:
- Stop all heparin exposure, including LMWH, prophylactic heparin, heparin locks or flushes, and remove heparin-coated catheters. - Start anticoagulation with a non-heparin, HIT-safe anticoagulant such as fondaparinux, argatroban, a direct oral anticoagulant (DOAC), bivalirudin, or danaparoid (see Table 2 for dosing). If a new thrombotic event is present (HIT with thrombosis, or "HITT"), then the acute VTE treatment regimen for the DOAC is preferred, rather than the maintenance dosing regimen. For example, rivaroxaban should be initiated at 15 mg BID x 3 weeks followed by 20 mg daily. - Consider if the patient may already have had a thromboembolic event. Patients with suspected venous or arterial thrombosis should have objective confirmation since this will affect the duration of HIT-safe anticoagulant use. Even without a clinical suspicion of deep vein thrombosis (DVT), bilateral leg ultrasonography to screen for asymptomatic DVT are recommended, especially if the patient has additional risk factors for VTE. - Avoid platelet transfusions unless the patient is bleeding or requires a procedure associated with a high risk of bleeding. - Early use of warfarin should be avoided in acute HIT since it may make the prothrombotic state worse. If warfarin has already been started when HIT is diagnosed, it should be stopped, and vitamin K administered to reverse the warfarin effect. Warfarin alone is insufficient to protect against thrombosis secondary to HIT as long as HIT is considered active (i.e. platelets less than 150 x 10 9 /L). - Warfarin or a DOAC are appropriate for longer-term anticoagulation, if indicated, after thrombocytopenia has resolved. If transitioning to warfarin from a HIT-safe anticoagulant, such as fondaparinux, bivalirudin, or danaparoid: -Do not initiate warfarin until platelet count is ≥150 x 10 9 /L.
-Overlap warfarin with therapeutic doses of the HIT-safe anticoagulant for ≥5 days and until the international normalized ratio (INR) is therapeutic. Caution should be used when transitioning to warfarin from argatroban because it also increases the INR. - Duration of anticoagulation for HIT with thrombosis: at least 3 months.
- Duration of anticoagulation for HIT without thrombosis: at least 4 weeks.
- Heparin or LMWH should not be given to a patient with previous HIT without consultation with a specialist.
# SPECIAL CONSIDERATIONS:
# Pediatrics:
The incidence of HIT is less than in adults, but the approach to investigation and management is similar. Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with HIT. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# Pregnancy:
HIT is infrequent in pregnancy. The approach to investigation is as outlined above. Danaparoid does not cross the placenta and has been used to treat HIT in pregnancy. The use of fondaparinux (with the cautions noted above) is an option where danaparoid is not available; however, this drug has been reported to cross the placenta in small amounts and experience with fondaparinux in pregnancy is very limited (especially during the first trimester). DOACs should not be prescribed during pregnancy.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES
# Date of Version: 23October2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
|
To assist clinicians with the investigation and management of suspected and documented heparin-induced thrombocytopenia (HIT). * This table does not address special populations and circumstances such as children, pregnancy, percutaneous coronary interventions, cardiac surgery, vascular surgery, and renal replacement therapy. **Apixaban and dabigatran have also been used to treat patients with HIT; however, there is very limited trial data# BACKGROUND:
HIT is a transient, immune-mediated adverse drug reaction in patients recently exposed to heparin that causes thrombocytopenia and often results in venous and/or arterial thrombosis. HIT occurs in up to 5% of patients receiving unfractionated heparin (UFH) for longer than 4 days and in <1% who receive low molecular weight heparin (LMWH). HIT is characterised by immunoglobulin G (IgG) antibodies that recognize an antigen complex of platelet factor 4 (PF4) bound to heparin. These antibodies trigger a highly prothrombotic state by causing intravascular platelet aggregation, intense platelet, monocyte and endothelial cell activation, and excessive thrombin generation.
# CLINICAL FEATURES:
HIT typically presents with a fall in platelet count with or without venous and/or arterial thrombosis.
• Thrombocytopenia: A platelet count fall >30% beginning 5-10 days after UFH or LMWH exposure, in the absence of other causes of thrombocytopenia, should be considered to be HIT, unless proven otherwise. A more rapid onset of platelet count fall (often within 24 hours of heparin exposure) can occur when there is a history of heparin exposure within the preceding 3 months. Bleeding is very infrequent. • Thrombosis: HIT is associated with a high risk (30-50%) of new venous or arterial thromboembolism. Thrombosis may be the presenting clinical manifestation of HIT or can occur during or shortly after the thrombocytopenia. • Other clinical manifestations of HIT: Less frequent manifestations include heparin-induced skin lesions, adrenal hemorrhagic infarction (secondary to adrenal vein thrombosis), transient global amnesia, and acute systemic reactions (e.g. chills, dyspnea, cardiac or respiratory arrest following IV heparin bolus).
# DIAGNOSIS:
The diagnosis of HIT is based on three criteria:
1) The patient is receiving or has had recent exposure to UFH or LMWH.
2) At least one clinical feature of the syndrome is present (significant fall in platelet count, new venous and/or arterial thrombosis). 3) There is laboratory evidence of HIT antibodies. 1 provide a rational approach to suspected HIT.
# Figure 1 and Table
# HIT ASSAYS:
Therapeutic decisions, including the cessation of UFH or LMWH and the administration of a HITsafe, alternative anticoagulant (see below), should not be delayed pending the results of laboratory testing if the clinical suspicion of HIT is not low. There are two main types of tests for HIT:
1) immunologic assays which detect antibodies to PF4/heparin complexes ("HIT antibodies"; e.g. enzyme-linked immunosorbent assay [ELISA], particle gel immunoassay, latex particle agglutination assay), and; 2) functional assays (e.g. serotonin release assay [SRA], heparin-induced platelet aggregation [HIPA]).
In most centres, only the immunologic assay results are available on an urgent basis.
Although both assay types are sensitive for HIT (>90%), false positives are common with the immunologic assays.
# 4TS SCORE:
Criteria for the 4Ts score, which is used to determine the likelihood that a patient has HIT, are outlined in Table 1. Given the high negative predictive value of the 4Ts score, laboratory testing for HIT is not always required for patients with low pre-test probability according to the 4Ts score, as long as all the elements of the score are known. Occasionally, there may be uncertainty about the score due to multiple missing platelet counts, unclear history of recent heparin exposure or concurrent potential causes of thrombocytopenia; in this case, testing for HIT should be done.
Since the majority of patients with a positive immunologic assay do not have HIT, and because of the long-term implications of a HIT diagnosis, obtaining a confirmatory functional assay should be considered in patients with an intermediate 4Ts score and/or ELISA optical density <2.0.
# MANAGEMENT:
Patients with HIT are best managed by, or in consultation with, a specialist experienced in managing HIT.
Each of the following points is important in the management of HIT:
• Stop all heparin exposure, including LMWH, prophylactic heparin, heparin locks or flushes, and remove heparin-coated catheters. • Start anticoagulation with a non-heparin, HIT-safe anticoagulant such as fondaparinux, argatroban, a direct oral anticoagulant (DOAC), bivalirudin, or danaparoid (see Table 2 for dosing). If a new thrombotic event is present (HIT with thrombosis, or "HITT"), then the acute VTE treatment regimen for the DOAC is preferred, rather than the maintenance dosing regimen. For example, rivaroxaban should be initiated at 15 mg BID x 3 weeks followed by 20 mg daily. • Consider if the patient may already have had a thromboembolic event. Patients with suspected venous or arterial thrombosis should have objective confirmation since this will affect the duration of HIT-safe anticoagulant use. Even without a clinical suspicion of deep vein thrombosis (DVT), bilateral leg ultrasonography to screen for asymptomatic DVT are recommended, especially if the patient has additional risk factors for VTE. • Avoid platelet transfusions unless the patient is bleeding or requires a procedure associated with a high risk of bleeding. • Early use of warfarin should be avoided in acute HIT since it may make the prothrombotic state worse. If warfarin has already been started when HIT is diagnosed, it should be stopped, and vitamin K administered to reverse the warfarin effect. Warfarin alone is insufficient to protect against thrombosis secondary to HIT as long as HIT is considered active (i.e. platelets less than 150 x 10 9 /L). • Warfarin or a DOAC are appropriate for longer-term anticoagulation, if indicated, after thrombocytopenia has resolved. If transitioning to warfarin from a HIT-safe anticoagulant, such as fondaparinux, bivalirudin, or danaparoid: -Do not initiate warfarin until platelet count is ≥150 x 10 9 /L.
-Overlap warfarin with therapeutic doses of the HIT-safe anticoagulant for ≥5 days and until the international normalized ratio (INR) is therapeutic. Caution should be used when transitioning to warfarin from argatroban because it also increases the INR. • Duration of anticoagulation for HIT with thrombosis: at least 3 months.
• Duration of anticoagulation for HIT without thrombosis: at least 4 weeks.
• Heparin or LMWH should not be given to a patient with previous HIT without consultation with a specialist.
# SPECIAL CONSIDERATIONS:
# Pediatrics:
The incidence of HIT is less than in adults, but the approach to investigation and management is similar. Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with HIT. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
# Pregnancy:
HIT is infrequent in pregnancy. The approach to investigation is as outlined above. Danaparoid does not cross the placenta and has been used to treat HIT in pregnancy. The use of fondaparinux (with the cautions noted above) is an option where danaparoid is not available; however, this drug has been reported to cross the placenta in small amounts and experience with fondaparinux in pregnancy is very limited (especially during the first trimester). DOACs should not be prescribed during pregnancy.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES
# Date of Version: 23October2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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# Background
Chemotherapy-and radiation-induced nausea and vomiting (CINV/RINV) is a common side effect of patients undergoing cancer treatment. Without appropriate antiemetic therapy, 70% to 80% of cancer patients undergoing chemotherapy develop CINV. 1 Similarly, upward of 50% to 80% of patients treated with radiation therapy (RT) develop RINV. 2 CINV/RINV can lead to morbidity, poor performance status and decreased quality of life in patients. 1,3 CINV. The common patient-related factors for CINV include younger age ( 90% of patients;
- Moderate emetogenic chemotherapy (MEC) -affects 30-90% of patients;
- Low emetogenic chemotherapy (LEC) -affects 10-30% of patients; and,
- Minimal emetogenic chemotherapy -affects <10% of patients.
CINV can also be classified according to its onset relative to the start of chemotherapy and the patients' previous responses to antiemetic prophylaxis: 8,12 - Acute -occurs within 24 hours after chemotherapy;
- Delayed -occurs more than 24 hours after chemotherapy;
- Breakthrough -occurs within 5 days of chemotherapy after the use of appropriate prophylactic antiemetic agents; - Anticipatory -a conditioned response that occurs in patients who experienced CINV during previous cycles of chemotherapy; and, - Refractory -occurs in subsequent cycles of chemotherapy, after the use of appropriate prophylactic antiemetic agents have failed in earlier cycles.
Neurotransmitters including dopamine, serotonin, and substance P are thought to be important mediators of CINV (Hesketh 2008). Chemotherapy agents can cause nausea and vomiting by activating neurotransmitter receptors present in the area postrema of the brain (central pathway) and the enterochromaffin cells of the gastrointestinal tract (peripheral pathway). 13 Effective antiemetic agents provide control of vomiting by blocking neurotransmitter receptors and thus inhibiting stimulation of the chemoreceptor trigger zone. RINV. Only previous treatment with chemotherapy has been identified as a patient-related risk factor for RINV. 14,15 The risk of emesis from RT is categorized according to the radiation field: 9,10,16
- High emetogenic RT -total body irradiation
- Moderate emetogenic RT -upper abdomen, craniospinal - Low emetogenic RT -brain, head and neck, thorax, pelvis - Minimal emetogenic RT -extremities, breast
The risk levels listed above do not take into account radiation dose, fractionation, or technique and are mainly based on incidence of emesis in clinical studies and expert opinions. 16 While little is known about the pathophysiology of RINV, the causal factors underlying RINV and CINV are believed to be related. 17 The goal of antiemetic therapy is to prevent CINV/RINV, and while significant progress has been made to develop a number of effective and well-tolerated antiemetic treatments, CINV/RINV remains a serious side effect of cancer treatment. The objective of this guideline is to provide clinicians with recommendations for the prevention and management of CINV/RINV. This document describes Alberta Health Services (AHS) endorsement of the 2017 American Society of Clinical Oncology (ASCO) clinical practice guideline for antiemetics. 9
Note: Some chemotherapy agents recommended by ASCO do not appear in this document because they are not currently available in Alberta (see Appendix A). Similarly, some drug delivery systems (e.g. oral dissolving films, transdermal patches) have been omitted because they are not available from the cancer center pharmacies.
Guideline Questions The recommendations in the present guideline have been adapted from the evidence-based clinical guideline Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Beyond this, the working group updated the guideline by including supplementary supporting research and evidence-based recommendations from the literature searches.
Evidence tables are available upon request from GURU@ahs.ca.
# Target Population
Adult patients receiving potentially emetogenic chemotherapy and/or radiotherapy for cancer.
# Recommendations
# Combination Chemotherapy. ENDORSED
Patients who are treated with combination chemotherapy should be offered antiemetics that are appropriate for the agent with the highest emetogenic level. Please refer to Appendix B and Appendix C to identify the risk level of single oral and IV antineoplastic agents in adults, respectively.
# Highly Emetogenic Chemotherapy (>90% frequency of emesis). ENDORSED WITH ADAPTATIONS a)
Patients who are treated with cisplatin and other highly emetogenic single agents should be offered a four-drug combination of a neurokinin 1 (NK1) receptor antagonist (RA), a serotonin (5-HT3) RA, dexamethasone, and olanzapine. Dexamethasone and olanzapine should be continued on days 2 to 4. Single agent palonosetron 0.5 mg PO or 0.25 mg IV may also be used, but is not listed on the AHS Drug Formulary. ŧ The dexamethasone dose is for patients who are receiving the recommended four-drug regimen for highly emetic chemotherapy. If patients do not receive an NK1 RA, the dexamethasone dose should be adjusted to 20 mg on day 1 and to 16 mg on days 2-4. § The decision to include a lower olanzapine dose differs from the ASCO recommendations and is based on data showing comparable efficacy between 10 mg and 5 mg and the risk of increased sedation. Olanzapine may be used on a scheduled or PRN basis. If you choose to use olanzapine, we recommend against using metoclopramide, prochlorperazine, or haloperidol because of an increased risk of extrapyramidal symptoms. Single agent palonosetron 0.5 mg PO or 0.25 mg IV may also be used, but is not listed on the AHS Drug Formulary. ŧ The dexamethasone dose is for patients who are receiving the recommended four-drug regimen for highly emetic chemotherapy. If patients do not receive an NK1 RA, the dexamethasone dose should be adjusted to 20 mg on day 1 and to 16 mg on days 2-4. If palonosetron is the 5-HT3 RA used, dexamethasone does not need to continue after day 1. If other 5-HT3 RAs are used, the need for dexamethasone beyond day 1 is uncertain. β The decision to include a lower olanzapine dose differs from the ASCO recommendations and is based on data showing comparable efficacy between 10 mg and 5 mg and the risk of increased sedation. Olanzapine may be used on a scheduled or PRN basis. If you choose to use olanzapine, we recommend against using metoclopramide, prochlorperazine, or haloperidol because of an increased risk of extrapyramidal symptoms.
# Moderately Emetogenic Chemotherapy (30-90% frequency of emesis). ENDORSED WITH ADAPTATIONS a)
# Low Emetogenic Chemotherapy (10-30% frequency of emesis). ENDORSED WITH ADAPTATIONS
Patients who are treated with low-emetic-risk chemotherapy agents should be offered a single dose of a 5-HT3 RA or dexamethasone before chemotherapy treatment.
# Drug Dose on Day of Chemotherapy
5-HT3 RA † - Ondansetron, or - Granisetron Or, - Dexamethasone- §
- 8 mg PO bid or 8 mg ODT bid or 8 mg IV - 2 mg PO or 1 mg IV 8 mg PO/IV † Single agent palonosetron 0.5 mg PO or 0.25 mg IV may also be used, but is not listed on the AHS Drug Formulary. *The Working Group agreed with NCCN guidance that a single dose of a dopamine antagonist, e.g. metoclopramide (10 mg PO/IV) or prochlorperazine (10 mg PO/IV), is a reasonable alternative to dexamethasone. 11 Single agent palonosetron 0.5 mg PO or 0.25 mg IV may also be used, but is not listed on the AHS Drug Formulary. ŧ The decision to add dexamethasone on subsequent days differs from the ASCO recommendations. The Working Group agreed with NCCN guidance that dexamethasone may be offered to patients at high risk for emesis or those with poorly controlled CINV on days 2 and 3. 11 Lower doses, given for shorter durations may be acceptable based on patient characteristics. If dexamethasone is eliminated on subsequent days for delayed nausea and emesis prevention, consider other alternative antiemetics (e.g. olanzapine).
# Drug
# Drug
Dose on Day of Chemotherapy § When dexamethasone is required as premedication for drugs with higher risk of hypersensitivity reactions (e.g. docetaxel, paclitaxel, etc.), or other reasons (e.g. pemetrexed), the dose and dosing schedule as a premedication may be different than antiemetic doses. The dexamethasone dose should be considered in the calculation of the required antiemetic dosage.
# Minimal Emetogenic Chemotherapy (<10%). REJECTED AND REVISED
ASCO recommends that patients who are treated with minimal-emetic-risk chemotherapy agents should not be offered routine antiemetic prophylaxis. However, the Working Group agreed that prophylactic antiemetics may be administered to patients who have had emesis with prior low-risk regimens, or on an as needed basis. Examples include, dexamethasone (4 to 8 mg PO/IV), prochlorperazine (10 mg PO/IV), or metoclopramide (10 mg PO/IV).
# Adjunctive Drugs. ENDORSED WITH ADAPTATIONS
Lorazepam is not recommended as a single-agent antiemetic, but is a useful adjunct to antiemetic drugs because it reduces anxiety and anticipatory nausea and/or vomiting. The Working Group agreed with NCCN guidance that a proton pump inhibitor (e.g. omeprazole 20 mg PO daily) or H2 blocker (e.g. ranitidine 150 mg PO bid) may also be considered to prevent or manage dyspepsia. 11
# Cannabinoids. ENDORSED WITH ADAPTATIONS
In agreement with ASCO and Canadian-developed guidelines 22 for prescribing medical cannabinoids, the Working Group agreed that medical cannabis (inhaled, oils, or edibles), as well as nabiximols are not recommended for CINV/RINV. In addition, the Working Group agreed against the use of medical cannabinoids as first-or second-line therapy for CINV/RINV due to a lack of randomized clinical trial data. However, medical cannabinoids may be considered for treatment of refractory CINV/RINV assuming that patients have had a reasonable therapeutic trial of standard therapies, and they are used as adjuncts to other prescribed therapies. 11, Nabilone (1 to 2 mg PO bid) is recommended. 11,22,23 Dose reduction may be required when prescribing for medically frail patients. Clinicians should discuss the risks and benefits of medical cannabinoids for CINV/RINV with patients before prescribing. 22,
# Complementary and Alternative Therapies. ENDORSED
Evidence is insufficient to make a recommendation for or against the use of ginger, acupuncture /acupressure, and other complementary or alternative therapies for the prevention of NV in patients with cancer. 9
# High-Dose Chemotherapy with Stem Cell or Bone Marrow Transplantation. ENDORSED WITH ADAPTATIONS
The Working Group agreed with ASCO that patients who are treated with high-dose chemotherapy and stem cell or bone marrow transplantation should be offered a three-drug combination of an NK1 RA, a 5-HT3 RA, and dexamethasone before chemotherapy. However, the use of steroids is not recommended with cellular therapies, including preparative lymphodepleting chemotherapy regimens because the risk of inactivating the immune response is very high with even small doses of steroids. 27,28 NCCN recommends avoiding the use of corticosteroid antiemetic premedication for 3-5 days prior to and 90 days after CAR T-cell therapies. 11 However, because prednisone, methylprednisone and dexamethasone have half-lives of only several hours, the Working Group agreed that corticosteroids may be used as late as on day -1.
# Immune Checkpoint Inhibitors
There is currently inconclusive data regarding interactions between concurrent corticosteroid use and immune checkpoint inhibitors. 11 The Working Group recommends a corticosteroid-sparing approach to antiemetic prophylaxis where feasible and on a case-by-case basis of individual regimens when immune checkpoint inhibitors are administered with chemotherapy.
# Multiday Chemotherapy. ENDORSED WITH ADAPTATIONS a)
Patients who are treated with multiday highly emetogenic chemotherapy (e.g. 3 or 5-day cisplatin regimens) should be offered a three-drug combination of an NK1 RA, a 5-HT3 RA, and dexamethasone administered on each day of chemotherapy and for up to 2 days after chemotherapy is completed. 9
b) Patients who are treated with multiday moderately or low emetogenic chemotherapy should be offered antiemetics before treatment that are appropriate for the emetic risk of the chemotherapy agent administered on each day of the chemotherapy treatment, and for up to 2 days after the completion of the chemotherapy regimen. 9
# Breakthrough Nausea and Vomiting. ENDORSED WITH ADAPTATIONS a)
Clinicians should re-evaluate emetic risk to ascertain that the best regimen is being administered, as well as re-evaluate disease status, concurrent illnesses and medications to assess for possible other mechanisms of nausea and vomiting. Isolated vomiting without substantial nausea is usually related to motility problems.
b) Patients who experience nausea or vomiting despite optimal prophylaxis, and who did not receive olanzapine prophylactically should be offered olanzapine (2.5 to 5 mg PO daily as a starting dose to a maximum of 10 mg PO daily) 21 in addition to continuing the standard antiemetic regimen. Alternatively, clinicians may choose metoclopramide 10 to 20 mg PO every 4-6 hours or prochlorperazine 10 mg PO every 6 hours. 11 c) In addition to continuing the standard antiemetic regimen, patients who experience nausea or vomiting despite optimal prophylaxis, and who have already received olanzapine, may be offered a drug of a different class including one or more of the following (not a comprehensive list): 11,21,23 - Proton pump inhibitor (e.g. omeprazole 20 mg PO daily) or H2 blocker (e.g. ranitidine 150 mg PO bid) - Dimenhydrinate 50 mg PO every 4-6 h - Scopolamine patch - Nabilone 1 to 2 mg PO bid - Dopamine antagonists may be used at low doses with close monitoring for extrapyramidal and/or central nervous system depression. Options include: prochlorperazine 5 mg PO every 6 h, haloperidol 0.5 mg PO bid Note: If the clinician chooses to use olanzapine, we recommend against using metoclopramide due to an increased risk of extrapyramidal symptoms or neuroleptic malignant syndrome.
# Anticipatory Nausea and Vomiting. ENDORSED WITH ADAPTATIONS
For the prevention of anticipatory nausea and vomiting, all patients should receive optimal antiemetic therapy beginning with the initial cycles of chemotherapy as opposed to assessing the patient's emetic response to a less effective antiemetic treatment. The most common cause of anticipatory nausea and vomiting is anxiety. Therefore, for patients who do develop anticipatory nausea and vomiting, benzodiazepines and behavioral therapy are recommended (e.g. relaxation/systematic desensitization, hypnosis, relaxation exercises, yoga). 11,23
# Highly Emetogenic Radiation Therapy. ENDORSED
Patients who are treated with highly emetogenic RT (total body) should be offered a two-drug combination of a 5-HT3 RA and dexamethasone before each fraction and on the day after each fraction if RT is not planned for that day. 9 Use as rescue therapy -titrate up as needed to maximum of 3-4 administrations daily Ɨ Ɨ Depending on the severity of symptoms and the remaining duration of RT, patients can receive subsequent rescue therapy as needed or begin receiving prophylactic therapy for the remainder of RT.
# Drug
# Minimal Emetogenic Radiation Therapy. ENDORSED
Patients who are treated with minimal-emetic-risk RT (extremities, breast) should be offered rescue therapy with a 5-HT3 RA, dexamethasone, or a dopamine RA.
# Concurrent Chemotherapy and Radiation Therapy. ENDORSED
Patients who are treated with concurrent chemotherapy and RT should receive antiemetic therapy that is appropriate for the emetic risk level of chemotherapy agents, unless the risk level of the RT is higher. During periods when prophylactic antiemetic therapy for chemotherapy agents has ended and ongoing RT would normally be managed with its own prophylactic therapy, patients should receive prophylactic therapy that is appropriate for the emetic risk of the RT until the next period of chemotherapy, rather than receiving rescue therapy for chemotherapy agents as needed.
# Development and Revision History
This guideline was reviewed and endorsed by members of the Alberta Provincial Tumour Teams. Members include medical oncologists, radiation oncologists, hematologists, pharmacists, and allied health. Evidence was selected and reviewed by a small working group of clinicians and the Guideline Resource Unit (GURU). A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2019.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Abbreviations
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# Background
Chemotherapy-and radiation-induced nausea and vomiting (CINV/RINV) is a common side effect of patients undergoing cancer treatment. Without appropriate antiemetic therapy, 70% to 80% of cancer patients undergoing chemotherapy develop CINV. 1 Similarly, upward of 50% to 80% of patients treated with radiation therapy (RT) develop RINV. 2 CINV/RINV can lead to morbidity, poor performance status and decreased quality of life in patients. 1,3 CINV. The common patient-related factors for CINV include younger age (<50 years), female gender, history of motion sickness and/or pregnancy-related nausea and vomiting, anxiety and non-habitual alcohol intake. [4][5][6] However, the main risk factor for CINV is the type of chemotherapy agents being administered. Chemotherapy agents are classified according to their relative emetogenic risk potential: [7][8][9][10][11] • High emetogenic chemotherapy (HEC) -affects > 90% of patients;
• Moderate emetogenic chemotherapy (MEC) -affects 30-90% of patients;
• Low emetogenic chemotherapy (LEC) -affects 10-30% of patients; and,
• Minimal emetogenic chemotherapy -affects <10% of patients.
CINV can also be classified according to its onset relative to the start of chemotherapy and the patients' previous responses to antiemetic prophylaxis: 8,12 • Acute -occurs within 24 hours after chemotherapy;
• Delayed -occurs more than 24 hours after chemotherapy;
• Breakthrough -occurs within 5 days of chemotherapy after the use of appropriate prophylactic antiemetic agents; • Anticipatory -a conditioned response that occurs in patients who experienced CINV during previous cycles of chemotherapy; and, • Refractory -occurs in subsequent cycles of chemotherapy, after the use of appropriate prophylactic antiemetic agents have failed in earlier cycles.
Neurotransmitters including dopamine, serotonin, and substance P are thought to be important mediators of CINV (Hesketh 2008). Chemotherapy agents can cause nausea and vomiting by activating neurotransmitter receptors present in the area postrema of the brain (central pathway) and the enterochromaffin cells of the gastrointestinal tract (peripheral pathway). 13 Effective antiemetic agents provide control of vomiting by blocking neurotransmitter receptors and thus inhibiting stimulation of the chemoreceptor trigger zone. RINV. Only previous treatment with chemotherapy has been identified as a patient-related risk factor for RINV. 14,15 The risk of emesis from RT is categorized according to the radiation field: 9,10,16
• High emetogenic RT -total body irradiation
• Moderate emetogenic RT -upper abdomen, craniospinal • Low emetogenic RT -brain, head and neck, thorax, pelvis • Minimal emetogenic RT -extremities, breast
The risk levels listed above do not take into account radiation dose, fractionation, or technique and are mainly based on incidence of emesis in clinical studies and expert opinions. 16 While little is known about the pathophysiology of RINV, the causal factors underlying RINV and CINV are believed to be related. 17 The goal of antiemetic therapy is to prevent CINV/RINV, and while significant progress has been made to develop a number of effective and well-tolerated antiemetic treatments, CINV/RINV remains a serious side effect of cancer treatment. The objective of this guideline is to provide clinicians with recommendations for the prevention and management of CINV/RINV. This document describes Alberta Health Services (AHS) endorsement of the 2017 American Society of Clinical Oncology (ASCO) clinical practice guideline for antiemetics. 9
Note: Some chemotherapy agents recommended by ASCO do not appear in this document because they are not currently available in Alberta (see Appendix A). Similarly, some drug delivery systems (e.g. oral dissolving films, transdermal patches) have been omitted because they are not available from the cancer center pharmacies.
Guideline Questions The recommendations in the present guideline have been adapted from the evidence-based clinical guideline Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Beyond this, the working group updated the guideline by including supplementary supporting research and evidence-based recommendations from the literature searches.
Evidence tables are available upon request from GURU@ahs.ca.
# Target Population
Adult patients receiving potentially emetogenic chemotherapy and/or radiotherapy for cancer.
# Recommendations
# Combination Chemotherapy. ENDORSED
Patients who are treated with combination chemotherapy should be offered antiemetics that are appropriate for the agent with the highest emetogenic level. Please refer to Appendix B and Appendix C to identify the risk level of single oral and IV antineoplastic agents in adults, respectively.
# Highly Emetogenic Chemotherapy (>90% frequency of emesis). ENDORSED WITH ADAPTATIONS a)
Patients who are treated with cisplatin and other highly emetogenic single agents should be offered a four-drug combination of a neurokinin 1 (NK1) receptor antagonist (RA), a serotonin (5-HT3) RA, dexamethasone, and olanzapine. Dexamethasone and olanzapine should be continued on days 2 to 4. Single agent palonosetron 0.5 mg PO or 0.25 mg IV may also be used, but is not listed on the AHS Drug Formulary. ŧ The dexamethasone dose is for patients who are receiving the recommended four-drug regimen for highly emetic chemotherapy. If patients do not receive an NK1 RA, the dexamethasone dose should be adjusted to 20 mg on day 1 and to 16 mg on days 2-4. § The decision to include a lower olanzapine dose differs from the ASCO recommendations and is based on data showing comparable efficacy between 10 mg and 5 mg and the risk of increased sedation. [18][19][20] Olanzapine may be used on a scheduled or PRN basis. If you choose to use olanzapine, we recommend against using metoclopramide, prochlorperazine, or haloperidol because of an increased risk of extrapyramidal symptoms. Single agent palonosetron 0.5 mg PO or 0.25 mg IV may also be used, but is not listed on the AHS Drug Formulary. ŧ The dexamethasone dose is for patients who are receiving the recommended four-drug regimen for highly emetic chemotherapy. If patients do not receive an NK1 RA, the dexamethasone dose should be adjusted to 20 mg on day 1 and to 16 mg on days 2-4. ** If palonosetron is the 5-HT3 RA used, dexamethasone does not need to continue after day 1. If other 5-HT3 RAs are used, the need for dexamethasone beyond day 1 is uncertain. β The decision to include a lower olanzapine dose differs from the ASCO recommendations and is based on data showing comparable efficacy between 10 mg and 5 mg and the risk of increased sedation. [18][19][20] Olanzapine may be used on a scheduled or PRN basis. If you choose to use olanzapine, we recommend against using metoclopramide, prochlorperazine, or haloperidol because of an increased risk of extrapyramidal symptoms.
# Moderately Emetogenic Chemotherapy (30-90% frequency of emesis). ENDORSED WITH ADAPTATIONS a)
# Low Emetogenic Chemotherapy (10-30% frequency of emesis). ENDORSED WITH ADAPTATIONS
Patients who are treated with low-emetic-risk chemotherapy agents should be offered a single dose of a 5-HT3 RA or dexamethasone before chemotherapy treatment.
# Drug Dose on Day of Chemotherapy
5-HT3 RA † • Ondansetron, or • Granisetron Or, • Dexamethasone* §
• 8 mg PO bid or 8 mg ODT bid or 8 mg IV • 2 mg PO or 1 mg IV 8 mg PO/IV † Single agent palonosetron 0.5 mg PO or 0.25 mg IV may also be used, but is not listed on the AHS Drug Formulary. *The Working Group agreed with NCCN guidance that a single dose of a dopamine antagonist, e.g. metoclopramide (10 mg PO/IV) or prochlorperazine (10 mg PO/IV), is a reasonable alternative to dexamethasone. 11 Single agent palonosetron 0.5 mg PO or 0.25 mg IV may also be used, but is not listed on the AHS Drug Formulary. ŧ The decision to add dexamethasone on subsequent days differs from the ASCO recommendations. The Working Group agreed with NCCN guidance that dexamethasone may be offered to patients at high risk for emesis or those with poorly controlled CINV on days 2 and 3. 11 Lower doses, given for shorter durations may be acceptable based on patient characteristics. If dexamethasone is eliminated on subsequent days for delayed nausea and emesis prevention, consider other alternative antiemetics (e.g. olanzapine).
# Drug
# Drug
Dose on Day of Chemotherapy § When dexamethasone is required as premedication for drugs with higher risk of hypersensitivity reactions (e.g. docetaxel, paclitaxel, etc.), or other reasons (e.g. pemetrexed), the dose and dosing schedule as a premedication may be different than antiemetic doses. The dexamethasone dose should be considered in the calculation of the required antiemetic dosage.
# Minimal Emetogenic Chemotherapy (<10%). REJECTED AND REVISED
ASCO recommends that patients who are treated with minimal-emetic-risk chemotherapy agents should not be offered routine antiemetic prophylaxis. However, the Working Group agreed that prophylactic antiemetics may be administered to patients who have had emesis with prior low-risk regimens, or on an as needed basis. Examples include, dexamethasone (4 to 8 mg PO/IV), prochlorperazine (10 mg PO/IV), or metoclopramide (10 mg PO/IV).
# Adjunctive Drugs. ENDORSED WITH ADAPTATIONS
Lorazepam is not recommended as a single-agent antiemetic, but is a useful adjunct to antiemetic drugs because it reduces anxiety and anticipatory nausea and/or vomiting. The Working Group agreed with NCCN guidance that a proton pump inhibitor (e.g. omeprazole 20 mg PO daily) or H2 blocker (e.g. ranitidine 150 mg PO bid) may also be considered to prevent or manage dyspepsia. 11
# Cannabinoids. ENDORSED WITH ADAPTATIONS
In agreement with ASCO and Canadian-developed guidelines 22 for prescribing medical cannabinoids, the Working Group agreed that medical cannabis (inhaled, oils, or edibles), as well as nabiximols are not recommended for CINV/RINV. In addition, the Working Group agreed against the use of medical cannabinoids as first-or second-line therapy for CINV/RINV due to a lack of randomized clinical trial data. However, medical cannabinoids may be considered for treatment of refractory CINV/RINV assuming that patients have had a reasonable therapeutic trial of standard therapies, and they are used as adjuncts to other prescribed therapies. 11,[21][22][23] Nabilone (1 to 2 mg PO bid) is recommended. 11,22,23 Dose reduction may be required when prescribing for medically frail patients. Clinicians should discuss the risks and benefits of medical cannabinoids for CINV/RINV with patients before prescribing. 22,[24][25][26]
# Complementary and Alternative Therapies. ENDORSED
Evidence is insufficient to make a recommendation for or against the use of ginger, acupuncture /acupressure, and other complementary or alternative therapies for the prevention of NV in patients with cancer. 9
# High-Dose Chemotherapy with Stem Cell or Bone Marrow Transplantation. ENDORSED WITH ADAPTATIONS
The Working Group agreed with ASCO that patients who are treated with high-dose chemotherapy and stem cell or bone marrow transplantation should be offered a three-drug combination of an NK1 RA, a 5-HT3 RA, and dexamethasone before chemotherapy. However, the use of steroids is not recommended with cellular therapies, including preparative lymphodepleting chemotherapy regimens because the risk of inactivating the immune response is very high with even small doses of steroids. 27,28 NCCN recommends avoiding the use of corticosteroid antiemetic premedication for 3-5 days prior to and 90 days after CAR T-cell therapies. 11 However, because prednisone, methylprednisone and dexamethasone have half-lives of only several hours, the Working Group agreed that corticosteroids may be used as late as on day -1.
# Immune Checkpoint Inhibitors
There is currently inconclusive data regarding interactions between concurrent corticosteroid use and immune checkpoint inhibitors. 11 The Working Group recommends a corticosteroid-sparing approach to antiemetic prophylaxis where feasible and on a case-by-case basis of individual regimens when immune checkpoint inhibitors are administered with chemotherapy.
# Multiday Chemotherapy. ENDORSED WITH ADAPTATIONS a)
Patients who are treated with multiday highly emetogenic chemotherapy (e.g. 3 or 5-day cisplatin regimens) should be offered a three-drug combination of an NK1 RA, a 5-HT3 RA, and dexamethasone administered on each day of chemotherapy and for up to 2 days after chemotherapy is completed. 9
b) Patients who are treated with multiday moderately or low emetogenic chemotherapy should be offered antiemetics before treatment that are appropriate for the emetic risk of the chemotherapy agent administered on each day of the chemotherapy treatment, and for up to 2 days after the completion of the chemotherapy regimen. 9
# Breakthrough Nausea and Vomiting. ENDORSED WITH ADAPTATIONS a)
Clinicians should re-evaluate emetic risk to ascertain that the best regimen is being administered, as well as re-evaluate disease status, concurrent illnesses and medications to assess for possible other mechanisms of nausea and vomiting. Isolated vomiting without substantial nausea is usually related to motility problems.
b) Patients who experience nausea or vomiting despite optimal prophylaxis, and who did not receive olanzapine prophylactically should be offered olanzapine (2.5 to 5 mg PO daily as a starting dose to a maximum of 10 mg PO daily) 21 in addition to continuing the standard antiemetic regimen. Alternatively, clinicians may choose metoclopramide 10 to 20 mg PO every 4-6 hours or prochlorperazine 10 mg PO every 6 hours. 11 c) In addition to continuing the standard antiemetic regimen, patients who experience nausea or vomiting despite optimal prophylaxis, and who have already received olanzapine, may be offered a drug of a different class including one or more of the following (not a comprehensive list): 11,21,23 • Proton pump inhibitor (e.g. omeprazole 20 mg PO daily) or H2 blocker (e.g. ranitidine 150 mg PO bid) • Dimenhydrinate 50 mg PO every 4-6 h • Scopolamine patch • Nabilone 1 to 2 mg PO bid • Dopamine antagonists may be used at low doses with close monitoring for extrapyramidal and/or central nervous system depression. Options include: prochlorperazine 5 mg PO every 6 h, haloperidol 0.5 mg PO bid Note: If the clinician chooses to use olanzapine, we recommend against using metoclopramide due to an increased risk of extrapyramidal symptoms or neuroleptic malignant syndrome.
# Anticipatory Nausea and Vomiting. ENDORSED WITH ADAPTATIONS
For the prevention of anticipatory nausea and vomiting, all patients should receive optimal antiemetic therapy beginning with the initial cycles of chemotherapy as opposed to assessing the patient's emetic response to a less effective antiemetic treatment. The most common cause of anticipatory nausea and vomiting is anxiety. Therefore, for patients who do develop anticipatory nausea and vomiting, benzodiazepines and behavioral therapy are recommended (e.g. relaxation/systematic desensitization, hypnosis, relaxation exercises, yoga). 11,23
# Highly Emetogenic Radiation Therapy. ENDORSED
Patients who are treated with highly emetogenic RT (total body) should be offered a two-drug combination of a 5-HT3 RA and dexamethasone before each fraction and on the day after each fraction if RT is not planned for that day. 9 Use as rescue therapy -titrate up as needed to maximum of 3-4 administrations daily Ɨ Ɨ Depending on the severity of symptoms and the remaining duration of RT, patients can receive subsequent rescue therapy as needed or begin receiving prophylactic therapy for the remainder of RT.
# Drug
# Minimal Emetogenic Radiation Therapy. ENDORSED
Patients who are treated with minimal-emetic-risk RT (extremities, breast) should be offered rescue therapy with a 5-HT3 RA, dexamethasone, or a dopamine RA.
# Concurrent Chemotherapy and Radiation Therapy. ENDORSED
Patients who are treated with concurrent chemotherapy and RT should receive antiemetic therapy that is appropriate for the emetic risk level of chemotherapy agents, unless the risk level of the RT is higher. During periods when prophylactic antiemetic therapy for chemotherapy agents has ended and ongoing RT would normally be managed with its own prophylactic therapy, patients should receive prophylactic therapy that is appropriate for the emetic risk of the RT until the next period of chemotherapy, rather than receiving rescue therapy for chemotherapy agents as needed.
# Development and Revision History
This guideline was reviewed and endorsed by members of the Alberta Provincial Tumour Teams. Members include medical oncologists, radiation oncologists, hematologists, pharmacists, and allied health. Evidence was selected and reviewed by a small working group of clinicians and the Guideline Resource Unit (GURU). A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2019.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Abbreviations
# Funding Source
Financial support for the development of CancerControl Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerControl Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Generated using the standard COI form.
Dr. Elizabeth Kurien has nothing to disclose.
Dr. Jay Easaw has nothing to disclose.
Margaret Longworth has nothing to disclose.
Patrick Yau has nothing to disclose.
Dr. Lyle Galloway has nothing to disclose.
Reanne Booker has nothing to disclose.
Amy Driga has nothing to disclose.
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To provide a diagnostic approach to patients with suspected acute pulmonary embolism (PE).Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disease, affecting approximately 1-2 in 1,000 adults per year. The diagnosis of PE has increased significantly since the advent of computed tomography pulmonary angiography (CTPA) with its widespread availability and enhanced sensitivity. The majority of PE originates in the proximal deep veins of the leg, despite the observation that only 25-50% of patients with PE have clinically evident DVT at the time of PE diagnosis. While active malignancy, surgery (especially orthopedic), hospitalization, air travel >8 hours, and hormone use/pregnancy are common transient provoking factors, approximately 50% of first-time PEs appear to be unprovoked. Symptoms of PE may include sudden onset dyspnea, pleuritic chest pain, hemoptysis, and syncope. Signs of PE may include tachypnea, tachycardia, hypoxemia, hypotension, and features of right ventricular dysfunction (distended jugular veins). There may be accompanying signs and symptoms of DVT. The ECG may show right ventricular strain (S1Q3T3, right bundle branch block and T-inversion in leads V1-V4). Up to 10% of symptomatic PEs are fatal within the first hour of symptom onset. Independent predictors of mortality within the first few days after diagnosis of PE include hypotension (systolic blood pressure <90 mmHg), clinical right heart failure, right ventricular dilatation on CTPA/echocardiography, positive troponin, and elevated brain natriuretic peptide (BNP). Early diagnosis and treatment of PE reduces morbidity and mortality.# DIAGNOSIS OF PE:
The constellation of symptoms and signs may be suggestive of PE but do not alone have the sensitivity or specificity to rule in or rule out the diagnosis. When the diagnosis of PE is considered, the clinical stability of the patient and associated pre-test probability will dictate the diagnostic approach (see Figure 1).
In patients without hypotension (SBP >90 mmHg), pre-test probability can be assessed by a validated clinical prediction rule (see Table 1). In patients with low pretest probability of PE, further testing is not necessary if all clinical features/criteria in the Pulmonary Embolism Rule-out Criteria (PERC) are present (see Table 2). In cases with PE unlikely pre-test probability, a negative high sensitivity D-dimer result rules out the diagnosis of PE. However, a positive D-dimer test must be followed up with a definitive test to confirm/refute the diagnosis of PE.
When a high-sensitive d-dimer assay is used, age-adjusted D-dimer levels can increase the specificity of D-dimer testing without sacrificing sensitivity. In patients over the age of 50, a D-dimer result is considered negative if it is less than the patient age multiplied by 10 (for example, in a 76-year-old, a negative result is less than 760 µg/L). For patients under the age of 50, a D-dimer value less than 500 µg/L remains the cutoff for a negative result. A similar strategy of modifying D-dimer threshold according to pre-test probability has also been shown safe. In institutions using a high sensitivity Ddimer assay with a usual threshold of 500 ng/mL, the combination of a Wells Score of 4.0 or less and a D-dimer of less than 1000 ng/mL can identify a group with a low likelihood of PE who do not require additional testing to exclude PE.
With a PE likely pre-test probability, there is no role for ordering a D-dimer, as the clinical likelihood of PE remains unacceptably high among those with a negative D-dimer result. Therefore, when the Wells score is 4.5 or greater, one should go directly to imaging to establish the diagnosis.
Multidetector CTPA is widely available in Canada and is sufficiently sensitive and specific to exclude the diagnosis of PE when it is negative and to confirm it when positive. Limitations of CTPA include radiation exposure (that may increase breast cancer rates in young women), risk of contrast nephropathy, and detection of small filling defects of uncertain clinical significance. Ventilationperfusion (V/Q) lung scanning has high sensitivity and specificity in patients with a normal chest X-ray who do not have significant lung disease. V/Q scanning should be considered in patients with renal insufficiency, contrast allergy, in young patients with a normal chest X-ray, and in pregnant women.
# FIGURE 1: SUGGESTED DIAGNOSTIC ALGORITHM FOR SUSPECTED PULMONARY EMBOLISM
a Consideration for thrombolysis without diagnostic test confirmation should be made if the patient has a high clinical suspicion of PE and is very unstable b Excluding a diagnosis of PE with a PE unlikely pre-test probability requires the use of a highly sensitive D-dimer assay. The use of age-specific or pre-test probability specific D-dimer cut-off values, if available, appears to improve the specificity of D-dimer testing. c V/Q is the preferred test in patients with a contrast allergy or severe renal dysfunction and young patients with a normal chest X-ray and should be considered in pregnancy. If the perfusion scan is normal, further testing is not required. When the V/Q scan is neither normal nor high probability for PE (diagnostic for PE), serial compression ultrasounds (CUS) of the legs should be undertaken.
d Features on echocardiography suggestive of massive PE include severe right ventricle (RV) dysfunction and RV/main pulmonary artery embolus e Where clinical suspicion for PE remains high with a negative initial CTPA, additional testing with VQ scan and/or proximal ultrasound of the lower extremities may be considered f If patient condition stabilizes, consideration should be given to performing CTPA to confirm the diagnosis In patients with hypotension who are too unstable to undergo CTPA or if CTPA is not immediately available, an urgent echocardiogram should be obtained to look for evidence of right heart overload or embolus in the right ventricle (RV) or main pulmonary arteries. If present, and in the absence of an alternative diagnosis, treatment for PE should be initiated. However, RV dysfunction alone does not prove PE; therefore, if feasible, confirmatory evidence of VTE should be sought with further imaging (CTPA, V/Q or lower extremity compression ultrasounds ). If a hypotensive patient does not have echocardiographic features of RV dysfunction, it is unlikely that hemodynamic instability is due to massive PE (although this does not exclude smaller PE).
# YEARS algorithm:
The YEARS algorithm is a simplified diagnostic strategy in which 3 clinical items of the Wells score (clinical signs of DVT, hemoptysis, and PE most likely diagnosis) along with differential D-dimer cutoff values was developed to reduce CTPA in patients with suspected PE. The algorithm was recently assessed for its external validity in three prospective cohorts. Overall, the YEARS algorithm safely ruled out PE with a low 3-month thromboembolism risk. However, a higher failure rate of the YEARS algorithm was observed for patients with no YEARS items and a D-dimer < 1000 ng/ml but above their respective age-adjusted D-dimer cutoff. As a result, further external validation is required before the YEARS algorithm can be recommended for non-pregnant patients with suspected PE.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES
# Date of version: 14November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To provide a diagnostic approach to patients with suspected acute pulmonary embolism (PE).Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disease, affecting approximately 1-2 in 1,000 adults per year. The diagnosis of PE has increased significantly since the advent of computed tomography pulmonary angiography (CTPA) with its widespread availability and enhanced sensitivity. The majority of PE originates in the proximal deep veins of the leg, despite the observation that only 25-50% of patients with PE have clinically evident DVT at the time of PE diagnosis. While active malignancy, surgery (especially orthopedic), hospitalization, air travel >8 hours, and hormone use/pregnancy are common transient provoking factors, approximately 50% of first-time PEs appear to be unprovoked. Symptoms of PE may include sudden onset dyspnea, pleuritic chest pain, hemoptysis, and syncope. Signs of PE may include tachypnea, tachycardia, hypoxemia, hypotension, and features of right ventricular dysfunction (distended jugular veins). There may be accompanying signs and symptoms of DVT. The ECG may show right ventricular strain (S1Q3T3, right bundle branch block and T-inversion in leads V1-V4). Up to 10% of symptomatic PEs are fatal within the first hour of symptom onset. Independent predictors of mortality within the first few days after diagnosis of PE include hypotension (systolic blood pressure [SBP] <90 mmHg), clinical right heart failure, right ventricular dilatation on CTPA/echocardiography, positive troponin, and elevated brain natriuretic peptide (BNP). Early diagnosis and treatment of PE reduces morbidity and mortality.# DIAGNOSIS OF PE:
The constellation of symptoms and signs may be suggestive of PE but do not alone have the sensitivity or specificity to rule in or rule out the diagnosis. When the diagnosis of PE is considered, the clinical stability of the patient and associated pre-test probability will dictate the diagnostic approach (see Figure 1).
In patients without hypotension (SBP >90 mmHg), pre-test probability can be assessed by a validated clinical prediction rule (see Table 1). In patients with low pretest probability of PE, further testing is not necessary if all clinical features/criteria in the Pulmonary Embolism Rule-out Criteria (PERC) are present (see Table 2). In cases with PE unlikely pre-test probability, a negative high sensitivity D-dimer result rules out the diagnosis of PE. However, a positive D-dimer test must be followed up with a definitive test to confirm/refute the diagnosis of PE.
When a high-sensitive d-dimer assay is used, age-adjusted D-dimer levels can increase the specificity of D-dimer testing without sacrificing sensitivity. In patients over the age of 50, a D-dimer result is considered negative if it is less than the patient age multiplied by 10 (for example, in a 76-year-old, a negative result is less than 760 µg/L). For patients under the age of 50, a D-dimer value less than 500 µg/L remains the cutoff for a negative result. A similar strategy of modifying D-dimer threshold according to pre-test probability has also been shown safe. In institutions using a high sensitivity Ddimer assay with a usual threshold of 500 ng/mL, the combination of a Wells Score of 4.0 or less and a D-dimer of less than 1000 ng/mL can identify a group with a low likelihood of PE who do not require additional testing to exclude PE.
With a PE likely pre-test probability, there is no role for ordering a D-dimer, as the clinical likelihood of PE remains unacceptably high among those with a negative D-dimer result. Therefore, when the Wells score is 4.5 or greater, one should go directly to imaging to establish the diagnosis.
Multidetector CTPA is widely available in Canada and is sufficiently sensitive and specific to exclude the diagnosis of PE when it is negative and to confirm it when positive. Limitations of CTPA include radiation exposure (that may increase breast cancer rates in young women), risk of contrast nephropathy, and detection of small filling defects of uncertain clinical significance. Ventilationperfusion (V/Q) lung scanning has high sensitivity and specificity in patients with a normal chest X-ray who do not have significant lung disease. V/Q scanning should be considered in patients with renal insufficiency, contrast allergy, in young patients with a normal chest X-ray, and in pregnant women.
# FIGURE 1: SUGGESTED DIAGNOSTIC ALGORITHM FOR SUSPECTED PULMONARY EMBOLISM
a Consideration for thrombolysis without diagnostic test confirmation should be made if the patient has a high clinical suspicion of PE and is very unstable b Excluding a diagnosis of PE with a PE unlikely pre-test probability requires the use of a highly sensitive D-dimer assay. The use of age-specific or pre-test probability specific D-dimer cut-off values, if available, appears to improve the specificity of D-dimer testing. c V/Q is the preferred test in patients with a contrast allergy or severe renal dysfunction and young patients with a normal chest X-ray and should be considered in pregnancy. If the perfusion scan is normal, further testing is not required. When the V/Q scan is neither normal nor high probability for PE (diagnostic for PE), serial compression ultrasounds (CUS) of the legs should be undertaken.
d Features on echocardiography suggestive of massive PE include severe right ventricle (RV) dysfunction and RV/main pulmonary artery embolus e Where clinical suspicion for PE remains high with a negative initial CTPA, additional testing with VQ scan and/or proximal ultrasound of the lower extremities may be considered f If patient condition stabilizes, consideration should be given to performing CTPA to confirm the diagnosis In patients with hypotension who are too unstable to undergo CTPA or if CTPA is not immediately available, an urgent echocardiogram should be obtained to look for evidence of right heart overload or embolus in the right ventricle (RV) or main pulmonary arteries. If present, and in the absence of an alternative diagnosis, treatment for PE should be initiated. However, RV dysfunction alone does not prove PE; therefore, if feasible, confirmatory evidence of VTE should be sought with further imaging (CTPA, V/Q or lower extremity compression ultrasounds [CUS]). If a hypotensive patient does not have echocardiographic features of RV dysfunction, it is unlikely that hemodynamic instability is due to massive PE (although this does not exclude smaller PE).
# YEARS algorithm:
The YEARS algorithm is a simplified diagnostic strategy in which 3 clinical items of the Wells score (clinical signs of DVT, hemoptysis, and PE most likely diagnosis) along with differential D-dimer cutoff values was developed to reduce CTPA in patients with suspected PE. The algorithm was recently assessed for its external validity in three prospective cohorts. Overall, the YEARS algorithm safely ruled out PE with a low 3-month thromboembolism risk. However, a higher failure rate of the YEARS algorithm was observed for patients with no YEARS items and a D-dimer < 1000 ng/ml but above their respective age-adjusted D-dimer cutoff. As a result, further external validation is required before the YEARS algorithm can be recommended for non-pregnant patients with suspected PE.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES
# Date of version: 14November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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This publication is intended for information purposes only, and is not intended to be interpreted or used as a standard of medical practice. Best efforts were used to ensure that the information in this publication is accurate; however, the publisher and every person involved in the creation of this publication disclaim any warranty as to the accuracy, completeness or currency of the contents of this publication. This publication is distributed with the understanding that neither the publisher nor any person involved in the creation of this publication is rendering professional advice. Physicians and other readers must determine the appropriate clinical care for each individual patient on the basis of all the clinical data available for the individual case. The publisher and every person involved in the creation of this publication disclaim any liability arising from contract, negligence, or any other cause of action, to any party, for the publication contents or any consequences arising from its use. The views expressed herein do not necessarily represent the views of Health Canada.
We encourage the copy and distribution of these guidelines; provided that the appropriate attribution is given. Please see the suggested citation below.
# Suggested citation: Canadian Guidelines on Cannabis
Use Disorder Among Older Adults. Canadian Coalition for Seniors ' Mental Health, Toronto, Canada (2019) Funding for the Canadian Coalition for Seniors' Mental Health (CCSMH) Substance Use Disorder Guidelines was provided by Health Canada, Substance Use and Addictions Program. The CCSMH gratefully acknowledges Health Canada for its ongoing support and continued commitment to the area of seniors' mental health.
In addition, special thanks to the Co-Leads and individual Working Group members who dedicated a countless number of hours and engaged in the creation of guidelines and recommendations.
We would also like to thank Dr. Michael Beazley, Dr. Kim Corace, and Dr. Meldon Kahan for their support in reviewing and for providing their perspectives on this document.
We would like to thank the Canadian Centre on Substance Use and Addiction and the Behavioural Supports Ontario Substance Use Collaborative for their support and contributions throughout the development of the Guidelines and Tonya Mahar (Manager, Library Services, Baycrest) for her assistance with literature searches.
Finally, the CCSMH would like to acknowledge the continued dedication of its Steering Committee members and the outstanding contributions of our Director, Claire Checkland and our Project Coordinators: Indira Fernando, Natasha Kachan, and Marc-André LeBlanc.
The CCSMH is a project of the Canadian Academy of Geriatric Psychiatry.
# Table of Contents 4
Canadian Guidelines on Cannabis Use Disorder Among Older Adults Scope T he Canadian Coalition for Seniors' Mental Health (CCSMH) received a grant from the Substance Use and Addictions Program (SUAP) of Health Canada to create a set of four guidelines on the prevention, assessment, and treatment of substance use disorders (SUDs) among older adults on the topics of alcohol, benzodiazepine receptor agonists (BZRAs), cannabis, and opioids . The GRADE approach was utilized in the creation of these guidelines . The methodology can be found in a separate document at ccsmh .ca . An introduction to these guidelines which highlights issues of relevance to all four can also be found at ccsmh .ca . These guidelines are not intended to provide a comprehensive guide on the use of these substances either by medical authorization or non-medical use .
The goal of this document is to provide useful guidance for clinicians on either preventing the development of Cannabis Use Disorder (CUD) or optimally assessing and treating older adults who have developed such a disorder . These guidelines have been developed due to the paucity of information that surrounds the relationship between cannabis use and the impact of aging processes such as changing physiology, metabolism, and the increase in polypharmacy . These guidelines should be used as a complement to other reliable sources of information . While clinicians may choose to authorize cannabis for medical purposes in older patients this document will not focus on possible medical uses, but instead it seeks to address issues of non-medical cannabis use and CUD in older adults .
Cannabis Use Disorder: According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Cannabis Use Disorder (CUD) is a problematic pattern of cannabis use leading to clinically significant impairment or distress as manifested by at least two of the criteria below occurring in a 12-month period (American Psychiatric Association, 2013) . It is important to note that among older adults, some of these criteria may be modified by the aging process or their social roles (e .g ., retirement from work), resulting in more subtle presentations (Kuerbis et al . , 2014) .
✚ Cannabis is often taken in larger amounts over a longer period than was intended .
✚ There is a persistent desire or insignificant effort to cut down or control cannabis use .
✚ A great deal of time is spent in activities necessary to obtain cannabis, use cannabis, or recover from its effects .
✚ Craving or a strong desire or urge to use cannabis .
✚ Recurrent cannabis use resulting in failure to fulfill major role obligations at work, school, or home .
✚ Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis .
✚ Important social, occupational, or recreational activities are given up or reduced because of cannabis use .
✚ Recurrent cannabis use in situations which are physically hazardous .
✚ Cannabis use is continued despite knowledge of having persistent or recurrent physical or psychological problems that are unlikely to have been caused or exacerbated by cannabis .
# Definition of Key Terms
✚ Tolerance, as defined by either:
-A need for markedly increased amounts of cannabis to achieve intoxication and desired effect, or -A markedly diminished effect with continued use of the same amount of cannabis .
# Remission
✚ Following treatment, 3-12 months of abstinence is considered early remission .
✚ More than 12 months is considered sustained remission .
# Summary of Recommendations and Grades
W e used the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation) as a method of grading the quality of evidence and the strength of recommendations . In following the GRADE process, the initial step was to grade the quality of available evidence supporting each recommendation . Subsequently, we identified the overall strength of the recommendation taking into account the quality of the evidence but also other factors such as the potential to do harm, the cost and feasibility .
We have also developed a separate category for recommendations which are not primarily based on empirical evidence; but have agreement that they represent best clinical practice . Examples would include: optimal assessment processes and those related to education and/or policy . These recommendations have been categorized as "C" for consensus . We did not use the GRADE process for these recommendations . Other guideline groups have used a similar approach e .g . British Association for Psychopharmacology Guidelines (Lingford-Hughes et al ., 2012) . While such recommendations lack empirical evidence, we believe they are also useful and important . The quality of evidence for each recommendation is determined through an examination of the following factors: (1) Study design and the quality of the studies that were included, (2) the directness of the evidence (generalizability or applicability) and
(3) the confidence that patients will benefit from the treatment .
The strength of each recommendation is determined through an examination of the following factors:
(1) The balance between benefits and undesirable effects/ risks, (2) uncertainty or variability of patient values and preferences and (3) the resources associated with management options .
# GRADE
# QUALITY OF EVIDENCE
# STRENGTH OF RECOMMENDATION
# HIGH
Further research is unlikely to change confidence in the estimate of effect
# MODERATE
Further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate
# LOW
Further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate
# STRONG
Strong recommendations indicate high confidence that desirable consequences of the proposed course of action outweigh the undesirable consequences or vice versa .
# WEAK
Weak recommendations indicate that there is either a close balance between benefits and down sides (including adverse effects and burden of treatment), uncertainty regarding the magnitude of benefits and down sides, uncertainty or great variability in patients' values and preferences, or that the cost or burden of the proposed intervention may not be justified .
# RECOMMENDATION #3:
In order to support the retention of information, clinicians should provide education and counselling with regard to cannabis and cannabinoids to older patients and their family members/caregivers both verbally and in writing.
# RECOMMENDATION #4:
Clinicians should counsel patients, caregivers, and families to be aware that older adults can be more susceptible than younger adults to some dose-related adverse events associated with cannabis use.
# RECOMMENDATION #14:
Clinicians should be aware that the diagnostic accuracy of some screening tools may be variable given that some of the symptoms of aging may overlap with those of CUD.
# Rationale
C annabis use for medical purposes has become a topic of great interest in recent years . Increased attention has been paid to the many product types available (dried product, oils, edible cannabis, etc .) as well as its effects . However, evidence is limited with regard to the potential benefits and harms of cannabis use, especially among older adults . Those who were born between 1946-1964, many of whom are now older adults, have a higher lifetime prevalence of use and past year use than any generation that precedes them (Simoni-Wastila & Yang, 2006) . This lack of evidence and increased lifetime exposure of many adults, coupled with the recent legalization of non-medical cannabis use in Canada and subsequent increase in public interest, has driven concern for potential problematic cannabis use and Cannabis Use Disorder among older adults .
# Canadian Guidelines on Cannabis Use Disorder Among Older Adults
# KEY POINTS FOR THIS GUIDELINE
✚ The evidence base for harms and potential benefits associated with cannabis use in older adults is limited but growing .
✚ Given that the adverse effects of cannabis may vary considerably based on routes of administration and subtype of strain, as well as the lack of evidence regarding older adults, we have developed these guidelines utilizing a cautionary approach .
✚ Hopefully as research advances and capacity improves in the upcoming years, the risks and benefits of cannabis use among older adults, as well as the risk of developing Cannabis Use Disorder, will be better understood .
Much of the limited evidence related to cannabis is due to its longstanding classification as an illegal drug . This has impeded clinical research on its use, the effects of its use, and its potentially beneficial and adverse health outcomes . It is important to consider these questions broadly, but also specifically for different patient groups, such as older adults .
Older adults face unique physical and socioeconomic circumstances that may influence their response to cannabis use . Physiological changes that impact sleep, mobility, diet, exercise, and overall quality of life, along with issues such as polypharmacy and cognitive decline are all confounding factors in the effects and response of cannabis use in this population . All of these factors should be taken into consideration in the clinical evaluation of the patient and in decision-making when considering cannabis .
As the current state of evidence on cannabis use in older adults is largely absent, further clinical investigation is needed to understand the extent of effects, specifically within the context of substance use and aging . Despite this, there is an abundance of anecdotal (and sometimes conflicting) advice available to consumers, based on personal and collective narratives acquired over decades of use . There is a clear need to not only reconcile anecdotal and self-reported experiences (positive and negative) with the evidence to guide clinical decision-making, but also to more fully understand the impact of physiological and socioeconomic implications of cannabis use among older adults . Applying some of the available evidence for younger adults in the counselling of older adults and cannabis use is necessary until we are able to fully understand the effects of cannabis use and aging .
Aging presents unique considerations for cannabis use particularly when coupled with multiple comorbidities, the use of multiple medicines, and the use of a psychoactive substance by a population more prone to vision, mobility, and cognitive issues, among other concerns . These factors coupled with the ongoing diversification of the cannabis market present a rapidly changing landscape where little is known of consumer habits and emerging products . As such, healthcare professionals need to be aware of the fact that older adults do use cannabis, should be asked about it, and need guidance for helping ensure that they can use cannabis safely and access appropriate treatments if their use is problematic .
The information contained within this document is based on the most current and reliable English language research at the time of publication . With the amount of variability in reliability of data surrounding medical and non-medical cannabis use there is a need for unbiased information and systematic evidence-based approaches to clinical practice . It is in this setting that we hope this guideline will support health care professionals, patients, and families alike .
# Background
C annabis is a plant that contains hundreds of compounds including cannabinoids, which act on the endogenous cannabinoid (endocannabinoid) system . This complex system is involved in bonding, sleep, appetite, immune response, and pain regulation . Certain cannabinoids act by influencing reward, motivation, and substance-related cues . Delta-9tetrahydro-cannabinol (THC) and cannabidiol (CBD) are two cannabinoids that have the most available literature . They exert various effects by binding to the cannabinoid receptors; CB1 is located centrally in the brain, and CB2 is located primarily peripherally and on the circulating immune system throughout the body . The primary psychoactive ingredient in cannabis is THC, which mimics the endocannabinoid anandamide and binds to cannabinoid-1 (CB1) receptors in the brain, often producing a high or sense of euphoria . THC is also vasoconstrictive to blood vessels in the heart and brain and as such may increase the risk of cardiovascular events including stroke, cardiac arrhythmia, and myocardial infarction . In contrast, CBD binds weakly to CB1 receptors and may interfere with the binding of THC, resulting in a lack of euphoric and reinforcing effect (Cohen & Weinstein, 2018) . Also, CBD has been shown to be an agonist similar to another endocannabinoid, 2-AG, and binds primarily to CB2 receptor sites .
It is important to note that the cannabinoid composition of a cannabis plant is wide ranging and varies by strain . Some are higher in CBD and others contain more THC . As a result, the effects of cannabis use are also wide ranging and exhibit a variety of psychosomatic properties . While neither taking CBD nor THC has been found to be directly fatal in adults, there have been overdoses in children who have ingested edible cannabis derivative products (e .g ., gummy bears), and there is an increased risk of a variety of problems in adults that can lead to harm and even death, among them motor vehicle collisions in those driving after using cannabis and psychosis leading to accidents (Els, 2018) . Also, high THC use has been linked to long-term negative psychiatric effects, increasing depression, anxiety, worsening post-traumatic stress disorder symptoms, panic attacks, and suicidal ideation, attempts, and completion rates (Volkow et al ., 2014; National Academies of Sciences, Engineering, and Medicine , 2017) . Cannabinoids exhibit differential uptake in the body based on the mode of consumption (inhaling vs . ingesting) .
Physicians and other health professionals need to be aware of the most recent research on the use of cannabis for medical and non-medical purposes, as they will find that a number of people they care for choose to use cannabis . In Canada, cannabis use rates in older adults have been rising over the last decade as baby boomers age into their older years, and supply has become more readily available . One study showed the percentage of older adults using cannabis in Ontario doubled from 2005-2015, and has increased fivefold since 1977 (Ialomiteanu et al ., 2016 et al ., 2018) . There is a growing body of evidence which is supportive of some other possible indications (Kalant & Porath, 2016) . The pace and scope of cannabis research may require clinical recommendations, such as those below, to be updated and modified more frequently in order to stay current .
# RECOMMENDATION #1:
Cannabis should generally be avoided by older adults who have: The endocannabinoid system modulates the functions of many organ systems throughout the body . Cannabis and certain cannabinoids therefore affect the central and peripheral nervous systems, respiration, and cardiovascular, skeletal, muscle, and bone function . The effects of cannabis can also resemble the effects of various disease states and age-related changes in these organ systems or can accentuate these conditions in older adults . For example, regular cannabis smoking can lead to chronic bronchitis and respiratory symptoms (Ribeiro and Ind, 2016) . Cannabis in other forms may cause osteoporosis and can impair cognitive and motor functions (Health Canada, 2018) . Clinical case reports and case series have indicated that regular cannabis use can be associated with stroke even among younger adults without other known risk factors (Hackam, 2015;Hemachandra et al ., 2016) . Since older adults have a higher frequency of risk factors for stroke, the possibility exists that cannabis use might also increase frequency of stroke among older adults . Therefore, individuals with existing health conditions or age-related physiological changes can have these conditions aggravated by cannabis, and should be advised of these risks and generally advised to avoid cannabis use . The potential benefits of cannabis in certain limited situations where it is medically indicated (e .g ., treatment of nausea due to chemotherapy) need to be balanced against potential risks .
There is strong evidence that persons with CUDs have an increased risk of developing alcohol, tobacco, or other SUDs and should be monitored appropriately for these conditions (Choi et al ., 2017) . Additionally, older adults with other substance use disorders have an increased risk of developing a CUD . Cannabis can precipitate or aggravate mental health conditions such as psychosis, depression, and anxiety,
# Prevention of Cannabis Use Disorder Among Older Adults
particularly in those with current experience, a personal history, or a strong family history of these conditions . There has not yet been research distinguishing between THC and CBD as it pertains to specific health outcomes (e . g . , psychosis, anxiety, depression, and addiction) . As such, we recommend that individuals with current experience, a personal history, or a strong family history of these conditions avoid cannabis (NASEM, 2017) .
# Clinician Education
# RECOMMENDATION #2:
Clinicians should be aware of the following: These medical products should be considered for prescription first, prior to consideration of non-prescription cannabis products for medical purposes .
A comprehensive systematic review conducted in 2017 (NASEM, 2017) identified only three conditions for which there is conclusive or substantial evidence that cannabis or cannabinoids are effective in treating specific symptoms . These include muscle spasms related to multiple sclerosis, nausea and vomiting associated with chemotherapy, and chronic pain, especially of neuropathic origin . These findings were supported by a more recent Canadian review of systematic reviews of medical cannabinoids .
Clinicians should be familiar with the distinction between THC and CBD, the different methods of administration for cannabis preparations, and potency and dosage of different cannabis preparations (Health Canada, 2018) . All of these elements are very relevant in understanding cannabis administration and require further research to convey an accurate representation of the therapeutic effects of cannabis, as well as a proper understanding of the psychoactive effects and other effects of relevance to older adults . Common symptoms associated with cannabis use, including adverse effects, are described in Table 1 .
It is important to review the specific risks associated with cannabis use on an individual basis . This may include the patterns of use as well as the particular kinds of cannabis being used to thoroughly understand the potential risks associated with it . The particular implications of cannabis use among older adults should be considered, including a higher risk of falls, cognitive impairment, confusion, drug-drug interactions, and other factors associated with age-and disease-related physiological changes . However, evidence also suggests that many older adults use cannabis without severe complications or adverse events and the possibility of use within these relatively safe limits should be acknowledged during screening for CUD (Choi et al ., 2015) .
Comorbid psychiatric conditions, such as depression, anxiety, and schizophrenia, have been associated with CUD and should be assessed clinically .
# Patient and Family/Caregiver Education:
RECOMMENDATION #3:
In order to support the retention of information, clinicians should provide education and counselling with regard to cannabis and cannabinoids to older patients and their family members/caregivers both verbally and in writing.
Available evidence suggests that when presented with relevant, accurate, and properly contextualized information concerning the health effects of cannabis use, adults who use cannabis may moderate the quantity or types of cannabis used and/or the ways in which they consume it (Murphy et al ., 2015) .
Existing guidelines suggest that clinicians should provide education and counseling concerning cannabis use to patients . Although the evidence concerning educational interventions among older adults is limited, and there are no randomized controlled trials studying the provision of patient education about the risks and benefits specifically related to cannabis use in older adults, the use of written or printed material may help the patient to retain and reinforce this information and facilitate discussions with family members or friends .
# RECOMMENDATION #4:
Clinicians should counsel patients, caregivers, and families to be aware that older adults can be more susceptible than younger adults to some dose-related adverse events associated with cannabis use. Education and counselling are important in order for older adults to avoid potential harms due to adverse effects including changes in depth perception risking balance instability and falls, changes in appetite, cognitive impairment, cardiac arrhythmia, anxiety, panic, and psychosis . The potential for greater harm in older adults exists because of more vulnerable physiology, the prevalence of medical comorbidities, and potential drug interactions when initiating any cannabis use . Patients who intend to use cannabis should be encouraged to seek out products with lower THC content (< 10%) and to introduce use with a "low and slow" approach to watch for side effects and/or complications .
# RECOMMENDATION #5:
Clinicians should advise patients, caregivers, and families about potentially increased risks associated with higher potency delta-9-tetrahydro-cannabinol (THC) extracts, or higher potency strains of cannabis when compared to those with lower THC content.
There are several forms of cannabis products with higher THC concentrations (e .g ., those with street names such as Shatter, Dab, Wax, and Budder), and clinicians should advise patients of the potential harmful effects of using such products . Both patients and clinicians should be aware that these products are not available through the legal avenues for purchasing cannabis such as licensed producers and other governmentregulated producers, although some of these products will be regulated under the Cannabis Act in October 2019 and will be available for sale as early as December 2020 . Use of products with higher THC content exacerbates the risks associated with acute cannabis consumption including increased risk of motor vehicle crashes, especially fatal collisions (Karila et al ., 2014) .
* Please note that the majority of existing literature describing adverse effects of cannabis use is focused on the impact of THC . There are common sideeffects applicable to both THC and CBD, however much of the information pertains to THC-based products . It is important to note that adverse effects can be experienced with both acute and chronic use, and also vary depending on formulation, concentration, and dose (MacCallum & Russo, 2018) . Cannabis products, regardless of THC and CBD content, come in various forms including those that can be inhaled, those that are ingested, and those that can be applied topically . Clinicians should understand the basic pharmacokinetic differences between formulations and their associated risks (Health Canada, 2018) . While the evidence is limited for CBD products, clinicians should advise that CBD products may induce some of the adverse effects associated with THC, but CBD's effects on the nervous system differ markedly . For any type of cannabis product, inhaled formulations have a quicker onset of action than ingestible forms (MacCallum & Russo, 2018) . Risks associated with chronic use of inhaled formulations include but are not limited to increased risk for bronchospasm mediated by bronchial irritation . Certain cannabis oil pens are made using butane, a carcinogen (Miller et al ., 2016) .
Ingestible forms of cannabis, such as edibles and oils, have a delayed onset of action and typically have a longer duration of action (NASEM, 2017) . This may result in the use of larger than intended doses due to the delayed and cumulative effects from repeated acute ingestions .
Patients should be cautioned against using multiple doses of orally administered cannabis in short time periods due to these risks .
Topically administered cannabis products bypass the first phase of hepatic metabolism and some sources have speculated that this route of administration may therefore be associated with fewer adverse effects . However, the evidence for this conjecture is limited and topical formulations require further research (Huestis, 2007) . Based on clinical experience, patients rarely report cognitive side effects when using topical cannabis derivatives for pain, especially CBD-only products, so it may be a lower risk starting point for those without contraindications who wish to try a cannabis product .
# RECOMMENDATION #7:
Clinicians should educate patients to avoid illegal synthetic cannabinoids (e.g., K2 and SPICE,) because of the potential to cause serious harm.
Illicit synthetic cannabinoid products such as K2 and SPICE are more potent than other forms of cannabis and present a greater risk of adverse events among older adults . Using these products can lead to severe health problems such as seizures, irregular heartbeat, and hallucinations (Gunderson et al ., 2012;Seely et al ., 2012;Harris & Brown, 2013;van Amsterdam et al ., 2015) . In rare instances, death can occur (Seely et al ., 2012;Harris & Brown, 2013;van Amsterdam et al ., 2015) .
# RECOMMENDATION #8:
Clinicians Initiation of cannabis for medical or non-medical use can result in physiological, cognitive, perceptual, and emotional changes, including impairment . The risk of impairment with cannabis is increased with formulations containing higher concentrations of THC . Use of cannabis products with THC concentrations of >20% under any circumstance is unwarranted . Claims made for the potential benefits of cannabis in product promotions may not be scientifically supported and patients should be cautious of information provided by manufacturers or distributors of cannabis products . In addition, caution is advised in reviewing information that is available online as the credibility of sources may vary . Patients need to be aware of the THC concentration in cannabis preparations and be aware that impairment in attention, reaction time, mood, memory, depth and time perception, and cardiac function are all possible adverse effects that are more common when preparations with higher THC concentrations are used . Only medical grade cannabinoids available on prescription have accurate dosing supported by Health Canada . Caution needs to be applied when purchasing from dispensaries or the illicit market . One study of randomly chosen edible cannabis products available at dispensaries in the United States and tested in an independent laboratory found only 17% were accurately labelled for THC and 0% had accurate CBD labeling (Vandrey et al ., 2015) .
# RECOMMENDATION #9:
Clinicians As more older adults begin using cannabis for both medical and non-medical reasons, many may use cannabis chronically rather than intermittently and thus be at increased risk of long-term health effects . These risks can include respiratory and cardiovascular problems (Hall & Degenhardt, 2014), skeletal changes that increase risk of fractures (Sophocleous et al ., 2017), emotional and cognitive disorders (NASEM, 2017), and SUDs involving not only cannabis itself but also opioids and other pain relievers (Choi et al ., 2017) . Though there is no conclusive evidence of a causal link between prolonged use of cannabis and cancer, an association cannot be ruled out as precancerous changes in respiratory epithelium have been observed in people who chronically smoke cannabis (Barsky et al ., 1998) . Clinicians should be aware that some of the products made by licensed medical cannabis producers in Canada have higher THC concentrations (>20% THC), and should advise patients to avoid such products as they may further increase the risk of mental health problems over time .
# RECOMMENDATION #10:
Clinicians should advise patients, caregivers, and families that: Due to the varying potencies and durations of effect of different cannabis products, it is important to emphasize the significant impact that cannabis has on driving performance and the high potential to cause impairment while driving .
Numerous experimental studies have shown that THC impairs cognition, psychomotor function, and actual driving performance in a dose-related manner (Ramaekers et al ., 2004) . Furthermore, surveys that established recent use of cannabis by directly measuring THC in blood showed that individuals who test positive for THC, particularly at higher levels of THC, are approximately three to seven times more likely to be responsible for their crash as compared to drivers that had not used drugs or alcohol (Ramaekers et al ., 2004) . A recent systematic review showed the odds ratio of a motor vehicle collision after using cannabis was between 2 .49-2 .84 (Els et al ., 2019) . Of note, the effects of CBD on driving are not well known, and currently most of the evidence on driving impairment is related to THC use (Beirness & Porath, 2019) . However, in childhood epilepsy studies where pure CBD was used, 30% of participants reported significant sedation (Ali et al ., 2019) . Thus Dr . Charl Els and colleagues, in a position paper endorsed by the Occupational and Environmental Medical Association of Canada and the Canadian Society of Addiction Medicine, recommend not using cannabis (with any concentration of THC and/or CBD) within 24 hours of safety sensitive work (Els et al . , 2018) . Specifically, the document notes "it is not advisable to operate motor vehicles or equipment, or engage in other safety-sensitive tasks for 24 hours following cannabis consumption, or for longer if impairment persists . "
Due to the variation of effects of THC on driving as THC/CBD formulations change, it is essential to note that the consumption of cannabis and alcohol together will have a synergistic effect on impairment, and that those who may be below the legal allowable blood alcohol levels may still be unsafe to operate a motor vehicle when alcohol is consumed with cannabis (Neavyn et al . , 2014) .
# RECOMMENDATION #11:
Patients, caregivers, and families should be provided with information about the signs, symptoms, and risks of cannabis withdrawal.
Cannabis withdrawal symptoms will be more pronounced with abstinence after long-term use of higher amounts of cannabis .
Most research has investigated symptoms in young adults rather than older adults . Typical symptoms of withdrawal include fluctuating behaviour and mood and physical symptoms such as weakness, sweating, restlessness, dysphoria, sleeping problems, decreased appetite, nervousness/anxiety, irritability, aggression, and craving . The desensitization and downregulation of the CB1 receptors begin to reverse within the first two days of abstinence and return to more natural functioning within four weeks of abstinence . The severity of withdrawal is highly variable and dependent on the amount of cannabis used, sex, and patient and contextual factors .
# Screening for Cannabis Use Disorder
C linicians may underestimate the likelihood of problematic substance use or a SUD among older adults . It is therefore important to conduct a comprehensive history of current and past use of substances, including cannabis and cannabinoids . A comprehensive assessment is recommended when a SUD is suspected .
# RECOMMENDATION #12:
Clinicians should initiate non-judgmental discussions related to cannabis and cannabinoid use. Careful histories should be obtained from patients, caregivers, and families about signs and symptoms of CUD that may be similar to those of age-related nervous system changes, such as drowsiness, dizziness, memory impairment, and falls.
Just as with other substances, discussions with older adults about cannabis use and the possibility of CUD should be nonjudgmental and supportive in nature . Ensure that screening for CUD in older adults is age appropriate; employs active listening; is supportive; uses a health or medical frame; accounts for memory impairment or cognitive decline; and is non-threatening and non-stigmatizing . The DSM-5 criteria for Cannabis Use Disorder require impairment in meeting social and occupational obligations and the specific social and functional roles of older adults should be considered when assessing the impact of cannabis use on them . It is important to respect older adults' autonomy and confidentiality but it is also helpful to obtain collateral information from family, friends, and other caregivers, with the patient's consent if it is available, particularly for individuals who may have cognitive impairment due either to cannabis or to comorbid medical or psychiatric conditions . Many symptoms of CUD such as drowsiness, dizziness, memory impairment, and falls are relatively common among older adults without CUD, but CUD should be considered as a potential cause or contributor to these symptoms in older adults NASEM, 2017) .
# RECOMMENDATION #13:
All patients regardless of age should be screened for: All patients should be screened for cannabis use . Particular attention should be paid to individuals with a past history of substance misuse, recent bereavement, depression, social isolation, significant self-neglect, and chronic pain . Answers to the screening questions may vary according to the individual depending on how the question is asked . Older patients might not think to mention medical use when asked about cannabis . The CUDIT is quite useful for identifying if problems found in a given case may not be attributable to cannabis use . If quantity, potency, and frequency of use are low and there are higher scores in memory or functional issues, the problem may not be related to cannabis .
# RECOMMENDATION #14:
Clinicians should be aware that the diagnostic accuracy of some screening tools may be variable given that some of the symptoms of aging may overlap with those of CUD.
For patients who are using cannabis either medically or nonmedically it is important to assess potential for CUD . There are a number of challenges involved in detecting and diagnosing a substance use disorder in older adults (Kuerbis et al ., 2014) . DSM-5 criteria for SUDs include a number of criteria that measure impairment based on the impact of substance use on fulfilling social or interpersonal roles or performance in areas that are not always applicable to older adults (such as at work, school or while driving) .
CUD can also be overlooked because of the increased presence of coexisting medical morbidities whose symptoms may mask CUD in older people . (Ialomiteanu et al ., 2016) . This route adversely affects respiratory health outcomes (Lee & Hancox, 2011;Pletcher et al . , 2012;Gates et al ., 2014;Tashkin, 2014;Martinasek et al ., 2016), and poses the greatest health risk . The use of edible cannabis, liquids, and oils may eliminate respiratory risk but these forms of administration introduce the risk of potential use of larger than intended doses because of the delayed onset of effect (Wang et al ., 2013;Monte et al ., 2015) . The mode of use should be explored carefully when there is a history of adverse effects that appear to be disproportionate to the effects typically observed with the reported amount of consumption .
# Assessment of Cannabis Use Disorder
Frequency and dose used during each episode of use are strong predictors of the risk of both acute and chronic cannabis-related problems (Solowij et al ., 2016) . Systematic reviews have found associations between the frequency or dose of cannabis use and various adverse health outcomes, including mental health problems, cardiovascular problems, motor vehicle collisions, suicidality, and cognitive effects (Moore et al ., 2007;Reece, 2009;Lorenzetti et al ., 2010;Elvik, 2013;Gibbs et al ., 2015;Ganzer et al ., 2016) . In the assessment of CUD, cannabis-related anxiety and cannabis dependence are important to identify . The risk of anxiety and cannabis dependence are strongly associated with daily or near daily use (Coffey et al ., 2002;Degenhardt et al ., 2013;Silins et al ., 2014) . Assessment of CUD in older adults should also include comprehensive assessment of potential physical manifestations of CUD or consequences of cannabis use . As with other SUDs, the DSM-5 criteria for CUD may not adequately aid with assessment of severity of CUD in older adults Kuerbis et al ., 2014) .
# RECOMMENDATION #16:
Clinical assessment of CUD in older adults should evaluate the signs and symptoms of cannabis withdrawal, with consideration that the rapid reduction or abrupt discontinuation of cannabis use may also be associated with withdrawal symptoms. Like all substances with addictive potential, cannabis can be associated with a withdrawal syndrome . It can appear when individuals who use cannabis rapidly reduce their use . Cannabis withdrawal syndrome typically emerges after 1-3 days of abstinence from cannabis . Symptoms tend to peak between 2-6 days and can last up to 14 days . Cannabis withdrawal symptoms can be reliably assessed using the Cannabis Withdrawal checklist which includes questions about the commonly observed symptoms such as: shakiness/tremulousness, depressed mood, decreased appetite, nausea, irritability, sleep difficulty, sweating, craving to smoke marijuana, restlessness, nervousness/anxiety, increased aggression, headaches, stomach pains, strange dreams, and increased anger . Cannabis withdrawal symptoms therefore can be confused with some of the self-reported reasons individuals give for using cannabis products . Not unlike alcohol and opioid withdrawal, during cannabis withdrawal, symptom relief can occur with taking the substance once again, thus reinforcing use . Individuals who screen positive for cannabis use should be assessed for withdrawal symptoms .
The frequency of cannabis withdrawal syndrome is dependent on factors such as duration and frequency of use and amount of cannabis used . In most studies, withdrawal reactions occur in approximately 20-30% of individuals who frequently use cannabis . The symptoms are frequently severe enough to give rise to a high rate of relapse . Current approaches to treatment of the withdrawal syndrome are discussed in Recommendation 22 .
# RECOMMENDATION #17:
When assessing patients, clinicians should be aware of the risk of cannabis hyperemesis syndrome in association with chronic cannabis use, especially with higher potency preparations. Cannabis hyperemesis syndrome is characterized by recurrent episodes of nausea and vomiting accompanied by abdominal pain typically occurring in individuals with prolonged use of high dose cannabis . The prevalence of hyperemesis syndrome among individuals with CUD is not well known although overall it appears to be a relatively uncommon, although distressing and potentially dangerous, condition . Management of hyperemesis syndrome is largely supportive to ensure adequate hydration and administration of antiemetics . It typically resolves within 48 hours of cessation of cannabis use (Galli et al ., 2011) . Hyperemesis syndrome can develop in association with any frequency of cannabis use but most often is observed in individuals who have been using cannabis for one year or longer at a frequency of daily to weekly (Sorensen et al ., 2017) .
# Treatment of Cannabis Use Disorder
T his section focuses on the treatment of older adults who have developed CUD . Current treatments to date for CUD have focused primarily on psychotherapy and contingency management . Pharmacotherapy trials have been conducted as adjunctive interventions to psychosocial treatment, however, no pharmacologic treatment has emerged as efficacious .
# RECOMMENDATION #18:
The Screening, Brief Intervention, and Referral to Treatment (SBIRT) approach should be considered for assessing and managing CUD similarly to other SUDs.
The use of SBIRT approaches in the context of CUD treatment has been a relatively unexplored area . However there is significant evidence supporting the use of brief interventions (e .g ., motivational enhancement and brief advice) among older adults (Fleming et al ., 1999;Gordon et al ., 2003;Fink et al ., 2005;Schonfeld et al ., 2010;Moore et al ., 2011;Schonfeld et al ., 2015) . SBIRT initiatives are known to effectively reduce problem drinking among older adults which might otherwise go unnoticed by substance abuse services (Schonfeld et al . , 2010) .
# RECOMMENDATION #19:
Peer support programs should be considered for individuals with CUD. Peer support programs can be a valuable recovery tool for patients with CUD (Tracey & Wallace, 2016) . One of the factors which exacerbates SUDs/CUD is lack of social connection (Sarkar et al, 2015) . Older adults are at elevated risk of losing social connections due to retirement, loss of friends/loved ones, etc . Clinicians need to be aware of what peer support programs are available in their areas and can support patients in their engagement in a program to support their recovery process . The most efficacious treatments to date include a combination of MET/CBT/CM including computer-delivered treatments, which show some of the highest abstinence rates to date, comparable to results obtained in treatment of cocaine use disorder, but lower efficacy than with alcohol . One meta-analysis found lower abstinence rates for people who use cannabis compared to people who use cocaine, opiates, and polysubstances (Sherman & McRae-Clark, 2016) . A brief online CM self-help intervention showed a significant decrease in past month quantity, frequency of cannabis use, and lower severity of dependence scores (Copeland et al ., 2017), though the eligible participants were not all diagnosed with CUD (median age 26, but including adults up to 65) . MET has been shown to improve cannabis-related outcomes among treatment-seeking adults, non-treatment seekers, and individuals with co-occurring disorders (Danovitch & Gorelick, 2012) . Technology based interventions that deliver CBT, MET, or MI, ideally in combination, have shown similar rates of effectiveness to therapist-delivered modalities (TDM), albeit without the randomization or follow up that are included in the more proven TDM . These should be considered if TDM access is restricted . In a randomized controlled trial where SUDs were broadly addressed using Mindfulness Based Relapse Prevention (MBRP) after intensive inpatient or outpatient treatment, there was demonstration of empirical promise for the feasibility and initial efficacy of MBRP in aftercare treatment of SUDs . Of the participants in this study, 5 .4% cited marijuana as their primary substance of choice (Banes et al ., 2014) .
# RECOMMENDATION #20:
# RECOMMENDATION #21:
There are currently no established pharmacological treatments that have been demonstrated to be safe and effective for either cannabis withdrawal symptoms or CUD. Certain medications have demonstrated potential in the area of withdrawal and cravings management . Gabapentin has been shown to address the attenuation of withdrawal symptoms while N-acetylcysteine (NAC) has demonstrated some promise in the reduction of cravings . A review by Sherman et al (2016) suggests some evidence for gabapentin and the most evidence for NAC . The potential side effects of drowsiness, dizziness, and fatigue are cited among others as challenges that outweigh any existing promise, combined with insufficient evidence to demonstrate efficacy for improving withdrawal symptoms or abstinence rates (Marshall et al ., 2014;Hassell et al ., 2017) . However, a systematic review by Werneck et al (2018) concluded that cannabinoid replacement therapy (with nabilone or dronabinol) has sufficient promise to warrant more extensive clinical trials . This off-label treatment should only be considered for highly intransigent cases that have not responded to all other interventions, where benefits are likely to outweigh risks, and very cautious dosing should be applied .
There are no studies on the treatment of insomnia due to cannabis or cannabinoid withdrawal in older adults . In younger adults, trazodone has been used .
# RECOMMENDATION #22:
Accredited residential treatment should be considered as appropriate for treating CUD if the individual is unable to effectively reduce or cease their cannabis use. Drawing from evidence used for the management of other SUDs that can be applied as reasonable principles for all SUD management, most experienced clinicians may manage older adults with mild to moderate CUD . Patients with more severe or complex disorders may benefit from involvement with a team or program specializing in SUDs including, when available, in an inpatient setting . Subsequently, the threshold to admit an older adult with social, psychological, or physical comorbidities to either residential or hospital care for treatment of CUD or withdrawal management may involve a lower threshold than what would be used for a younger adult .
# Future Directions
F uture research into cannabis use and CUD among older adults needs to start by recognizing and understanding patterns of and motivations for use in this population . It is clear that older adults use cannabis, but what is less clear is how and why this population uses it, what the prevalence of use across the life course is, how multiple factors unique to aging may positively or negatively impact on patterns of use, and the harms associated with it . While the perception that cannabis use poses a significant risk of negative consequences has decreased, it is nonetheless associated with cognitive impairment, increased risk for psychiatric disorders, and other mental health problems . Compounding this are the realities of aging, accompanied by changing physiologies that may alter the way cannabis is metabolized and experienced, a higher prevalence of multimorbidity that may increase the likelihood of a chronic or acute health condition being exacerbated, or of an unintended drug interaction .
Despite these limitations, clinicians need to discuss cannabis and cannabinoid use with their patients, to help promote healthy behaviours and to identify potential risks or harms or problematic use that warrant follow-up or intervention . Clinicians also need to be mindful of the social context within which cannabis-a widely-used, now legal, and widelyavailable substance-is situated . This includes anecdotal narratives about its medicinal properties, which although potentially promising, are largely unsubstantiated and open to exploitation . In addition to this; the reality that cannabis occupies a counter culture image that is now being commercialized as legal markets open up poses a risk for older adults to be specific demographic targets in cannabis marketing .
Regulation and quality control within a legal market have arguable benefits for reducing certain harms, but the implications for rates of use remain unknown for the older adult population, even in jurisdictions with a longer history of legal non-medical cannabis .
It is in this context that clinicians must be aware of the current state of evidence and practice in cannabis use disorder and cannabis use in older adults . Keeping in mind that older adults are using cannabis, likely have questions, and deserve evidence-informed answers and guidance . These guidelines provide recommendations on the basis of available evidence and the experience of clinicians, and acknowledge that gaps in the evidence clearly exist . Patients will undoubtedly have questions, and it is important that clinicians have answers grounded in evidence, rather than conjecture or anecdotes about cannabis use .
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This publication is intended for information purposes only, and is not intended to be interpreted or used as a standard of medical practice. Best efforts were used to ensure that the information in this publication is accurate; however, the publisher and every person involved in the creation of this publication disclaim any warranty as to the accuracy, completeness or currency of the contents of this publication. This publication is distributed with the understanding that neither the publisher nor any person involved in the creation of this publication is rendering professional advice. Physicians and other readers must determine the appropriate clinical care for each individual patient on the basis of all the clinical data available for the individual case. The publisher and every person involved in the creation of this publication disclaim any liability arising from contract, negligence, or any other cause of action, to any party, for the publication contents or any consequences arising from its use. The views expressed herein do not necessarily represent the views of Health Canada.
We encourage the copy and distribution of these guidelines; provided that the appropriate attribution is given. Please see the suggested citation below.
# Suggested citation: Canadian Guidelines on Cannabis
Use Disorder Among Older Adults. Canadian Coalition for Seniors ' Mental Health, Toronto, Canada (2019) Funding for the Canadian Coalition for Seniors' Mental Health (CCSMH) Substance Use Disorder Guidelines was provided by Health Canada, Substance Use and Addictions Program. The CCSMH gratefully acknowledges Health Canada for its ongoing support and continued commitment to the area of seniors' mental health.
In addition, special thanks to the Co-Leads and individual Working Group members who dedicated a countless number of hours and engaged in the creation of guidelines and recommendations.
We would also like to thank Dr. Michael Beazley, Dr. Kim Corace, and Dr. Meldon Kahan for their support in reviewing and for providing their perspectives on this document.
We would like to thank the Canadian Centre on Substance Use and Addiction and the Behavioural Supports Ontario Substance Use Collaborative for their support and contributions throughout the development of the Guidelines and Tonya Mahar (Manager, Library Services, Baycrest) for her assistance with literature searches.
Finally, the CCSMH would like to acknowledge the continued dedication of its Steering Committee members and the outstanding contributions of our Director, Claire Checkland and our Project Coordinators: Indira Fernando, Natasha Kachan, and Marc-André LeBlanc.
The CCSMH is a project of the Canadian Academy of Geriatric Psychiatry.
# Table of Contents 4
Canadian Guidelines on Cannabis Use Disorder Among Older Adults Scope T he Canadian Coalition for Seniors' Mental Health (CCSMH) received a grant from the Substance Use and Addictions Program (SUAP) of Health Canada to create a set of four guidelines on the prevention, assessment, and treatment of substance use disorders (SUDs) among older adults on the topics of alcohol, benzodiazepine receptor agonists (BZRAs), cannabis, and opioids . The GRADE approach was utilized in the creation of these guidelines . The methodology can be found in a separate document at ccsmh .ca . An introduction to these guidelines which highlights issues of relevance to all four can also be found at ccsmh .ca . These guidelines are not intended to provide a comprehensive guide on the use of these substances either by medical authorization or non-medical use .
The goal of this document is to provide useful guidance for clinicians on either preventing the development of Cannabis Use Disorder (CUD) or optimally assessing and treating older adults who have developed such a disorder . These guidelines have been developed due to the paucity of information that surrounds the relationship between cannabis use and the impact of aging processes such as changing physiology, metabolism, and the increase in polypharmacy . These guidelines should be used as a complement to other reliable sources of information . While clinicians may choose to authorize cannabis for medical purposes in older patients this document will not focus on possible medical uses, but instead it seeks to address issues of non-medical cannabis use and CUD in older adults .
Cannabis Use Disorder: According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Cannabis Use Disorder (CUD) is a problematic pattern of cannabis use leading to clinically significant impairment or distress as manifested by at least two of the criteria below occurring in a 12-month period (American Psychiatric Association, 2013) . It is important to note that among older adults, some of these criteria may be modified by the aging process or their social roles (e .g ., retirement from work), resulting in more subtle presentations (Kuerbis et al . , 2014) .
✚ Cannabis is often taken in larger amounts over a longer period than was intended .
✚ There is a persistent desire or insignificant effort to cut down or control cannabis use .
✚ A great deal of time is spent in activities necessary to obtain cannabis, use cannabis, or recover from its effects .
✚ Craving or a strong desire or urge to use cannabis .
✚ Recurrent cannabis use resulting in failure to fulfill major role obligations at work, school, or home .
✚ Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis .
✚ Important social, occupational, or recreational activities are given up or reduced because of cannabis use .
✚ Recurrent cannabis use in situations which are physically hazardous .
✚ Cannabis use is continued despite knowledge of having persistent or recurrent physical or psychological problems that are unlikely to have been caused or exacerbated by cannabis .
# Definition of Key Terms
✚ Tolerance, as defined by either:
-A need for markedly increased amounts of cannabis to achieve intoxication and desired effect, or -A markedly diminished effect with continued use of the same amount of cannabis .
# Remission
✚ Following treatment, 3-12 months of abstinence is considered early remission .
✚ More than 12 months is considered sustained remission .
# Summary of Recommendations and Grades
W e used the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation) as a method of grading the quality of evidence and the strength of recommendations . In following the GRADE process, the initial step was to grade the quality of available evidence supporting each recommendation . Subsequently, we identified the overall strength of the recommendation taking into account the quality of the evidence but also other factors such as the potential to do harm, the cost and feasibility .
We have also developed a separate category for recommendations which are not primarily based on empirical evidence; but have agreement that they represent best clinical practice . Examples would include: optimal assessment processes and those related to education and/or policy . These recommendations have been categorized as "C" for consensus . We did not use the GRADE process for these recommendations . Other guideline groups have used a similar approach e .g . British Association for Psychopharmacology Guidelines (Lingford-Hughes et al ., 2012) . While such recommendations lack empirical evidence, we believe they are also useful and important . The quality of evidence for each recommendation is determined through an examination of the following factors: (1) Study design and the quality of the studies that were included, (2) the directness of the evidence (generalizability or applicability) and
(3) the confidence that patients will benefit from the treatment .
The strength of each recommendation is determined through an examination of the following factors:
(1) The balance between benefits and undesirable effects/ risks, (2) uncertainty or variability of patient values and preferences and (3) the resources associated with management options .
# GRADE
# QUALITY OF EVIDENCE
# STRENGTH OF RECOMMENDATION
# HIGH
Further research is unlikely to change confidence in the estimate of effect
# MODERATE
Further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate
# LOW
Further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate
# STRONG
Strong recommendations indicate high confidence that desirable consequences of the proposed course of action outweigh the undesirable consequences or vice versa .
# WEAK
Weak recommendations indicate that there is either a close balance between benefits and down sides (including adverse effects and burden of treatment), uncertainty regarding the magnitude of benefits and down sides, uncertainty or great variability in patients' values and preferences, or that the cost or burden of the proposed intervention may not be justified .
# RECOMMENDATION #3:
In order to support the retention of information, clinicians should provide education and counselling with regard to cannabis and cannabinoids to older patients and their family members/caregivers both verbally and in writing.
[Consensus]
# RECOMMENDATION #4:
Clinicians should counsel patients, caregivers, and families to be aware that older adults can be more susceptible than younger adults to some dose-related adverse events associated with cannabis use.
# RECOMMENDATION #14:
Clinicians should be aware that the diagnostic accuracy of some screening tools may be variable given that some of the symptoms of aging may overlap with those of CUD.
# Rationale
C annabis use for medical purposes has become a topic of great interest in recent years . Increased attention has been paid to the many product types available (dried product, oils, edible cannabis, etc .) as well as its effects . However, evidence is limited with regard to the potential benefits and harms of cannabis use, especially among older adults . Those who were born between 1946-1964, many of whom are now older adults, have a higher lifetime prevalence of use and past year use than any generation that precedes them (Simoni-Wastila & Yang, 2006) . This lack of evidence and increased lifetime exposure of many adults, coupled with the recent legalization of non-medical cannabis use in Canada and subsequent increase in public interest, has driven concern for potential problematic cannabis use and Cannabis Use Disorder among older adults .
# Canadian Guidelines on Cannabis Use Disorder Among Older Adults
# KEY POINTS FOR THIS GUIDELINE
✚ The evidence base for harms and potential benefits associated with cannabis use in older adults is limited but growing .
✚ Given that the adverse effects of cannabis may vary considerably based on routes of administration and subtype of strain, as well as the lack of evidence regarding older adults, we have developed these guidelines utilizing a cautionary approach .
✚ Hopefully as research advances and capacity improves in the upcoming years, the risks and benefits of cannabis use among older adults, as well as the risk of developing Cannabis Use Disorder, will be better understood .
Much of the limited evidence related to cannabis is due to its longstanding classification as an illegal drug . This has impeded clinical research on its use, the effects of its use, and its potentially beneficial and adverse health outcomes . It is important to consider these questions broadly, but also specifically for different patient groups, such as older adults .
Older adults face unique physical and socioeconomic circumstances that may influence their response to cannabis use . Physiological changes that impact sleep, mobility, diet, exercise, and overall quality of life, along with issues such as polypharmacy and cognitive decline are all confounding factors in the effects and response of cannabis use in this population . All of these factors should be taken into consideration in the clinical evaluation of the patient and in decision-making when considering cannabis .
As the current state of evidence on cannabis use in older adults is largely absent, further clinical investigation is needed to understand the extent of effects, specifically within the context of substance use and aging . Despite this, there is an abundance of anecdotal (and sometimes conflicting) advice available to consumers, based on personal and collective narratives acquired over decades of use . There is a clear need to not only reconcile anecdotal and self-reported experiences (positive and negative) with the evidence to guide clinical decision-making, but also to more fully understand the impact of physiological and socioeconomic implications of cannabis use among older adults . Applying some of the available evidence for younger adults in the counselling of older adults and cannabis use is necessary until we are able to fully understand the effects of cannabis use and aging .
Aging presents unique considerations for cannabis use particularly when coupled with multiple comorbidities, the use of multiple medicines, and the use of a psychoactive substance by a population more prone to vision, mobility, and cognitive issues, among other concerns . These factors coupled with the ongoing diversification of the cannabis market present a rapidly changing landscape where little is known of consumer habits and emerging products . As such, healthcare professionals need to be aware of the fact that older adults do use cannabis, should be asked about it, and need guidance for helping ensure that they can use cannabis safely and access appropriate treatments if their use is problematic .
The information contained within this document is based on the most current and reliable English language research at the time of publication . With the amount of variability in reliability of data surrounding medical and non-medical cannabis use there is a need for unbiased information and systematic evidence-based approaches to clinical practice . It is in this setting that we hope this guideline will support health care professionals, patients, and families alike .
# Background
C annabis is a plant that contains hundreds of compounds including cannabinoids, which act on the endogenous cannabinoid (endocannabinoid) system . This complex system is involved in bonding, sleep, appetite, immune response, and pain regulation . Certain cannabinoids act by influencing reward, motivation, and substance-related cues . Delta-9tetrahydro-cannabinol (THC) and cannabidiol (CBD) are two cannabinoids that have the most available literature . They exert various effects by binding to the cannabinoid receptors; CB1 is located centrally in the brain, and CB2 is located primarily peripherally and on the circulating immune system throughout the body . The primary psychoactive ingredient in cannabis is THC, which mimics the endocannabinoid anandamide and binds to cannabinoid-1 (CB1) receptors in the brain, often producing a high or sense of euphoria . THC is also vasoconstrictive to blood vessels in the heart and brain and as such may increase the risk of cardiovascular events including stroke, cardiac arrhythmia, and myocardial infarction . In contrast, CBD binds weakly to CB1 receptors and may interfere with the binding of THC, resulting in a lack of euphoric and reinforcing effect (Cohen & Weinstein, 2018) . Also, CBD has been shown to be an agonist similar to another endocannabinoid, 2-AG, and binds primarily to CB2 receptor sites .
It is important to note that the cannabinoid composition of a cannabis plant is wide ranging and varies by strain . Some are higher in CBD and others contain more THC . As a result, the effects of cannabis use are also wide ranging and exhibit a variety of psychosomatic properties . While neither taking CBD nor THC has been found to be directly fatal in adults, there have been overdoses in children who have ingested edible cannabis derivative products (e .g ., gummy bears), and there is an increased risk of a variety of problems in adults that can lead to harm and even death, among them motor vehicle collisions in those driving after using cannabis and psychosis leading to accidents (Els, 2018) . Also, high THC use has been linked to long-term negative psychiatric effects, increasing depression, anxiety, worsening post-traumatic stress disorder symptoms, panic attacks, and suicidal ideation, attempts, and completion rates (Volkow et al ., 2014; National Academies of Sciences, Engineering, and Medicine [NASEM], 2017) . Cannabinoids exhibit differential uptake in the body based on the mode of consumption (inhaling vs . ingesting) .
Physicians and other health professionals need to be aware of the most recent research on the use of cannabis for medical and non-medical purposes, as they will find that a number of people they care for choose to use cannabis . In Canada, cannabis use rates in older adults have been rising over the last decade as baby boomers age into their older years, and supply has become more readily available . One study showed the percentage of older adults using cannabis in Ontario doubled from 2005-2015, and has increased fivefold since 1977 (Ialomiteanu et al ., 2016 et al ., 2018) . There is a growing body of evidence which is supportive of some other possible indications (Kalant & Porath, 2016) . The pace and scope of cannabis research may require clinical recommendations, such as those below, to be updated and modified more frequently in order to stay current .
# RECOMMENDATION #1:
Cannabis should generally be avoided by older adults who have: The endocannabinoid system modulates the functions of many organ systems throughout the body . Cannabis and certain cannabinoids therefore affect the central and peripheral nervous systems, respiration, and cardiovascular, skeletal, muscle, and bone function . The effects of cannabis can also resemble the effects of various disease states and age-related changes in these organ systems or can accentuate these conditions in older adults . For example, regular cannabis smoking can lead to chronic bronchitis and respiratory symptoms (Ribeiro and Ind, 2016) . Cannabis in other forms may cause osteoporosis and can impair cognitive and motor functions (Health Canada, 2018) . Clinical case reports and case series have indicated that regular cannabis use can be associated with stroke even among younger adults without other known risk factors (Hackam, 2015;Hemachandra et al ., 2016) . Since older adults have a higher frequency of risk factors for stroke, the possibility exists that cannabis use might also increase frequency of stroke among older adults . Therefore, individuals with existing health conditions or age-related physiological changes can have these conditions aggravated by cannabis, and should be advised of these risks and generally advised to avoid cannabis use . The potential benefits of cannabis in certain limited situations where it is medically indicated (e .g ., treatment of nausea due to chemotherapy) need to be balanced against potential risks .
There is strong evidence that persons with CUDs have an increased risk of developing alcohol, tobacco, or other SUDs and should be monitored appropriately for these conditions (Choi et al ., 2017) . Additionally, older adults with other substance use disorders have an increased risk of developing a CUD . Cannabis can precipitate or aggravate mental health conditions such as psychosis, depression, and anxiety,
# Prevention of Cannabis Use Disorder Among Older Adults
particularly in those with current experience, a personal history, or a strong family history of these conditions . There has not yet been research distinguishing between THC and CBD as it pertains to specific health outcomes (e . g . , psychosis, anxiety, depression, and addiction) . As such, we recommend that individuals with current experience, a personal history, or a strong family history of these conditions avoid cannabis (NASEM, 2017) .
# Clinician Education
# RECOMMENDATION #2:
Clinicians should be aware of the following: These medical products should be considered for prescription first, prior to consideration of non-prescription cannabis products for medical purposes .
A comprehensive systematic review conducted in 2017 (NASEM, 2017) identified only three conditions for which there is conclusive or substantial evidence that cannabis or cannabinoids are effective in treating specific symptoms . These include muscle spasms related to multiple sclerosis, nausea and vomiting associated with chemotherapy, and chronic pain, especially of neuropathic origin . These findings were supported by a more recent Canadian review of systematic reviews of medical cannabinoids .
Clinicians should be familiar with the distinction between THC and CBD, the different methods of administration for cannabis preparations, and potency and dosage of different cannabis preparations (Health Canada, 2018) . All of these elements are very relevant in understanding cannabis administration and require further research to convey an accurate representation of the therapeutic effects of cannabis, as well as a proper understanding of the psychoactive effects and other effects of relevance to older adults . Common symptoms associated with cannabis use, including adverse effects, are described in Table 1 .
It is important to review the specific risks associated with cannabis use on an individual basis . This may include the patterns of use as well as the particular kinds of cannabis being used to thoroughly understand the potential risks associated with it . The particular implications of cannabis use among older adults should be considered, including a higher risk of falls, cognitive impairment, confusion, drug-drug interactions, and other factors associated with age-and disease-related physiological changes . However, evidence also suggests that many older adults use cannabis without severe complications or adverse events and the possibility of use within these relatively safe limits should be acknowledged during screening for CUD (Choi et al ., 2015) .
Comorbid psychiatric conditions, such as depression, anxiety, and schizophrenia, have been associated with CUD and should be assessed clinically .
# Patient and Family/Caregiver Education:
RECOMMENDATION #3:
In order to support the retention of information, clinicians should provide education and counselling with regard to cannabis and cannabinoids to older patients and their family members/caregivers both verbally and in writing.
[Consensus]
Available evidence suggests that when presented with relevant, accurate, and properly contextualized information concerning the health effects of cannabis use, adults who use cannabis may moderate the quantity or types of cannabis used and/or the ways in which they consume it (Murphy et al ., 2015) .
Existing guidelines suggest that clinicians should provide education and counseling concerning cannabis use to patients . Although the evidence concerning educational interventions among older adults is limited, and there are no randomized controlled trials studying the provision of patient education about the risks and benefits specifically related to cannabis use in older adults, the use of written or printed material may help the patient to retain and reinforce this information and facilitate discussions with family members or friends .
# RECOMMENDATION #4:
Clinicians should counsel patients, caregivers, and families to be aware that older adults can be more susceptible than younger adults to some dose-related adverse events associated with cannabis use. [GRADE: Evidence: High; Strength: Strong] Education and counselling are important in order for older adults to avoid potential harms due to adverse effects including changes in depth perception risking balance instability and falls, changes in appetite, cognitive impairment, cardiac arrhythmia, anxiety, panic, and psychosis . The potential for greater harm in older adults exists because of more vulnerable physiology, the prevalence of medical comorbidities, and potential drug interactions when initiating any cannabis use . Patients who intend to use cannabis should be encouraged to seek out products with lower THC content (< 10%) and to introduce use with a "low and slow" approach to watch for side effects and/or complications .
# RECOMMENDATION #5:
Clinicians should advise patients, caregivers, and families about potentially increased risks associated with higher potency delta-9-tetrahydro-cannabinol (THC) extracts, or higher potency strains of cannabis when compared to those with lower THC content. [GRADE: Evidence: Low; Strength: Strong]
There are several forms of cannabis products with higher THC concentrations (e .g ., those with street names such as Shatter, Dab, Wax, and Budder), and clinicians should advise patients of the potential harmful effects of using such products . Both patients and clinicians should be aware that these products are not available through the legal avenues for purchasing cannabis such as licensed producers and other governmentregulated producers, although some of these products will be regulated under the Cannabis Act in October 2019 and will be available for sale as early as December 2020 . Use of products with higher THC content exacerbates the risks associated with acute cannabis consumption including increased risk of motor vehicle crashes, especially fatal collisions (Karila et al ., 2014) .
*** Please note that the majority of existing literature describing adverse effects of cannabis use is focused on the impact of THC . There are common sideeffects applicable to both THC and CBD, however much of the information pertains to THC-based products . It is important to note that adverse effects can be experienced with both acute and chronic use, and also vary depending on formulation, concentration, and dose (MacCallum & Russo, 2018) . Cannabis products, regardless of THC and CBD content, come in various forms including those that can be inhaled, those that are ingested, and those that can be applied topically . Clinicians should understand the basic pharmacokinetic differences between formulations and their associated risks (Health Canada, 2018) . While the evidence is limited for CBD products, clinicians should advise that CBD products may induce some of the adverse effects associated with THC, but CBD's effects on the nervous system differ markedly . For any type of cannabis product, inhaled formulations have a quicker onset of action than ingestible forms (MacCallum & Russo, 2018) . Risks associated with chronic use of inhaled formulations include but are not limited to increased risk for bronchospasm mediated by bronchial irritation . Certain cannabis oil pens are made using butane, a carcinogen (Miller et al ., 2016) .
Ingestible forms of cannabis, such as edibles and oils, have a delayed onset of action and typically have a longer duration of action (NASEM, 2017) . This may result in the use of larger than intended doses due to the delayed and cumulative effects from repeated acute ingestions .
Patients should be cautioned against using multiple doses of orally administered cannabis in short time periods due to these risks .
Topically administered cannabis products bypass the first phase of hepatic metabolism and some sources have speculated that this route of administration may therefore be associated with fewer adverse effects . However, the evidence for this conjecture is limited and topical formulations require further research (Huestis, 2007) . Based on clinical experience, patients rarely report cognitive side effects when using topical cannabis derivatives for pain, especially CBD-only products, so it may be a lower risk starting point for those without contraindications who wish to try a cannabis product .
# RECOMMENDATION #7:
Clinicians should educate patients to avoid illegal synthetic cannabinoids (e.g., K2 and SPICE,) because of the potential to cause serious harm. [GRADE: Evidence: Low; Strength: Strong]
Illicit synthetic cannabinoid products such as K2 and SPICE are more potent than other forms of cannabis and present a greater risk of adverse events among older adults . Using these products can lead to severe health problems such as seizures, irregular heartbeat, and hallucinations (Gunderson et al ., 2012;Seely et al ., 2012;Harris & Brown, 2013;van Amsterdam et al ., 2015) . In rare instances, death can occur (Seely et al ., 2012;Harris & Brown, 2013;van Amsterdam et al ., 2015) .
# RECOMMENDATION #8:
Clinicians Initiation of cannabis for medical or non-medical use can result in physiological, cognitive, perceptual, and emotional changes, including impairment . The risk of impairment with cannabis is increased with formulations containing higher concentrations of THC . Use of cannabis products with THC concentrations of >20% under any circumstance is unwarranted . Claims made for the potential benefits of cannabis in product promotions may not be scientifically supported and patients should be cautious of information provided by manufacturers or distributors of cannabis products . In addition, caution is advised in reviewing information that is available online as the credibility of sources may vary . Patients need to be aware of the THC concentration in cannabis preparations and be aware that impairment in attention, reaction time, mood, memory, depth and time perception, and cardiac function are all possible adverse effects that are more common when preparations with higher THC concentrations are used . Only medical grade cannabinoids available on prescription have accurate dosing supported by Health Canada . Caution needs to be applied when purchasing from dispensaries or the illicit market . One study of randomly chosen edible cannabis products available at dispensaries in the United States and tested in an independent laboratory found only 17% were accurately labelled for THC and 0% had accurate CBD labeling (Vandrey et al ., 2015) .
# RECOMMENDATION #9:
Clinicians As more older adults begin using cannabis for both medical and non-medical reasons, many may use cannabis chronically rather than intermittently and thus be at increased risk of long-term health effects . These risks can include respiratory and cardiovascular problems (Hall & Degenhardt, 2014), skeletal changes that increase risk of fractures (Sophocleous et al ., 2017), emotional and cognitive disorders (NASEM, 2017), and SUDs involving not only cannabis itself but also opioids and other pain relievers (Choi et al ., 2017) . Though there is no conclusive evidence of a causal link between prolonged use of cannabis and cancer, an association cannot be ruled out as precancerous changes in respiratory epithelium have been observed in people who chronically smoke cannabis (Barsky et al ., 1998) . Clinicians should be aware that some of the products made by licensed medical cannabis producers in Canada have higher THC concentrations (>20% THC), and should advise patients to avoid such products as they may further increase the risk of mental health problems over time .
# RECOMMENDATION #10:
Clinicians should advise patients, caregivers, and families that: Due to the varying potencies and durations of effect of different cannabis products, it is important to emphasize the significant impact that cannabis has on driving performance and the high potential to cause impairment while driving .
Numerous experimental studies have shown that THC impairs cognition, psychomotor function, and actual driving performance in a dose-related manner (Ramaekers et al ., 2004) . Furthermore, surveys that established recent use of cannabis by directly measuring THC in blood showed that individuals who test positive for THC, particularly at higher levels of THC, are approximately three to seven times more likely to be responsible for their crash as compared to drivers that had not used drugs or alcohol (Ramaekers et al ., 2004) . A recent systematic review showed the odds ratio of a motor vehicle collision after using cannabis was between 2 .49-2 .84 (Els et al ., 2019) . Of note, the effects of CBD on driving are not well known, and currently most of the evidence on driving impairment is related to THC use (Beirness & Porath, 2019) . However, in childhood epilepsy studies where pure CBD was used, 30% of participants reported significant sedation (Ali et al ., 2019) . Thus Dr . Charl Els and colleagues, in a position paper endorsed by the Occupational and Environmental Medical Association of Canada and the Canadian Society of Addiction Medicine, recommend not using cannabis (with any concentration of THC and/or CBD) within 24 hours of safety sensitive work (Els et al . , 2018) . Specifically, the document notes "it is not advisable to operate motor vehicles or equipment, or engage in other safety-sensitive tasks for 24 hours following cannabis consumption, or for longer if impairment persists . "
Due to the variation of effects of THC on driving as THC/CBD formulations change, it is essential to note that the consumption of cannabis and alcohol together will have a synergistic effect on impairment, and that those who may be below the legal allowable blood alcohol levels may still be unsafe to operate a motor vehicle when alcohol is consumed with cannabis (Neavyn et al . , 2014) .
# RECOMMENDATION #11:
Patients, caregivers, and families should be provided with information about the signs, symptoms, and risks of cannabis withdrawal. [GRADE: Evidence: High; Strength: Strong]
Cannabis withdrawal symptoms will be more pronounced with abstinence after long-term use of higher amounts of cannabis .
Most research has investigated symptoms in young adults rather than older adults . Typical symptoms of withdrawal include fluctuating behaviour and mood and physical symptoms such as weakness, sweating, restlessness, dysphoria, sleeping problems, decreased appetite, nervousness/anxiety, irritability, aggression, and craving . The desensitization and downregulation of the CB1 receptors begin to reverse within the first two days of abstinence and return to more natural functioning within four weeks of abstinence . The severity of withdrawal is highly variable and dependent on the amount of cannabis used, sex, and patient and contextual factors .
# Screening for Cannabis Use Disorder
C linicians may underestimate the likelihood of problematic substance use or a SUD among older adults . It is therefore important to conduct a comprehensive history of current and past use of substances, including cannabis and cannabinoids . A comprehensive assessment is recommended when a SUD is suspected .
# RECOMMENDATION #12:
Clinicians should initiate non-judgmental discussions related to cannabis and cannabinoid use. Careful histories should be obtained from patients, caregivers, and families about signs and symptoms of CUD that may be similar to those of age-related nervous system changes, such as drowsiness, dizziness, memory impairment, and falls.
[GRADE: Evidence: High; Strength: Strong] Just as with other substances, discussions with older adults about cannabis use and the possibility of CUD should be nonjudgmental and supportive in nature . Ensure that screening for CUD in older adults is age appropriate; employs active listening; is supportive; uses a health or medical frame; accounts for memory impairment or cognitive decline; and is non-threatening and non-stigmatizing . The DSM-5 criteria for Cannabis Use Disorder require impairment in meeting social and occupational obligations and the specific social and functional roles of older adults should be considered when assessing the impact of cannabis use on them . It is important to respect older adults' autonomy and confidentiality but it is also helpful to obtain collateral information from family, friends, and other caregivers, with the patient's consent if it is available, particularly for individuals who may have cognitive impairment due either to cannabis or to comorbid medical or psychiatric conditions . Many symptoms of CUD such as drowsiness, dizziness, memory impairment, and falls are relatively common among older adults without CUD, but CUD should be considered as a potential cause or contributor to these symptoms in older adults NASEM, 2017) .
# RECOMMENDATION #13:
All patients regardless of age should be screened for: All patients should be screened for cannabis use . Particular attention should be paid to individuals with a past history of substance misuse, recent bereavement, depression, social isolation, significant self-neglect, and chronic pain . Answers to the screening questions may vary according to the individual depending on how the question is asked . Older patients might not think to mention medical use when asked about cannabis . The CUDIT is quite useful for identifying if problems found in a given case may not be attributable to cannabis use . If quantity, potency, and frequency of use are low and there are higher scores in memory or functional issues, the problem may not be related to cannabis .
# RECOMMENDATION #14:
Clinicians should be aware that the diagnostic accuracy of some screening tools may be variable given that some of the symptoms of aging may overlap with those of CUD.
[GRADE: Evidence: Moderate; Strength: Weak]
For patients who are using cannabis either medically or nonmedically it is important to assess potential for CUD . There are a number of challenges involved in detecting and diagnosing a substance use disorder in older adults (Kuerbis et al ., 2014) . DSM-5 criteria for SUDs include a number of criteria that measure impairment based on the impact of substance use on fulfilling social or interpersonal roles or performance in areas that are not always applicable to older adults (such as at work, school or while driving) .
CUD can also be overlooked because of the increased presence of coexisting medical morbidities whose symptoms may mask CUD in older people . (Ialomiteanu et al ., 2016) . This route adversely affects respiratory health outcomes (Lee & Hancox, 2011;Pletcher et al . , 2012;Gates et al ., 2014;Tashkin, 2014;Martinasek et al ., 2016), and poses the greatest health risk . The use of edible cannabis, liquids, and oils may eliminate respiratory risk but these forms of administration introduce the risk of potential use of larger than intended doses because of the delayed onset of effect (Wang et al ., 2013;Monte et al ., 2015) . The mode of use should be explored carefully when there is a history of adverse effects that appear to be disproportionate to the effects typically observed with the reported amount of consumption .
# Assessment of Cannabis Use Disorder
Frequency and dose used during each episode of use are strong predictors of the risk of both acute and chronic cannabis-related problems (Solowij et al ., 2016) . Systematic reviews have found associations between the frequency or dose of cannabis use and various adverse health outcomes, including mental health problems, cardiovascular problems, motor vehicle collisions, suicidality, and cognitive effects (Moore et al ., 2007;Reece, 2009;Lorenzetti et al ., 2010;Elvik, 2013;Gibbs et al ., 2015;Ganzer et al ., 2016) . In the assessment of CUD, cannabis-related anxiety and cannabis dependence are important to identify . The risk of anxiety and cannabis dependence are strongly associated with daily or near daily use (Coffey et al ., 2002;Degenhardt et al ., 2013;Silins et al ., 2014) . Assessment of CUD in older adults should also include comprehensive assessment of potential physical manifestations of CUD or consequences of cannabis use . As with other SUDs, the DSM-5 criteria for CUD may not adequately aid with assessment of severity of CUD in older adults Kuerbis et al ., 2014) .
# RECOMMENDATION #16:
Clinical assessment of CUD in older adults should evaluate the signs and symptoms of cannabis withdrawal, with consideration that the rapid reduction or abrupt discontinuation of cannabis use may also be associated with withdrawal symptoms. [GRADE: Evidence: High; Strength: Strong] Like all substances with addictive potential, cannabis can be associated with a withdrawal syndrome . It can appear when individuals who use cannabis rapidly reduce their use . Cannabis withdrawal syndrome typically emerges after 1-3 days of abstinence from cannabis . Symptoms tend to peak between 2-6 days and can last up to 14 days . Cannabis withdrawal symptoms can be reliably assessed using the Cannabis Withdrawal checklist which includes questions about the commonly observed symptoms such as: shakiness/tremulousness, depressed mood, decreased appetite, nausea, irritability, sleep difficulty, sweating, craving to smoke marijuana, restlessness, nervousness/anxiety, increased aggression, headaches, stomach pains, strange dreams, and increased anger . Cannabis withdrawal symptoms therefore can be confused with some of the self-reported reasons individuals give for using cannabis products . Not unlike alcohol and opioid withdrawal, during cannabis withdrawal, symptom relief can occur with taking the substance once again, thus reinforcing use . Individuals who screen positive for cannabis use should be assessed for withdrawal symptoms .
The frequency of cannabis withdrawal syndrome is dependent on factors such as duration and frequency of use and amount of cannabis used . In most studies, withdrawal reactions occur in approximately 20-30% of individuals who frequently use cannabis . The symptoms are frequently severe enough to give rise to a high rate of relapse . Current approaches to treatment of the withdrawal syndrome are discussed in Recommendation 22 .
# RECOMMENDATION #17:
When assessing patients, clinicians should be aware of the risk of cannabis hyperemesis syndrome in association with chronic cannabis use, especially with higher potency preparations. [GRADE: Evidence: High; Strength: Strong] Cannabis hyperemesis syndrome is characterized by recurrent episodes of nausea and vomiting accompanied by abdominal pain typically occurring in individuals with prolonged use of high dose cannabis . The prevalence of hyperemesis syndrome among individuals with CUD is not well known although overall it appears to be a relatively uncommon, although distressing and potentially dangerous, condition . Management of hyperemesis syndrome is largely supportive to ensure adequate hydration and administration of antiemetics . It typically resolves within 48 hours of cessation of cannabis use (Galli et al ., 2011) . Hyperemesis syndrome can develop in association with any frequency of cannabis use but most often is observed in individuals who have been using cannabis for one year or longer at a frequency of daily to weekly (Sorensen et al ., 2017) .
# Treatment of Cannabis Use Disorder
T his section focuses on the treatment of older adults who have developed CUD . Current treatments to date for CUD have focused primarily on psychotherapy and contingency management . Pharmacotherapy trials have been conducted as adjunctive interventions to psychosocial treatment, however, no pharmacologic treatment has emerged as efficacious .
# RECOMMENDATION #18:
The Screening, Brief Intervention, and Referral to Treatment (SBIRT) approach should be considered for assessing and managing CUD similarly to other SUDs.
[GRADE: Evidence: Low; Strength: Strong] The use of SBIRT approaches in the context of CUD treatment has been a relatively unexplored area . However there is significant evidence supporting the use of brief interventions (e .g ., motivational enhancement and brief advice) among older adults (Fleming et al ., 1999;Gordon et al ., 2003;Fink et al ., 2005;Schonfeld et al ., 2010;Moore et al ., 2011;Schonfeld et al ., 2015) . SBIRT initiatives are known to effectively reduce problem drinking among older adults which might otherwise go unnoticed by substance abuse services (Schonfeld et al . , 2010) .
# RECOMMENDATION #19:
Peer support programs should be considered for individuals with CUD. [GRADE: Evidence: Moderate; Strength: Strong] Peer support programs can be a valuable recovery tool for patients with CUD (Tracey & Wallace, 2016) . One of the factors which exacerbates SUDs/CUD is lack of social connection (Sarkar et al, 2015) . Older adults are at elevated risk of losing social connections due to retirement, loss of friends/loved ones, etc . Clinicians need to be aware of what peer support programs are available in their areas and can support patients in their engagement in a program to support their recovery process . The most efficacious treatments to date include a combination of MET/CBT/CM including computer-delivered treatments, which show some of the highest abstinence rates to date, comparable to results obtained in treatment of cocaine use disorder, but lower efficacy than with alcohol . One meta-analysis found lower abstinence rates for people who use cannabis compared to people who use cocaine, opiates, and polysubstances (Sherman & McRae-Clark, 2016) . A brief online CM self-help intervention showed a significant decrease in past month quantity, frequency of cannabis use, and lower severity of dependence scores (Copeland et al ., 2017), though the eligible participants were not all diagnosed with CUD (median age 26, but including adults up to 65) . MET has been shown to improve cannabis-related outcomes among treatment-seeking adults, non-treatment seekers, and individuals with co-occurring disorders (Danovitch & Gorelick, 2012) . Technology based interventions that deliver CBT, MET, or MI, ideally in combination, have shown similar rates of effectiveness to therapist-delivered modalities (TDM), albeit without the randomization or follow up that are included in the more proven TDM . These should be considered if TDM access is restricted . In a randomized controlled trial where SUDs were broadly addressed using Mindfulness Based Relapse Prevention (MBRP) after intensive inpatient or outpatient treatment, there was demonstration of empirical promise for the feasibility and initial efficacy of MBRP in aftercare treatment of SUDs . Of the participants in this study, 5 .4% cited marijuana as their primary substance of choice (Banes et al ., 2014) .
# RECOMMENDATION #20:
# RECOMMENDATION #21:
There are currently no established pharmacological treatments that have been demonstrated to be safe and effective for either cannabis withdrawal symptoms or CUD. [Consensus] Certain medications have demonstrated potential in the area of withdrawal and cravings management . Gabapentin has been shown to address the attenuation of withdrawal symptoms while N-acetylcysteine (NAC) has demonstrated some promise in the reduction of cravings . A review by Sherman et al (2016) suggests some evidence for gabapentin and the most evidence for NAC . The potential side effects of drowsiness, dizziness, and fatigue are cited among others as challenges that outweigh any existing promise, combined with insufficient evidence to demonstrate efficacy for improving withdrawal symptoms or abstinence rates (Marshall et al ., 2014;Hassell et al ., 2017) . However, a systematic review by Werneck et al (2018) concluded that cannabinoid replacement therapy (with nabilone or dronabinol) has sufficient promise to warrant more extensive clinical trials . This off-label treatment should only be considered for highly intransigent cases that have not responded to all other interventions, where benefits are likely to outweigh risks, and very cautious dosing should be applied .
There are no studies on the treatment of insomnia due to cannabis or cannabinoid withdrawal in older adults . In younger adults, trazodone has been used .
# RECOMMENDATION #22:
Accredited residential treatment should be considered as appropriate for treating CUD if the individual is unable to effectively reduce or cease their cannabis use. [GRADE: Evidence: Low; Strength: Strong] Drawing from evidence used for the management of other SUDs that can be applied as reasonable principles for all SUD management, most experienced clinicians may manage older adults with mild to moderate CUD . Patients with more severe or complex disorders may benefit from involvement with a team or program specializing in SUDs including, when available, in an inpatient setting . Subsequently, the threshold to admit an older adult with social, psychological, or physical comorbidities to either residential or hospital care for treatment of CUD or withdrawal management may involve a lower threshold than what would be used for a younger adult .
# Future Directions
F uture research into cannabis use and CUD among older adults needs to start by recognizing and understanding patterns of and motivations for use in this population . It is clear that older adults use cannabis, but what is less clear is how and why this population uses it, what the prevalence of use across the life course is, how multiple factors unique to aging may positively or negatively impact on patterns of use, and the harms associated with it . While the perception that cannabis use poses a significant risk of negative consequences has decreased, it is nonetheless associated with cognitive impairment, increased risk for psychiatric disorders, and other mental health problems . Compounding this are the realities of aging, accompanied by changing physiologies that may alter the way cannabis is metabolized and experienced, a higher prevalence of multimorbidity that may increase the likelihood of a chronic or acute health condition being exacerbated, or of an unintended drug interaction .
Despite these limitations, clinicians need to discuss cannabis and cannabinoid use with their patients, to help promote healthy behaviours and to identify potential risks or harms or problematic use that warrant follow-up or intervention . Clinicians also need to be mindful of the social context within which cannabis-a widely-used, now legal, and widelyavailable substance-is situated . This includes anecdotal narratives about its medicinal properties, which although potentially promising, are largely unsubstantiated and open to exploitation . In addition to this; the reality that cannabis occupies a counter culture image that is now being commercialized as legal markets open up poses a risk for older adults to be specific demographic targets in cannabis marketing .
Regulation and quality control within a legal market have arguable benefits for reducing certain harms, but the implications for rates of use remain unknown for the older adult population, even in jurisdictions with a longer history of legal non-medical cannabis .
It is in this context that clinicians must be aware of the current state of evidence and practice in cannabis use disorder and cannabis use in older adults . Keeping in mind that older adults are using cannabis, likely have questions, and deserve evidence-informed answers and guidance . These guidelines provide recommendations on the basis of available evidence and the experience of clinicians, and acknowledge that gaps in the evidence clearly exist . Patients will undoubtedly have questions, and it is important that clinicians have answers grounded in evidence, rather than conjecture or anecdotes about cannabis use .
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To provide an evidence-based approach to the evaluation of patients with suspected deep vein thrombosis (DVT).An estimated 45,000 patients in Canada are affected by DVT each year, with an incidence of approximately 1-2 cases per 1,000 persons annually. This translates into 2-4 DVTs per year in a typical, solo Canadian family practice. Since only 10-20% of patients with suspected DVT actually have the disease, a typical family practice will evaluate 20-40 patients with symptoms and/or signs suggestive of DVT each year. The ability to rapidly and accurately assess patients for DVT is crucial. A validated diagnostic algorithm should be used in the evaluation of patients with suspected DVT. Treatment of DVT once diagnosed prevents thrombus extension and pulmonary embolism (PE) and initiation of anticoagulation should be considered prior to confirmation of DVT while awaiting diagnostic tests, unless contraindications exist . The accurate exclusion of DVT eliminates unnecessary exposure to long term anticoagulants, which has treatment burdens and bleeding risks.# DIAGNOSIS:
The diagnosis of DVT is based on:
# 1) Pre-test probability (clinical suspicion)
It is recommended that a validated clinical decision rule be used to characterize pre-test probability of DVT. There are several formal models available, of these, the Wells Score is the most widely used (see Table 1). For DVT diagnosis, both a three-level (low, intermediate, high pre-test probability) and two-level (unlikely, likely) Wells score have been prospectively validated. The two-level score is displayed in the table and diagnostic algorithm below.
# CLINICAL FINDINGS POINTS
Paralysis, paresis or recent orthopedic casting of lower extremity 1
Bedridden >3 days recently or major surgery within past 12 weeks 1
Localized tenderness of the deep veins 1
Swelling of entire leg 1
Calf swelling 3 cm greater than other leg (measured 10 cm below the tibial tuberosity)
Pitting edema greater in the symptomatic leg 1
# Non-varicose collateral superficial veins 1
Active cancer or cancer treated within 6 months 1
# 3) D-Dimer
D-Dimer is a sensitive but non-specific marker of thrombosis. Although D-dimer is elevated in patients with DVT, it is also elevated in a variety of other common conditions including, but not limited to, inflammatory diseases, malignancy, pregnancy, surgery, hospitalization, trauma, and advanced age. This renders the test useful to help rule out DVT when negative but of little diagnostic value when positive. Although there are several D-dimer assays available, those that are typically used in Canada are all highly sensitive assays (sensitivity of greater than 90%) and can be used in combination with an unlikely pre-test probability to exclude DVT. However, clinicians should check with their laboratory to confirm the sensitivity of the D-dimer assay used locally.
There is good evidence for the use of a fixed, standard D-dimer cutoff with validated clinical prediction rules to exclude DVT. The use of a three level Well's score pre-test probability specific D-dimer cutoff was evaluated in one randomized trial that showed this strategy to be as safe as using a fixed cutoff. A second prospective management study has been completed, and preliminary results similarly show it to be a safe strategy for ruling out DVT while reducing the need for CUS. The role of a pre-test probability specific D-dimer cut-off with the two level Well's score has not been investigated. The use of an age-adjusted Ddimer cutoff has not been well validated for excluding DVT (unlike for PE). As such, its use for DVT diagnosis is not routinely recommended at this time.
Community-based physicians are often unlikely to receive timely D-dimer results from outside laboratories and may not be able to use strategies involving sequential tests. Alternative management approaches include diagnostic algorithms incorporating pre-test probability assessment and CUS (outlined below). In some centres, the option of referring patients to a Thrombosis Clinic may be available to facilitate rapid assessment.
# DIAGNOSTIC STRATEGY:
Patients with suspected DVT should first undergo a history and physical exam focused on the components of the Wells Score, as well as symptoms and signs of PE .
- Patients with an unlikely pre-test probability for DVT should then undergo D-dimer testing with management as outlined in Figure 1 below. - Patients with a likely pre-test probability should have proximal CUS as the recommended first-line test. Those with a negative proximal CUS should undergo Ddimer testing (to determine the need for repeat CUS) or repeat CUS in 5-7 days to exclude the possibility of distal DVT that has extended proximally.
In jurisdictions where proximal CUS is readily available in a timely manner and where D-dimer turnaround times are long, proceeding directly to proximal CUS for all patients suspected of a DVT is a reasonable but more costly strategy. With this approach, a negative proximal CUS and unlikely pre-test probability excludes DVT, while patients with a likely pre-test probability and negative proximal CUS should have CUS repeated in 5-7 days.
If whole leg CUS is undertaken and isolated distal DVT is detected, anticoagulation can be offered if severe symptoms are present or if the risk of proximal extension is high . Alternatively, patients may be followed with serial CUS over a 1-2 week period, after which time thrombus extension is unlikely. Those unlikely or unable to return for follow-up testing should generally be treated. Risk factors for proximal extension of a distal DVT include: positive D-dimer, calf DVT that is extensive or close to the proximal veins, absence of a reversible provoking risk factor, cancer, previous history of venous thromboembolism, lower extremity immobilization (e.g. plaster casting, neuromuscular disease), and in-patient status.
Figure 1. Suggested diagnostic strategy for patients with suspected DVT. *Clinical probability can be assessed by clinical decision rule, such as two-level Wells score. D-dimer should be measured using a highly sensitive assay to rule out DVT using this algorithm; if D-dimer testing is not available, CUS should be performed in all patients; a negative CUS and unlikely pre-test probability excludes DVT, while patients with a likely pre-test probability and negative CUS should have CUS repeated in 5-7 days. pCUS, proximal compression ultrasound.
# SPECIAL CONSIDERATIONS:
# Timing of diagnostic testing:
Testing should be undertaken as quickly as possible. However, if there will be a significant delay (greater than 4 hours), patients with a moderate/high or likely pre-test probability of DVT should receive a rapidly acting anticoagulant (e.g. low-molecular-weight heparin or a direct oral anticoagulant) until testing is performed, unless they are at high risk of bleeding or have another contraindication to anticoagulant therapy.
# Suspected recurrent DVT:
In the case of suspected recurrent ipsilateral DVT, CUS can be problematic because residual compression abnormalities are often present from the previous DVT. In such cases, it is important to compare CUS results with those from prior examinations. Recurrent DVT can only be definitively diagnosed with evidence of new thrombosis, including non-compressibility in previously normal venous segments or increases of at least 4 mm in compression diameter from prior studies. A negative D-dimer may make the diagnosis of recurrence less likely and may be helpful when no prior CUS studies are available for comparison. Consultation with an expert in the field may be helpful in this setting and especially when no prior CUS is available for comparison.
# Upper extremity DVT (UEDVT):
UEDVT is uncommon with an annual incidence of approximately 3/100,000 persons. Most patients with UEDVT have risk factors including central venous catheter, recent pacemaker or malignancy. Spontaneous UEDVT is often related to sudden physical effort and narrowing of the thoracic outlet (Paget-Schroetter syndrome, thoracic outlet syndrome). Clinical manifestations include acute and chronic arm pain, swelling, discoloration, and dilated collateral veins over the arm, neck or upper chest.
Pre-test probability for UEDVT is typically determined by clinical gestalt. The Constans Decision Score (which includes central venous catheter or pacemaker, localized pain, or unilateral edema) has also been shown to safely exclude UEDVT when used in combination with highsensitivity D-dimer. However, this approach has had only limited validation in one prospective management study. In general, combined CUS and color Doppler flow studies (duplex ultrasound) generally are used to evaluate patients with suspected UEDVT:
- In patients with low/unlikely pre-test probability, a strategy starting with D-dimer is suggested, followed by duplex ultrasound if D-dimer is positive. If D-dimer is not readily available, performing duplex ultrasound alone is acceptable.
- In patients with high/likely pre-test probability, duplex ultrasound should be performed to exclude UEDVT. If the initial US is negative, the diagnosis can be considered excluded unless the clinical suspicion remains high. In that case, further testing with D-dimer (with additional imaging if positive), repeat ultrasound, or traditional contrast venography, CT venography, or MRI is suggested.
# Pediatrics:
The incidence of DVT in children is lower than adults (0.7 to 0.14 per 10,000 children) and when it does occur it is more often associated with or use of central venous catheters, a primary disease (such as cancer and congenital heart disease), after intervention. The use of clinical decision rules and D-dimer testing has not been validated in children. Diagnosis of DVT is initiated with a CUS. While CUS testing is non-invasive, it may not be accurate for the upper extremity venous system and there have been few studies in the lower venous system. If the clinical suspicion is high for DVT with a negative CUS, the use of magnetic resonance imaging or computed tomography may be considered.
# Suspected DVT in pregnancy:
See Clinical Guide Pregnancy: Diagnosis of DVT and PE.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Central Venous Catheter-Related Venous Thrombosis
# Date of Version: 20July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To provide an evidence-based approach to the evaluation of patients with suspected deep vein thrombosis (DVT).An estimated 45,000 patients in Canada are affected by DVT each year, with an incidence of approximately 1-2 cases per 1,000 persons annually. This translates into 2-4 DVTs per year in a typical, solo Canadian family practice. Since only 10-20% of patients with suspected DVT actually have the disease, a typical family practice will evaluate 20-40 patients with symptoms and/or signs suggestive of DVT each year. The ability to rapidly and accurately assess patients for DVT is crucial. A validated diagnostic algorithm should be used in the evaluation of patients with suspected DVT. Treatment of DVT once diagnosed prevents thrombus extension and pulmonary embolism (PE) and initiation of anticoagulation should be considered prior to confirmation of DVT while awaiting diagnostic tests, unless contraindications exist [see Clinical Guide Deep Vein Thrombosis (DVT): Treatment]. The accurate exclusion of DVT eliminates unnecessary exposure to long term anticoagulants, which has treatment burdens and bleeding risks.# DIAGNOSIS:
The diagnosis of DVT is based on:
# 1) Pre-test probability (clinical suspicion)
It is recommended that a validated clinical decision rule be used to characterize pre-test probability of DVT. There are several formal models available, of these, the Wells Score is the most widely used (see Table 1). For DVT diagnosis, both a three-level (low, intermediate, high pre-test probability) and two-level (unlikely, likely) Wells score have been prospectively validated. The two-level score is displayed in the table and diagnostic algorithm below.
# CLINICAL FINDINGS POINTS
Paralysis, paresis or recent orthopedic casting of lower extremity 1
Bedridden >3 days recently or major surgery within past 12 weeks 1
Localized tenderness of the deep veins 1
Swelling of entire leg 1
Calf swelling 3 cm greater than other leg (measured 10 cm below the tibial tuberosity)
1
Pitting edema greater in the symptomatic leg 1
# Non-varicose collateral superficial veins 1
Active cancer or cancer treated within 6 months 1
# 3) D-Dimer
D-Dimer is a sensitive but non-specific marker of thrombosis. Although D-dimer is elevated in patients with DVT, it is also elevated in a variety of other common conditions including, but not limited to, inflammatory diseases, malignancy, pregnancy, surgery, hospitalization, trauma, and advanced age. This renders the test useful to help rule out DVT when negative but of little diagnostic value when positive. Although there are several D-dimer assays available, those that are typically used in Canada are all highly sensitive assays (sensitivity of greater than 90%) and can be used in combination with an unlikely pre-test probability to exclude DVT. However, clinicians should check with their laboratory to confirm the sensitivity of the D-dimer assay used locally.
There is good evidence for the use of a fixed, standard D-dimer cutoff with validated clinical prediction rules to exclude DVT. The use of a three level Well's score pre-test probability specific D-dimer cutoff was evaluated in one randomized trial that showed this strategy to be as safe as using a fixed cutoff. A second prospective management study has been completed, and preliminary results similarly show it to be a safe strategy for ruling out DVT while reducing the need for CUS. The role of a pre-test probability specific D-dimer cut-off with the two level Well's score has not been investigated. The use of an age-adjusted Ddimer cutoff has not been well validated for excluding DVT (unlike for PE). As such, its use for DVT diagnosis is not routinely recommended at this time.
Community-based physicians are often unlikely to receive timely D-dimer results from outside laboratories and may not be able to use strategies involving sequential tests. Alternative management approaches include diagnostic algorithms incorporating pre-test probability assessment and CUS (outlined below). In some centres, the option of referring patients to a Thrombosis Clinic may be available to facilitate rapid assessment.
# DIAGNOSTIC STRATEGY:
Patients with suspected DVT should first undergo a history and physical exam focused on the components of the Wells Score, as well as symptoms and signs of PE [see Clinical Guide Pulmonary Embolism (PE) Diagnosis].
• Patients with an unlikely pre-test probability for DVT should then undergo D-dimer testing with management as outlined in Figure 1 below. • Patients with a likely pre-test probability should have proximal CUS as the recommended first-line test. Those with a negative proximal CUS should undergo Ddimer testing (to determine the need for repeat CUS) or repeat CUS in 5-7 days to exclude the possibility of distal DVT that has extended proximally.
In jurisdictions where proximal CUS is readily available in a timely manner and where D-dimer turnaround times are long, proceeding directly to proximal CUS for all patients suspected of a DVT is a reasonable but more costly strategy. With this approach, a negative proximal CUS and unlikely pre-test probability excludes DVT, while patients with a likely pre-test probability and negative proximal CUS should have CUS repeated in 5-7 days.
If whole leg CUS is undertaken and isolated distal DVT is detected, anticoagulation can be offered if severe symptoms are present or if the risk of proximal extension is high [see Clinical Guide Deep Vein Thrombosis (DVT): Treatment]. Alternatively, patients may be followed with serial CUS over a 1-2 week period, after which time thrombus extension is unlikely. Those unlikely or unable to return for follow-up testing should generally be treated. Risk factors for proximal extension of a distal DVT include: positive D-dimer, calf DVT that is extensive or close to the proximal veins, absence of a reversible provoking risk factor, cancer, previous history of venous thromboembolism, lower extremity immobilization (e.g. plaster casting, neuromuscular disease), and in-patient status.
Figure 1. Suggested diagnostic strategy for patients with suspected DVT. *Clinical probability can be assessed by clinical decision rule, such as two-level Wells score. **D-dimer should be measured using a highly sensitive assay to rule out DVT using this algorithm; if D-dimer testing is not available, CUS should be performed in all patients; a negative CUS and unlikely pre-test probability excludes DVT, while patients with a likely pre-test probability and negative CUS should have CUS repeated in 5-7 days. pCUS, proximal compression ultrasound.
# SPECIAL CONSIDERATIONS:
# Timing of diagnostic testing:
Testing should be undertaken as quickly as possible. However, if there will be a significant delay (greater than 4 hours), patients with a moderate/high or likely pre-test probability of DVT should receive a rapidly acting anticoagulant (e.g. low-molecular-weight heparin or a direct oral anticoagulant) until testing is performed, unless they are at high risk of bleeding or have another contraindication to anticoagulant therapy.
# Suspected recurrent DVT:
In the case of suspected recurrent ipsilateral DVT, CUS can be problematic because residual compression abnormalities are often present from the previous DVT. In such cases, it is important to compare CUS results with those from prior examinations. Recurrent DVT can only be definitively diagnosed with evidence of new thrombosis, including non-compressibility in previously normal venous segments or increases of at least 4 mm in compression diameter from prior studies. A negative D-dimer may make the diagnosis of recurrence less likely and may be helpful when no prior CUS studies are available for comparison. Consultation with an expert in the field may be helpful in this setting and especially when no prior CUS is available for comparison.
# Upper extremity DVT (UEDVT):
[See also Clinical Guide Central Venous Catheter-Related Deep Vein Thrombosis]
UEDVT is uncommon with an annual incidence of approximately 3/100,000 persons. Most patients with UEDVT have risk factors including central venous catheter, recent pacemaker or malignancy. Spontaneous UEDVT is often related to sudden physical effort and narrowing of the thoracic outlet (Paget-Schroetter syndrome, thoracic outlet syndrome). Clinical manifestations include acute and chronic arm pain, swelling, discoloration, and dilated collateral veins over the arm, neck or upper chest.
Pre-test probability for UEDVT is typically determined by clinical gestalt. The Constans Decision Score (which includes central venous catheter or pacemaker, localized pain, or unilateral edema) has also been shown to safely exclude UEDVT when used in combination with highsensitivity D-dimer. However, this approach has had only limited validation in one prospective management study. In general, combined CUS and color Doppler flow studies (duplex ultrasound) generally are used to evaluate patients with suspected UEDVT:
• In patients with low/unlikely pre-test probability, a strategy starting with D-dimer is suggested, followed by duplex ultrasound if D-dimer is positive. If D-dimer is not readily available, performing duplex ultrasound alone is acceptable.
• In patients with high/likely pre-test probability, duplex ultrasound should be performed to exclude UEDVT. If the initial US is negative, the diagnosis can be considered excluded unless the clinical suspicion remains high. In that case, further testing with D-dimer (with additional imaging if positive), repeat ultrasound, or traditional contrast venography, CT venography, or MRI is suggested.
# Pediatrics:
The incidence of DVT in children is lower than adults (0.7 to 0.14 per 10,000 children) and when it does occur it is more often associated with or use of central venous catheters, a primary disease (such as cancer and congenital heart disease), after intervention. The use of clinical decision rules and D-dimer testing has not been validated in children. Diagnosis of DVT is initiated with a CUS. While CUS testing is non-invasive, it may not be accurate for the upper extremity venous system and there have been few studies in the lower venous system. If the clinical suspicion is high for DVT with a negative CUS, the use of magnetic resonance imaging or computed tomography may be considered.
# Suspected DVT in pregnancy:
See Clinical Guide Pregnancy: Diagnosis of DVT and PE.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Central Venous Catheter-Related Venous Thrombosis
# Date of Version: 20July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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# Background
Generally, metastatic colorectal cancer represents an incurable situation for which only palliative options (e.g.: best supportive care, palliative chemotherapy) should be considered. However, there are specific circumstances where an attempt at metastatectomy (surgical resection of a metastasis) may be possible and where five-year survivals may reach 40 percent. In addition, cytoreductive surgery ("peritoneal stripping") and heated intra-peritoneal chemotherapy may be considered for limited intra-peritoneal metastases. 4 Such treatments require involvement of a multidisciplinary team that should include a hepatobiliary surgeon, thoracic surgeon, and surgical oncologist (see Appendix A ). Consider post-operative ("adjuvant") therapy (an extrapolation from Clinical Practice Guidelines for Early Stage Colon Cancer) along with careful surveillance for patients with no evidence of residual disease (also an extrapolation from Clinical Practice Guidelines for Colorectal Cancer Surveillance):
# Post-Metastatectomy Colorectal Cancer Surveillance Guidelines 5
If resection of another recurrence from liver and/or lung is clinically appropriate,
- Obtain a CEA every three months for five years (progressive rises warrant a workup for recurrent disease); and - Obtain a CT scan of the thorax, abdomen, and pelvis at the discretion of the treating physician.
Stereotactic body radiation (SBRT), radiofrequency ablation (RFA) 6 or other local therapies may be considered for patients with otherwise resectable liver metastases who are unable to consider surgery due to medical comorbidities (e.g.: lung disease, significant heart disease).
It is recommended that surgery (e.g.: colon resection, diverting colostomy) or endoscopic procedure (e.g. stent placement) be considered to relieve or prevent a bowel obstruction. Tumor resection or palliative radiation may be considered for bleeding. Surgery is not recommended for patients with an asymptomatic (or minimally symptomatic) primary colorectal cancer and clearly incurable metastatic disease.
Palliative chemotherapy regimens are generally continued as long as tumor shrinkage or stability is confirmed, the side effects remain manageable, the patient wishes to continue, and the treatment remains medically reasonable. Palliative radiotherapy may help control local problems (e.g. pain from bone metastases, bleeding from in situ rectal cancer).
Guideline Questions
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with metastatic colorectal cancer. Different principles may apply to pediatric patients.
# Recommendations
Goals of Therapy 1. To maintain or to improve the patient's quality of life (to control or to delay the onset of tumourrelated symptoms). 2. To prolong life, if possible. 9 Pooled retrospective analyses establish the predictive and prognostic value of primary tumor site using Cetuximab and Panitumumab. 10,11 In a retrospective evaluation of 38% of the 5,760 patients enrolled in the CRYSTAL, FIRE-3, PEAK, PRIME, 181, and CALGB 80405 studies (trials with different populations, control arms, treatments, etc.), primary tumor location confers both prognostic effect (outcomes are worse for disease that arises from the proximal colon, regardless of the treatment received) and predictive effect (first-line use of anti-EGFR therapy improves outcomes in RAS wild-type disease that arises from the distal colon but offers no benefit when disease arises from the proximal colon). 12 The Alberta Provincial Gastrointestinal Tumour Team supports the use of EGFR inhibitors in first-line treatment for patients with Ras wild-type, MSS/MMR proficient metastatic colorectal cancer (i.e. non-mutated Kras or Nras) with left sided primary tumors. Selection of first-line therapy should now consider the results of a rigorous molecular analysis as well as reference to the primary tumor location (in addition to patient preferences, extent of cancer, goals of care, mutations in RAS, medical comorbidities, performance status, etc.). 9. Mutations in Kras and Nras predict a lack of response in anti-Epidermal Growth Factor Receptor (EGFR) therapy in patients with metastatic colorectal cancer. 13 Patients with known Ras mutations should not be treated with either cetuximab or panitumumab. a. Note: The recommendation for Ras testing should not necessarily indicate a preference regarding regimen selection in the first-line setting. Rather, early identification of Ras status is intended to plan for the treatment continuum. b. When compared to best supportive care in patients with Kras wild-type colorectal cancer refractory or intolerant to a fluoropyrimidine (e.g.: 5-Fluorouracil, Capecitabine), Irinotecan, and Oxaliplatin, the use of monoclonal antibodies directed at the EGFR delays disease progression and deterioration in quality of life. Panitumumab prolongs progression-free survival compared to best supportive care . 14,15 Only Panitumumab is funded for patients with Kras wild-type disease on the Alberta Health Services Cancer Drug Benefit Program. Refer to the Panitumumab and Cetuximab: Toxicity Management Guidelines.
# Recommendations
The EGFR signaling pathway is activated in response to binding of the ligand to the extracellular domain of the EGFR. The resultant signaling cascade regulates genes that control progression through the cell cycle. Kras regulates this cascade. The Kras gene may be "wild-type" (in up to 65% of cases) or "mutated". Wild-type Kras remains active only transiently after interaction of EGFR with its ligand. Mutated Kras remains constitutively active irrespective of activation of EGFR. This permits unregulated proliferation and enhances survival, metastasis, and angiogenesis.
Monoclonal antibodies directed against EGFR block activation of the EGFR and, thereby, the downstream events. A constitutively active ("mutant") Kras would not be influenced by such therapy. Kras testing by quantitative PCR (or direct DNA sequencing) is highly specific for mutations known to confer constitutive activation. 17 They were randomized to encorafenib, binimetinib and cetuximab, encorafenib and cetuximab or dealer's choice of irinotecan+ cetuximab or FOLFIRI plus cetuximab (argued to be the standard treatment). The analysis was powered to compare the triplet regimen against the standard treatment arm. In an updated overall survival analysis, median OS was similar in patients treated with encorafenib + cetuximab with or without binimetinib (9.3 mo and 9.3 mo, respectively). Median OS in the standard treatment arm was 5.9 mo. Treatment with encorafenib + cetuximab with or without binimetinib was associated with longer maintenance of quality of life across different QOL assessment tools compared to the standard arm. 17 In Alberta, encorafenib is administered with panitumumab. pERC and clinical experts noted that concurrent administration with panitumumab instead of cetuximab would lead to less frequent chemotherapy sessions, and it is expected that patients who receive encorafenib in combination with panitumumab would respond similarly to patients treated with cetuximab. 11. Whether treatment is with combination chemotherapy or sequential monotherapy (with or without Bevacizumab) depends upon the patient's goals, their physical status, and other life circumstances, as assessed by their treating oncologist. Sequences of therapy may include: a. 12 - Involves the administration of Irinotecan (180 mg/m 2 IV) and Leucovorin (400 mg/m 2 IV) concurrently over two hours followed by 5-Fluorouracil (400 mg/m 2 IV bolus and then an IV infusion of 2,400 mg/m 2 over forty-six hours) in every two-week cycle. This regimen requires placement of a port, central venous catheter (CVC), or peripherally inserted central catheter (PICC). - For patients who have complications with, or contraindications to, placement of a port, CVC, or PICC along with the capacity to tolerate the potential for greater toxicity, consider CAPIRI (administers Irinotecan 200 mg/m 2 IV over ninety minutes followed by Capecitabine 800 mg/m 2 PO Q12h for fourteen days in every twenty-one day cycle). 24 - Supplement with Bevacizumab, where appropriate (see below).
- Consider a switch to FOLFOX6 (or CAPOX) at progression, provided it is medically reasonable and the patient wishes further therapy. The sequence of FOLFIRI followed by FOLFOX6 is equivalent to the sequence of FOLFOX6 followed by FOLFIRI. 25 - Due to Oxaliplatin's propensity to cause a cumulative peripheral sensory neuropathy, consider a non-Oxaliplatin-containing regimen before an Oxaliplatinbased regimen. Irinotecan should be considered relatively contraindicated (or consider a dose modification) for patients with an elevated bilirubin due to metastatic disease or Gilbert's syndrome Regimen Details - Gilbert's syndrome results from impaired activity of uridine diphosphate glucuronyltransferase isoform 1A1 (UGT1A1). It delays the metabolism of Irinotecan and thereby increases the risk of severe toxicity. CAPOX and mFOLFOX6 - CAPOX involves the administration of Oxaliplatin (130 mg/m 2 IV over two hours) and Capecitabine 1,000 mg/m 2 PO Q12h for fourteen days in every twenty-one day cycle. - mFOLFOX6 involves the administration of Oxaliplatin (85 mg/m 2 IV) and Leucovorin (400 mg/m 2 IV) concurrently over two hours followed by 5-Fluorouracil (400 mg/m 2 IV bolus and then an intravenous infusion of 2,400 mg/m 2 over forty-six hours) in every two-week cycle. This regimen requires placement of a port, central venous catheter (CVC), or peripherally inserted central catheter (PICC). - Supplement with Bevacizumab, where appropriate (see below).
- Consider a switch to FOLFIRI or Irinotecan at progression, provided it is medically reasonable and the patient wishes further therapy. The sequence of FOLFIRI followed by FOLFOX6 is equivalent to the sequence of FOLFOX6 followed by FOLFIRI. 25 - Due to Oxaliplatin's propensity to cause a cumulative peripheral sensory neuropathy, consider a non-Oxaliplatin-containing regimen before an Oxaliplatinbased regimen. - For patients with persistent grade ≥ 2 peripheral neuropathy, considering holding or reducing the doses of Oxaliplatin. FOLFOXIRI 15 - Involves the administration of a 90 minute infusion of Irinotecan (165 mg/m 2 ), a 120 minute infusion of Oxaliplatin (85 mg/m 2 ), and a concomitant 120 minute infusion of Leucovorin (400 mg/m 2 ), followed by a 48-hour continuous infusion 5-Fluorouracil (total dose 3200 mg/m 2 ) in every two-week cycle. This regimen requires placement of a port, central venous catheter (CVC), or peripherally inserted central catheter (PICC). - Supplement with Bevacizumab, where appropriate (see below).
- FOLFOXIRI is usually reserved for patients with excellent performance status as the progression free survival and overall survival improvement associated with FOLFOXIRI and Bevacizumab in the TRIBE study were accompanied with increased toxicity. 16 Capecitabine 16 - Involves the administration of Capecitabine 1,250 mg/m 2 PO Q12h for fourteen days in every twenty-one day cycle. Refer to "Capecitabine: A Guide for Patient Care." - Supplement with Bevacizumab, where appropriate (see below). Irinotecan 17 - Involves the administration of Irinotecan (350 mg/m 2 IV over ninety minutes) in every three-week cycle. - Decrease the dose by 20% for patients over seventy years of age or for patients who have received prior radiotherapy to the pelvis. - Irinotecan should be considered relatively contraindicated (or consider a dose modification) for patients with an elevated bilirubin due to metastatic disease or Gilbert's syndrome - Gilbert's syndrome results from impaired activity of uridine diphosphate glucuronyltransferase isoform 1A1 (UGT1A1). It delays the metabolism of Irinotecan and thereby increases the risk of severe toxicity. 5-Fluorouracil (simplified LV5FU2)
- Involves the administration of Leucovorin (400 mg/m 2 IV over two hours) followed by 5-Fluorouracil (400 mg/m 2 IV bolus and then an intravenous infusion of 2,400 mg/m 2 over forty-six hours) in every two-week cycle. - This regimen requires placement of a port, central venous catheter (CVC), or
Patients who have progressed on all standard therapy should be encouraged to participate in clinical trials. The following trials have been conducted in patients who have progressed on or were intolerant to a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an EGFR inhibitor (if KRAS/NRAS wild type):
The phase III CORRECT trial randomized 760 patients who progressed on standard therapy to best supportive care with placebo or regorafenib.38 OS for patients on regorafenib was 6.4 months versus 5.0 months for the placebo arm (HR 0.77, 95% CI 0.64-0.94, p=0.005). PFS improved modestly but significantly (1.9 months versus 1.7 months; HR 0.49, 95% CI 0.42 -0.58, p<0.000001). The most common adverse events observed in the trial were hand-foot skin reactions (17%), fatigue (10%), hypertension (7%), diarrhea (7%) and rash/desquamation (6%). Regorafenib is currently not funded by the Alberta Health Services Outpatient Cancer Drug Benefit Program. The phase III RECOURSE trial randomized 800 patients to trifluridine-tipiracil or placebo. Median OS was significantly prolonged in patients treated with trifluridine-tipiracil compared to placebo (7.1 versus 5.3 months, HR 0.68, 95% CI 0.58-0.81; P<0.001), and this benefit was irrespective of prior regorafenib use. Trifluridine-tipiracil is currently not funded by the Alberta Health Services Outpatient Cancer Drug Benefit Program. 38 - For patients with metastatic colorectal cancer, optimal palliative chemotherapy offers two-year survivals under 40% and five-year survivals under 5% whereas resection of liver metastases offers two-year survivals of 60% to 70% and five-year survivals of 30%. - Resection of lung metastases offers a five-year overall survival of 48% (39.6% for R0 and 0% for R1 or R2 resections). 3 - Assigning one point to each factor (node-positive primary, disease-free interval under twelve months, two or more hepatic metastases, largest metastasis over 5 cm, and CEA level over 200 µg/L) to generate a clinical risk ("Fong") score; it is highly predictive of outcome. 1.8 Years - The definition of resectable liver metastases continues to evolve. Currently, resection is considered possible if both an R0 resection and an adequate- future liver remnant are anticipated, and two contiguous liver segments can be preserved. - For patients with a normal liver, hepatic insufficiency is rare when the future liver remnant exceeds 20% of the total liver volume. 38 For patients extensively pre-treated with chemotherapy, a future liver remnant that exceeds 30% of the total liver volume is required.
For patients with underlying liver disease (e.g.: cirrhosis), a future liver remnant that exceeds 40% of the total liver volume is necessary to avoid cholestasis, fluid retention, and liver failure. - The use of EGFR inhibitors for resectable colorectal liver metastases is not recommended. The New EPOC trial randomized operable metastatic patients with KRAS wild-type metastatic colorectal cancer to FOLFOX with or without cetuximab. The addition of cetuximab was associated with significantly worse PFS (median 15.5 mo vs. 22.2 mo) and OS (median 81.0 mo vs. 55.4 mo; HR: 1.45; 95%CI: 1.02-2.05; p=0.036). 42
# Marginally resectable liver metastases
- Pre-operative chemotherapy can downsize tumors, 43,44 identify responders (progression predicts for a poor outcome), 44 and improve three-year progression-free survival (42.4% versus 33.2% in resected patients, HR 0.73, CI95% 0.55-0.97, p = 0.025). 20 - In the situation where a liver metastatectomy could be facilitated by reduction in the size of the liver metastasis, patients should be treated with Oxaliplatin-based chemotherapy to optimal resectability rather than to maximal response or progression. The general approach for consideration of a biologic agent for non-liver limited mCRC should be used. Kras wild type, left sided primary, consider panitumumab; 22 Kras mutant, consider bevacizumab. 23 - As the post-operative morbidity increases with the number of cycles of chemotherapy administered pre-operatively, only a limited number of cycles of chemotherapy should be delivered. 45 The type of hepatic injury is regimen specific: 46 - 5-Fluorouracil predisposes to steatosis, a typically indolent manifestation of non-alcoholic fatty liver disease (NAFLD) that can increase the risks of post-operative infectious complications. - Irinotecan predisposes to non-alcoholic steatohepatitis (NASH), a serious complication of non-alcoholic fatty liver disease that includes fatty infiltration, inflammation, and hepatocyte damage. This can affect the hepatic reserve and increase morbidity and mortality after partial hepatectomy (ninety-day mortality of 1.6% versus 14.7%, p = 0.001). 21 - Oxaliplatin predisposes to sinusoidal obstruction (characterized by peri-sinusoidal inflammation, congestion, fibrosis, and venous occlusion). Some studies 21 suggest that it fails to increase the risk of peri-operative death while others 47 suggest that it increases morbidity (from 6.3% to 40.0%, p < 0.026) and prolongs length-of-stay (from 10.9 days to 17.0 days, p < 0.006) after hepatectomy. - Bevacizumab reduces the sinusoidal dilation induced by Oxaliplatin (all grades: from 53.5% to 27.4%; moderate or severe grades: from 27.9% to 8.1%, p < 0.01) as well as the degree of tumor viability when used in combination with 5-Fluorouracil and Leucovorin (32.9% versus 45.3%, p = 0.02). 48 Bevacizumab fails to impair liver regeneration after portal vein embolization. 49 - In a retrospective analysis of patients with initially unresectable metastatic disease, 50 12.5% became resectable after pre-operative FOLFOX. This was associated with a five-year survival of 33% -similar to the results achieved in "initially operable" patients. - In a retrospective analysis of patients who underwent pre-operative chemotherapy and resection of colorectal liver metastases, the degree of pathologic response correlated with outcome (five-year survival of 75% for complete response, 56% for major response, and 33% for minor response). The predictors for complete or major response were CEA ≤ 5 µg/L, tumor size ≤ 3 cm, and chemotherapy with fluoropyrimidine, Oxaliplatin, and Bevacizumab. 51 - Portal vein occlusion by pre-operative embolization or intra-operative ligation can increase the volume of the left lobe by 30 to 40%. Metastases in the future liver remnant should be resected before portal vein embolization. 52 - The addition of Oxaliplatin 53,54 but not Irinotecan to 5-Fluorouracil and Leucovorin in the adjuvant treatment of stage III colon cancer improves outcomes. Therefore, if the metastatic disease is resected, give subsequent consideration to "adjuvant" chemotherapy to complete a total course of therapy equivalent to six months (see Clinical Practice Guidelines for Early Stage Colon Cancer). 58
# Radiofrequency ablation
- Radiofrequency ablation applies multiple four-to six-minute cycles of current to create irreversible damage and protein coagulation around a percutaneously-placed needle. It can be applied to liver metastases under 5 cm (preferably under 3 cm) that are located away from large blood vessels ("heat sinks"). Although hemorrhage, bile leak, and infection can occur, major complications arise in only about 2% of patients treated. Incomplete ablation is identified in 20 to 30% of cases. While needle-track recurrences occur, this is reduced by ablation upon withdrawal. Retrospective studies suggest that radiofrequency ablation is associated with a higher local recurrence rate and a lower recurrence-free and overall survival when compared to resection of a hepatic metastasis. Peritoneal carcinomatosis - Cytoreductive surgery in combination with heated intra-peritoneal chemotherapy (HIPEC) followed by systemic 5-Fluorouracil and Leucovorin provides superior outcomes when compared to the same systemic chemotherapy regimen with or without palliative surgery (median survival 22.3 months versus 12.6 months, HR 0.55, CI95% 0.32-0.95, p = 0.032). 4 Patients with involvement of zero to five of the seven regions of the abdominal cavity have a significantly better survival than patients with six or seven affected regions. Macroscopically complete cytoreduction (R1) confers a significantly superior survival than patients with residual disease (R2). - Cytoreductive surgery 62 involves the complete removal of macroscopic disease (e.g.: peritonectomy, omentectomy, cholecystectomy, splenectomy, abdominal organs involved with tumor), lysis of intra-abdominal adhesions (to permit optimal exposure to heated intraperitoneal chemotherapy), and reconstitution of the gastrointestinal tract. Hyperthermia exerts a direct cytotoxic effect that impairs DNA repair, denatures proteins, induces heat-shock proteins, induces apoptosis, inhibits angiogenesis, and blocks oxidative metabolism 64 . Hyperthermia is synergistic with cytotoxic agents. 63 The process is associated with a reported morbidity and mortality rates of 22.9% and 4%, respectively. 64 Unresectable disease
- Consider palliative chemotherapy. click here for more details - Resection of an asymptomatic primary colorectal cancer provides only minimal palliative benefit, risks morbidity and mortality, and delays initiation of systemic therapy. 65,66 Obstruction and bleeding complicate only 13.9% and 3.0% of cases treated with palliative chemotherapy when the primary tumor is left in situ. Therefore, when a patient presents with an unequivocally unresectable metastatic disease and an asymptomatic primary colorectal cancer, palliative chemotherapy can be initiated; resection of the primary tumor can be reserved for the small proportion of patients who develop a complication related to the primary tumor. Resection, diversion, placement of a stent, or radiation is indicated for a symptomatic primary colorectal cancer.
# Stereotactic Body Radiotherapy (SBRT)
- Liver SBRT is used to deliver high doses of radiation accurately to ablate and destroy all normal and tumour cells within a small geographic area. SBRT can provide moderate rates of local control for patients with liver metastases (50-100% at 1 year, 45-80% at 2 years), however, literature is limited to single institution retrospective studies. - Patients should be discussed at multidisciplinary rounds. SBRT can be considered for unresectable disease when alternative therapies have failed or are contraindicated.
- Liver SBRT is currently under investigation in Phase II clinical trials open at the TBCC and CCI. Consider referral of patients with good liver function (Child Pugh A, B) and a limited number of metastases of an amenable size for participation in these studies.
- Continued clinical trials in the use of liver SBRT are recommended. Enrollment of patients into clinical trials or investigational protocols should be encouraged.
# Appendix A: Approach to Metastatic Colorectal Cancer
Resectable lung or liver metastases - Consider upfront resection especially for patients with favorable criteria: metachronous, fewer lesions, unilobar disease, no extra-hepatic disease. 39 - Perioperative oxaliplatin based chemotherapy, with 3 months pre-hepatic resection and 3 months post-hepatic resection can be considered for patients with resectable liver metastases, especially when the prognosis is unclear. This strategy improved three-year progression-free survival (423.4% versus 33.2% in resected patients, HR=0.73;95%CI: 0.55-0.97; p=00.025) in EORTC 40983, however, overall survival was not improved (Level II). 20,40 - The optimal role of adjuvant chemotherapy after upfront resection is unclear. Postoperative oxaliplatin based chemotherapy for 6 months improved disease-free survival HR 0.67, 95% CI (0.50-0.92, one sided p = 0.006) but not overall survival HR 1.25 (0.78-2.00) two sided P=0.42. 41 - The use of chemotherapy in this setting may be influenced by the clinical presentation: synchronous versus metachronous presentation, technical criteria for resectability, and/or number and size of metastases. 39
# Appendix B -Synchronous Metastatic Rectal Cancer Paradigm
Emerging evidence suggests that it may be important to consider the following approaches to potentially resectable metastatic disease, especially for rectal cancer.
# Synchronous Metastatic
|
# Background
Generally, metastatic colorectal cancer represents an incurable situation for which only palliative options (e.g.: best supportive care, palliative chemotherapy) should be considered. However, there are specific circumstances where an attempt at metastatectomy (surgical resection of a metastasis) may be possible and where five-year survivals may reach 40 percent. [1][2][3] In addition, cytoreductive surgery ("peritoneal stripping") and heated intra-peritoneal chemotherapy may be considered for limited intra-peritoneal metastases. 4 Such treatments require involvement of a multidisciplinary team that should include a hepatobiliary surgeon, thoracic surgeon, and surgical oncologist (see Appendix A [Link]). Consider post-operative ("adjuvant") therapy (an extrapolation from Clinical Practice Guidelines for Early Stage Colon Cancer) along with careful surveillance for patients with no evidence of residual disease (also an extrapolation from Clinical Practice Guidelines for Colorectal Cancer Surveillance):
# Post-Metastatectomy Colorectal Cancer Surveillance Guidelines 5
If resection of another recurrence from liver and/or lung is clinically appropriate,
• Obtain a CEA every three months for five years (progressive rises warrant a workup for recurrent disease); and • Obtain a CT scan of the thorax, abdomen, and pelvis at the discretion of the treating physician.
Stereotactic body radiation (SBRT), radiofrequency ablation (RFA) 6 or other local therapies may be considered for patients with otherwise resectable liver metastases who are unable to consider surgery due to medical comorbidities (e.g.: lung disease, significant heart disease).
It is recommended that surgery (e.g.: colon resection, diverting colostomy) or endoscopic procedure (e.g. stent placement) be considered to relieve or prevent a bowel obstruction. Tumor resection or palliative radiation may be considered for bleeding. Surgery is not recommended for patients with an asymptomatic (or minimally symptomatic) primary colorectal cancer and clearly incurable metastatic disease.
Palliative chemotherapy regimens are generally continued as long as tumor shrinkage or stability is confirmed, the side effects remain manageable, the patient wishes to continue, and the treatment remains medically reasonable. Palliative radiotherapy may help control local problems (e.g. pain from bone metastases, bleeding from in situ rectal cancer).
Guideline Questions
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with metastatic colorectal cancer. Different principles may apply to pediatric patients.
# Recommendations
Goals of Therapy 1. To maintain or to improve the patient's quality of life (to control or to delay the onset of tumourrelated symptoms). 2. To prolong life, if possible. 9 Pooled retrospective analyses establish the predictive and prognostic value of primary tumor site using Cetuximab and Panitumumab. 10,11 In a retrospective evaluation of 38% of the 5,760 patients enrolled in the CRYSTAL, FIRE-3, PEAK, PRIME, 181, and CALGB 80405 studies (trials with different populations, control arms, treatments, etc.), primary tumor location confers both prognostic effect (outcomes are worse for disease that arises from the proximal colon, regardless of the treatment received) and predictive effect (first-line use of anti-EGFR therapy improves outcomes in RAS wild-type disease that arises from the distal colon but offers no benefit when disease arises from the proximal colon). 12 The Alberta Provincial Gastrointestinal Tumour Team supports the use of EGFR inhibitors in first-line treatment for patients with Ras wild-type, MSS/MMR proficient metastatic colorectal cancer (i.e. non-mutated Kras or Nras) with left sided primary tumors. Selection of first-line therapy should now consider the results of a rigorous molecular analysis as well as reference to the primary tumor location (in addition to patient preferences, extent of cancer, goals of care, mutations in RAS, medical comorbidities, performance status, etc.). 9. Mutations in Kras and Nras predict a lack of response in anti-Epidermal Growth Factor Receptor (EGFR) therapy in patients with metastatic colorectal cancer. 13 Patients with known Ras mutations should not be treated with either cetuximab or panitumumab. a. Note: The recommendation for Ras testing should not necessarily indicate a preference regarding regimen selection in the first-line setting. Rather, early identification of Ras status is intended to plan for the treatment continuum. b. When compared to best supportive care in patients with Kras wild-type colorectal cancer refractory or intolerant to a fluoropyrimidine (e.g.: 5-Fluorouracil, Capecitabine), Irinotecan, and Oxaliplatin, the use of monoclonal antibodies directed at the EGFR delays disease progression and deterioration in quality of life. Panitumumab prolongs progression-free survival compared to best supportive care [Level I Evidence]. 14,15 Only Panitumumab is funded for patients with Kras wild-type disease on the Alberta Health Services Cancer Drug Benefit Program. Refer to the Panitumumab and Cetuximab: Toxicity Management Guidelines.
# Recommendations
The EGFR signaling pathway is activated in response to binding of the ligand to the extracellular domain of the EGFR. The resultant signaling cascade regulates genes that control progression through the cell cycle. Kras regulates this cascade. The Kras gene may be "wild-type" (in up to 65% of cases) or "mutated". Wild-type Kras remains active only transiently after interaction of EGFR with its ligand. Mutated Kras remains constitutively active irrespective of activation of EGFR. This permits unregulated proliferation and enhances survival, metastasis, and angiogenesis.
Monoclonal antibodies directed against EGFR block activation of the EGFR and, thereby, the downstream events. A constitutively active ("mutant") Kras would not be influenced by such therapy. Kras testing by quantitative PCR (or direct DNA sequencing) is highly specific for mutations known to confer constitutive activation. 17 They were randomized to encorafenib, binimetinib and cetuximab, encorafenib and cetuximab or dealer's choice of irinotecan+ cetuximab or FOLFIRI plus cetuximab (argued to be the standard treatment). The analysis was powered to compare the triplet regimen against the standard treatment arm. In an updated overall survival analysis, median OS was similar in patients treated with encorafenib + cetuximab with or without binimetinib (9.3 mo and 9.3 mo, respectively). Median OS in the standard treatment arm was 5.9 mo. Treatment with encorafenib + cetuximab with or without binimetinib was associated with longer maintenance of quality of life across different QOL assessment tools compared to the standard arm. 17 In Alberta, encorafenib is administered with panitumumab. pERC and clinical experts noted that concurrent administration with panitumumab instead of cetuximab would lead to less frequent chemotherapy sessions, and it is expected that patients who receive encorafenib in combination with panitumumab would respond similarly to patients treated with cetuximab. 11. Whether treatment is with combination chemotherapy or sequential monotherapy (with or without Bevacizumab) depends upon the patient's goals, their physical status, and other life circumstances, as assessed by their treating oncologist. Sequences of therapy may include: a. 12 • Involves the administration of Irinotecan (180 mg/m 2 IV) and Leucovorin (400 mg/m 2 IV) concurrently over two hours followed by 5-Fluorouracil (400 mg/m 2 IV bolus and then an IV infusion of 2,400 mg/m 2 over forty-six hours) in every two-week cycle. This regimen requires placement of a port, central venous catheter (CVC), or peripherally inserted central catheter (PICC). • For patients who have complications with, or contraindications to, placement of a port, CVC, or PICC along with the capacity to tolerate the potential for greater toxicity, consider CAPIRI (administers Irinotecan 200 mg/m 2 IV over ninety minutes followed by Capecitabine 800 mg/m 2 PO Q12h for fourteen days in every twenty-one day cycle). 24 • Supplement with Bevacizumab, where appropriate (see below).
• Consider a switch to FOLFOX6 (or CAPOX) at progression, provided it is medically reasonable and the patient wishes further therapy. The sequence of FOLFIRI followed by FOLFOX6 is equivalent to the sequence of FOLFOX6 followed by FOLFIRI. 25 • Due to Oxaliplatin's propensity to cause a cumulative peripheral sensory neuropathy, consider a non-Oxaliplatin-containing regimen before an Oxaliplatinbased regimen. Irinotecan should be considered relatively contraindicated (or consider a dose modification) for patients with an elevated bilirubin due to metastatic disease or Gilbert's syndrome Regimen Details • Gilbert's syndrome results from impaired activity of uridine diphosphate glucuronyltransferase isoform 1A1 (UGT1A1). It delays the metabolism of Irinotecan and thereby increases the risk of severe toxicity. CAPOX and mFOLFOX6 [12][13][14] • CAPOX involves the administration of Oxaliplatin (130 mg/m 2 IV over two hours) and Capecitabine 1,000 mg/m 2 PO Q12h for fourteen days in every twenty-one day cycle. • mFOLFOX6 involves the administration of Oxaliplatin (85 mg/m 2 IV) and Leucovorin (400 mg/m 2 IV) concurrently over two hours followed by 5-Fluorouracil (400 mg/m 2 IV bolus and then an intravenous infusion of 2,400 mg/m 2 over forty-six hours) in every two-week cycle. This regimen requires placement of a port, central venous catheter (CVC), or peripherally inserted central catheter (PICC). • Supplement with Bevacizumab, where appropriate (see below).
• Consider a switch to FOLFIRI or Irinotecan at progression, provided it is medically reasonable and the patient wishes further therapy. The sequence of FOLFIRI followed by FOLFOX6 is equivalent to the sequence of FOLFOX6 followed by FOLFIRI. 25 • Due to Oxaliplatin's propensity to cause a cumulative peripheral sensory neuropathy, consider a non-Oxaliplatin-containing regimen before an Oxaliplatinbased regimen. • For patients with persistent grade ≥ 2 peripheral neuropathy, considering holding or reducing the doses of Oxaliplatin. FOLFOXIRI 15 • Involves the administration of a 90 minute infusion of Irinotecan (165 mg/m 2 ), a 120 minute infusion of Oxaliplatin (85 mg/m 2 ), and a concomitant 120 minute infusion of Leucovorin (400 mg/m 2 ), followed by a 48-hour continuous infusion 5-Fluorouracil (total dose 3200 mg/m 2 ) in every two-week cycle. This regimen requires placement of a port, central venous catheter (CVC), or peripherally inserted central catheter (PICC). • Supplement with Bevacizumab, where appropriate (see below).
• FOLFOXIRI is usually reserved for patients with excellent performance status as the progression free survival and overall survival improvement associated with FOLFOXIRI and Bevacizumab in the TRIBE study were accompanied with increased toxicity. 16 Capecitabine 16 • Involves the administration of Capecitabine 1,250 mg/m 2 PO Q12h for fourteen days in every twenty-one day cycle. Refer to "Capecitabine: A Guide for Patient Care." • Supplement with Bevacizumab, where appropriate (see below). Irinotecan 17 • Involves the administration of Irinotecan (350 mg/m 2 IV over ninety minutes) in every three-week cycle. • Decrease the dose by 20% for patients over seventy years of age or for patients who have received prior radiotherapy to the pelvis. • Irinotecan should be considered relatively contraindicated (or consider a dose modification) for patients with an elevated bilirubin due to metastatic disease or Gilbert's syndrome • Gilbert's syndrome results from impaired activity of uridine diphosphate glucuronyltransferase isoform 1A1 (UGT1A1). It delays the metabolism of Irinotecan and thereby increases the risk of severe toxicity. 5-Fluorouracil (simplified LV5FU2)
• Involves the administration of Leucovorin (400 mg/m 2 IV over two hours) followed by 5-Fluorouracil (400 mg/m 2 IV bolus and then an intravenous infusion of 2,400 mg/m 2 over forty-six hours) in every two-week cycle. • This regimen requires placement of a port, central venous catheter (CVC), or
# 14.
Patients who have progressed on all standard therapy should be encouraged to participate in clinical trials. The following trials have been conducted in patients who have progressed on or were intolerant to a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an EGFR inhibitor (if KRAS/NRAS wild type):
The phase III CORRECT trial randomized 760 patients who progressed on standard therapy to best supportive care with placebo or regorafenib.38 OS for patients on regorafenib was 6.4 months versus 5.0 months for the placebo arm (HR 0.77, 95% CI 0.64-0.94, p=0.005). PFS improved modestly but significantly (1.9 months versus 1.7 months; HR 0.49, 95% CI 0.42 -0.58, p<0.000001). The most common adverse events observed in the trial were hand-foot skin reactions (17%), fatigue (10%), hypertension (7%), diarrhea (7%) and rash/desquamation (6%). Regorafenib is currently not funded by the Alberta Health Services Outpatient Cancer Drug Benefit Program. The phase III RECOURSE trial randomized 800 patients to trifluridine-tipiracil or placebo. Median OS was significantly prolonged in patients treated with trifluridine-tipiracil compared to placebo (7.1 versus 5.3 months, HR 0.68, 95% CI 0.58-0.81; P<0.001), and this benefit was irrespective of prior regorafenib use. Trifluridine-tipiracil is currently not funded by the Alberta Health Services Outpatient Cancer Drug Benefit Program. 38 • For patients with metastatic colorectal cancer, optimal palliative chemotherapy offers two-year survivals under 40% and five-year survivals under 5% whereas resection of liver metastases offers two-year survivals of 60% to 70% and five-year survivals of 30%. • Resection of lung metastases offers a five-year overall survival of 48% (39.6% for R0 and 0% for R1 or R2 resections). 3 • Assigning one point to each factor (node-positive primary, disease-free interval under twelve months, two or more hepatic metastases, largest metastasis over 5 cm, and CEA level over 200 µg/L) to generate a clinical risk ("Fong") score; it is highly predictive of outcome. 1.8 Years • The definition of resectable liver metastases continues to evolve. Currently, resection is considered possible if both an R0 resection and an adequate* future liver remnant are anticipated, and two contiguous liver segments can be preserved. • For patients with a normal liver, hepatic insufficiency is rare when the future liver remnant exceeds 20% of the total liver volume. 38 For patients extensively pre-treated with chemotherapy, a future liver remnant that exceeds 30% of the total liver volume is required.
For patients with underlying liver disease (e.g.: cirrhosis), a future liver remnant that exceeds 40% of the total liver volume is necessary to avoid cholestasis, fluid retention, and liver failure. • The use of EGFR inhibitors for resectable colorectal liver metastases is not recommended. The New EPOC trial randomized operable metastatic patients with KRAS wild-type metastatic colorectal cancer to FOLFOX with or without cetuximab. The addition of cetuximab was associated with significantly worse PFS (median 15.5 mo vs. 22.2 mo) and OS (median 81.0 mo vs. 55.4 mo; HR: 1.45; 95%CI: 1.02-2.05; p=0.036). 42
# Marginally resectable liver metastases
• Pre-operative chemotherapy can downsize tumors, 43,44 identify responders (progression predicts for a poor outcome), 44 and improve three-year progression-free survival (42.4% versus 33.2% in resected patients, HR 0.73, CI95% 0.55-0.97, p = 0.025). 20 • In the situation where a liver metastatectomy could be facilitated by reduction in the size of the liver metastasis, patients should be treated with Oxaliplatin-based chemotherapy to optimal resectability rather than to maximal response or progression. The general approach for consideration of a biologic agent for non-liver limited mCRC should be used. Kras wild type, left sided primary, consider panitumumab; 22 Kras mutant, consider bevacizumab. 23 • As the post-operative morbidity increases with the number of cycles of chemotherapy administered pre-operatively, only a limited number of cycles of chemotherapy should be delivered. 45 The type of hepatic injury is regimen specific: 46 • 5-Fluorouracil predisposes to steatosis, a typically indolent manifestation of non-alcoholic fatty liver disease (NAFLD) that can increase the risks of post-operative infectious complications. • Irinotecan predisposes to non-alcoholic steatohepatitis (NASH), a serious complication of non-alcoholic fatty liver disease that includes fatty infiltration, inflammation, and hepatocyte damage. This can affect the hepatic reserve and increase morbidity and mortality after partial hepatectomy (ninety-day mortality of 1.6% versus 14.7%, p = 0.001). 21 • Oxaliplatin predisposes to sinusoidal obstruction (characterized by peri-sinusoidal inflammation, congestion, fibrosis, and venous occlusion). Some studies 21 suggest that it fails to increase the risk of peri-operative death while others 47 suggest that it increases morbidity (from 6.3% to 40.0%, p < 0.026) and prolongs length-of-stay (from 10.9 days to 17.0 days, p < 0.006) after hepatectomy. • Bevacizumab reduces the sinusoidal dilation induced by Oxaliplatin (all grades: from 53.5% to 27.4%; moderate or severe grades: from 27.9% to 8.1%, p < 0.01) as well as the degree of tumor viability when used in combination with 5-Fluorouracil and Leucovorin (32.9% versus 45.3%, p = 0.02). 48 Bevacizumab fails to impair liver regeneration after portal vein embolization. 49 • In a retrospective analysis of patients with initially unresectable metastatic disease, 50 12.5% became resectable after pre-operative FOLFOX. This was associated with a five-year survival of 33% -similar to the results achieved in "initially operable" patients. • In a retrospective analysis of patients who underwent pre-operative chemotherapy and resection of colorectal liver metastases, the degree of pathologic response correlated with outcome (five-year survival of 75% for complete response, 56% for major response, and 33% for minor response). The predictors for complete or major response were CEA ≤ 5 µg/L, tumor size ≤ 3 cm, and chemotherapy with fluoropyrimidine, Oxaliplatin, and Bevacizumab. 51 • Portal vein occlusion by pre-operative embolization or intra-operative ligation can increase the volume of the left lobe by 30 to 40%. Metastases in the future liver remnant should be resected before portal vein embolization. 52 • The addition of Oxaliplatin 53,54 but not Irinotecan [55][56][57] to 5-Fluorouracil and Leucovorin in the adjuvant treatment of stage III colon cancer improves outcomes. Therefore, if the metastatic disease is resected, give subsequent consideration to "adjuvant" chemotherapy to complete a total course of therapy equivalent to six months (see Clinical Practice Guidelines for Early Stage Colon Cancer). 58
# Radiofrequency ablation [Level II]
• Radiofrequency ablation applies multiple four-to six-minute cycles of current to create irreversible damage and protein coagulation around a percutaneously-placed needle. It can be applied to liver metastases under 5 cm (preferably under 3 cm) that are located away from large blood vessels ("heat sinks"). Although hemorrhage, bile leak, and infection can occur, major complications arise in only about 2% of patients treated. Incomplete ablation is identified in 20 to 30% of cases. While needle-track recurrences occur, this is reduced by ablation upon withdrawal. Retrospective studies [59][60][61] suggest that radiofrequency ablation is associated with a higher local recurrence rate and a lower recurrence-free and overall survival when compared to resection of a hepatic metastasis. Peritoneal carcinomatosis • Cytoreductive surgery in combination with heated intra-peritoneal chemotherapy (HIPEC) followed by systemic 5-Fluorouracil and Leucovorin provides superior outcomes when compared to the same systemic chemotherapy regimen with or without palliative surgery (median survival 22.3 months versus 12.6 months, HR 0.55, CI95% 0.32-0.95, p = 0.032). 4 Patients with involvement of zero to five of the seven regions of the abdominal cavity have a significantly better survival than patients with six or seven affected regions. Macroscopically complete cytoreduction (R1) confers a significantly superior survival than patients with residual disease (R2). • Cytoreductive surgery 62 involves the complete removal of macroscopic disease (e.g.: peritonectomy, omentectomy, cholecystectomy, splenectomy, abdominal organs involved with tumor), lysis of intra-abdominal adhesions (to permit optimal exposure to heated intraperitoneal chemotherapy), and reconstitution of the gastrointestinal tract. Hyperthermia exerts a direct cytotoxic effect that impairs DNA repair, denatures proteins, induces heat-shock proteins, induces apoptosis, inhibits angiogenesis, and blocks oxidative metabolism 64 . Hyperthermia is synergistic with cytotoxic agents. 63 The process is associated with a reported morbidity and mortality rates of 22.9% and 4%, respectively. 64 Unresectable disease
• Consider palliative chemotherapy. click here for more details • Resection of an asymptomatic primary colorectal cancer provides only minimal palliative benefit, risks morbidity and mortality, and delays initiation of systemic therapy. 65,66 Obstruction and bleeding complicate only 13.9% and 3.0% of cases treated with palliative chemotherapy when the primary tumor is left in situ. Therefore, when a patient presents with an unequivocally unresectable metastatic disease and an asymptomatic primary colorectal cancer, palliative chemotherapy can be initiated; resection of the primary tumor can be reserved for the small proportion of patients who develop a complication related to the primary tumor. Resection, diversion, placement of a stent, or radiation is indicated for a symptomatic primary colorectal cancer.
# Stereotactic Body Radiotherapy (SBRT) [Level III]
• Liver SBRT is used to deliver high doses of radiation accurately to ablate and destroy all normal and tumour cells within a small geographic area. SBRT can provide moderate rates of local control for patients with liver metastases (50-100% at 1 year, 45-80% at 2 years), however, literature is limited to single institution retrospective studies. [67][68][69][70][71][72][73] • Patients should be discussed at multidisciplinary rounds. SBRT can be considered for unresectable disease when alternative therapies have failed or are contraindicated.
• Liver SBRT is currently under investigation in Phase II clinical trials open at the TBCC and CCI. Consider referral of patients with good liver function (Child Pugh A, B) and a limited number of metastases of an amenable size for participation in these studies.
• Continued clinical trials in the use of liver SBRT are recommended. Enrollment of patients into clinical trials or investigational protocols should be encouraged.
# Appendix A: Approach to Metastatic Colorectal Cancer
Resectable lung or liver metastases • Consider upfront resection especially for patients with favorable criteria: metachronous, fewer lesions, unilobar disease, no extra-hepatic disease. 39 • Perioperative oxaliplatin based chemotherapy, with 3 months pre-hepatic resection and 3 months post-hepatic resection can be considered for patients with resectable liver metastases, especially when the prognosis is unclear. This strategy improved three-year progression-free survival (423.4% versus 33.2% in resected patients, HR=0.73;95%CI: 0.55-0.97; p=00.025) in EORTC 40983, however, overall survival was not improved (Level II). 20,40 • The optimal role of adjuvant chemotherapy after upfront resection is unclear. Postoperative oxaliplatin based chemotherapy for 6 months improved disease-free survival HR 0.67, 95% CI (0.50-0.92, one sided p = 0.006) but not overall survival HR 1.25 (0.78-2.00) two sided P=0.42. 41 • The use of chemotherapy in this setting may be influenced by the clinical presentation: synchronous versus metachronous presentation, technical criteria for resectability, and/or number and size of metastases. 39
# Appendix B -Synchronous Metastatic Rectal Cancer Paradigm
Emerging evidence suggests that it may be important to consider the following approaches to potentially resectable metastatic disease, especially for rectal cancer.
# Synchronous Metastatic
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This protocol aims to describe the provision of medical abortion (MA) in a setting where direct access to abortion providers may be difficult, particularly during a period of social disruption or a pandemic. This protocol may deviate from approved indications or previous clinical practice.# When a request for abortion is received:
- Confirm patient identity and ensure patient has privacy and safety to discuss 2. Provide written information (for example, by email or fax) on medication and surgical abortion as well as instructions on medication abortion (), in advance of consultation 3. If not already done, ask the patient to obtain and take a qualitative urine high sensitivity pregnancy test from pharmacy 4. Schedule a first virtual visit via telephone or video to provide consultation
# Pre-abortion assessment via telephone or video (consultation):
- Review pregnancy options counselling 1 2. Establish pregnancy and gestational age: a. Review date of last menstrual period (LMP), and date of positive qualitative pregnancy test b. Review relevant medical history, particularly risk factors and signs/symptoms for ectopic pregnancy and method of contraception used at the time of conception if any c. If either intrauterine device (IUD) or intrauterine system (IUS) is present, arrange an ultrasound and appointment for IUD/IUS removal or consider surgical abortion 3. Determine need for an ultrasound; h. Allergy to mifepristone, misoprostol or other prostaglandins 5. Determine the need for laboratory investigation prior to MA (a 2 nd pre-abortion assessment via telephone or video may be required): a. Complete blood count is required if suspected severe anaemia or hemoglobinopathy i. Hemoglobin should be over 9,5 g/dl before starting MA b. Rhesus (Rh) status can be considered if not documented elsewhere (e.g. donor card, previous results) AND if patient would accept Rh immunoglobulins: according to current evidence, Rh testing is required when gestational age (GA) is over 56 days. 5,6 However, during the COVID-19 pandemic, expert opinion recommends that Rh testing may be withheld up to 70 days GA. 7,8 c. Sexually transmitted infection (STI):
i. If the patient must come to the office for any reason, offer screening of Chlamydia and gonorrhea ii. If the patient does not have to be seen in person, but there are risk factors for STI, consider remote testing if available, and discuss the potential need for antibiotic prophylaxis (such as Doxycycline 100 mg twice a day for 7 days, starting the same day as
# Follow-up #1 -7 days post-treatment via telephone or video:
- Review abortion experience and progress with patient: a. Dates of taking mifepristone and misoprostol b. Side effects of medication c. Bleeding pattern since taking mifepristone and misoprostol d. Pain during the process and current pain, if any e. Whether or not expulsion occurred f. Presence of current symptoms of pregnancy g. Warning signs of ectopic pregnancy or infection 2. Advise an urgent assessment or emergency visit if signs of ectopic pregnancy, signs of pelvic infection, heavy bleeding, excessive pain 3. Obtain an ultrasound if history suggests failed abortion or ongoing pregnancy and consider additional dose of misoprostol or surgical aspiration as needed 4. If history suggest successful abortion, no current symptoms of pregnancy, normal bleeding and pain, and no warning signs, instruct the patient to perform a first qualitative urine pregnancy 3 weeks from now, which is 4 weeks after taking misoprostol. Ensure that the patient will have her first pregnancy test result available at the time of follow-up #2
Follow-up #2 -4 weeks post-treatment via telephone or video:
- Review the date first pregnancy test was done. Ensure test was performed at least 3 weeks after misoprostol was taken 2. If first pregnancy test is negative, reassure the patient that abortion is complete. Do not repeat pregnancy test 3. If first pregnancy test is positive, review signs and symptoms of retained product of conception, ongoing pregnancy or ectopic pregnancy: a. If present, consider evaluation with ultrasound and/or serum hCGs and: i. Retained product of conception: consider additional dose of misoprostol or surgical aspiration ii. Ongoing pregnancy: consider surgical aspiration iii. Ectopic pregnancy suspected or confirmed: manage accordingly and refer to gynecologist as needed iv. Negative ultrasound: consider new pregnancy, have the patient repeat urine pregnancy test (second) in one week. Ensure that the patient will have her second pregnancy test result available at the time of follow-up #3 b. If no warning signs and no ultrasound: have the patient repeat urine pregnancy test (second) in one week. Ensure that the patient will have her second pregnancy test result available at the time of follow-up #3 Follow-up #3 -5 weeks post-treatment via telephone or video:
- Review the date second pregnancy test was done. Ensure test was performed 1 week after last (first) pregnancy test 2. If second urine pregnancy is negative, reassure the patient that abortion is complete.
# Contraception provision of long acting reversible contraception:
- Plan an in-clinic follow-up contact for insertion of implant, IUD or IUS once abortion is deemed completed or according to clinician's advice, and following patient's preference and consent for long acting reversible contraception (LARC).
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This protocol aims to describe the provision of medical abortion (MA) in a setting where direct access to abortion providers may be difficult, particularly during a period of social disruption or a pandemic. This protocol may deviate from approved indications or previous clinical practice.# When a request for abortion is received:
1. Confirm patient identity and ensure patient has privacy and safety to discuss 2. Provide written information (for example, by email or fax) on medication and surgical abortion as well as instructions on medication abortion (https://www.shorecentre.ca/wpcontent/uploads/NEW-Mifegymiso-Information-Brochure-min.pdf), in advance of consultation 3. If not already done, ask the patient to obtain and take a qualitative urine high sensitivity pregnancy test from pharmacy 4. Schedule a first virtual visit via telephone or video to provide consultation
# Pre-abortion assessment via telephone or video (consultation):
1. Review pregnancy options counselling 1 2. Establish pregnancy and gestational age: a. Review date of last menstrual period (LMP), and date of positive qualitative pregnancy test b. Review relevant medical history, particularly risk factors and signs/symptoms for ectopic pregnancy and method of contraception used at the time of conception if any c. If either intrauterine device (IUD) or intrauterine system (IUS) is present, arrange an ultrasound and appointment for IUD/IUS removal or consider surgical abortion 3. Determine need for an ultrasound; [1][2][3][4] h. Allergy to mifepristone, misoprostol or other prostaglandins 5. Determine the need for laboratory investigation prior to MA (a 2 nd pre-abortion assessment via telephone or video may be required): a. Complete blood count is required if suspected severe anaemia or hemoglobinopathy i. Hemoglobin should be over 9,5 g/dl before starting MA b. Rhesus (Rh) status can be considered if not documented elsewhere (e.g. donor card, previous results) AND if patient would accept Rh immunoglobulins: according to current evidence, Rh testing is required when gestational age (GA) is over 56 days. 5,6 However, during the COVID-19 pandemic, expert opinion recommends that Rh testing may be withheld up to 70 days GA. 7,8 c. Sexually transmitted infection (STI):
i. If the patient must come to the office for any reason, offer screening of Chlamydia and gonorrhea ii. If the patient does not have to be seen in person, but there are risk factors for STI, consider remote testing if available, and discuss the potential need for antibiotic prophylaxis (such as Doxycycline 100 mg twice a day for 7 days, starting the same day as
# Follow-up #1 -7 days post-treatment via telephone or video:
1. Review abortion experience and progress with patient: a. Dates of taking mifepristone and misoprostol b. Side effects of medication c. Bleeding pattern since taking mifepristone and misoprostol d. Pain during the process and current pain, if any e. Whether or not expulsion occurred f. Presence of current symptoms of pregnancy g. Warning signs of ectopic pregnancy or infection 2. Advise an urgent assessment or emergency visit if signs of ectopic pregnancy, signs of pelvic infection, heavy bleeding, excessive pain 3. Obtain an ultrasound if history suggests failed abortion or ongoing pregnancy and consider additional dose of misoprostol or surgical aspiration as needed 4. If history suggest successful abortion, no current symptoms of pregnancy, normal bleeding and pain, and no warning signs, instruct the patient to perform a first qualitative urine pregnancy 3 weeks from now, which is 4 weeks after taking misoprostol. Ensure that the patient will have her first pregnancy test result available at the time of follow-up #2
Follow-up #2 -4 weeks post-treatment via telephone or video:
1. Review the date first pregnancy test was done. Ensure test was performed at least 3 weeks after misoprostol was taken 2. If first pregnancy test is negative, reassure the patient that abortion is complete. Do not repeat pregnancy test 3. If first pregnancy test is positive, review signs and symptoms of retained product of conception, ongoing pregnancy or ectopic pregnancy: a. If present, consider evaluation with ultrasound and/or serum hCGs and: i. Retained product of conception: consider additional dose of misoprostol or surgical aspiration ii. Ongoing pregnancy: consider surgical aspiration iii. Ectopic pregnancy suspected or confirmed: manage accordingly and refer to gynecologist as needed iv. Negative ultrasound: consider new pregnancy, have the patient repeat urine pregnancy test (second) in one week. Ensure that the patient will have her second pregnancy test result available at the time of follow-up #3 b. If no warning signs and no ultrasound: have the patient repeat urine pregnancy test (second) in one week. Ensure that the patient will have her second pregnancy test result available at the time of follow-up #3 Follow-up #3 -5 weeks post-treatment via telephone or video:
1. Review the date second pregnancy test was done. Ensure test was performed 1 week after last (first) pregnancy test 2. If second urine pregnancy is negative, reassure the patient that abortion is complete.
# Contraception provision of long acting reversible contraception:
1. Plan an in-clinic follow-up contact for insertion of implant, IUD or IUS once abortion is deemed completed or according to clinician's advice, and following patient's preference and consent for long acting reversible contraception (LARC).
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This document outlines recommendations for physiotherapy management for COVID-19 in the acute hospital setting. It includes recommendations for physiotherapy workforce planning and preparation, a screening tool for determining requirement of physiotherapy, recommendations for the selection of physiotherapy treatments and personal protective equipment.# ACKNOWLEDGEMENTS:
This work was adapted from a guideline originally prepared by Dr Peter Thomas and endorsed by the Queensland Cardiorespiratory Physiotherapy Network (QCRPN). The QCRPN was involved in the design of the work and development of statements. Representatives included: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus that emerged in 2019 and causes Coronavirus Disease 2019 (COVID-19) .
SARS-CoV-2 is highly contagious. It varies from other respiratory viruses in that it appears that human-to-human transmission occurs approximately 2 to 10 days prior to the individual becoming symptomatic . The virus is transmitted from person to person through respiratory secretions. Large droplets from coughing, sneezing, or a runny nose land on surfaces within two meters of the infected person. SARS-CoV-2 remains viable for at least 24 hours on hard surfaces and up to eight hours on soft surfaces . The virus is transferred to another person through hand contact on a contaminated surface then touching the mouth, nose, or eyes. Aerosol airborne infected particles created during a sneeze or cough remain viable in the air for at least three hours . These airborne particles of SARS-CoV-2 can then be inhaled by another person or land on the mucosal membranes of the eyes.
Individuals with COVID-19 can present with an influenza like illness and respiratory tract infection demonstrating fever (89%), cough (68%), fatigue (38%), sputum production (34%) and/or shortness of breath (19%) . The spectrum of disease severity ranges from an asymptomatic infection, mild upper respiratory tract illness, severe viral pneumonia with respiratory failure and/or death. Current reports estimate that 80% of cases are asymptomatic or mild; 15% of cases are severe (infection requiring oxygen); and 5% are critical requiring ventilation and life support .
Preliminary reports indicate that chest radiographs may have diagnostic limitations in COVID-19 . Clinicians need to be aware of lung CT scan findings that often include multiple mottling and ground-glass opacity . Lung ultrasound is also being utilised at the bedside with findings of multi-lobar distribution of B-lines and diffuse lung consolidation At present, the mortality rate is 3 to 5%, with new reports of up to 9%, in contrast to influenza, which is around 0.1% .The rates of admission to an intensive care unit (ICU) are approximately 5% . Half of patients admitted to hospital (42%) will require oxygen therapy . Based on emerging data, individuals at highest risk of developing severe COVID-19 disease requiring hospitalisation and/or ICU support are those who are older, male, have at least one co-existing comorbidity, higher severity of illness scores (measured via SOFA scores), elevated d-dimer levels and/or lymphocytopenia .
# PURPOSE:
This document has been prepared to provide information to physiotherapists and acute care healthcare facilities about the potential role of physiotherapy in the management of hospitaladmitted patients with confirmed and/or suspected COVID-19.
Physiotherapists who work in primary healthcare facilities are likely to have a role in the management of patients admitted to hospital with confirmed and/or suspected COVID-19.
Physiotherapy is an established profession throughout the world. In Australia and overseas, physiotherapists often work in acute hospital wards and the ICU. In particular, cardiorespiratory physiotherapy is focussed on the management of acute and chronic respiratory conditions and aims to improve physical recovery following an acute illness.
Physiotherapy may be beneficial in the respiratory treatment and physical rehabilitation of patients with COVID-19. Although a productive cough is a less common symptom (34%) , physiotherapy may be indicated if patients with COVID-19 present with copious airway secretions that they are unable to independently clear. This may be evaluated on a caseby-case basis and interventions applied based on clinical indicators. High risk patients may also benefit. For example, patients with existing comorbidities that may be associated with hypersecretion or ineffective cough (e.g. neuromuscular disease, respiratory disease, cystic fibrosis etc). Physiotherapists who practice in the ICU environment may also provide airway clearance techniques for ventilated patients who show signs of inadequate airway clearance and they can assist in positioning patients with severe respiratory failure associated with COVID-19, including the use of prone position to optimise oxygenation .
Given the intensive medical management for some COVID-19 patients including prolonged protective lung ventilation, sedation and use of neuromuscular blocking agents, patients with COVID-19 who are admitted to ICU may be at high risk of developing ICU acquired weakness (ICU-AW) . This may worsen their morbidity and mortality . It is therefore essential to anticipate early rehabilitation after the acute phase of ARDS in order to limit the severity of ICU-AW and promote rapid functional recovery. Physiotherapy will have a role in providing exercise, mobilisation and rehabilitation interventions to survivors of critical illness associated with COVID-19 in order to enable a functional return to home.
# SCOPE:
This document is focused on the adult acute hospital setting.
The recommendations for physiotherapists are outlined below and focus on the specific health questions of this guideline:
- SECTION 1: Workforce planning and preparation including screening to determine indications for physiotherapy. - SECTION 2: Delivery of physiotherapy interventions including both respiratory and mobilisation / rehabilitation as well as PPE requirements.
It is recognised that physiotherapy practices vary across the world. When utilising this guideline, the scope of practice within the local context should be considered.
# GUIDELINE METHODOLOGY AND CONSENSUS APPROACH:
A group of international experts in cardiorespiratory physiotherapy came together to rapidly prepare a clinical practice guideline for physiotherapy management of COVID-19. Our guideline group initially convened on Friday March 20, 2020 at 10:00am (Australian Eastern Standard Time) to discuss the urgent need for acute care physiotherapy guidance world-wide in relation to COVID-19. We quickly prioritised our efforts to develop specific guidance for physiotherapists in the acute care settings.
The AGREE II framework was used to guide our development, recognising the expediency of our work required pragmatic, yet transparent reporting. We modelled our conduct after the GRADE Adolopment Process and Evidence to Decision framework for recommendations and decision-making. Our expertise includes ICU and acute inpatient physiotherapy (all), rehabilitation interventions in the intensive care unit (all), physiotherapy administration (PT, IB, RG, AJ, RM, ShP), systematic reviews (PT, CB, CG, RG, CH, MK, SP, ShP, LV), guideline methodology (PT, IB, RG, CH, MK, RM, ShP, LV), and epidemiology (CH, MK). We documented all conflicts of interest a priori using the World Health Organisation (WHO) form.
Through a web search and personal files, we identified recently developed guidelines for COVID-19 management of critically ill patients from international agencies (i.e. WHO), critical care professional societies or groups (e.g. Australia and New Zealand Intensive Care Society, Society of Critical Care Medicine / European Society of Intensive Care Medicine), or physiotherapist professional societies up to March 21 2020. These guidelines were used to inform the consensus guideline developed in conjunction with expert opinion of the guideline authorship group.
A priori we decided to develop a consensus guideline, given the time sensitive nature of our guidance. We agreed that we required ≥ 70% agreement for a recommendation. On Friday March 20, 2020 the lead author (PT) circulated draft recommendations to all guideline panel members. All guideline panel members returned comments to the lead author independently. The lead author (PT) collated all comments for further discussion. We discussed all guideline recommendations in a teleconference on Sunday, March 22, 2020 at 10:00am (Australian Eastern Standard Time).
14 people participated in the guideline process. We developed 66 recommendations. A consensus of >70% was achieved for all items. Further discussion was focused on greater clarity in wording and/or reduction of items where overlap occurred.
We sought endorsement for our guideline from physiotherapy societies, physiotherapy professional groups and the World Confederation for Physical Therapy. We circulated our guideline to these groups on March 23, 2020 (Australia Eastern Standard Time) requesting endorsement. Endorsements will be updated as these are confirmed.
# STRENGTHS OF THIS GUIDELINE:
Our guideline has several strengths. We respond to an urgent need for clinical guidance for acute care physiotherapists worldwide. We base our guidance on the most recent, relevant COVID-19 clinical practice guidelines from highly respected organizations, national physiotherapy organizations, and from peer-reviewed studies and transparently report our evidence sources. We represent an international group of physiotherapists, with extensive clinical experience in the ICU and on the wards. We are also academic physiotherapists with experience in the leadership, conduct, and execution of rigorous systematic reviews, clinical studies (including prospective cohort studies and international multi-centre trials), and clinical practice guidelines. We sought endorsement from international physiotherapy organizations.
# LIMITATIONS OF THIS GUIDELINE:
Our guideline also has limitations. Given the recency in presentation of COVID-19, clinical guidance may change as we learn more about the natural history of this disease. We extrapolated our recommendations based on best evidence for current management of critically ill patients and long-term outcomes in critical illness survivors. We did not include a patient in our guideline development group. While our guideline applies to physiotherapy interventions in the acute care setting, longer-term follow-up of survivors is needed.
# SECTION 1: PHYSIOTHERAPY WORKFORCE PLANNING AND PREPARATION RECOMMENDATIONS
COVID-19 is placing significant demands on healthcare resources throughout the world. Table 1 outlines recommendations to assist the physiotherapy workforce to plan and respond to this demand. Tables 2 and 3 provide recommendations for determining whom physiotherapists should treat when patients have presumed or suspected COVID-19. Table 4 provides an example of a resource plan for ICU physiotherapy from Tier 0 (business as usual) through to Tier 4 (large scale emergency). Local context, resources and expertise should be considered when utilising this example resource plan. It is recommended that staff who are pregnant avoid exposure to COVID-19. It is known that pregnant women are potentially at increased risk of complications from any respiratory disease due to the physiological changes that occur in pregnancy.
Presently there is not enough information available about the impacts of COVID-19 on the pregnant mother or their baby.
1.9 Workforce planning should include consideration for pandemic specific requirements, such as additional workload from donning and doffing PPE, and the need to allocate staff to key non-clinical duties such as enforcing infection control procedures .
1.10 Consider organisation of the workforce into teams that will manage COVID-19 versus non-infectious patients. Minimise or prevent movement of staff between teams. Liaise with local infection control services for recommendations.
1.11 Be aware of and comply to relevant international, national, state and/or hospital guidelines for infection control in health care facilities. For example, World Health Organisation (WHO) "Guidelines for Infection prevention and control during health care when novel coronavirus infection is suspected" .
1.12 Senior physiotherapists should be involved in determining the appropriateness of physiotherapy interventions for patients with suspected and/or proven COVID-19 in consultation with senior medical staff and according to a referral guideline.
1.13 Identify hospital-wide plans for allocation / cohorting of patients with COVID-19. Utilise these plans to prepare resource plans that may be required. For example, Table 4 below is an example of a resource plan for ICU physiotherapy.
1.14 Identify additional physical resources that may be required for physiotherapy interventions and how the risk of cross-infection can be minimised (e.g. respiratory equipment; mobilisation, exercise and rehabilitation equipment, equipment storage).
Identify and develop a facility inventory of respiratory, mobilisation, exercise and rehabilitation equipment and determine process of equipment allocation as pandemic levels increase (i.e. to prevent movement of equipment between infectious and non-infectious areas).
It should be recognised that staff will likely have an increased workload with a heightened risk of anxiety both at work and at home . Staff should be supported during and beyond the active treatment phases (e.g. via access to employee assistance programs, counselling, facilitated debriefing sessions).
1.17 Consider and/or promote debriefing and psychological support; staff morale may be adversely affected due to the increased workload, anxiety over personal safety and the health of family members .
Physiotherapy interventions should only be provided when there are clinical indicators, so that staff exposure to patients with COVID-19 is minimised. Unnecessary review of patients with COVID-19 within their isolation room/areas will also have a negative impact on PPE supplies.
Physiotherapists should meet regularly with senior medical staff to determine indications for physiotherapy review in patients with confirmed or suspected COVID-19 and screen according to set/agreed guidelines (Table 3 provides a suggested framework). 2.6 Physiotherapy staff should not be routinely entering isolation rooms where patients with confirmed or suspected COVID-19 are isolated or cohorted just to screen for referrals.
Options for screening of patients via subjective review and basic assessment whilst not being in direct contact with the patient should be trialled first whenever possible e.g. calling the patients' isolation room telephone and conducting a subjective assessment for mobility information and/or providing education on airway clearance techniques.
# Use droplet precautions
Use airborne precautions if close contact required or possible aerosol generating procedures.
If not ventilated, patients should wear a surgical mask during any physiotherapy whenever possible. Patients with COVID-19 only allocated to beds with reverse flow isolation rooms.
There is limited availability of reverse flow rooms within most hospitals.
e.g. additional 1 FTE per 4 ICU beds .
1 Senior PT will screen patients with COVID-19 in consultation with an ICU medical Consultant.
Patients will be provided treatment in isolation rooms.
If needed, 1 stretcher chair allocated and quarantined for use.
# Medical management of COVID-19:
It is important for physiotherapists to be aware of the medical management for patients with COVID-19. For the purposes of this guideline we have summarised some of the recommendations available from medical guidelines developed by professional societies as listed on page 6. Oxygen therapy: Oxygen therapy targets may vary depending on the presentation of the patient.
- For patients presenting with severe respiratory distress, hypoxaemia or shock, SpO2 >94% is targeted - Once a patient is stable, the target is >90% in non-pregnant adults and 92-95% in pregnant patients . - In adults with COVID-19 and acute hypoxaemic respiratory failure, the SpO2 target should not be maintained higher than 96% Nebulisation: The use of nebulised agents (e.g. salbutamol, saline) for the treatment of non-intubated patients with COVID-19 is not recommended as it increases the risk of aerosolization and transmission of infection to health care workers in the immediate vicinity.
Use of metered dose inhalers / spacers are preferred where possible . If a nebulizer is required, liaise with local guidelines for directions to minimise aerosolization e.g. use of a Pari sprint with inline viral filter.
Use of nebulisers, NIV, HFNO and spirometry should be avoided and agreement to their use sought from senior medical staff . If deemed essential, airborne precautions should be used.
For patients admitted to ICU, additional strategies may be utilised which are summarised below. With increasing acuity, there is an increased risk of dispersion of aerosolised virus into the healthcare environment due to the nature of critical illness, higher viral load and the performance of AGPs. It is recommended that airborne PPE precautions should be used to care for all patients with COVID-19 in ICU .
Intubation and mechanical ventilation: Patients with worsening hypoxia, hypercapnia, acidaemia, respiratory fatigue, haemodynamic instability or those with altered mental status should be considered for early invasive mechanical ventilation if appropriate .
The risk of aerosol transmission is reduced once a patient is intubated with a closed ventilator circuit .
Recruitment manoeuvres: Although current evidence does not support the routine use of recruitment manoeuvres in non-COVID-19 ARDS, they could be considered in patients with COVID-19 on a case by case basis .
Prone positioning: Anecdotal reports from international centres dealing with large numbers of critically ill patients with COVID-19 related ARDS suggest that prone ventilation is an effective strategy in mechanically ventilated patients .
In adult patients with COVID-19 and severe ARDS, prone ventilation for 12-16 hours per day is recommended . It requires sufficient human resources and expertise to be performed safely to prevent known complications including pressure areas and airway complications. Physiotherapists also play an integral role in the management of patients with a tracheostomy. 5 outlines recommendations for providing respiratory care to patients with COVID-19.
# COVID-19 poses significant considerations for respiratory physiotherapy interventions due to their aerosol generating potential. Table
Cough etiquette: Both patients and staff should practice cough etiquette and hygiene.
During techniques which may provoke a cough, education should be provided to enhance cough etiquette and hygiene.
- Ask patient to turn head away during cough and expectoration
- Patients who are able should "catch their cough" with a tissue, dispose of tissue and perform hand hygiene. If patients are unable to do this independently then staff should assist. - In addition, if possible, physiotherapists should position themselves ≥ 2m from the patient and out of the "blast zone" or line of cough.
Many respiratory physiotherapy interventions are potentially aerosol generating procedures. While there are insufficient investigations confirming the AGPs of various physiotherapy interventions , the combination with cough for airway clearance makes all techniques potentially AGPs.
These include:
- Cough generating procedures e.g. cough during treatment or huff.
- Positioning / gravity assisted drainage techniques and manual techniques (e.g. expiratory vibrations, percussion, manual assisted cough) that may trigger a cough and the expectoration of sputum Therefore, there is a risk of creating an airborne transmission of COVID-19 during treatments. Physiotherapists should weigh up the risk versus benefit to completing these interventions and use airborne precautions.
Where AGPs are indicated and considered essential, they should be undertaken in a negative-pressure room, if available, or in a single room with the door closed.
Only the minimum number of required staff should be present, and they must all wear PPE as described. Entry and exit from the room should be minimised during the procedure .
This may not be able to be maintained when cohorting is required due to the volume of patients presenting with COVID-19.
BubblePEP is not recommended for patients with COVID-19 because of uncertainty around the potential for aerosolization, similar to the caution the WHO places on bubble CPAP .
There is no evidence for incentive spirometry in patients with COVID-19.
Avoid the use of MI-E, NIV, IPPB devices or HFO devices. However, if clinically indicated and alternative options have not been effective, consult with both senior medical staff and Infection Prevention and Monitoring Services within local facilities prior to use. If used, ensure machines can be decontaminated after use and e.g. protect machines with viral filters over machine and patient ends of circuits.
- Use disposable circuits for these devices.
- Maintain a log for devices that includes patient details for tracking and infection monitoring (if required). - Use airborne precautions.
Where respiratory equipment is used, whenever possible use single patient use, disposable options e.g. single patient use PEP devices.
Re-usable respiratory equipment should be avoided if possible.
Physiotherapists should not implement humidification or NIV or other AGPs without consultation and agreement with a senior doctor (e.g. medical Consultant).
Sputum inductions should not be performed.
Requests for sputum samples. In the first instance, ascertain whether the patient is productive of sputum and able to clear sputum independently. If so, physiotherapy is not required for a sputum sample.
If physiotherapy interventions are required to facilitate a sputum sample then full airborne PPE should be worn. The handling of sputum samples should adhere to local policies. Generally, once a sputum sample has been obtained the following points should be followed:
- All sputum specimens and request forms should be marked with a biohazard label. - The specimen should be double-bagged. The specimen should be placed in the first bag in the isolation room by a staff member wearing recommended PPE. - Specimens should be hand delivered to the laboratory by someone who understands the nature of the specimens. Pneumatic tube systems must not be used to transport specimens.
Saline nebulisation. Do not use saline nebulisation. It should be noted that some UK guidelines allow use of nebulisers, but this is currently not recommended in Australia.
Manual hyperinflation: As it involves disconnection / opening of a ventilator circuit, avoid MHI and utilise ventilator hyperinflation (VHI) if indicated e.g. for suppurative presentations in ICU and if local procedures are in place.
Positioning including gravity assisted drainage: Physiotherapists can continue to advise on positioning requirements for patients.
Prone positioning: Physiotherapists may have a role in the implementation of prone positioning in ICU. This may include leadership within ICU "prone teams", providing staff education on prone positioning (e.g. simulation-based education sessions), or assisting in turns as part of the ICU team.
Tracheostomy management: The presence of a tracheostomy and related procedures are potentially aerosol generating.
- Cuff deflation trials and inner tube changes/cleaning can be aerosol generating - Closed, in-line suction is recommended.
- The use of inspiratory muscle training, speaking valves and leak speech should not be attempted until patients are over the acute infection and the risk of transmission is reduced. - Airborne precautions are recommended with infectious patients with COVID-19 with a tracheostomy.
# Physiotherapy management principlesmobilisation, exercise and rehabilitation interventions:
Physiotherapists are responsible for the provision of musculoskeletal / neurological / cardiopulmonary rehabilitation tasks including:
- Passive, active assisted, active, or resisted joint range of motion exercises to maintain or improve joint integrity and range of motion and muscle strength - Mobilisation and rehabilitation (e.g. bed mobility, sitting out of bed, sitting balance, sit to stand, walking, tilt table, standing hoists, upper limb or lower limb ergometry, exercise programs).
Table 6 outlines recommendations for the implementation of these activities in patients with COVID-19. PPE: Droplet precautions should be appropriate for the provision of mobilisation, exercise and rehabilitation in most circumstances. However, physiotherapists are likely to be in close contact with the patient e.g. for mobilisation, exercise or rehabilitation interventions that require assistance. In these cases, consider use of a high filtration mask (e.g. P2/N95). Mobilisation and exercise may also result in the patient coughing or expectorating mucous or with ventilated patients there may be circuit disconnections.
Refer to local guidelines regarding ability to mobilise patients outside of their isolation room. If mobilising outside of the isolation room, ensure the patient is wearing a surgical mask.
Screening: Physiotherapists will actively screen and/or accept referrals for mobilisation, exercise and rehabilitation.
When screening, discussion with nursing staff, the patient (e.g. via phone) or family is recommended before deciding to enter the patient's isolation room. For example, to try to minimise staff who come in to contact with patients with COVID-19, physiotherapists may screen to determine an appropriate aid to trial. A trial of the aid may then be performed by the nursing staff already in an isolation room, with guidance provided if needed by the physiotherapist who is outside the room.
Direct physiotherapy interventions should only be considered when there are significant functional limitations, e.g. (risk for) ICU-acquired weakness, frailty, multiple comorbidities and advanced age.
Early mobilisation is encouraged. Actively mobilize the patient early in the course of illness when safe to do so .
Patients should be encouraged to maintain function as able within their rooms - Sit out of bed - Perform simple exercises and activities of daily living
Mobilisation and exercise prescription should involve careful consideration of the patients' state (e.g. stable clinical presentation with stable respiratory and haemodynamic function) .
Mobility and exercise equipment: The use of equipment should be carefully considered and discussed with local infection monitoring and prevention service staff before used with patients with COVID-19 to ensure it can be properly decontaminated.
Use equipment that can be single patient use. For example, use Theraband rather than distributing hand weights.
Larger equipment (e.g. mobility aids, ergometers, chairs, tilt tables) must be easily decontaminated. Avoid use of specialised equipment unless necessary for basic functional tasks. For example, stretcher chairs or tilt tables may be deemed appropriate if they can be decontaminated with appropriate cleaning and are indicated for progression of sitting / standing.
# PPE considerations
It is imperative that physiotherapists understand the measures in place to prevent transmission of COVID-19. Table 7 provides recommendations for this. Patients with presumed or confirmed COVID-19 will be managed with either droplet or airborne precautions . Additionally, they will be placed in isolation. Hospitals are often able to contain patients with droplet or airborne spread within dedicated isolation rooms. However, there are a limited number of negative pressure bays and pods and/or rooms across Australia and New Zealand , so isolation within dedicated rooms may not be possible with COVID-19 due to the large volume of patient admissions.
It is important for physiotherapists to understand the different types of isolation rooms which exist in hospitals. Class S rooms (standard single rooms, no negative pressure capability) which can be used for isolating patients capable of transmitting infection by droplet or contact routes and Class N rooms (single negative pressure isolation rooms) which are beneficial in isolating patients with transmittable airborne infections . The preference would be for patients with confirmed and/or suspected COVID-19 to be isolated in Class N rooms . If this is not possible then Class S single rooms with clearly designated areas for PPE donning and doffing are recommended . In the event of all single Class N and S rooms being fully occupied, then the recommendation is for patients with COVID-19 to be cohorted separate to patients without COVID-19 within the hospital . In an open ICU or ward cohorted areas with one or more patients with COVID-19, it is recommended that staff members in the whole area are required to use airborne PPE precautions . Table 7 describes how the movement from dedicated isolation rooms to open cohorting might evolve within an ICU. 7.2 "Fit testing" is recommended when available, but the evidence for fit testing effectiveness is limited and the variation in supply of N95 mask types may make any recommendation on fit testing difficult to implement from a practical perspective .
Staff with beards should be encouraged to remove facial hair to ensure good mask fit 7.4 For all suspected and confirmed cases, at a minimum droplet precautions are implemented. Staff will wear the following items:
- Surgical mask - Fluid resistant long-sleeved gown - Goggles/face shield - Gloves 7.5 Recommended PPE for staff caring for COVID-19 infected patients includes added precautions for patients with significant respiratory illness, when AGPs are likely and/or prolonged or very close contact with the patient is likely. In these cases, Airborne precautions are followed including:
- An N95/P2 mask - Fluid resistant long-sleeved gown - Goggles/face shield - Gloves 7.6 In addition, the following can be considered:
- Hair cover for AGPs - Shoes that are impermeable to liquids and can be wiped down Recurrent use of shoe covers is not recommended as repeated removal is likely to increase the risk of staff contamination .
7.7 PPE must remain in place and be worn correctly for the duration of exposure to potentially contaminated areas. PPE, particularly masks should not be adjusted during patient care .
7.8 Use a step-by-step process for don/doff PPE as per local guidelines .
Check local guidelines for information on laundering uniforms and/or wearing uniforms outside of work if exposed to COVID-19. For example, changing into scrubs may be recommended in local guidelines and/or staff may be encouraged to get changed out of their uniform before leaving work and to transport worn uniforms home in a plastic bag for washing at home. .
Hair should be tied back out of the face and eyes . 7.12 When a unit is caring for a patient with confirmed or suspected COVID-19 it is recommended that all donning and doffing are supervised by an additional appropriately trained staff member .
Avoid sharing equipment. Preferentially use only single use equipment.
Wear an additional plastic apron if high volumes of fluid exposure is expected .
If reusable PPE items are used, e.g. gogglesthese must be cleaned and disinfected prior to re-use .
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This document outlines recommendations for physiotherapy management for COVID-19 in the acute hospital setting. It includes recommendations for physiotherapy workforce planning and preparation, a screening tool for determining requirement of physiotherapy, recommendations for the selection of physiotherapy treatments and personal protective equipment.# ACKNOWLEDGEMENTS:
This work was adapted from a guideline originally prepared by Dr Peter Thomas and endorsed by the Queensland Cardiorespiratory Physiotherapy Network (QCRPN). The QCRPN was involved in the design of the work and development of statements. Representatives included: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus that emerged in 2019 and causes Coronavirus Disease 2019 (COVID-19) [1,2].
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SARS-CoV-2 is highly contagious. It varies from other respiratory viruses in that it appears that human-to-human transmission occurs approximately 2 to 10 days prior to the individual becoming symptomatic [2][3][4]. The virus is transmitted from person to person through respiratory secretions. Large droplets from coughing, sneezing, or a runny nose land on surfaces within two meters of the infected person. SARS-CoV-2 remains viable for at least 24 hours on hard surfaces and up to eight hours on soft surfaces [5]. The virus is transferred to another person through hand contact on a contaminated surface then touching the mouth, nose, or eyes. Aerosol airborne infected particles created during a sneeze or cough remain viable in the air for at least three hours [5]. These airborne particles of SARS-CoV-2 can then be inhaled by another person or land on the mucosal membranes of the eyes.
Individuals with COVID-19 can present with an influenza like illness and respiratory tract infection demonstrating fever (89%), cough (68%), fatigue (38%), sputum production (34%) and/or shortness of breath (19%) [4]. The spectrum of disease severity ranges from an asymptomatic infection, mild upper respiratory tract illness, severe viral pneumonia with respiratory failure and/or death. Current reports estimate that 80% of cases are asymptomatic or mild; 15% of cases are severe (infection requiring oxygen); and 5% are critical requiring ventilation and life support [2].
Preliminary reports indicate that chest radiographs may have diagnostic limitations in COVID-19 [6]. Clinicians need to be aware of lung CT scan findings that often include multiple mottling and ground-glass opacity [7]. Lung ultrasound is also being utilised at the bedside with findings of multi-lobar distribution of B-lines and diffuse lung consolidation [8] At present, the mortality rate is 3 to 5%, with new reports of up to 9%, in contrast to influenza, which is around 0.1% [2].The rates of admission to an intensive care unit (ICU) are approximately 5% [4]. Half of patients admitted to hospital (42%) will require oxygen therapy [4]. Based on emerging data, individuals at highest risk of developing severe COVID-19 disease requiring hospitalisation and/or ICU support are those who are older, male, have at least one co-existing comorbidity, higher severity of illness scores (measured via SOFA scores), elevated d-dimer levels and/or lymphocytopenia [2,4,[9][10][11].
# PURPOSE:
This document has been prepared to provide information to physiotherapists and acute care healthcare facilities about the potential role of physiotherapy in the management of hospitaladmitted patients with confirmed and/or suspected COVID-19.
Physiotherapists who work in primary healthcare facilities are likely to have a role in the management of patients admitted to hospital with confirmed and/or suspected COVID-19.
Physiotherapy is an established profession throughout the world. In Australia and overseas, physiotherapists often work in acute hospital wards and the ICU. In particular, cardiorespiratory physiotherapy is focussed on the management of acute and chronic respiratory conditions and aims to improve physical recovery following an acute illness.
Physiotherapy may be beneficial in the respiratory treatment and physical rehabilitation of patients with COVID-19. Although a productive cough is a less common symptom (34%) [4], physiotherapy may be indicated if patients with COVID-19 present with copious airway secretions that they are unable to independently clear. This may be evaluated on a caseby-case basis and interventions applied based on clinical indicators. High risk patients may also benefit. For example, patients with existing comorbidities that may be associated with hypersecretion or ineffective cough (e.g. neuromuscular disease, respiratory disease, cystic fibrosis etc). Physiotherapists who practice in the ICU environment may also provide airway clearance techniques for ventilated patients who show signs of inadequate airway clearance and they can assist in positioning patients with severe respiratory failure associated with COVID-19, including the use of prone position to optimise oxygenation [12].
Given the intensive medical management for some COVID-19 patients including prolonged protective lung ventilation, sedation and use of neuromuscular blocking agents, patients with COVID-19 who are admitted to ICU may be at high risk of developing ICU acquired weakness (ICU-AW) [13]. This may worsen their morbidity and mortality [14]. It is therefore essential to anticipate early rehabilitation after the acute phase of ARDS in order to limit the severity of ICU-AW and promote rapid functional recovery. Physiotherapy will have a role in providing exercise, mobilisation and rehabilitation interventions to survivors of critical illness associated with COVID-19 in order to enable a functional return to home.
# SCOPE:
This document is focused on the adult acute hospital setting.
The recommendations for physiotherapists are outlined below and focus on the specific health questions of this guideline:
• SECTION 1: Workforce planning and preparation including screening to determine indications for physiotherapy. • SECTION 2: Delivery of physiotherapy interventions including both respiratory and mobilisation / rehabilitation as well as PPE requirements.
It is recognised that physiotherapy practices vary across the world. When utilising this guideline, the scope of practice within the local context should be considered.
# GUIDELINE METHODOLOGY AND CONSENSUS APPROACH:
A group of international experts in cardiorespiratory physiotherapy came together to rapidly prepare a clinical practice guideline for physiotherapy management of COVID-19. Our guideline group initially convened on Friday March 20, 2020 at 10:00am (Australian Eastern Standard Time) to discuss the urgent need for acute care physiotherapy guidance world-wide in relation to COVID-19. We quickly prioritised our efforts to develop specific guidance for physiotherapists in the acute care settings.
The AGREE II framework [15] was used to guide our development, recognising the expediency of our work required pragmatic, yet transparent reporting. We modelled our conduct after the GRADE Adolopment Process [16] and Evidence to Decision framework [17] for recommendations and decision-making. Our expertise includes ICU and acute inpatient physiotherapy (all), rehabilitation interventions in the intensive care unit (all), physiotherapy administration (PT, IB, RG, AJ, RM, ShP), systematic reviews (PT, CB, CG, RG, CH, MK, SP, ShP, LV), guideline methodology (PT, IB, RG, CH, MK, RM, ShP, LV), and epidemiology (CH, MK). We documented all conflicts of interest a priori using the World Health Organisation (WHO) form.
Through a web search and personal files, we identified recently developed guidelines for COVID-19 management of critically ill patients from international agencies (i.e. WHO), critical care professional societies or groups (e.g. Australia and New Zealand Intensive Care Society, Society of Critical Care Medicine / European Society of Intensive Care Medicine), or physiotherapist professional societies up to March 21 2020. These guidelines were used to inform the consensus guideline developed in conjunction with expert opinion of the guideline authorship group.
A priori we decided to develop a consensus guideline, given the time sensitive nature of our guidance. We agreed that we required ≥ 70% agreement for a recommendation. On Friday March 20, 2020 the lead author (PT) circulated draft recommendations to all guideline panel members. All guideline panel members returned comments to the lead author independently. The lead author (PT) collated all comments for further discussion. We discussed all guideline recommendations in a teleconference on Sunday, March 22, 2020 at 10:00am (Australian Eastern Standard Time).
14 people participated in the guideline process. We developed 66 recommendations. A consensus of >70% was achieved for all items. Further discussion was focused on greater clarity in wording and/or reduction of items where overlap occurred.
We sought endorsement for our guideline from physiotherapy societies, physiotherapy professional groups and the World Confederation for Physical Therapy. We circulated our guideline to these groups on March 23, 2020 (Australia Eastern Standard Time) requesting endorsement. Endorsements will be updated as these are confirmed.
# STRENGTHS OF THIS GUIDELINE:
Our guideline has several strengths. We respond to an urgent need for clinical guidance for acute care physiotherapists worldwide. We base our guidance on the most recent, relevant COVID-19 clinical practice guidelines from highly respected organizations, national physiotherapy organizations, and from peer-reviewed studies and transparently report our evidence sources. We represent an international group of physiotherapists, with extensive clinical experience in the ICU and on the wards. We are also academic physiotherapists with experience in the leadership, conduct, and execution of rigorous systematic reviews, clinical studies (including prospective cohort studies and international multi-centre trials), and clinical practice guidelines. We sought endorsement from international physiotherapy organizations.
# LIMITATIONS OF THIS GUIDELINE:
Our guideline also has limitations. Given the recency in presentation of COVID-19, clinical guidance may change as we learn more about the natural history of this disease. We extrapolated our recommendations based on best evidence for current management of critically ill patients and long-term outcomes in critical illness survivors. We did not include a patient in our guideline development group. While our guideline applies to physiotherapy interventions in the acute care setting, longer-term follow-up of survivors is needed.
# ===========
# SECTION 1: PHYSIOTHERAPY WORKFORCE PLANNING AND PREPARATION RECOMMENDATIONS
COVID-19 is placing significant demands on healthcare resources throughout the world. Table 1 outlines recommendations to assist the physiotherapy workforce to plan and respond to this demand. Tables 2 and 3 provide recommendations for determining whom physiotherapists should treat when patients have presumed or suspected COVID-19. Table 4 provides an example of a resource plan for ICU physiotherapy from Tier 0 (business as usual) through to Tier 4 (large scale emergency). Local context, resources and expertise should be considered when utilising this example resource plan. It is recommended that staff who are pregnant avoid exposure to COVID-19. It is known that pregnant women are potentially at increased risk of complications from any respiratory disease due to the physiological changes that occur in pregnancy.
Presently there is not enough information available about the impacts of COVID-19 on the pregnant mother or their baby.
1.9 Workforce planning should include consideration for pandemic specific requirements, such as additional workload from donning and doffing PPE, and the need to allocate staff to key non-clinical duties such as enforcing infection control procedures [12].
1.10 Consider organisation of the workforce into teams that will manage COVID-19 versus non-infectious patients. Minimise or prevent movement of staff between teams. Liaise with local infection control services for recommendations.
1.11 Be aware of and comply to relevant international, national, state and/or hospital guidelines for infection control in health care facilities. For example, World Health Organisation (WHO) "Guidelines for Infection prevention and control during health care when novel coronavirus infection is suspected" [19].
1.12 Senior physiotherapists should be involved in determining the appropriateness of physiotherapy interventions for patients with suspected and/or proven COVID-19 in consultation with senior medical staff and according to a referral guideline.
1.13 Identify hospital-wide plans for allocation / cohorting of patients with COVID-19. Utilise these plans to prepare resource plans that may be required. For example, Table 4 below is an example of a resource plan for ICU physiotherapy.
1.14 Identify additional physical resources that may be required for physiotherapy interventions and how the risk of cross-infection can be minimised (e.g. respiratory equipment; mobilisation, exercise and rehabilitation equipment, equipment storage).
# 1.15
Identify and develop a facility inventory of respiratory, mobilisation, exercise and rehabilitation equipment and determine process of equipment allocation as pandemic levels increase (i.e. to prevent movement of equipment between infectious and non-infectious areas).
# 1.16
It should be recognised that staff will likely have an increased workload with a heightened risk of anxiety both at work and at home [12]. Staff should be supported during and beyond the active treatment phases (e.g. via access to employee assistance programs, counselling, facilitated debriefing sessions).
1.17 Consider and/or promote debriefing and psychological support; staff morale may be adversely affected due to the increased workload, anxiety over personal safety and the health of family members [12].
# 2.4
Physiotherapy interventions should only be provided when there are clinical indicators, so that staff exposure to patients with COVID-19 is minimised. Unnecessary review of patients with COVID-19 within their isolation room/areas will also have a negative impact on PPE supplies.
# 2.5
Physiotherapists should meet regularly with senior medical staff to determine indications for physiotherapy review in patients with confirmed or suspected COVID-19 and screen according to set/agreed guidelines (Table 3 provides a suggested framework). 2.6 Physiotherapy staff should not be routinely entering isolation rooms where patients with confirmed or suspected COVID-19 are isolated or cohorted just to screen for referrals.
# 2.7
Options for screening of patients via subjective review and basic assessment whilst not being in direct contact with the patient should be trialled first whenever possible e.g. calling the patients' isolation room telephone and conducting a subjective assessment for mobility information and/or providing education on airway clearance techniques.
# Use droplet precautions
Use airborne precautions if close contact required or possible aerosol generating procedures.
If not ventilated, patients should wear a surgical mask during any physiotherapy whenever possible. Patients with COVID-19 only allocated to beds with reverse flow isolation rooms.
There is limited availability of reverse flow rooms within most hospitals.
e.g. additional 1 FTE per 4 ICU beds [21].
1 Senior PT will screen patients with COVID-19 in consultation with an ICU medical Consultant.
Patients will be provided treatment in isolation rooms.
If needed, 1 stretcher chair allocated and quarantined for use.
# Medical management of COVID-19:
It is important for physiotherapists to be aware of the medical management for patients with COVID-19. For the purposes of this guideline we have summarised some of the recommendations available from medical guidelines developed by professional societies as listed on page 6. Oxygen therapy: Oxygen therapy targets may vary depending on the presentation of the patient.
• For patients presenting with severe respiratory distress, hypoxaemia or shock, SpO2 >94% is targeted [23] • Once a patient is stable, the target is >90% [24] in non-pregnant adults and 92-95% in pregnant patients [23] . • In adults with COVID-19 and acute hypoxaemic respiratory failure, the SpO2 target should not be maintained higher than 96% [22] Nebulisation: The use of nebulised agents (e.g. salbutamol, saline) for the treatment of non-intubated patients with COVID-19 is not recommended as it increases the risk of aerosolization and transmission of infection to health care workers in the immediate vicinity.
Use of metered dose inhalers / spacers are preferred where possible [12]. If a nebulizer is required, liaise with local guidelines for directions to minimise aerosolization e.g. use of a Pari sprint with inline viral filter.
Use of nebulisers, NIV, HFNO and spirometry should be avoided and agreement to their use sought from senior medical staff [20]. If deemed essential, airborne precautions should be used.
For patients admitted to ICU, additional strategies may be utilised which are summarised below. With increasing acuity, there is an increased risk of dispersion of aerosolised virus into the healthcare environment due to the nature of critical illness, higher viral load and the performance of AGPs. It is recommended that airborne PPE precautions should be used to care for all patients with COVID-19 in ICU [12].
Intubation and mechanical ventilation: Patients with worsening hypoxia, hypercapnia, acidaemia, respiratory fatigue, haemodynamic instability or those with altered mental status should be considered for early invasive mechanical ventilation if appropriate [12].
The risk of aerosol transmission is reduced once a patient is intubated with a closed ventilator circuit [12].
Recruitment manoeuvres: Although current evidence does not support the routine use of recruitment manoeuvres in non-COVID-19 ARDS, they could be considered in patients with COVID-19 on a case by case basis [12].
Prone positioning: Anecdotal reports from international centres dealing with large numbers of critically ill patients with COVID-19 related ARDS suggest that prone ventilation is an effective strategy in mechanically ventilated patients [12].
In adult patients with COVID-19 and severe ARDS, prone ventilation for 12-16 hours per day is recommended [22,23]. It requires sufficient human resources and expertise to be performed safely to prevent known complications including pressure areas and airway complications. Physiotherapists also play an integral role in the management of patients with a tracheostomy. 5 outlines recommendations for providing respiratory care to patients with COVID-19.
# COVID-19 poses significant considerations for respiratory physiotherapy interventions due to their aerosol generating potential. Table
# 5.2
Cough etiquette: Both patients and staff should practice cough etiquette and hygiene.
During techniques which may provoke a cough, education should be provided to enhance cough etiquette and hygiene.
• Ask patient to turn head away during cough and expectoration
• Patients who are able should "catch their cough" with a tissue, dispose of tissue and perform hand hygiene. If patients are unable to do this independently then staff should assist. • In addition, if possible, physiotherapists should position themselves ≥ 2m from the patient and out of the "blast zone" or line of cough.
# 5.3
Many respiratory physiotherapy interventions are potentially aerosol generating procedures. While there are insufficient investigations confirming the AGPs of various physiotherapy interventions [25], the combination with cough for airway clearance makes all techniques potentially AGPs.
These include:
• Cough generating procedures e.g. cough during treatment or huff.
• Positioning / gravity assisted drainage techniques and manual techniques (e.g. expiratory vibrations, percussion, manual assisted cough) that may trigger a cough and the expectoration of sputum Therefore, there is a risk of creating an airborne transmission of COVID-19 during treatments. Physiotherapists should weigh up the risk versus benefit to completing these interventions and use airborne precautions.
# 5.4
Where AGPs are indicated and considered essential, they should be undertaken in a negative-pressure room, if available, or in a single room with the door closed.
Only the minimum number of required staff should be present, and they must all wear PPE as described. Entry and exit from the room should be minimised during the procedure [12].
This may not be able to be maintained when cohorting is required due to the volume of patients presenting with COVID-19.
# 5.5
BubblePEP is not recommended for patients with COVID-19 because of uncertainty around the potential for aerosolization, similar to the caution the WHO places on bubble CPAP [23].
# 5.6
There is no evidence for incentive spirometry in patients with COVID-19.
# 5.7
Avoid the use of MI-E, NIV, IPPB devices or HFO devices. However, if clinically indicated and alternative options have not been effective, consult with both senior medical staff and Infection Prevention and Monitoring Services within local facilities prior to use. If used, ensure machines can be decontaminated after use and e.g. protect machines with viral filters over machine and patient ends of circuits.
• Use disposable circuits for these devices.
• Maintain a log for devices that includes patient details for tracking and infection monitoring (if required). • Use airborne precautions.
# 5.8
Where respiratory equipment is used, whenever possible use single patient use, disposable options e.g. single patient use PEP devices.
Re-usable respiratory equipment should be avoided if possible.
# 5.9
Physiotherapists should not implement humidification or NIV or other AGPs without consultation and agreement with a senior doctor (e.g. medical Consultant).
# 5.10
Sputum inductions should not be performed.
# 5.11
Requests for sputum samples. In the first instance, ascertain whether the patient is productive of sputum and able to clear sputum independently. If so, physiotherapy is not required for a sputum sample.
If physiotherapy interventions are required to facilitate a sputum sample then full airborne PPE should be worn. The handling of sputum samples should adhere to local policies. Generally, once a sputum sample has been obtained the following points should be followed:
• All sputum specimens and request forms should be marked with a biohazard label. • The specimen should be double-bagged. The specimen should be placed in the first bag in the isolation room by a staff member wearing recommended PPE. • Specimens should be hand delivered to the laboratory by someone who understands the nature of the specimens. Pneumatic tube systems must not be used to transport specimens.
# 5.12
Saline nebulisation. Do not use saline nebulisation. It should be noted that some UK guidelines allow use of nebulisers, but this is currently not recommended in Australia.
# 5.13
Manual hyperinflation: As it involves disconnection / opening of a ventilator circuit, avoid MHI and utilise ventilator hyperinflation (VHI) if indicated e.g. for suppurative presentations in ICU and if local procedures are in place.
# 5.14
Positioning including gravity assisted drainage: Physiotherapists can continue to advise on positioning requirements for patients.
# 5.15
Prone positioning: Physiotherapists may have a role in the implementation of prone positioning in ICU. This may include leadership within ICU "prone teams", providing staff education on prone positioning (e.g. simulation-based education sessions), or assisting in turns as part of the ICU team.
# 5.16
Tracheostomy management: The presence of a tracheostomy and related procedures are potentially aerosol generating.
• Cuff deflation trials and inner tube changes/cleaning can be aerosol generating • Closed, in-line suction is recommended.
• The use of inspiratory muscle training, speaking valves and leak speech should not be attempted until patients are over the acute infection and the risk of transmission is reduced. • Airborne precautions are recommended with infectious patients with COVID-19 with a tracheostomy.
# Physiotherapy management principlesmobilisation, exercise and rehabilitation interventions:
Physiotherapists are responsible for the provision of musculoskeletal / neurological / cardiopulmonary rehabilitation tasks including:
• Passive, active assisted, active, or resisted joint range of motion exercises to maintain or improve joint integrity and range of motion and muscle strength • Mobilisation and rehabilitation (e.g. bed mobility, sitting out of bed, sitting balance, sit to stand, walking, tilt table, standing hoists, upper limb or lower limb ergometry, exercise programs).
Table 6 outlines recommendations for the implementation of these activities in patients with COVID-19. PPE: Droplet precautions should be appropriate for the provision of mobilisation, exercise and rehabilitation in most circumstances. However, physiotherapists are likely to be in close contact with the patient e.g. for mobilisation, exercise or rehabilitation interventions that require assistance. In these cases, consider use of a high filtration mask (e.g. P2/N95). Mobilisation and exercise may also result in the patient coughing or expectorating mucous or with ventilated patients there may be circuit disconnections.
Refer to local guidelines regarding ability to mobilise patients outside of their isolation room. If mobilising outside of the isolation room, ensure the patient is wearing a surgical mask.
# 6.2
Screening: Physiotherapists will actively screen and/or accept referrals for mobilisation, exercise and rehabilitation.
When screening, discussion with nursing staff, the patient (e.g. via phone) or family is recommended before deciding to enter the patient's isolation room. For example, to try to minimise staff who come in to contact with patients with COVID-19, physiotherapists may screen to determine an appropriate aid to trial. A trial of the aid may then be performed by the nursing staff already in an isolation room, with guidance provided if needed by the physiotherapist who is outside the room.
# 6.3
Direct physiotherapy interventions should only be considered when there are significant functional limitations, e.g. (risk for) ICU-acquired weakness, frailty, multiple comorbidities and advanced age.
# 6.4
Early mobilisation is encouraged. Actively mobilize the patient early in the course of illness when safe to do so [23].
# 6.5
Patients should be encouraged to maintain function as able within their rooms • Sit out of bed • Perform simple exercises and activities of daily living
# 6.6
Mobilisation and exercise prescription should involve careful consideration of the patients' state (e.g. stable clinical presentation with stable respiratory and haemodynamic function) [26,27].
# 6.7
Mobility and exercise equipment: The use of equipment should be carefully considered and discussed with local infection monitoring and prevention service staff before used with patients with COVID-19 to ensure it can be properly decontaminated.
# 6.8
Use equipment that can be single patient use. For example, use Theraband rather than distributing hand weights.
# 6.9
Larger equipment (e.g. mobility aids, ergometers, chairs, tilt tables) must be easily decontaminated. Avoid use of specialised equipment unless necessary for basic functional tasks. For example, stretcher chairs or tilt tables may be deemed appropriate if they can be decontaminated with appropriate cleaning and are indicated for progression of sitting / standing.
# PPE considerations
It is imperative that physiotherapists understand the measures in place to prevent transmission of COVID-19. Table 7 provides recommendations for this. Patients with presumed or confirmed COVID-19 will be managed with either droplet or airborne precautions [12]. Additionally, they will be placed in isolation. Hospitals are often able to contain patients with droplet or airborne spread within dedicated isolation rooms. However, there are a limited number of negative pressure bays and pods and/or rooms across Australia and New Zealand [12], so isolation within dedicated rooms may not be possible with COVID-19 due to the large volume of patient admissions.
It is important for physiotherapists to understand the different types of isolation rooms which exist in hospitals. Class S rooms (standard single rooms, no negative pressure capability) which can be used for isolating patients capable of transmitting infection by droplet or contact routes [12] and Class N rooms (single negative pressure isolation rooms) which are beneficial in isolating patients with transmittable airborne infections [12]. The preference would be for patients with confirmed and/or suspected COVID-19 to be isolated in Class N rooms [12]. If this is not possible then Class S single rooms with clearly designated areas for PPE donning and doffing are recommended [12]. In the event of all single Class N and S rooms being fully occupied, then the recommendation is for patients with COVID-19 to be cohorted separate to patients without COVID-19 within the hospital [12]. In an open ICU or ward cohorted areas with one or more patients with COVID-19, it is recommended that staff members in the whole area are required to use airborne PPE precautions [12]. Table 7 describes how the movement from dedicated isolation rooms to open cohorting might evolve within an ICU. 7.2 "Fit testing" is recommended when available, but the evidence for fit testing effectiveness is limited and the variation in supply of N95 mask types may make any recommendation on fit testing difficult to implement from a practical perspective [12].
# 7.3
Staff with beards should be encouraged to remove facial hair to ensure good mask fit [24] 7.4 For all suspected and confirmed cases, at a minimum droplet precautions are implemented. Staff will wear the following items:
• Surgical mask • Fluid resistant long-sleeved gown • Goggles/face shield • Gloves [22] 7.5 Recommended PPE for staff caring for COVID-19 infected patients includes added precautions for patients with significant respiratory illness, when AGPs are likely and/or prolonged or very close contact with the patient is likely. In these cases, Airborne precautions are followed including:
• An N95/P2 mask • Fluid resistant long-sleeved gown • Goggles/face shield • Gloves [24] 7.6 In addition, the following can be considered:
• Hair cover for AGPs • Shoes that are impermeable to liquids and can be wiped down Recurrent use of shoe covers is not recommended as repeated removal is likely to increase the risk of staff contamination [12].
7.7 PPE must remain in place and be worn correctly for the duration of exposure to potentially contaminated areas. PPE, particularly masks should not be adjusted during patient care [24].
7.8 Use a step-by-step process for don/doff PPE as per local guidelines [24].
# 7.9
Check local guidelines for information on laundering uniforms and/or wearing uniforms outside of work if exposed to COVID-19. For example, changing into scrubs may be recommended in local guidelines [12] and/or staff may be encouraged to get changed out of their uniform before leaving work and to transport worn uniforms home in a plastic bag for washing at home. [19,23].
Hair should be tied back out of the face and eyes [24]. 7.12 When a unit is caring for a patient with confirmed or suspected COVID-19 it is recommended that all donning and doffing are supervised by an additional appropriately trained staff member [12].
# 7.13
Avoid sharing equipment. Preferentially use only single use equipment.
# 7.14
Wear an additional plastic apron if high volumes of fluid exposure is expected [24].
# 7.15
If reusable PPE items are used, e.g. gogglesthese must be cleaned and disinfected prior to re-use [24].
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Également disponible en français sous le titre : Une déclaration d'un comité consultatif (DCC) Comité consultatif national de l'immunisation (CCNI) Chapitre sur la grippe du Guide canadien d'immunisation et Déclaration sur la vaccination antigrippale pour la saison 2019-2020 This publication can be made available in alternative formats upon request.# PREAMBLE
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, the Public Health Agency of Canada has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# I. INTRODUCTION
This document, the National Advisory Committee on Immunization (NACI): Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2019-2020, updates NACI's recommendations regarding the use of seasonal influenza vaccines.
I.1 New or Updated Information for 2019-2020 New influenza vaccine product Afluria ® Tetra (Seqirus) is a split virus quadrivalent inactivated influenza vaccine that was authorized for use in Canada in adults and children 5 years of age and older on February 22, 2018. Based on a review of available pre-licensure clinical trial data, NACI has concluded that Afluria Tetra has a comparable safety and immunogenicity profile to already authorized quadrivalent inactivated influenza vaccines. Therefore, NACI recommends that Afluria Tetra may be considered among the quadrivalent inactivated influenza vaccines offered to adults and children 5 years of age and older (Discretionary NACI Recommendation). Refer to the NACI Supplemental Statement on Afluria ® Tetra for additional information supporting this recommendation.
Comparative effectiveness and immunogenicity of subunit and split virus inactivated influenza vaccines in adults 65 years of age and older Unadjuvanted subunit and split virus inactivated influenza vaccines are two commonly used types of seasonal influenza vaccines in Canada. A difference in vaccine effectiveness between these formulations would be especially important for adults 65 years of age or older, since there is evidence that older adults experience more severe illness due to influenza and that influenza vaccines are less effective in this age group, compared to younger adults. Based on a systematic review of the literature, NACI has concluded that there is insufficient evidence at this time on the comparative effectiveness and immunogenicity of unadjuvanted subunit and split virus inactivated influenza vaccines in adults 65 years of age and older to support specific recommendations on the differential use of these vaccines (Grade I Evidence). Refer to the NACI Literature Review on the Comparative Effectiveness and Immunogenicity of Subunit and Split Virus Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for additional information supporting this conclusion.
# Updated presentation of the statement
The presentation of this document has been updated from previous seasons' statements to improve readability. The content in some sections has been reduced in length, while maintaining a focus on key information required for decision making. Links to other published NACI documents containing the additional content removed from the statement have been added.
# Updated abbreviations for influenza vaccines
With the availability of many different influenza vaccines in Canada, the abbreviations used in this document have been updated to describe the defining features of the various types of influenza vaccines better. The new NACI abbreviations are as follows: Abbreviations: IIV: inactivated influenza vaccine; IIV3: trivalent inactivated influenza vaccine; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standarddose trivalent inactivated influenza vaccine; IIV4: quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV: live attenuated influenza vaccine; LAIV3: trivalent live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine. - The numeric suffix denotes the number of antigens contained in the vaccine ("3" refers to the trivalent formulation and "4" refers to the quadrivalent formulation). The hyphenated suffix "-SD" is used when referring to IIV products that do not have an adjuvant, contain 15 µg hemagglutinin (HA) per strain and are administered as a 0.5 mL dose by intramuscular injection; "-Adj" refers to an IIV with an adjuvant (e.g., IIV3-Adj for Fluad ® or Fluad Pediatric ® ); and "-HD" refers to an IIV that contains higher antigen content than 15 µg HA per strain (e.g., IIV3-HD for Fluzone ® High-Dose). † 15 µg HA per strain. ‡ 7.5 µg (in 0.25 mL) or 15 µg (in 0.5 mL) HA per strain. § 60 µg HA per strain.
# Influenza vaccine category
Formulation
# I.2 Background
The World Health Organization's (WHO) recommendations on the composition of influenza virus vaccines are typically available in February of each year for the upcoming season in the Northern Hemisphere. The WHO recommends that, where available, seasonal quadrivalent influenza vaccines contain the recommended three viruses for the trivalent vaccine, as well as the influenza B virus lineage that is not included in the trivalent vaccine.
Annual recommendations on the use of influenza vaccine in Canada are developed by the NACI Influenza Working Group (IWG) for consideration by NACI. Recommendations are developed based on a review of a variety of issues, which can include: the burden of influenza illness and the target populations for vaccination; efficacy, effectiveness, immunogenicity, and safety of influenza vaccines; vaccine schedules; and other aspects of influenza immunization. Details regarding NACI's evidence-based process for developing a statement are outlined in Evidencebased Recommendations for Immunization − Methods of the National Advisory Committee on Immunization.
Health care providers in Canada should offer the seasonal influenza vaccine as soon as feasible after it becomes available in the fall, since seasonal influenza activity may start as early as November in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing, and intensity), opportune moments for vaccination, as well as programmatic considerations. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local public health agencies.
Although vaccination before the onset of the influenza season is strongly preferred, vaccine may still be administered up until the end of the season. Although its utility may be compromised if exposure to influenza has already occurred, vaccine providers should use every opportunity to give influenza vaccine to individuals at risk who have not been immunized during the current season, even after influenza activity has been documented in the community.
# II. CANADIAN IMMUNIZATION GUIDE CHAPTER ON INFLUENZA: CLINICAL INFORMATION FOR VACCINE PROVIDERS
The Canadian Immunization Guide (CIG) is written primarily for health care providers (frontline clinicians and public health practitioners) but is also used by policy makers, program planners, and the general public. The CIG has been a trusted, reader-friendly summary of the vaccine statements provided by NACI since 1979.
The information in this section constitutes the influenza chapter of the CIG and is adapted for inclusion in the NACI Statement on Seasonal Influenza Vaccine. With a new NACI Statement on Seasonal Influenza Vaccine required each year, readers will have quick access to the information that they require within one document, whether it is the relevant influenza vaccine information written primarily for frontline vaccine providers as is found in this section, or the more detailed technical information that is found in the rest of this statement, commencing in Section III.
# II.1 Key Information
The following highlights key information for vaccine providers. Please refer to the remainder of this statement for additional details.
# What
- Influenza is a respiratory infection caused primarily by influenza A and B viruses. In Canada, influenza generally occurs each year in the late fall and winter months. Influenza occurs globally with an annual attack rate estimated at 5-10% in adults and 20-30% in children (1) .
- Symptoms of influenza typically include: sudden onset of fever, cough, and muscle aches. Other common symptoms include: headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week or 10 days, but some are at greater risk of more severe complications, such as pneumonia. People with chronic diseases may have worsening of their underlying disease.
- Both inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) are authorized for use in Canada; some protect against 3 strains of influenza (i.e., trivalent formulation, IIV3) and some protect against 4 strains of influenza (i.e., quadrivalent formulation, IIV4 or LAIV4).
- Influenza vaccine is safe and well-tolerated. Influenza vaccine cannot cause influenza illness because inactivated influenza vaccines do not contain live virus and live attenuated influenza vaccines contain weakened viruses.
# Who
NACI makes the following recommendations for individual-level and public health program-level decision making.
# Recommendation for individual-level decision making
(i.e., individuals wishing to protect themselves from influenza or vaccine providers wishing to advise individual patients about preventing influenza)
- NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see List 1). These groups include:
-people at high risk of influenza-related complications or hospitalization; -people capable of transmitting influenza to those at high risk; -people who provide essential community services; and -people in direct contact with poultry infected with avian influenza during culling operations.
Influenza vaccine is less immunogenic in infants less than 6 months of age than in older children and adults and does not confer sufficient protection to make it useful before 6 months of age (2) . Currently available influenza vaccines are not authorized for use for infants less than 6 months of age. For these reasons, NACI recommends that influenza vaccine should not be offered to infants less than 6 months of age, noting that influenza vaccine should be offered to their household contacts and care providers (see List 1).
# Recommendation for public health program-level decision-making
(i.e., provinces/territories making decisions for publicly funded immunization programs)
The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors.
- NACI recommends that influenza vaccine should be offered as a priority to the groups for whom influenza vaccination is particularly recommended (see List 1).
# List 1: Groups for whom influenza vaccination is particularly recommended
People at high risk of influenza-related complications or hospitalization
# People capable of transmitting influenza to those at high risk
- Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; - Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated: -household contacts of individuals at high risk; -household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine; -members of a household expecting a newborn during the influenza season; - Those providing regular child care to children 6-59 months of age, whether in or out of the home; and - Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a ship).
# Others
- People who provide essential community services; and
- People who are in direct contact with poultry infected with avian influenza during culling operations. 11
# How
Benefits and risks of influenza vaccination, as well as the risks of not being immunized, should be discussed prior to vaccination.
# Choice of influenza vaccine
A variety of influenza vaccines are available for use in Canada, some of which are authorized for use only in specific age groups. Therefore, the choice of influenza vaccine has become more complex. Refer to Section II.5 below for recommendations on choice of influenza vaccine by age group.
# Dose and route of administration
The dose and route of administration varies by product (see Section II.6 below for details):
- MF59-adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj; Fluad Pediatric ® ) for children 6-23 months of age is 0.25 mL by intramuscular (IM) injection;
- All other IIVs for all age groups is 0.5 mL by IM injection; and
- LAIV (FluMist ® Quadrivalent) for people 2-59 years of age is 0.2 mL given intranasally (0.1 mL in each nostril).
# Schedule
NACI recommends that:
- Children 9 years of age and older and adults should receive 1 dose of influenza vaccine each year; and
- Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.
# Contraindications
For all influenza vaccines (IIV and LAIV), NACI recommends that influenza vaccination should not be given to:
- People who have had an anaphylactic reaction to a previous dose of influenza vaccine;
- People who have had an anaphylactic reaction to any of the vaccine components, with the exception of egg (refer to Section II.7 below for more information); -If an individual is found to have an allergy to a component in one influenza vaccine, consideration may be given to offering another influenza vaccine if there is a formulation not containing the implicated component, in consultation with an allergy expert. Individuals who have an allergy to substances that are not components of the influenza vaccine are not at increased risk of allergy to influenza vaccine. -Egg allergy is not a contraindication for influenza vaccination as there is a low risk of adverse events associated with the trace amounts of ovalbumin allowed in influenza vaccines manufactured using eggs. Egg-allergic individuals may be vaccinated against influenza using any age-appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg, and in any setting where vaccines are routinely administered. -As with any vaccine product, vaccine providers should be prepared for and have the necessary equipment to respond to a vaccine emergency at all times.
- People who have developed Guillain-Barré Syndrome (GBS) within 6 weeks of a previous influenza vaccination (refer to Section II.7 below for more information).
-The potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
For LAIV, in addition to the above-mentioned contraindications, NACI also recommends that LAIV should not be given to:
- People with immune compromising conditions, due to underlying disease, therapy, or both, as the vaccine contains live attenuated virus;
- People with severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing) or medically attended wheezing in the 7 days prior to the proposed date of vaccination; -LAIV is not contraindicated for people with a history of stable asthma or recurrent wheeze.
- Children less than 24 months of age, due to increased risk of wheezing.
- Children 2-17 years of age currently receiving aspirin or aspirin-containing therapy, because of the association of Reye's syndrome with aspirin and wild-type influenza infection; -Aspirin-containing products in children less than 18 years of age should be delayed for 4 weeks after receipt of LAIV.
- Pregnant women, because it is a live attenuated vaccine and there is a lack of safety data at this time; -LAIV is not contraindicated in breastfeeding mothers.
Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 of the CIG for a list of all vaccines authorized for use in Canada and their contents and to Vaccine Safety in Part 2 of the CIG for information regarding the management of adverse events, including anaphylaxis.
# Precautions
NACI recommends that:
- Influenza vaccination should usually be postponed in people with serious acute illnesses until their symptoms have abated; -Vaccination should not be delayed because of minor acute illness, with or without fever.
- If significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa, IIV can be administered or LAIV can be deferred until resolution of the congestion;
- LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection; and
- LAIV should not be administered until 48 hours after antiviral agents active against influenza (e.g., oseltamivir, zanamivir) are stopped, and those antiviral agents, unless medically indicated, should not be administered until 2 weeks after receipt of LAIV so that the antiviral agents do not kill the replicating vaccine virus.
-If antiviral agents are administered within this time frame (i.e., from 48 hours before to 2 weeks after LAIV is given), revaccination should take place at least 48 hours after the antivirals are stopped, or IIV could be given at any time.
Refer to Section II.8 below for additional information on influenza vaccine-related precautions.
# Simultaneous administration with other vaccines
NACI recommends that:
- All seasonal influenza vaccines, including LAIV, may be considered for administration at the same time as, or at any time before or after, administration of other live attenuated or inactivated vaccines (see Section II.6 below for details); and
- Different injection sites and separate needles and syringes should be used for concomitant parenteral injections.
# Why
- Vaccination is the most effective way to prevent influenza and its complications.
- Annual vaccination is required because the specific strains in the vaccine are reviewed each year by WHO and often changed to provide a better match against the viruses expected to circulate, and because the body's immune response to influenza vaccination is transient and unlikely to persist beyond a year.
# II.2 Epidemiology Disease description
Influenza is a respiratory illness caused by the influenza A and B viruses and can cause mild to severe illness, which can result in hospitalization or death. Certain populations, such as young children, older adults, and those with chronic health conditions, may be at higher risk for serious influenza complications such as viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions.
# Infectious agent
There Over time, antigenic variation (antigenic drift) of strains occurs within an influenza A subtype or a B lineage. The ever-present possibility of antigenic drift, which may occur in one or more influenza virus strains, requires seasonal influenza vaccines to be reformulated annually, with one or more vaccine strains changing in most seasons.
# Transmission
Influenza is primarily transmitted by droplets spread through coughing or sneezing and through direct or indirect contact with respiratory secretions. The incubation period of seasonal influenza is usually 2 days but can range from 1-4 days. Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.
# Risk factors
The people at greatest risk of influenza-related complications are adults and children with chronic health conditions (see List 1), residents of nursing homes and other chronic care facilities, adults 65 years of age and older, children 6-59 months of age, pregnant women, and Indigenous peoples.
# Seasonal and temporal patterns
Influenza activity in Canada is usually low in the late spring and summer, begins to increase over the fall, and peaks in the winter months. Depending on the year, the peak may occur as early as fall or as late as spring.
# Spectrum of clinical illness
Symptoms typically include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week or 10 days. However, adults and children with chronic health conditions, adults 65 years of age and older, and children 6-59 months of age are at greater risk of more severe complications or worsening of their underlying condition.
# Disease incidence
# Global
Worldwide, annual epidemics result in approximately one billion cases of influenza, three to five million cases of severe illness, and 290,000 to 650,000 deaths. For current international influenza activity information, refer to WHO's FluNet website.
# National
Together, influenza and pneumonia are ranked among the top 10 leading causes of death in Canada (3) . FluWatch is Canada's national influenza surveillance system that collects data and information from various sources to provide a national picture of influenza activity. Since the 2010-2011 season, an average of 30,000 laboratory-confirmed cases of influenza are reported to FluWatch each year. Although the burden of influenza can vary from year to year, it is estimated that there are an average of 12,200 hospitalizations related to influenza and approximately 3,500 deaths attributable to influenza annually (4,5) . Current influenza activity information can be found on the FluWatch website.
It should be noted that the incidence of influenza is often underreported since the illness may be confused with other viral illnesses and many people with influenza-like illness (ILI) do not seek medical care or have viral diagnostic testing done.
# II.3 Vaccine Products Available for Use in Canada
This section describes the influenza vaccine products that are available for use in Canada for the 2019-2020 season. All influenza vaccines available in Canada have been authorized by Health Canada. However, not all products authorized for use are necessarily available in the marketplace. The vaccine manufacturers determine whether they will make any or all of their products available in a given market. Provincial and territorial health authorities then determine which of the available products will be used in their respective publicly funded influenza immunization programs and for which population groups.
The antigenic characteristics of circulating influenza virus strains provide the basis for selecting the strains included in each year's vaccine. Vaccine selection by the WHO generally occurs more than 6 months prior to the start of the influenza season to allow time for the vaccine manufacturers to produce the required quantity of vaccine. All manufacturers that distribute influenza vaccine products in Canada confirm to Health Canada that the vaccines to be marketed in Canada for the upcoming influenza season contain the WHO-recommended antigenic strains for the Northern Hemisphere. Vaccine producers may use antigenically equivalent strains because of their growth properties.
There are two categories of influenza vaccine authorized for use in Canada: inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV). Trivalent (3 strain) vaccines contain one A(H1N1) strain, one A(H3N2) strain, and one influenza B strain from one of the two lineages. Quadrivalent (4 strain) vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage. All influenza vaccines currently authorized for use in Canada are made from influenza viruses grown in eggs.
A summary of the characteristics of influenza vaccines available in Canada can be found in Appendix A. For complete prescribing information, readers should consult the product leaflet or information contained within the product monographs available through Health Canada's Drug Product Database.
# Standard-dose inactivated influenza vaccine (IIV-SD)
The standard-dose inactivated influenza vaccines (IIV-SDs) currently authorized for use in Canada are a mix of split virus and subunit vaccines. In split virus vaccines, the virus has been disrupted by a detergent. In subunit vaccines, HA and NA have been further purified by removal of other viral components. These vaccines are unadjuvanted, contain 15 µg HA per strain, and are administered as a 0.5 mL dose by IM injection. Refer to Basic Immunology and Vaccinology in Part 1 of the CIG for more information about inactivated vaccines.
Both trivalent (IIV3-SD; Agriflu ® , Fluviral ® , and Influvac ® ) and quadrivalent (IIV4-SD; Afluria ® Tetra, Flulaval ® Tetra, and Fluzone ® Quadrivalent) products are available.
# Adjuvanted inactivated influenza vaccine (IIV-Adj)
The adjuvanted inactivated influenza vaccine (IIV-Adj) currently authorized for use in Canada is a subunit IIV that contains the adjuvant MF59, which is an oil-in-water emulsion composed of squalene as the oil phase that is stabilized with the surfactants polysorbate 80 and sorbitan triolate in citrate buffer. IIV-Adj contains 7.5 µg HA per strain administered as a 0.25 mL dose by IM injection for children 6-23 months of age or 15 µg HA per strain administered as a 0.5 mL dose by IM injection for adults 65 years of age and older. Other IIVs do not contain an adjuvant.
Trivalent products (IIV3-Adj) for children 6-23 months of age (Fluad Pediatric ® ) and adults 65 years of age and older (Fluad ® ) are available.
# High-dose inactivated influenza vaccine (IIV-HD)
The high-dose inactivated influenza vaccine (IIV-HD) currently authorized for use in Canada is an unadjuvanted, split virus IIV that contains 60 µg HA per strain and is administered as a 0.5 mL dose by IM injection.
A trivalent product (IIV3-HD; Fluzone ® High-Dose) for adults 65 years of age and older is available.
# Live attenuated influenza vaccine (LAIV)
LAIV is given as an intranasal spray. The influenza viruses contained in LAIV are attenuated so that they do not cause influenza and are cold-adapted and temperature sensitive, so that they replicate in the nasal mucosa rather than the lower respiratory tract. LAIV contains standardized quantities of fluorescent focus units (FFU) of live attenuated reassortants and is given as a 0.2 mL dose (0.1 mL in each nostril).
A quadrivalent product (LAIV4; FluMist ® Quadrivalent) is authorized for use in Canada for children 2-17 years of age and adults 18-59 years of age. The trivalent formulation (LAIV3) is no longer available in Canada.
# II.4 Efficacy, Effectiveness, and Immunogenicity Efficacy and effectiveness
Influenza vaccine has been shown in randomized controlled clinical trials to be efficacious in providing protection against influenza infection and illness. However, the effectiveness of the vaccine-that is, how it performs in settings that are more reflective of usual health care practicecan vary from season to season and by influenza vaccine strain type and subtype.
Influenza vaccine effectiveness (VE) depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype, as well as the health and age of the individual receiving the vaccine. Even when there is a less-than-ideal match or lower effectiveness against one strain, the possibility of lower VE should not preclude vaccination, particularly for people at high risk of influenza-related complications and hospitalization, since vaccinated individuals are still more likely to be protected compared to those who are unvaccinated.
# Immunogenicity
Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are generally achieved by 2 weeks after vaccination; however, there may be some protection afforded before that time.
# II.5 Choice of Seasonal Influenza Vaccine
The decision to include specific influenza vaccines as part of publicly funded provincial and territorial programs depends on several factors, such as cost-effectiveness evaluation and other programmatic and operational factors, such as implementation strategies. Not all products will be made available in all jurisdictions and availability of some products may be limited; therefore, officials in individual provinces and territories should be consulted regarding the products available in individual jurisdictions.
With the availability of influenza vaccines that are designed to enhance immunogenicity in specific age groups or given through a different route of administration, the choice of product has become more complex.
# Choice of influenza vaccine by age group
Recommendations for individual-level decision making
- NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine. Table 1 provides age group-specific recommendations for the age-appropriate influenza vaccine types available for use in Canada.
# Recommendations for public health program-level decision making
- NACI recommends that any of the age-appropriate influenza vaccine types available for use may be considered for people without contraindications to the vaccine. Table 1 provides age group-specific recommendations for the age-appropriate influenza vaccine types available in Canada.
- IIV3-SD - IIV3-Adj - IIV4-SD
- Quadrivalent influenza vaccine should be used, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
- If a quadrivalent vaccine is not available, any of the available trivalent vaccines should be used.
# 2-17 years *
- IIV3-SD - IIV4-SD - LAIV4
- Either IIV4-SD or LAIV4 should be used in children without contraindications, including those with non-immune compromising chronic health conditions, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
- If IIV4-SD or LAIV4 is not available, IIV3-SD should be used.
- IIV4-SD should be used for children for whom LAIV is contraindicated, such as in children with: -severe asthma; -medically attended wheezing in the 7 days prior to vaccination; -current receipt of aspirin or aspirin-containing therapy; and -immune compromising conditions.
# Recipient by age group
# II.6 Vaccine Administration
Dose, route of administration, and schedule
With the variety of influenza vaccines available for use in Canada, it is important for vaccine providers to note the specific differences in age indication, route of administration, dosage and schedule for the products that they will be using (see Table 2). Key relevant details and differences between vaccine products are also highlighted in Appendix A.
For influenza vaccines given by the IM route, the deltoid muscle is the recommended site in adults and children 12 months of age and older, and the anterolateral thigh is the recommended site in children 6-12 months of age. For more information on vaccine administration, please refer to Vaccine Administration Practices in Part 1 of the CIG. ¶ Evidence suggests moderate improvement in antibody response in infants, without an increase in reactogenicity, with the use of full vaccine doses (0.5 mL) for unadjuvanted inactivated influenza vaccines (6,7) . This moderate improvement in antibody response without an increase in reactogenicity is the basis for the full dose recommendation for unadjuvanted inactivated vaccine for all ages. For more information, refer to Statement on Seasonal Influenza Vaccine for 2011-2012. Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.
# Booster doses and revaccination
Booster doses are not required within the same influenza season. However, children 6 months to less than 9 years of age who have not previously received the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses (see Table 2).
# Serological testing
Serologic testing is not necessary before or after receiving seasonal influenza vaccine.
# Storage requirements
Influenza vaccine should be stored at +2°C to +8°C and should not be frozen. Refer to the individual product monographs for further details. Refer to Storage and Handling of Immunizing Agents in Part 1 of the CIG for additional information.
# Simultaneous administration with other vaccines
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Studies have been done showing no interference when administering LAIV3 concomitantly with: measles, mumps, rubella (MMR); measles, mumps, rubella, varicella (MMRV); or oral polio live vaccines (8)(9)(10) . No studies have been done to assess the possibility of interference between LAIV and other live vaccines, or on LAIV given before or after other live vaccines. Additional information regarding simultaneous administration with other vaccines can be found in Section IV.4 of this statement.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. NACI recognizes that some vaccine providers may choose to give LAIV and other live vaccines simultaneously or separated by at least 4 weeks if a delay is chosen. Alternatively, an IIV may be given. Note that the timing rules related to two parenteral live vaccines (e.g., MMR and varicella vaccines) still apply. For more information regarding vaccination administration timing rules, please refer to Timing of Vaccine Administration in Part 1 of the CIG.
When more than one injection is given at a single clinic visit, it is preferable to administer them in different limbs. If it is not possible to do so, injections given in one limb should be separated by a distance of at least 2.5 cm (1 inch). A separate needle and syringe should be used for each injection.
The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. Vaccine providers should take the opportunity to vaccinate eligible people against pneumococcal disease when influenza vaccine is given.
# II.7 Vaccine Safety and Adverse Events
Data from post-marketing surveillance of influenza vaccines in Canada (Canadian Adverse Events Following Immunization Surveillance System ) have shown seasonal influenza vaccines to have a safe and stable profile for adverse events following immunization (AEFIs) with no unexpected events.
All influenza vaccines currently authorized for use in Canada are considered safe for use in people with latex allergies. The multi-dose vial formulations of inactivated influenza vaccine that are authorized for use in Canada contain minute quantities of thimerosal, which is used as a preservative (11,12) to keep the product sterile. Large cohort studies of administrative health databases have found no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders (13) . All single dose formulations of IIV and LAIV are thimerosal-free. Refer to Vaccine Safety in Part 2 of the CIG for additional information.
# Common adverse events
With IM administered influenza vaccines, injection site reactions are common but are generally classified as mild and transient. IIV3-Adj tends to produce more extensive injection site reactions than unadjuvanted IIV3, but these reactions are also generally mild and resolve spontaneously within a few days. IIV3-HD tends to induce higher rates of systemic reactions post-injection compared to IIV3-SD, but most of these reactions are mild and short-lived. The most common adverse events experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. Refer to the relevant subsections of Section IV for additional information.
Less common and serious or severe adverse events Serious adverse events are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some vaccine components. Refer to Section II.8 below for additional information.
Other reported adverse events and conditions
# Guillain-Barré syndrome
Studies suggest that the absolute risk of Guillain-Barré syndrome (GBS) in the period following seasonal and A(H1N1)pdm09 influenza vaccination is about one excess case per million vaccinations, and that the risk of GBS associated with influenza illness is larger (about 17 cases per million influenza-coded health care encounters, which are a proxy for influenza illness) than that associated with influenza vaccination.
Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
# Oculorespiratory syndrome
Oculorespiratory syndrome (ORS), which is defined as the presence of bilateral red eyes and one or more associated symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial edema, was found during the 2000-2001 influenza season; few cases have been reported since then. ORS is not considered to be an allergic response. People who have a recurrence of ORS upon revaccination do not necessarily experience further episodes with future vaccinations.
Individuals who have experienced ORS without lower respiratory tract symptoms may be safely revaccinated with influenza vaccine. Individuals who experienced ORS with lower respiratory tract symptoms should have an expert review. Health care providers who are unsure whether an individual previously experienced ORS versus an immunoglobulin E (IgE) mediated hypersensitivity immune response should seek advice. Data on clinically significant adverse events do not support the preference of one vaccine product over another when revaccinating those who have previously experienced ORS.
# Allergic reactions to previous vaccine doses
Expert review of the benefits and risks of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent significant allergic reaction to the vaccine, or any other symptoms that could indicate a significant allergic reaction (e.g., throat constriction, difficulty swallowing) that raise concern regarding the safety of revaccination. This advice may be obtained from experts in infectious disease, allergy, and immunology, or public health.
In view of the considerable morbidity and mortality associated with influenza, a diagnosis of influenza vaccine allergy should not be made without confirmation, which may involve consultation with an allergy or immunology expert.
# Drug interactions
Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterollowering actions. Two published studies have found that adults who are regular statin users (at least 65 years of age in one study and 45 years and older in the other) had an apparent decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT) (14) or reduced VE against medically attended acute respiratory illness (15) . Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concomitant statin use in adult populations could have implications for influenza VE and how this use is assessed in the measurement of VE. NACI will continue to monitor the literature related to this issue.
# Guidance on reporting adverse events following immunization (AEFI)
To ensure the ongoing safety of influenza vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. An AEFI is any untoward medical occurrence that follows vaccination and that does not necessarily have a causal relationship with the usage of a vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom, or disease. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported. An unexpected AEFI is an event that is not listed in the approved product monograph but may be due to the vaccination, or a change in the nature, severity, specificity, or outcome of a known AEFI.
For influenza vaccines, the following AEFIs are of particular interest:
- ORS; and
- GBS within 6 weeks following vaccination.
Refer to Reporting Adverse Events Following Immunization (AEFI) in Canada for additional information about AEFI reporting and to Vaccine Safety in Part 2 of the CIG for general vaccine safety information.
# II.8 Travellers
Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere).
- NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older, including travellers, who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see List 1).
Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination (i.e., boosting) of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity or difference between the Northern and Southern Hemisphere vaccines, the similarity or difference between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination.
Refer to Immunization of Travellers in Part 3 of the CIG for additional general information.
This concludes the summary of relevant influenza vaccine information typically found in the CIG. Additional technical information related to seasonal influenza vaccine can be found in the remainder of this statement.
# III. PARTICULARLY RECOMMENDED VACCINE RECIPIENTS: ADDITIONAL INFORMATION
The groups for whom influenza vaccination is particularly recommended are presented in List 1 of Section II. Additional information regarding these particularly recommended recipients is provided below.
# III.1 People at High Risk of Influenza-Related Complications or Hospitalization
All pregnant women NACI recommends the inclusion of all pregnant women, at any stage of pregnancy, among the particularly recommended recipients of IIV, due to the risk of influenza-associated morbidity in pregnant women (16)(17)(18)(19)(20) , evidence of adverse neonatal outcomes associated with maternal respiratory hospitalization or influenza during pregnancy (21)(22)(23)(24) , evidence that vaccination of pregnant women protects their newborns from influenza and influenza-related hospitalization (25)(26)(27)(28) , and evidence that infants born during influenza season to vaccinated women are less likely to be premature, small for gestational age, and of low birth weight (29)(30)(31)(32) .
The safety of IIV during pregnancy has been reviewed (33) . Active studies of influenza vaccination during pregnancy have not shown evidence of harm to the mother or fetus associated with influenza immunization (34) . Although the cumulative sample size of active studies of influenza vaccination in pregnant women is relatively small, particularly in the first trimester, passive surveillance has not raised any safety concerns despite widespread use of IIV during pregnancy over several decades (18,19,33,35) . Surveillance following the use of both adjuvanted and unadjuvanted 2009 pandemic influenza A(H1N1) vaccines in more than 100,000 pregnant women in Canada and more than 488,000 pregnant women in Europe has not revealed any safety concerns (36,37) .
# Refer to the Statement on Seasonal Influenza Vaccine for 2011-2012 and the Statement on Seasonal Influenza Vaccine for 2012-2013 for further details on influenza vaccination during pregnancy.
# Adults and children with chronic health conditions
A number of chronic health conditions, as noted in List 1, are associated with increased risk of influenza-related complications, and influenza can lead to exacerbation of the chronic disease. Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and human immunodeficiency virus (HIV)-infected people. Vaccine effectiveness may be lower in people with immune compromising conditions than in healthy adults.
# Neurologic or neurodevelopment conditions
Neurologic or neurodevelopment conditions (NNCs) include neuromuscular, neurovascular, neurodegenerative, neurodevelopment conditions, and seizure disorders (and, for children, include febrile seizures and isolated developmental delay), but exclude migraines and psychiatric conditions without neurological conditions. Based on reviews of evidence and expert opinion, NACI includes adults and children with NNCs among the groups for whom influenza vaccination is particularly recommended. Refer to the NACI Statement on Seasonal Influenza Vaccine for 2018-2019 for a summary of the rationale supporting this decision and the Literature Review on Individuals with Neurologic or Neurodevelopment Conditions and Risk of Serious Influenza-Related Complications for additional details of the evidence reviews.
# People of any age who are residents of nursing homes and other chronic care facilities
Residents of nursing homes and other chronic care facilities often have one or more chronic health conditions and live in institutional environments that may facilitate the spread of influenza.
# Adults 65 years of age and older
Hospitalization attributable to influenza in this age group is estimated at 125-228 per 100,000 healthy people (38) , and influenza-attributed mortality rates increase with increased age (39) .
# All children 6-59 months of age
On the basis of existing data, NACI recommends the inclusion of all children 6-59 months of age among the particularly recommended recipients of influenza vaccine.
# Indigenous peoples
Based on the body of evidence indicating a higher rate of influenza-associated hospitalization and death among Indigenous peoples, NACI recommends the inclusion of this population among the particularly recommended recipients of influenza vaccine.
It has been proposed that the increased risk of severe influenza outcomes in the Indigenous populations is a consequence of many factors, including high prevalence of chronic health conditions (e.g., diabetes, chronic lung disease, end-stage kidney disease, cardiovascular disease) (40) , obesity, delayed access to health care, and increased susceptibility to disease because of poor housing and overcrowding (41)(42)(43) . Refer to the Statement on Seasonal Influenza Vaccine for 2011-2012 for further details.
# III.2 People Capable of Transmitting Influenza to Those at High Risk of Influenza-Related Complications or Hospitalization
People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk individual has been immunized. Immunization of care providers decreases their own risk of illness (44,45) , as well as the risk of death and other serious outcomes among the individuals for whom they provide care (46)(47)(48)(49) . Immunization of care providers and residents of nursing homes is associated with decreased risk of ILI outbreaks (50) .
People who are more likely to transmit influenza to those at high risk of influenza-related complications or hospitalization include:
- Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; and - Contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated.
# Health care and other providers in facilities and community settings
This group includes HCWs, regular visitors, emergency response workers, and others who have contact with residents of continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. For the purposes of this statement, HCWs include any person, paid or unpaid, who provides services, works, volunteers, or trains in a health care setting.
Influenza immunization provides benefits to HCWs and to the patients for whom they care. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs for the protection of their patients.
Transmission of influenza between infected HCWs and their vulnerable patients results in significant morbidity and mortality. For example, randomized controlled trials (RCTs) conducted in geriatric long-term care settings have demonstrated that vaccination of HCWs is associated with substantial decreases in morbidity (47)(48)(49) and all-cause mortality (46)(47)(48)(49) in the residents. Therefore, HCWs should consider annual influenza vaccination included in their responsibility to provide the highest standard of care. In the absence of contraindications, refusal of HCWs to be vaccinated against influenza implies failure in their duty of care to patients.
As noted in PHAC's Guidance: Infection Prevention and Control Measures for Healthcare Workers in Acute Care and Long-term Care Settings for seasonal influenza, all health care organizations should have a written plan for managing an influenza outbreak in their facilities. Inherent in such plans should be policies and programs to optimize HCW's influenza immunization (51) . As part of outbreak management, the above-mentioned PHAC guidance suggests consideration of chemoprophylaxis for all unvaccinated HCWs, unless contraindications exist. Refer to the Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada) website for guidelines regarding the use of antiviral medications for prophylaxis.
# Contacts of individuals at high risk of influenza complications
Vaccination is recommended for contacts, both adults and children, of individuals at high risk of influenza-related complications or hospitalization (see List 1), whether or not the individual at high risk has been vaccinated. These contacts include: household contacts and care providers of individuals at high risk; household contacts and care providers of infants less than 6 months of age, as these infants are at high risk of complications from influenza but cannot receive influenza vaccine; members of a household expecting a newborn during the influenza season; household contacts and care providers (whether in or out of the home) of children 6-59 months of age, and providers of services within closed or relatively closed settings to people at high risk (e.g., crew on a ship).
# III.3 Others People who provide essential community services
Vaccination for these individuals should be encouraged to minimize the disruption of services and routine activities during annual influenza epidemics. People who provide essential community services, including healthy working adults, should consider annual influenza vaccination, as this intervention has been shown to decrease work absenteeism due to respiratory and related illnesses (44,45,(52)(53)(54) .
People in direct contact with poultry infected with avian influenza during culling operations
# Poultry workers
Although seasonal influenza vaccination will not prevent avian influenza infection, some countries (55) and provinces have recommended influenza vaccination on a yearly basis for poultry workers, based on the rationale that preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with human and avian influenza viruses (56) .
Therefore, NACI recommends seasonal influenza vaccination for people in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of avian influenza infection because of exposure during the culling operation (57)(58)(59)(60) . Refer to the Statement on Seasonal Influenza Vaccine for 2013-2014 for further information informing this recommendation. Direct contact may be defined as sufficient contact with infected poultry to allow transmission of an avian virus to the exposed person. The relevant individuals include those performing the cull, as well as others who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. It is recommended that biosecurity measures such as personal protective equipment and antivirals be used. Refer to Human Health Issues Related to Avian Influenza in Canada for PHAC recommendations on the management of domestic avian influenza outbreaks.
# Swine workers
NACI has concluded that there is insufficient evidence at this time to recommend routine influenza vaccination specifically for swine workers; however, NACI recommends that influenza vaccination should be offered to anyone 6 months of age and older who do not have contraindications to the vaccine.
Refer to the Statement on Seasonal Influenza Vaccine for 2013-2014 for further information informing this recommendation.
# IV. VACCINE PREPARATIONS AVAILABLE FOR USE IN CANADA: ADDITIONAL INFORMATION
The following sections describe information on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccine by type in two categories: IIV and LAIV. Refer to Appendix A for a summary of the characteristics of specific influenza vaccine products available in Canada for the 2019-2020 season.
NACI acknowledges that evidence related to influenza vaccine performance, particularly with respect to vaccine efficacy and effectiveness, is constantly evolving with advances in research methodology and accumulation of data over many influenza seasons. Therefore, the evidence summarized in this section may not include the latest studies. However, in accordance with usual practice, NACI continues to monitor closely the emerging evidence on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines to update and to make recommendations when warranted.
# IV.1 Inactivated Influenza vaccine (IIV)
IIVs contain standardized amounts of the HA protein from representative seed strains of the two human influenza A subtypes (H3N2 and H1N1) and either one (for trivalent vaccines) or both (for quadrivalent vaccines) of the two influenza B lineages (Yamagata or Victoria). IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines, both consisting of disrupted virus particles. Split virus vaccines contain whole inactivated viruses split with detergent, ether, or both, while subunit vaccines are made of purified HA and NA. The amount of NA in the vaccines is not standardized. HA-based serum antibody produced to one influenza A subtype is anticipated to provide little or no protection against strains belonging to the other subtype. The potential for trivalent vaccine to stimulate antibody protection across B lineages requires further evaluation and may be dependent upon factors such as age and prior antigenic experience with the two B lineages (61)(62)(63)(64)(65)(66) .
Because of potential changes in the circulating influenza virus from year to year and waning immunity in vaccine recipients, annual influenza vaccination is recommended. Although NACI is aware of some recent studies that suggest that vaccine induced protection may be greater in individuals who have no recent vaccine history, optimal protection against influenza, season after season, is best achieved through annual influenza vaccination (67,68) . NACI will continue to monitor this issue.
# Immunological considerations related to children
Young children have a high burden of illness and their vaccine-induced immune response is not as robust as older children. However, some studies suggest moderate improvement in antibody response in young children, without an increase in reactogenicity, with the use of a full vaccine dose (0.5 mL) for IIV-SDs (6,7,69) . On the basis of this moderate improvement in antibody response without an increase in reactogenicity, NACI recommends the use of a 0.5 mL dose for all recipients of IIV-SDs, including young children, which is thought to mitigate the reduced immune response observed in the studies with the 0.25 mL dose of IIV-SDs.
# Immunological considerations related to older adults and those with immune compromising conditions
Although the initial antibody response in older adults may be lower to some influenza vaccine components when compared to those in other age groups, a literature review identified no evidence for a subsequent antibody decline that was any more rapid in older adults than in younger age groups (70) .
Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patients (71)(72)(73)(74) .
Most studies have shown that administration of a second dose of influenza vaccine in the same season to older adults or other individuals who may have an altered immune response does not result in a clinically significant antibody boost (75)(76)(77)(78) .
# Standard-dose trivalent inactivated influenza vaccine (IIV3-SD)
Vaccines currently available for use:
- Agriflu ® (Seqirus) - Fluviral ® (GlaxoSmithKline) - Influvac ® (BGP Pharma ULC, operating as Mylan EPD)
# Efficacy and effectiveness
The NACI Literature Review on Influenza Vaccination in Healthy 5-18-Year-olds found that VE of IIV3-SD against laboratory-confirmed influenza was variable but was most frequently between 65-85% (79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97) . In the NACI literature review on Influenza Vaccine Effectiveness, Immunogenicity, and Safety in Healthy Adults 19-64 Years Old, efficacy against laboratoryconfirmed influenza for IIV3-SD in healthy adults 18-64 years of age ranged widely from as low as 15% to as high as 75%, with the majority of studies estimating efficacy at 50-60%. Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for a more detailed summary of efficacy and effectiveness evidence for IIV3-SD in healthy children 5-18 years of age and healthy adults 19-64 years of age.
In older adults, VE of IIV3-SD is about half of that in healthy adults and varies depending on the outcome measures and the study population (98,99) . Systematic reviews have demonstrated that influenza vaccine decreases the incidence of pneumonia, hospital admissions, and deaths in the elderly (98) and reduces exacerbations in people with chronic obstructive pulmonary disease (100) . The NACI Literature Review on the Comparative Effectiveness and Immunogenicity of Subunit and Split Virus Inactivated Influenza Vaccines in Adults 65 Years of Age and Older found no statistically significant differences in VE of subunit IIV3-SD compared with split virus IIV3-SD in adults 65 years of age and older against infection with any influenza virus strain, or against infection with influenza A(H1N1), A(H3N2), or B virus specifically.
In observational studies, influenza vaccination has been shown to reduce the number of physician visits, hospitalizations, and deaths in adults 18-64 years of age with high-risk medical conditions (101) , hospitalizations for cardiac disease and stroke in adults 65 years of age and older (102) , and hospitalization and deaths in adults 18 years of age and older with diabetes mellitus (103) during influenza epidemics. Observational studies that use non-specific clinical outcomes or that do not take into account differences in functional status or health-related behaviours should be interpreted with caution (104)(105)(106)(107)(108) .
# Immunogenicity
Both humoral and cell-mediated responses are thought to play a role in immunity to influenza. While humoral immunity is thought to play a primary role in protection against infection, cellmediated immunity, notably cytotoxic T lymphocyte responses to internal viral components, is increasingly invoked as important in protecting against severe outcomes of influenza, particularly those associated with subtype HA variations (shift and drift) (109) . The IM administration of IIV3-SD results in the production of circulating immunoglobulin G (IgG) antibodies to the viral HA and NA proteins, as well as a more limited cytotoxic T lymphocyte response.
# Safety
Studies evaluating the safety of IIV3-SDs in healthy children have found a good safety profile with no serious adverse events of note (110) . The most common solicited local reactions are pain and redness at the injection site, while the most common solicited systemic reactions are irritability, malaise, and headache. Mild injection site reactions, primarily soreness at the vaccination site, have been found to occur in 7% or less of healthy children who are less than 3 years of age (111)(112)(113) . Post-vaccination fever may be observed in 12% or less of vaccinated children 1-5 years of age (89,113) .
For adults, IIV3-SDs have been demonstrated to have a good safety profile with acceptable reactogenicity (110) . Common local reactions at injection site include redness, swelling, pain, and induration. These reactions last 2-3 days and rarely interfere with normal activities. Common systemic reactions include headache, malaise, myalgia, fatigue, arthralgia, and fever.
# Adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj)
Vaccines currently available for use:
- Fluad ® (Seqirus) - Fluad Pediatric ® (Seqirus)
# Fluad (adults 65 years of age and older) Efficacy and effectiveness
There is fair evidence that the MF59-adjuvanted Fluad (IIV3-Adj) may be effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to unvaccinated individuals. However, there is insufficient evidence that IIV3-Adj is more effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to those who received unadjuvanted subunit IIV3-SD. There remain no efficacy or effectiveness studies that compare IIV3-Adj with IIV3-HD or IIV4-SD. Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for more information on the efficacy and effectiveness of IIV3-Adj in adults 65 years of age and older.
# Immunogenicity
The mechanism of action of MF59 is not fully determined and has primarily been studied using in vitro and mouse models. From these studies, it appears that MF59 may act differently from aluminum-based adjuvants. These studies show that MF59 acts in the muscle fibres to create a local immune-stimulatory environment at the injection site (114) . MF59 allows for an increased influx of phagocytes (e.g., macrophages, monocytes) to the site of injection. The recruited phagocytes are further stimulated by MF59, thereby increasing the production of chemokines to attract more innate immune cells and inducing differentiation of monocytes into dendritic cells (115,116) . MF59 further facilitates the internalization of antigen by these dendritic cells (115,117) . The overall higher number of cells available locally increases the likelihood of interaction between an antigen presenting cell and the antigen, leading to more efficient transport of antigen to the lymph nodes, with resulting improved T cell priming (115) .
There is evidence from RCTs that IIV3-Adj elicits non-inferior immune responses compared to the unadjuvanted subunit and split virus IIV3-SDs; however, superiority of IIV3-Adj to these vaccines by pre-defined criteria has not been consistently demonstrated. Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for more information on the immunogenicity of IIV3-Adj in adults 65 years of age and older.
# Safety
IIV3-Adj produces injection site reactions (pain, erythema, and induration) significantly more frequently than IIV3-SD, but they are classified as mild and transient. Systemic reactions (myalgia, headache, fatigue, and malaise) are comparable or more frequent with IIV3-Adj compared to IIV3-SD and are rated as mild to moderate and transient. Serious adverse events were uncommon and were comparable to IIV3-SD. Refer to the Recommendations on the use of MF59-Adjuvanted Trivalent Influenza Vaccine (Fluad ® ): Supplemental Statement of Seasonal Influenza Vaccine for 2011-2012 for additional information on the safety of IIV3-Adj in adults 65 years of age and older.
# Fluad Pediatric (children 6-23 months of age) Efficacy and effectiveness
A pre-licensure efficacy trial in children 6-71 months of age found a higher relative efficacy for IIV-Adj than the unadjuvanted IIV3-SD (118) . However, the findings of this study should be interpreted with caution. The comparator unadjuvanted IIV3 used in this trial was shown, in an unrelated study, to induce a lower immune response compared to another unadjuvanted IIV3-SD. There were concerns raised by a European Medicines Agency inspection about the quality of diagnostic laboratory testing and validity of ascertainment of influenza cases. The study administered 0.25 mL doses of the comparator unadjuvanted IIV3-SD for children less than 36 months of age, which is lower than the dose of 0.5 mL of unadjuvanted IIV3-SD or IIV4-SD that is recommended for this age group in Canada. Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for more information on the efficacy and effectiveness of IIV3-Adj in children.
# Immunogenicity
In children, there is limited but consistent evidence that IIV3-Adj is more immunogenic than IIV3-SD against both influenza A and B (118)(119)(120)(121)(122)(123) . In particular, a single dose of IIV3-Adj is more immunogenic than a single dose of IIV3-SD, and has been shown in one study to produce greater GMTs than 2 doses of IIV3-SD against influenza A (123) . However, similar to IIV3-SD, IIV3-Adj generally induced a weaker hemagglutination-inhibition antibody response against B strains compared to A strains and therefore 2 doses of IIV3-Adj are still necessary to achieve a satisfactory immune response against influenza B. Almost all of the pre-licensure pediatric studies used vaccine formulations of 0.25 mL in children 6-35 months of age, both for IIV3-Adj and the comparator unadjuvanted influenza vaccine (NACI recommends 0.5 mL dosage of IIV3-SD or IIV4-SD for all age groups). There is limited immunogenicity evidence comparing IIV3-Adj at 0.25 mL dose to IIV3-SD or IIV4-SD at 0.5 mL dose in the 6-23 month age group. Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for more information on the immunogenicity of IIV3-Adj in children.
# Safety
The safety data in children are consistent with what is known about IIV3-Adj's safety profile in adults. In pediatric trials, IIV3-Adj was more reactogenic than IIV3-SD, with recipients experiencing 10-15% more solicited local and systemic reactions. However, most reactions were mild and resolved quickly. A dose-ranging study of MF59-adjuvanted and unadjuvanted IIV3 and IIV4 did not find an increased risk of adverse events associated with increased MF59 dose, antigen dose, or the addition of a second B strain; however, the reactogenicity of 15 µg formulations were slightly higher for both adjuvanted and unadjuvanted vaccines compared to the corresponding 7.5 µg formulations (121) .
There are currently no data on the effects of long-term or repeated administration of adjuvanted influenza vaccines in children. The most significant experience with an adjuvanted influenza vaccine in children was the AS03-adjuvanted A(H1N1) pandemic vaccine that has been associated with an increased risk of narcolepsy. A study comparing two AS03-adjuvanted A(H1N1) vaccine products (Pandemrix and Arepanrix) has suggested that the underlying immune mediated mechanism may not be initiated by the adjuvant, but by another component of the vaccine, specifically the A(H1N1) viral antigen (124) . However, the pandemic vaccine was a single strain adjuvanted vaccine administered only during one season, and it is unknown what effects a multi-strain adjuvanted vaccine or an adjuvanted vaccine administered for more than one season may have in young children.
Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for additional information on the safety of IIV3-Adj in children.
# High-dose trivalent inactivated influenza vaccine (IIV3-HD)
Vaccine currently available for use:
- Fluzone ® High-Dose (Sanofi Pasteur)
# Efficacy and effectiveness
There is good evidence that Fluzone High-Dose (IIV3-HD) provides superior protection compared with IIV3-SD in adults 65 years of age and older. A few studies found that IIV3-HD may provide greater benefit in the very elderly (e.g., 75 years of age and older) compared to younger elderly (e.g., 65-74 years of age) (125)(126)(127) ; however, additional studies are needed to validate this finding. There remain no efficacy or effectiveness studies that compare IIV3-HD with IIV3-Adj or IIV4-SD.
# Immunogenicity
Five studies compared the rates of seroconversion for study participants receiving IIV3-HD and IIV3-SD among those 65 years of age and older (128)(129)(130)(131)(132)(133) . Rates of seroconversion were found to be about 19% higher (ranging from 8-39%) for those receiving the higher dose vaccine across all three vaccine strains. Similarly, rates of seroconversion were higher for those receiving the high-compared to standard-dose vaccines for participants 75 years of age and older and for a cohort of participants with underlying cardiopulmonary disease.
Eight studies reported higher rates of seroprotection for older adults receiving IIV3-HD compared to those vaccinated with IIV3-SD (128)(129)(130)(131)(132)(133)(134)(135) . Seroprotection was significantly higher for all 3 strains in the vaccine in three of five studies assessing significance. There were different results in the remaining studies. In the study by Couch et al., seroprotection was higher only against A(H1N1), possibly attributed to the fact that 78% of participants were vaccinated against the same influenza strains within 6 months prior to the study (129) . In Nace et al., seroprotection was higher against A(H3N2) and B but not A(H1N1); this finding may be attributed to strain circulation during the study that made it difficult to assess seroprotection against this subtype (133) . Geometric mean titre ratios (GMTR) of participants' responses to high-versus standard-dose influenza vaccines were reported in several studies and were calculated for those that provided group-specific, post-vaccination titres for each of the vaccines (128)(129)(130)(131)(132)134,135) . Seroresponse to the B strains in the vaccines was about 1.5 times greater (1.3-1.7) in the IIV3-HD recipients than the IIV3-SD recipients. The GMTR of the A strains was about 1.8 times higher for those receiving IIV3-HD compared to IIV3-SD, ranging from 1.6-2.3.
# Safety
IIV3-HD has been observed to produce a higher rate of some systemic reactions than IIV3-SD. Studies have reported higher rates of malaise, myalgia, and moderate to severe fever. Most systemic reactions were mild and resolved within 3 days. Serious adverse events were rare and similar in frequency between standard-dose and high-dose vaccines. Refer to NACI's A Review of the Literature of High Dose Seasonal Influenza Vaccine for Adults 65 Years and Older for details.
# Standard-dose quadrivalent inactivated influenza vaccine (IIV4-SD)
Vaccines currently available for use:
- Afluria ® Tetra (Seqirus) - Flulaval ® Tetra (GlaxoSmithKline) - Fluzone ® Quadrivalent (Sanofi Pasteur)
# Efficacy and effectiveness
In the NACI Literature Review on Quadrivalent Influenza Vaccines, only one study was identified that measured IIV4-SD efficacy. In that study, efficacy was estimated at 59% in children 3-8 years of age, in comparison to children who received hepatitis A vaccine (136) . No literature was found in this review on efficacy or effectiveness directly comparing trivalent and quadrivalent formulations.
# Immunogenicity
In this same review of the literature, NACI reviewed the immunogenicity data for IIV4-SD produced by manufacturers who supplied influenza vaccine in Canada at the time of the literature review: AstraZeneca, GlaxoSmithKline, and Sanofi Pasteur. The results of phase II and III trials that compared trivalent formulations to quadrivalent formulations generally showed non-inferiority of the quadrivalent products for the A(H3N2), A(H1N1), and B strain contained in the trivalent formulations. As expected, these studies showed that the immune response to the B strain that was not in the trivalent formulation was better in subjects who received the quadrivalent vaccine, which contained the additional B strain. These findings were consistent across age groups. Refer to the Literature Review on Quadrivalent Influenza Vaccines for additional details.
In the phase III trials, recipients of the trivalent formulations showed, to a lesser degree, some immune response to the B strain not contained in the trivalent formulation. In one study of adults, both the trivalent and quadrivalent vaccines met all the Committee for Medicinal Products for Human Use (CHMP) and Centre for Biologics Evaluation and Research (CBER) criteria for evaluation of influenza vaccine immunogenicity, including those for the B strain not in the trivalent vaccine.
In all other studies, the trivalent vaccine failed at least one of the criteria for seroprotection or seroconversion for the missing B strain. It has been hypothesized that there is some level of cross-reactivity between B strains. The degree of cross protection against infection with one lineage provided by immunization against the other lineage is uncertain (137) .
# Safety
As IIV4-SD has higher antigenic content than IIV3-SD, increased reactogenicity may be a concern for the quadrivalent vaccine. However, pre-licensure clinical trials (refer to Literature Review on Quadrivalent Influenza Vaccines) and post-marketing surveillance showed that IIV4-SD had a similar safety profile to IIV3-SD (138) .
# IV.2 Live Attenuated Influenza Vaccine (LAIV)
LAIV contains standardized quantities of FFU of live attenuated influenza virus reassortants. The virus strains in LAIV are cold-adapted and temperature sensitive, so they replicate in the nasal mucosa rather than the lower respiratory tract, and they are attenuated, so they do not produce ILI. There have been no reported or documented cases, and no theoretical or scientific basis to suggest transmission of vaccine virus would occur to the individual administering LAIV. As a live replicating whole virus formulation administered intranasally, it elicits mucosal immunity, which may more closely mimic natural infection.
Vaccine currently available for use:
- FluMist ® Quadrivalent (AstraZeneca)
# Efficacy and effectiveness
After careful review of the available Canadian and international LAIV VE data over many influenza seasons, NACI concluded that the current evidence is consistent with LAIV's providing comparable protection against influenza to that afforded by IIV and does not support a recommendation for the preferential use of LAIV in children 2-17 years of age.
Observational studies from the United States of America found low effectiveness of LAIV against circulating post-2009 pandemic A(H1N1), or A(H1N1)pdm09, in 2013-2014 and 2015-2016; however, reduced LAIV effectiveness was not observed in Canada or any other countries that have investigated the issue.
Manufacturer investigation identified potential reduced replicative fitness of the A(H1N1)pdm09like LAIV viruses in the nasal mucosa from the two affected A(H1N1)-dominant seasons compared to pre-2009 pandemic influenza A(H1N1) LAIV viruses as contributing to the poor LAIV effectiveness against circulating A(H1N1) (139) . This finding led to the manufacturer replacing the A(H1N1)pdm09 component of LAIV with a new strain. In adults, studies have found IIV-SD to be similarly or more efficacious or effective compared with LAIV.
Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for detailed information supporting this recommendation.
# Immunogenicity
LAIV, which is administered by the intranasal route, is thought to result in an immune response that mimics that induced by natural infection with wild-type viruses, with the development of both mucosal and systemic immunity. Local mucosal antibodies protect the upper respiratory tract and may be more important for protection than serum antibody.
Studies have demonstrated that the presence of a hemagglutination-inhibition antibody response after the administration of LAIV3 is predictive of protection. However, efficacy studies have shown protection in the absence of a significant antibody response as well (140) . In these studies, LAIV3 has generally been shown to be equally, if not more, immunogenic compared to IIV3-SD for all 3 strains in children, whereas IIV3-SD was typically more immunogenic in adults than LAIV3. Greater rates of seroconversion to LAIV3 occurred in baseline seronegative individuals compared to baseline seropositive individuals in both pediatric and adult populations, because pre-existing immunity may interfere with response to a live vaccine. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for further details regarding the immunogenicity of LAIV3.
LAIV4 has shown non-inferiority based on immunogenicity compared to LAIV3 in both children and adults. The immune response to the B strain found only in the quadrivalent formulation was better in children who received the quadrivalent vaccine (141)(142)(143) .
# Safety
The most common adverse events experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. In a large efficacy trial, rates of wheezing were statistically higher among children 6-23 months of age for LAIV3 compared to IIV3-SD (140) . This finding is expected to be the same for recipients of LAIV4; however, pre-licensure clinical studies for LAIV4 were conducted in adults and children 2 years of age and older.
Studies on LAIV3 have shown that vaccine virus can be recovered by nasal swab in children and adults following immunization (i.e., "shedding"). The frequency of shedding decreases with increasing age and time since vaccination. Shedding is generally below the levels needed to transmit infection, although in rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated people. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for more information on LAIV and viral shedding.
# IV.3 Schedule
The first time that children 6 months to less than 9 years of age receive seasonal influenza immunization, a two-dose schedule is required to achieve protection (144)(145)(146) . Several studies have looked at whether these two initial doses need to be given in the same season (63,64,147) . Englund et al. reported similar immunogenicity in children 6-23 months of age whether 2 doses were given in the same or separate seasons when there was no change, or only minor vaccine strain change, in vaccine formulation between seasons (63,64) . However, seroprotection rates to the B component were considerably reduced in the subsequent season when there was a major B lineage change, suggesting that the major change in B virus lineage reduced the priming benefit of previous vaccination (62,64) . Issues related to effective prime-boost when there is a major change in influenza B lineage across sequential seasons require further evaluation (148) .
Because children 6-23 months of age are less likely to have had prior priming exposure to an influenza virus, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children in this age group.
# IV.4 Simultaneous Administration with Other Vaccines
In general, NACI recommends that two live parenteral vaccines be administered either on the same day or at least 4 weeks apart (149) . This recommendation is based largely on a single study from 1965 that demonstrated immune interference between smallpox vaccine and measles vaccine administered 9-15 days apart. Subsequent studies have revealed conflicting results on immune interference between live vaccines (150)(151)(152)(153) .
No studies were found on potential immune interference between LAIV and other live attenuated vaccines (oral or parenteral) administered within 4 weeks. A few studies on concomitant administration of LAIV3 with MMR, varicella, and oral polio vaccines did not find evidence of clinically significant immune interference (8)(9)(10) . One study reported a statistically significant but not clinically meaningful decrease in seroresponse rates to rubella antigen when administered concomitantly with LAIV.
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Possible immune mechanisms include: the inhibitory and immunomodulatory effects of systemic and locally produced cytokines on B-and T-cell response and viral replication; immunosuppression induced by certain viruses (such as measles); and direct viral interference as a result of competition for a common niche. Mucosal vaccines may have less impact on a parenteral vaccine and vice versa. The immune response with a mucosal vaccine may be compartmentalized to the mucosa while that to a parenteral vaccine is systemic. It is likely that there is some interaction between the systemic and mucosal compartments; however, the extent to which this interaction occurs is not known.
Given the lack of data for immune interference, based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. NACI recognizes that some vaccine providers may choose to give LAIV and other live vaccines simultaneously or separated by at least 4 weeks as a professional preference. Alternatively, an inactivated influenza vaccine may be given.
# IV.5 Additional Vaccine Safety Considerations
Influenza vaccine is safe and well tolerated. Contraindications, precautions, and common adverse events are described in Section II. Additional information regarding egg-allergic individuals and GBS is provided below.
# Egg-allergic individuals
After careful review of clinical and post-licensure safety data, NACI has concluded that eggallergic individuals may be vaccinated against influenza using any appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular consideration, including vaccination setting. The amount of trace ovalbumin allowed in influenza vaccines that are authorized for use in Canada is associated with a low risk of adverse events. The observation period post-vaccination is as recommended in Vaccine Safety in Part 2 of the CIG. As with all vaccine administration, vaccine providers should be prepared with the necessary equipment, knowledge, and skills to respond to a vaccine emergency at all times.
Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for safety data supporting this recommendation for IIV and LAIV.
# Guillain-Barré syndrome
In a review of studies conducted between 1976 and 2005, the United States Institute of Medicine concluded that the 1976 "swine flu" vaccine was associated with an elevated risk of GBS. However, evidence was inadequate to accept or to reject a causal relation between GBS in adults and seasonal influenza vaccination (154) .
The attributable risk of GBS in the period following seasonal and monovalent 2009 pandemic influenza vaccination is about one excess case per million vaccinations (155,156) . In a selfcontrolled study that explored the risk of GBS after seasonal influenza vaccination and after influenza health care encounters (a proxy for influenza illness), the attributable risks were 1.03 GBS admissions per million vaccinations compared with 17.2 GBS admissions per million influenza-coded health care encounters (156) .
This finding shows that both influenza vaccination and influenza illness are associated with small attributable risks of GBS, but the risk of GBS associated with influenza illness is notably higher than with influenza vaccination. The self-controlled study also found that the risk of GBS after vaccination was highest during weeks 2-4, whereas for influenza illness, the risk was greatest within the first week after a health care encounter and decreased thereafter, but remained significantly elevated for up to 4 weeks. The risk of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and all the other benefits of influenza vaccination (157)(158)(159)(160) .
# V. CHOICE OF SEASONAL INFLUENZA VACCINE: ADDITIONAL INFORMATION
With the recent availability of a number of new influenza vaccines, some of which are designed to enhance immunogenicity in specific age groups, the choice of product is now more complex. Section II.5 summarizes NACI's recommendations on the choice of currently available influenza vaccines. This section provides more details for these recommendations.
# V.1 Children
# Burden of disease in children
The proportion of disease burden due to influenza B infection is higher in children compared to other age groups. Canadian surveillance data from 2001-2002 to 2012-2013 has shown that influenza B strains accounted for 17% of laboratory-confirmed tests for influenza. Children less than 24 months of age comprise approximately 2% of the Canadian population (161) . (162) .
The IMPACT study also found that the proportion of deaths attributable to influenza was significantly greater for influenza B (1.1%) than influenza A (0.4%). The proportion of hospitalizations due to influenza B relative to all influenza hospitalizations has been generally similar to the proportion of influenza B detections relative to all influenza infections in the general population during the same time period. Additional information can be found in the Statement on Seasonal Influenza Vaccine for 2014-2015. Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that a quadrivalent influenza vaccine should be used. If a quadrivalent vaccine is not available, any of the available trivalent vaccines should be used.
There is insufficient evidence to make comparative recommendations on the use of IIV3-Adj over IIV3-SD.
Children 2-17 years of age Three types of influenza vaccine are available for use in children 2-17 years of age: IIV3-SD, IIV4-SD, and LAIV4.
Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that either IIV4-SD or LAIV4 should be used in children without contraindications. If IIV4-SD or LAIV4 is not available, IIV3-SD should be used.
The current evidence does not support a recommendation for the preferential use of LAIV in children and adolescents 2-17 years of age. Refer to the NACI Statement on Seasonal Influenza Vaccine for 2018-2019 for information supporting this recommendation.
# Children 2-17 years of age with chronic health conditions
NACI recommends that any age-appropriate influenza vaccine (IIV or LAIV) may be considered for children 2-17 years of age with chronic health conditions, with the exception of those with severe asthma (as defined as currently on oral or high-dose inhaled glucocorticosteroids), those with medically attended wheezing in the 7 days prior to vaccination, and those with immune compromising conditions, all of whom should receive IIV. If IIV is used, NACI recommends that a quadrivalent vaccine should be used. If a quadrivalent vaccine is not available, a trivalent vaccine should be used. NACI recommends that LAIV may be given to children with stable, non-severe asthma and children with cystic fibrosis who are not treated with immunosuppressive drugs, such as prolonged systemic corticosteroids.
Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for additional information supporting these recommendations.
# Summary of vaccine characteristics for decision making
IIV (IIV3-SD and IIV4-SD) and LAIV (LAIV4) are authorized for use in Canada for children 2-17 years of age. The comparison of the vaccine characteristics of IIV and LAIV, in Table 3 below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program.
# Efficacy and effectiveness
There was early evidence of superior efficacy of LAIV3 compared with IIV3-SD in children less than 6 years of age from RCTs, with weaker evidence of superior efficacy in older children. However, later postmarketing and surveillance studies across multiple influenza seasons found comparable protection against influenza for LAIV and IIV, with findings of reduced effectiveness against A(H1N1) in some studies.
Like IIV4-SD, LAIV4 is expected to provide additional protection against the influenza B strain not contained in IIV3-SD.
# Immunogenicity
LAIV3 has been shown to be as immunogenic as IIV3-SD, depending on age, with LAIV4 being non-inferior to LAIV3.
# Safety
Rhinitis (runny nose) and nasal congestion are more common with LAIV. Clinical studies and post-marketing studies showed a similar safety profile to IIV.
Contraindications There are vaccine contraindications specific to LAIV. LAIV is contraindicated for children with severe asthma, medically attended wheezing in the 7 days prior to vaccination, and immune compromising conditions, as well as those currently receiving aspirin or aspirincontaining therapy.
# Administration
Delivery of LAIV as a nasal spray may be preferable for children who are averse to receiving the vaccine by needle injection.
Abbreviations: IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; LAIV3: trivalent live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine.
# V.2 Adults
# Burden of disease in adults
A study focusing on estimates of deaths associated with influenza in the United States of America has established that the average annual rate of influenza-associated deaths for adults aged 65 years of age and older was 17.0 deaths per 100,000 (range: 2.4-36.7) (163) . The study also states that deaths among persons 65 years of age and older accounted for 87.9% of the overall estimated average annual influenza-associated deaths with underlying pneumonia and influenza causes.
When influenza-related deaths were estimated using underlying respiratory and circulatory causes, these estimates increased to 66.1 deaths per 100,000 (range: 8.0-121.1) and 89.4%, respectively. This study described a wide variation in the estimated number of deaths from season to season, which was closely related to the particular influenza virus types and subtypes in circulation.
Estimates presented in the study of yearly influenza-associated deaths with underlying pneumonia and influenza causes reveal a large difference between influenza type A and B with a calculated median of greater than 6,000 deaths associated with influenza type A and half of that number for influenza type B (approximately 3,360) for persons 65 years of age and older.
During the 22 seasons in which influenza A(H3N2) was the prominent strain, the average influenza-associated mortality rates were 2.7 times higher than for the nine seasons that it was not (all age groups combined), and on average, there were about 37% more annual influenzaassociated deaths, regardless of the underlying medical cause. A higher risk of hospitalization and death was also reported by Cromer et al. in adults 65 years of age and older, compared to younger adults in their assessment of the burden of influenza in England by age and clinical risk group (164) .
Canadian surveillance data show that hospitalization rates among adults 65 years of age and older were higher during the 2014-2015 season compared to the previous five influenza seasons and also compared to the 2012-2013 season when A(H3N2) also predominated; 2014-2015 was a season in which A(H3N2) circulation predominated and in which there was a vaccine mismatch with the circulating A(H3N2) strain.
Similar to the hospitalization rates, death rates among seniors were highest in the 2014-2015 season compared to the previous five seasons and compared to the previous A(H3N2) season in 2012-2013. Death rates among other age groups were similar to or lower than the previous five influenza seasons. Laboratory detections over this same time period showed that influenza seasons in which influenza subtype A(H3N2) predominated, disproportionally affected adults 65 years of age and older, while seasons with greater A(H1N1) detections resulted in a higher prevalence of positive cases in younger age groups. NACI recommends that any of the available influenza vaccines should be used.
# Adults 65 years of age and older
Four types of influenza vaccine are available for use in adults 65 years of age and older: IIV3-SD, IIV3-Adj, IIV3-HD, and IIV4-SD.
# Recommendation for individual-level decision making
NACI concludes that, given the burden of disease associated with influenza A(H3N2) and the good evidence of better efficacy compared to IIV3-SD in this age group, when available, IIV3-HD should be used over IIV3-SD.
There is insufficient evidence to make comparative recommendations on the use of IIV3-Adj or IIV4-SD over IIV3-SD or among IIV3-Adj, IIV3-HD, and IIV4-SD.
# Recommendation for public health program-level decision making
NACI recommends that any of the available influenza vaccines should be used.
IIV3-HD is expected to provide superior protection compared to IIV3-SD; however, with costeffectiveness assessments having been outside the scope of the evidence review and without data on the relative efficacy and effectiveness between IIV3-HD, IIV3-Adj, and IIV4-SD, there is insufficient evidence to make a comparative recommendation on the use of these vaccines at the programmatic level.
# Summary of vaccine characteristics for decision making
There are four types of inactivated influenza vaccines (IIV3-SD, IIV3-Adj, IIV3-HD, and IIV4-SD) authorized for use in Canada for adults 65 years of age and older. The comparison of vaccine characteristics across vaccine types, in Table 4 below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program. Due to a lack of available data directly comparing the performance of IIV3-Adj, IIV3-HD, and IIV4-SD, considerations for these vaccines in Table 4 are compared to IIV3-SD for which comparative data on efficacy, effectiveness, and/or immunogenicity with each of IIV3-Adj, IIV3-HD, and IIV4-SD are available. Higher rate of some systemic reactions than IIV3-SD; most systemic reactions were mild and transient.
Serious adverse events were rare and similar in frequency to IIV3-SD.
Pre-licensure clinical trials and postmarketing surveillance showed a similar safety profile to IIV3.
Abbreviations: IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine.
- NACI has not assessed the comparative cost-effectiveness of available influenza vaccine types for adults 65 years of age and older. The burden of influenza A(H3N2) disease is higher in adults 65 years of age and older compared to younger age groups. * Influenza vaccines are contraindicated in people who have had an anaphylactic reaction to any of the vaccine components, with the exception of egg. Please note that not all vaccines listed contain the same components.
Adults with chronic health conditions NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to adults with chronic health conditions identified in List 1, including those with immune compromising conditions.
Pregnant women NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to pregnant women.
Due to a lack of safety data at this time, LAIV should not be administered to pregnant women due to the theoretical risk to the fetus from administering a live virus vaccine. LAIV can be administered to breastfeeding women.
Health care workers NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to HCWs.
Comparative studies in healthy adults have found IIV to be similarly or more efficacious or effective compared with LAIV (140) . In addition, as a precautionary measure, LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection. Abbreviations: FFU: fluorescent focus units; HA: hemagglutinin; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine; NA: neuraminidase.
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Également disponible en français sous le titre : Une déclaration d'un comité consultatif (DCC) Comité consultatif national de l'immunisation (CCNI) Chapitre sur la grippe du Guide canadien d'immunisation et Déclaration sur la vaccination antigrippale pour la saison 2019-2020 This publication can be made available in alternative formats upon request.# PREAMBLE
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (hereafter referred to as PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, the Public Health Agency of Canada has expanded the mandate of NACI to include the consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# I. INTRODUCTION
This document, the National Advisory Committee on Immunization (NACI): Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2019-2020, updates NACI's recommendations regarding the use of seasonal influenza vaccines.
I.1 New or Updated Information for 2019-2020 New influenza vaccine product Afluria ® Tetra (Seqirus) is a split virus quadrivalent inactivated influenza vaccine that was authorized for use in Canada in adults and children 5 years of age and older on February 22, 2018. Based on a review of available pre-licensure clinical trial data, NACI has concluded that Afluria Tetra has a comparable safety and immunogenicity profile to already authorized quadrivalent inactivated influenza vaccines. Therefore, NACI recommends that Afluria Tetra may be considered among the quadrivalent inactivated influenza vaccines offered to adults and children 5 years of age and older (Discretionary NACI Recommendation). Refer to the NACI Supplemental Statement on Afluria ® Tetra for additional information supporting this recommendation.
Comparative effectiveness and immunogenicity of subunit and split virus inactivated influenza vaccines in adults 65 years of age and older Unadjuvanted subunit and split virus inactivated influenza vaccines are two commonly used types of seasonal influenza vaccines in Canada. A difference in vaccine effectiveness between these formulations would be especially important for adults 65 years of age or older, since there is evidence that older adults experience more severe illness due to influenza and that influenza vaccines are less effective in this age group, compared to younger adults. Based on a systematic review of the literature, NACI has concluded that there is insufficient evidence at this time on the comparative effectiveness and immunogenicity of unadjuvanted subunit and split virus inactivated influenza vaccines in adults 65 years of age and older to support specific recommendations on the differential use of these vaccines (Grade I Evidence). Refer to the NACI Literature Review on the Comparative Effectiveness and Immunogenicity of Subunit and Split Virus Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for additional information supporting this conclusion.
# Updated presentation of the statement
The presentation of this document has been updated from previous seasons' statements to improve readability. The content in some sections has been reduced in length, while maintaining a focus on key information required for decision making. Links to other published NACI documents containing the additional content removed from the statement have been added.
# Updated abbreviations for influenza vaccines
With the availability of many different influenza vaccines in Canada, the abbreviations used in this document have been updated to describe the defining features of the various types of influenza vaccines better. The new NACI abbreviations are as follows: Abbreviations: IIV: inactivated influenza vaccine; IIV3: trivalent inactivated influenza vaccine; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standarddose trivalent inactivated influenza vaccine; IIV4: quadrivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV: live attenuated influenza vaccine; LAIV3: trivalent live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine. * The numeric suffix denotes the number of antigens contained in the vaccine ("3" refers to the trivalent formulation and "4" refers to the quadrivalent formulation). The hyphenated suffix "-SD" is used when referring to IIV products that do not have an adjuvant, contain 15 µg hemagglutinin (HA) per strain and are administered as a 0.5 mL dose by intramuscular injection; "-Adj" refers to an IIV with an adjuvant (e.g., IIV3-Adj for Fluad ® or Fluad Pediatric ® ); and "-HD" refers to an IIV that contains higher antigen content than 15 µg HA per strain (e.g., IIV3-HD for Fluzone ® High-Dose). † 15 µg HA per strain. ‡ 7.5 µg (in 0.25 mL) or 15 µg (in 0.5 mL) HA per strain. § 60 µg HA per strain.
# Influenza vaccine category
Formulation
# I.2 Background
The World Health Organization's (WHO) recommendations on the composition of influenza virus vaccines are typically available in February of each year for the upcoming season in the Northern Hemisphere. The WHO recommends that, where available, seasonal quadrivalent influenza vaccines contain the recommended three viruses for the trivalent vaccine, as well as the influenza B virus lineage that is not included in the trivalent vaccine.
Annual recommendations on the use of influenza vaccine in Canada are developed by the NACI Influenza Working Group (IWG) for consideration by NACI. Recommendations are developed based on a review of a variety of issues, which can include: the burden of influenza illness and the target populations for vaccination; efficacy, effectiveness, immunogenicity, and safety of influenza vaccines; vaccine schedules; and other aspects of influenza immunization. Details regarding NACI's evidence-based process for developing a statement are outlined in Evidencebased Recommendations for Immunization − Methods of the National Advisory Committee on Immunization.
Health care providers in Canada should offer the seasonal influenza vaccine as soon as feasible after it becomes available in the fall, since seasonal influenza activity may start as early as November in the Northern Hemisphere. Decisions regarding the precise timing of vaccination in a given setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing, and intensity), opportune moments for vaccination, as well as programmatic considerations. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local public health agencies.
Although vaccination before the onset of the influenza season is strongly preferred, vaccine may still be administered up until the end of the season. Although its utility may be compromised if exposure to influenza has already occurred, vaccine providers should use every opportunity to give influenza vaccine to individuals at risk who have not been immunized during the current season, even after influenza activity has been documented in the community.
# II. CANADIAN IMMUNIZATION GUIDE CHAPTER ON INFLUENZA: CLINICAL INFORMATION FOR VACCINE PROVIDERS
The Canadian Immunization Guide (CIG) is written primarily for health care providers (frontline clinicians and public health practitioners) but is also used by policy makers, program planners, and the general public. The CIG has been a trusted, reader-friendly summary of the vaccine statements provided by NACI since 1979.
The information in this section constitutes the influenza chapter of the CIG and is adapted for inclusion in the NACI Statement on Seasonal Influenza Vaccine. With a new NACI Statement on Seasonal Influenza Vaccine required each year, readers will have quick access to the information that they require within one document, whether it is the relevant influenza vaccine information written primarily for frontline vaccine providers as is found in this section, or the more detailed technical information that is found in the rest of this statement, commencing in Section III.
# II.1 Key Information
The following highlights key information for vaccine providers. Please refer to the remainder of this statement for additional details.
# What
• Influenza is a respiratory infection caused primarily by influenza A and B viruses. In Canada, influenza generally occurs each year in the late fall and winter months. Influenza occurs globally with an annual attack rate estimated at 5-10% in adults and 20-30% in children (1) .
• Symptoms of influenza typically include: sudden onset of fever, cough, and muscle aches. Other common symptoms include: headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week or 10 days, but some are at greater risk of more severe complications, such as pneumonia. People with chronic diseases may have worsening of their underlying disease.
• Both inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV) are authorized for use in Canada; some protect against 3 strains of influenza (i.e., trivalent formulation, IIV3) and some protect against 4 strains of influenza (i.e., quadrivalent formulation, IIV4 or LAIV4).
• Influenza vaccine is safe and well-tolerated. Influenza vaccine cannot cause influenza illness because inactivated influenza vaccines do not contain live virus and live attenuated influenza vaccines contain weakened viruses.
# Who
NACI makes the following recommendations for individual-level and public health program-level decision making.
# Recommendation for individual-level decision making
(i.e., individuals wishing to protect themselves from influenza or vaccine providers wishing to advise individual patients about preventing influenza)
• NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see List 1). These groups include:
-people at high risk of influenza-related complications or hospitalization; -people capable of transmitting influenza to those at high risk; -people who provide essential community services; and -people in direct contact with poultry infected with avian influenza during culling operations.
Influenza vaccine is less immunogenic in infants less than 6 months of age than in older children and adults and does not confer sufficient protection to make it useful before 6 months of age (2) . Currently available influenza vaccines are not authorized for use for infants less than 6 months of age. For these reasons, NACI recommends that influenza vaccine should not be offered to infants less than 6 months of age, noting that influenza vaccine should be offered to their household contacts and care providers (see List 1).
# Recommendation for public health program-level decision-making
(i.e., provinces/territories making decisions for publicly funded immunization programs)
The national goal of the annual influenza immunization programs in Canada is to prevent serious illness caused by influenza and its complications, including death. Programmatic decisions to provide influenza vaccination to target populations as part of publicly funded provincial and territorial programs depend on many factors, such as cost-effectiveness evaluation and other programmatic and operational factors.
• NACI recommends that influenza vaccine should be offered as a priority to the groups for whom influenza vaccination is particularly recommended (see List 1).
# List 1: Groups for whom influenza vaccination is particularly recommended
People at high risk of influenza-related complications or hospitalization
# People capable of transmitting influenza to those at high risk
• Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; • Household contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated: -household contacts of individuals at high risk; -household contacts of infants less than 6 months of age, as these infants are at high risk but cannot receive influenza vaccine; -members of a household expecting a newborn during the influenza season; • Those providing regular child care to children 6-59 months of age, whether in or out of the home; and • Those who provide services within closed or relatively closed settings to people at high risk (e.g., crew on a ship).
# Others
• People who provide essential community services; and
• People who are in direct contact with poultry infected with avian influenza during culling operations. 11
# How
Benefits and risks of influenza vaccination, as well as the risks of not being immunized, should be discussed prior to vaccination.
# Choice of influenza vaccine
A variety of influenza vaccines are available for use in Canada, some of which are authorized for use only in specific age groups. Therefore, the choice of influenza vaccine has become more complex. Refer to Section II.5 below for recommendations on choice of influenza vaccine by age group.
# Dose and route of administration
The dose and route of administration varies by product (see Section II.6 below for details):
• MF59-adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj; Fluad Pediatric ® ) for children 6-23 months of age is 0.25 mL by intramuscular (IM) injection;
• All other IIVs for all age groups is 0.5 mL by IM injection; and
• LAIV (FluMist ® Quadrivalent) for people 2-59 years of age is 0.2 mL given intranasally (0.1 mL in each nostril).
# Schedule
NACI recommends that:
• Children 9 years of age and older and adults should receive 1 dose of influenza vaccine each year; and
• Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.
# Contraindications
For all influenza vaccines (IIV and LAIV), NACI recommends that influenza vaccination should not be given to:
• People who have had an anaphylactic reaction to a previous dose of influenza vaccine;
• People who have had an anaphylactic reaction to any of the vaccine components, with the exception of egg (refer to Section II.7 below for more information); -If an individual is found to have an allergy to a component in one influenza vaccine, consideration may be given to offering another influenza vaccine if there is a formulation not containing the implicated component, in consultation with an allergy expert. Individuals who have an allergy to substances that are not components of the influenza vaccine are not at increased risk of allergy to influenza vaccine. -Egg allergy is not a contraindication for influenza vaccination as there is a low risk of adverse events associated with the trace amounts of ovalbumin allowed in influenza vaccines manufactured using eggs. Egg-allergic individuals may be vaccinated against influenza using any age-appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg, and in any setting where vaccines are routinely administered. -As with any vaccine product, vaccine providers should be prepared for and have the necessary equipment to respond to a vaccine emergency at all times.
• People who have developed Guillain-Barré Syndrome (GBS) within 6 weeks of a previous influenza vaccination (refer to Section II.7 below for more information).
-The potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
For LAIV, in addition to the above-mentioned contraindications, NACI also recommends that LAIV should not be given to:
• People with immune compromising conditions, due to underlying disease, therapy, or both, as the vaccine contains live attenuated virus;
• People with severe asthma (defined as currently on oral or high-dose inhaled glucocorticosteroids or active wheezing) or medically attended wheezing in the 7 days prior to the proposed date of vaccination; -LAIV is not contraindicated for people with a history of stable asthma or recurrent wheeze.
• Children less than 24 months of age, due to increased risk of wheezing.
• Children 2-17 years of age currently receiving aspirin or aspirin-containing therapy, because of the association of Reye's syndrome with aspirin and wild-type influenza infection; -Aspirin-containing products in children less than 18 years of age should be delayed for 4 weeks after receipt of LAIV.
• Pregnant women, because it is a live attenuated vaccine and there is a lack of safety data at this time; -LAIV is not contraindicated in breastfeeding mothers.
Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 of the CIG for a list of all vaccines authorized for use in Canada and their contents and to Vaccine Safety in Part 2 of the CIG for information regarding the management of adverse events, including anaphylaxis.
# Precautions
NACI recommends that:
• Influenza vaccination should usually be postponed in people with serious acute illnesses until their symptoms have abated; -Vaccination should not be delayed because of minor acute illness, with or without fever.
• If significant nasal congestion is present that might impede delivery of LAIV to the nasopharyngeal mucosa, IIV can be administered or LAIV can be deferred until resolution of the congestion;
• LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection; and
• LAIV should not be administered until 48 hours after antiviral agents active against influenza (e.g., oseltamivir, zanamivir) are stopped, and those antiviral agents, unless medically indicated, should not be administered until 2 weeks after receipt of LAIV so that the antiviral agents do not kill the replicating vaccine virus.
-If antiviral agents are administered within this time frame (i.e., from 48 hours before to 2 weeks after LAIV is given), revaccination should take place at least 48 hours after the antivirals are stopped, or IIV could be given at any time.
Refer to Section II.8 below for additional information on influenza vaccine-related precautions.
# Simultaneous administration with other vaccines
NACI recommends that:
• All seasonal influenza vaccines, including LAIV, may be considered for administration at the same time as, or at any time before or after, administration of other live attenuated or inactivated vaccines (see Section II.6 below for details); and
• Different injection sites and separate needles and syringes should be used for concomitant parenteral injections.
# Why
• Vaccination is the most effective way to prevent influenza and its complications.
• Annual vaccination is required because the specific strains in the vaccine are reviewed each year by WHO and often changed to provide a better match against the viruses expected to circulate, and because the body's immune response to influenza vaccination is transient and unlikely to persist beyond a year.
# II.2 Epidemiology Disease description
Influenza is a respiratory illness caused by the influenza A and B viruses and can cause mild to severe illness, which can result in hospitalization or death. Certain populations, such as young children, older adults, and those with chronic health conditions, may be at higher risk for serious influenza complications such as viral pneumonia, secondary bacterial pneumonia, and worsening of underlying medical conditions.
# Infectious agent
There Over time, antigenic variation (antigenic drift) of strains occurs within an influenza A subtype or a B lineage. The ever-present possibility of antigenic drift, which may occur in one or more influenza virus strains, requires seasonal influenza vaccines to be reformulated annually, with one or more vaccine strains changing in most seasons.
# Transmission
Influenza is primarily transmitted by droplets spread through coughing or sneezing and through direct or indirect contact with respiratory secretions. The incubation period of seasonal influenza is usually 2 days but can range from 1-4 days. Adults may be able to spread influenza to others from 1 day before symptom onset to approximately 5 days after symptoms start. Children and people with weakened immune systems may be infectious longer.
# Risk factors
The people at greatest risk of influenza-related complications are adults and children with chronic health conditions (see List 1), residents of nursing homes and other chronic care facilities, adults 65 years of age and older, children 6-59 months of age, pregnant women, and Indigenous peoples.
# Seasonal and temporal patterns
Influenza activity in Canada is usually low in the late spring and summer, begins to increase over the fall, and peaks in the winter months. Depending on the year, the peak may occur as early as fall or as late as spring.
# Spectrum of clinical illness
Symptoms typically include the sudden onset of fever, cough, and muscle aches. Other common symptoms include headache, chills, loss of appetite, fatigue, and sore throat. Nausea, vomiting, and diarrhea may also occur, especially in children. Most people will recover within a week or 10 days. However, adults and children with chronic health conditions, adults 65 years of age and older, and children 6-59 months of age are at greater risk of more severe complications or worsening of their underlying condition.
# Disease incidence
# Global
Worldwide, annual epidemics result in approximately one billion cases of influenza, three to five million cases of severe illness, and 290,000 to 650,000 deaths. For current international influenza activity information, refer to WHO's FluNet website.
# National
Together, influenza and pneumonia are ranked among the top 10 leading causes of death in Canada (3) . FluWatch is Canada's national influenza surveillance system that collects data and information from various sources to provide a national picture of influenza activity. Since the 2010-2011 season, an average of 30,000 laboratory-confirmed cases of influenza are reported to FluWatch each year. Although the burden of influenza can vary from year to year, it is estimated that there are an average of 12,200 hospitalizations related to influenza and approximately 3,500 deaths attributable to influenza annually (4,5) . Current influenza activity information can be found on the FluWatch website.
It should be noted that the incidence of influenza is often underreported since the illness may be confused with other viral illnesses and many people with influenza-like illness (ILI) do not seek medical care or have viral diagnostic testing done.
# II.3 Vaccine Products Available for Use in Canada
This section describes the influenza vaccine products that are available for use in Canada for the 2019-2020 season. All influenza vaccines available in Canada have been authorized by Health Canada. However, not all products authorized for use are necessarily available in the marketplace. The vaccine manufacturers determine whether they will make any or all of their products available in a given market. Provincial and territorial health authorities then determine which of the available products will be used in their respective publicly funded influenza immunization programs and for which population groups.
The antigenic characteristics of circulating influenza virus strains provide the basis for selecting the strains included in each year's vaccine. Vaccine selection by the WHO generally occurs more than 6 months prior to the start of the influenza season to allow time for the vaccine manufacturers to produce the required quantity of vaccine. All manufacturers that distribute influenza vaccine products in Canada confirm to Health Canada that the vaccines to be marketed in Canada for the upcoming influenza season contain the WHO-recommended antigenic strains for the Northern Hemisphere. Vaccine producers may use antigenically equivalent strains because of their growth properties.
There are two categories of influenza vaccine authorized for use in Canada: inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV). Trivalent (3 strain) vaccines contain one A(H1N1) strain, one A(H3N2) strain, and one influenza B strain from one of the two lineages. Quadrivalent (4 strain) vaccines contain the strains in the trivalent vaccine plus an influenza B strain from the other lineage. All influenza vaccines currently authorized for use in Canada are made from influenza viruses grown in eggs.
A summary of the characteristics of influenza vaccines available in Canada can be found in Appendix A. For complete prescribing information, readers should consult the product leaflet or information contained within the product monographs available through Health Canada's Drug Product Database.
# Standard-dose inactivated influenza vaccine (IIV-SD)
The standard-dose inactivated influenza vaccines (IIV-SDs) currently authorized for use in Canada are a mix of split virus and subunit vaccines. In split virus vaccines, the virus has been disrupted by a detergent. In subunit vaccines, HA and NA have been further purified by removal of other viral components. These vaccines are unadjuvanted, contain 15 µg HA per strain, and are administered as a 0.5 mL dose by IM injection. Refer to Basic Immunology and Vaccinology in Part 1 of the CIG for more information about inactivated vaccines.
Both trivalent (IIV3-SD; Agriflu ® , Fluviral ® , and Influvac ® ) and quadrivalent (IIV4-SD; Afluria ® Tetra, Flulaval ® Tetra, and Fluzone ® Quadrivalent) products are available.
# Adjuvanted inactivated influenza vaccine (IIV-Adj)
The adjuvanted inactivated influenza vaccine (IIV-Adj) currently authorized for use in Canada is a subunit IIV that contains the adjuvant MF59, which is an oil-in-water emulsion composed of squalene as the oil phase that is stabilized with the surfactants polysorbate 80 and sorbitan triolate in citrate buffer. IIV-Adj contains 7.5 µg HA per strain administered as a 0.25 mL dose by IM injection for children 6-23 months of age or 15 µg HA per strain administered as a 0.5 mL dose by IM injection for adults 65 years of age and older. Other IIVs do not contain an adjuvant.
Trivalent products (IIV3-Adj) for children 6-23 months of age (Fluad Pediatric ® ) and adults 65 years of age and older (Fluad ® ) are available.
# High-dose inactivated influenza vaccine (IIV-HD)
The high-dose inactivated influenza vaccine (IIV-HD) currently authorized for use in Canada is an unadjuvanted, split virus IIV that contains 60 µg HA per strain and is administered as a 0.5 mL dose by IM injection.
A trivalent product (IIV3-HD; Fluzone ® High-Dose) for adults 65 years of age and older is available.
# Live attenuated influenza vaccine (LAIV)
LAIV is given as an intranasal spray. The influenza viruses contained in LAIV are attenuated so that they do not cause influenza and are cold-adapted and temperature sensitive, so that they replicate in the nasal mucosa rather than the lower respiratory tract. LAIV contains standardized quantities of fluorescent focus units (FFU) of live attenuated reassortants and is given as a 0.2 mL dose (0.1 mL in each nostril).
A quadrivalent product (LAIV4; FluMist ® Quadrivalent) is authorized for use in Canada for children 2-17 years of age and adults 18-59 years of age. The trivalent formulation (LAIV3) is no longer available in Canada.
# II.4 Efficacy, Effectiveness, and Immunogenicity Efficacy and effectiveness
Influenza vaccine has been shown in randomized controlled clinical trials to be efficacious in providing protection against influenza infection and illness. However, the effectiveness of the vaccine-that is, how it performs in settings that are more reflective of usual health care practicecan vary from season to season and by influenza vaccine strain type and subtype.
Influenza vaccine effectiveness (VE) depends on how well the vaccine strains match with circulating influenza viruses, the type and subtype, as well as the health and age of the individual receiving the vaccine. Even when there is a less-than-ideal match or lower effectiveness against one strain, the possibility of lower VE should not preclude vaccination, particularly for people at high risk of influenza-related complications and hospitalization, since vaccinated individuals are still more likely to be protected compared to those who are unvaccinated.
# Immunogenicity
Antibody response after vaccination depends on several factors, including the age of the recipient, prior and subsequent exposure to antigens, and the presence of immune compromising conditions. Protective levels of humoral antibodies, which correlate with protection against influenza infection, are generally achieved by 2 weeks after vaccination; however, there may be some protection afforded before that time.
# II.5 Choice of Seasonal Influenza Vaccine
The decision to include specific influenza vaccines as part of publicly funded provincial and territorial programs depends on several factors, such as cost-effectiveness evaluation and other programmatic and operational factors, such as implementation strategies. Not all products will be made available in all jurisdictions and availability of some products may be limited; therefore, officials in individual provinces and territories should be consulted regarding the products available in individual jurisdictions.
With the availability of influenza vaccines that are designed to enhance immunogenicity in specific age groups or given through a different route of administration, the choice of product has become more complex.
# Choice of influenza vaccine by age group
Recommendations for individual-level decision making
• NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older who does not have contraindications to the vaccine. Table 1 provides age group-specific recommendations for the age-appropriate influenza vaccine types available for use in Canada.
# Recommendations for public health program-level decision making
• NACI recommends that any of the age-appropriate influenza vaccine types available for use may be considered for people without contraindications to the vaccine. Table 1 provides age group-specific recommendations for the age-appropriate influenza vaccine types available in Canada.
• IIV3-SD • IIV3-Adj • IIV4-SD
• Quadrivalent influenza vaccine should be used, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
• If a quadrivalent vaccine is not available, any of the available trivalent vaccines should be used.
# 2-17 years *
• IIV3-SD • IIV4-SD • LAIV4
• Either IIV4-SD or LAIV4 should be used in children without contraindications, including those with non-immune compromising chronic health conditions, given the burden of influenza B disease in this age group and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine.
• If IIV4-SD or LAIV4 is not available, IIV3-SD should be used.
• IIV4-SD should be used for children for whom LAIV is contraindicated, such as in children with: -severe asthma; -medically attended wheezing in the 7 days prior to vaccination; -current receipt of aspirin or aspirin-containing therapy; and -immune compromising conditions.
# Recipient by age group
# II.6 Vaccine Administration
Dose, route of administration, and schedule
With the variety of influenza vaccines available for use in Canada, it is important for vaccine providers to note the specific differences in age indication, route of administration, dosage and schedule for the products that they will be using (see Table 2). Key relevant details and differences between vaccine products are also highlighted in Appendix A.
For influenza vaccines given by the IM route, the deltoid muscle is the recommended site in adults and children 12 months of age and older, and the anterolateral thigh is the recommended site in children 6-12 months of age. For more information on vaccine administration, please refer to Vaccine Administration Practices in Part 1 of the CIG. ¶ Evidence suggests moderate improvement in antibody response in infants, without an increase in reactogenicity, with the use of full vaccine doses (0.5 mL) for unadjuvanted inactivated influenza vaccines (6,7) . This moderate improvement in antibody response without an increase in reactogenicity is the basis for the full dose recommendation for unadjuvanted inactivated vaccine for all ages. For more information, refer to Statement on Seasonal Influenza Vaccine for 2011-2012. ** Children 6 months to less than 9 years of age receiving seasonal influenza vaccine for the first time in their life should be given 2 doses of influenza vaccine, with a minimum interval of 4 weeks between doses. Children 6 months to less than 9 years of age who have been properly vaccinated with one or more doses of seasonal influenza vaccine in the past should receive 1 dose of influenza vaccine per season thereafter.
# Booster doses and revaccination
Booster doses are not required within the same influenza season. However, children 6 months to less than 9 years of age who have not previously received the seasonal influenza vaccine require 2 doses of influenza vaccine, with a minimum of 4 weeks between doses (see Table 2).
# Serological testing
Serologic testing is not necessary before or after receiving seasonal influenza vaccine.
# Storage requirements
Influenza vaccine should be stored at +2°C to +8°C and should not be frozen. Refer to the individual product monographs for further details. Refer to Storage and Handling of Immunizing Agents in Part 1 of the CIG for additional information.
# Simultaneous administration with other vaccines
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Studies have been done showing no interference when administering LAIV3 concomitantly with: measles, mumps, rubella (MMR); measles, mumps, rubella, varicella (MMRV); or oral polio live vaccines (8)(9)(10) . No studies have been done to assess the possibility of interference between LAIV and other live vaccines, or on LAIV given before or after other live vaccines. Additional information regarding simultaneous administration with other vaccines can be found in Section IV.4 of this statement.
Given the lack of data for immune interference, and based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. NACI recognizes that some vaccine providers may choose to give LAIV and other live vaccines simultaneously or separated by at least 4 weeks if a delay is chosen. Alternatively, an IIV may be given. Note that the timing rules related to two parenteral live vaccines (e.g., MMR and varicella vaccines) still apply. For more information regarding vaccination administration timing rules, please refer to Timing of Vaccine Administration in Part 1 of the CIG.
When more than one injection is given at a single clinic visit, it is preferable to administer them in different limbs. If it is not possible to do so, injections given in one limb should be separated by a distance of at least 2.5 cm (1 inch). A separate needle and syringe should be used for each injection.
The target groups for influenza and pneumococcal polysaccharide vaccines overlap considerably. Vaccine providers should take the opportunity to vaccinate eligible people against pneumococcal disease when influenza vaccine is given.
# II.7 Vaccine Safety and Adverse Events
Data from post-marketing surveillance of influenza vaccines in Canada (Canadian Adverse Events Following Immunization Surveillance System [CAEFISS]) have shown seasonal influenza vaccines to have a safe and stable profile for adverse events following immunization (AEFIs) with no unexpected events.
All influenza vaccines currently authorized for use in Canada are considered safe for use in people with latex allergies. The multi-dose vial formulations of inactivated influenza vaccine that are authorized for use in Canada contain minute quantities of thimerosal, which is used as a preservative (11,12) to keep the product sterile. Large cohort studies of administrative health databases have found no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders (13) . All single dose formulations of IIV and LAIV are thimerosal-free. Refer to Vaccine Safety in Part 2 of the CIG for additional information.
# Common adverse events
With IM administered influenza vaccines, injection site reactions are common but are generally classified as mild and transient. IIV3-Adj tends to produce more extensive injection site reactions than unadjuvanted IIV3, but these reactions are also generally mild and resolve spontaneously within a few days. IIV3-HD tends to induce higher rates of systemic reactions post-injection compared to IIV3-SD, but most of these reactions are mild and short-lived. The most common adverse events experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. Refer to the relevant subsections of Section IV for additional information.
Less common and serious or severe adverse events Serious adverse events are rare following influenza vaccination, and in most cases, data are insufficient to determine a causal association. Allergic responses to influenza vaccine are a rare consequence of hypersensitivity to some vaccine components. Refer to Section II.8 below for additional information.
Other reported adverse events and conditions
# Guillain-Barré syndrome
Studies suggest that the absolute risk of Guillain-Barré syndrome (GBS) in the period following seasonal and A(H1N1)pdm09 influenza vaccination is about one excess case per million vaccinations, and that the risk of GBS associated with influenza illness is larger (about 17 cases per million influenza-coded health care encounters, which are a proxy for influenza illness) than that associated with influenza vaccination.
Although the evidence considering influenza vaccination and GBS is inadequate to accept or reject a causal relation between GBS in adults and seasonal influenza vaccination, avoiding subsequent influenza vaccination of individuals known to have had GBS without other known etiology within 6 weeks of a previous influenza vaccination appears prudent at this time. However, the potential risk of GBS recurrence associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and the benefits of influenza vaccination.
# Oculorespiratory syndrome
Oculorespiratory syndrome (ORS), which is defined as the presence of bilateral red eyes and one or more associated symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, or sore throat) that starts within 24 hours of vaccination, with or without facial edema, was found during the 2000-2001 influenza season; few cases have been reported since then. ORS is not considered to be an allergic response. People who have a recurrence of ORS upon revaccination do not necessarily experience further episodes with future vaccinations.
Individuals who have experienced ORS without lower respiratory tract symptoms may be safely revaccinated with influenza vaccine. Individuals who experienced ORS with lower respiratory tract symptoms should have an expert review. Health care providers who are unsure whether an individual previously experienced ORS versus an immunoglobulin E (IgE) mediated hypersensitivity immune response should seek advice. Data on clinically significant adverse events do not support the preference of one vaccine product over another when revaccinating those who have previously experienced ORS.
# Allergic reactions to previous vaccine doses
Expert review of the benefits and risks of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent significant allergic reaction to the vaccine, or any other symptoms that could indicate a significant allergic reaction (e.g., throat constriction, difficulty swallowing) that raise concern regarding the safety of revaccination. This advice may be obtained from experts in infectious disease, allergy, and immunology, or public health.
In view of the considerable morbidity and mortality associated with influenza, a diagnosis of influenza vaccine allergy should not be made without confirmation, which may involve consultation with an allergy or immunology expert.
# Drug interactions
Although influenza vaccine can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine. Statins have effects on the immune system in addition to their therapeutic cholesterollowering actions. Two published studies have found that adults who are regular statin users (at least 65 years of age in one study and 45 years and older in the other) had an apparent decreased response to influenza vaccination as measured by reduced geometric mean titres (GMT) (14) or reduced VE against medically attended acute respiratory illness (15) . Statins are widely used in the same adult populations who are also at-risk for influenza-related complications and hospitalizations. Therefore, if these preliminary findings are confirmed in future studies, concomitant statin use in adult populations could have implications for influenza VE and how this use is assessed in the measurement of VE. NACI will continue to monitor the literature related to this issue.
# Guidance on reporting adverse events following immunization (AEFI)
To ensure the ongoing safety of influenza vaccines in Canada, reporting of AEFIs by vaccine providers and other clinicians is critical, and in some jurisdictions, reporting is mandatory under the law.
Vaccine providers are asked to report AEFIs through local public health officials and to check for specific AEFI reporting requirements in their province or territory. An AEFI is any untoward medical occurrence that follows vaccination and that does not necessarily have a causal relationship with the usage of a vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom, or disease. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported. An unexpected AEFI is an event that is not listed in the approved product monograph but may be due to the vaccination, or a change in the nature, severity, specificity, or outcome of a known AEFI.
For influenza vaccines, the following AEFIs are of particular interest:
• ORS; and
• GBS within 6 weeks following vaccination.
Refer to Reporting Adverse Events Following Immunization (AEFI) in Canada for additional information about AEFI reporting and to Vaccine Safety in Part 2 of the CIG for general vaccine safety information.
# II.8 Travellers
Influenza occurs year-round in the tropics. In temperate northern and southern countries, influenza activity generally peaks during the winter season (November to March in the Northern Hemisphere and April to October in the Southern Hemisphere).
• NACI recommends that influenza vaccine should be offered annually to anyone 6 months of age and older, including travellers, who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended (see List 1).
Vaccines prepared specifically for use in the Southern Hemisphere are not available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. A decision for or against revaccination (i.e., boosting) of travellers to the Southern Hemisphere between April and October, if they had already been vaccinated in the preceding fall or winter with the Northern Hemisphere's vaccine, depends on individual risk assessment, the similarity or difference between the Northern and Southern Hemisphere vaccines, the similarity or difference between the Northern Hemisphere vaccine strains and currently circulating strains in the Southern Hemisphere, and the availability of a reliable and safe vaccine at the traveller's destination.
Refer to Immunization of Travellers in Part 3 of the CIG for additional general information.
This concludes the summary of relevant influenza vaccine information typically found in the CIG. Additional technical information related to seasonal influenza vaccine can be found in the remainder of this statement.
# III. PARTICULARLY RECOMMENDED VACCINE RECIPIENTS: ADDITIONAL INFORMATION
The groups for whom influenza vaccination is particularly recommended are presented in List 1 of Section II. Additional information regarding these particularly recommended recipients is provided below.
# III.1 People at High Risk of Influenza-Related Complications or Hospitalization
All pregnant women NACI recommends the inclusion of all pregnant women, at any stage of pregnancy, among the particularly recommended recipients of IIV, due to the risk of influenza-associated morbidity in pregnant women (16)(17)(18)(19)(20) , evidence of adverse neonatal outcomes associated with maternal respiratory hospitalization or influenza during pregnancy (21)(22)(23)(24) , evidence that vaccination of pregnant women protects their newborns from influenza and influenza-related hospitalization (25)(26)(27)(28) , and evidence that infants born during influenza season to vaccinated women are less likely to be premature, small for gestational age, and of low birth weight (29)(30)(31)(32) .
The safety of IIV during pregnancy has been reviewed (33) . Active studies of influenza vaccination during pregnancy have not shown evidence of harm to the mother or fetus associated with influenza immunization (34) . Although the cumulative sample size of active studies of influenza vaccination in pregnant women is relatively small, particularly in the first trimester, passive surveillance has not raised any safety concerns despite widespread use of IIV during pregnancy over several decades (18,19,33,35) . Surveillance following the use of both adjuvanted and unadjuvanted 2009 pandemic influenza A(H1N1) vaccines in more than 100,000 pregnant women in Canada and more than 488,000 pregnant women in Europe has not revealed any safety concerns (36,37) .
# Refer to the Statement on Seasonal Influenza Vaccine for 2011-2012 and the Statement on Seasonal Influenza Vaccine for 2012-2013 for further details on influenza vaccination during pregnancy.
# Adults and children with chronic health conditions
A number of chronic health conditions, as noted in List 1, are associated with increased risk of influenza-related complications, and influenza can lead to exacerbation of the chronic disease. Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and human immunodeficiency virus (HIV)-infected people. Vaccine effectiveness may be lower in people with immune compromising conditions than in healthy adults.
# Neurologic or neurodevelopment conditions
Neurologic or neurodevelopment conditions (NNCs) include neuromuscular, neurovascular, neurodegenerative, neurodevelopment conditions, and seizure disorders (and, for children, include febrile seizures and isolated developmental delay), but exclude migraines and psychiatric conditions without neurological conditions. Based on reviews of evidence and expert opinion, NACI includes adults and children with NNCs among the groups for whom influenza vaccination is particularly recommended. Refer to the NACI Statement on Seasonal Influenza Vaccine for 2018-2019 for a summary of the rationale supporting this decision and the Literature Review on Individuals with Neurologic or Neurodevelopment Conditions and Risk of Serious Influenza-Related Complications for additional details of the evidence reviews.
# People of any age who are residents of nursing homes and other chronic care facilities
Residents of nursing homes and other chronic care facilities often have one or more chronic health conditions and live in institutional environments that may facilitate the spread of influenza.
# Adults 65 years of age and older
Hospitalization attributable to influenza in this age group is estimated at 125-228 per 100,000 healthy people (38) , and influenza-attributed mortality rates increase with increased age (39) .
# All children 6-59 months of age
On the basis of existing data, NACI recommends the inclusion of all children 6-59 months of age among the particularly recommended recipients of influenza vaccine.
# Indigenous peoples
Based on the body of evidence indicating a higher rate of influenza-associated hospitalization and death among Indigenous peoples, NACI recommends the inclusion of this population among the particularly recommended recipients of influenza vaccine.
It has been proposed that the increased risk of severe influenza outcomes in the Indigenous populations is a consequence of many factors, including high prevalence of chronic health conditions (e.g., diabetes, chronic lung disease, end-stage kidney disease, cardiovascular disease) (40) , obesity, delayed access to health care, and increased susceptibility to disease because of poor housing and overcrowding (41)(42)(43) . Refer to the Statement on Seasonal Influenza Vaccine for 2011-2012 for further details.
# III.2 People Capable of Transmitting Influenza to Those at High Risk of Influenza-Related Complications or Hospitalization
People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk individual has been immunized. Immunization of care providers decreases their own risk of illness (44,45) , as well as the risk of death and other serious outcomes among the individuals for whom they provide care (46)(47)(48)(49) . Immunization of care providers and residents of nursing homes is associated with decreased risk of ILI outbreaks (50) .
People who are more likely to transmit influenza to those at high risk of influenza-related complications or hospitalization include:
• Health care and other care providers in facilities and community settings who, through their activities, are capable of transmitting influenza to those at high risk; and • Contacts, both adults and children, of individuals at high risk, whether or not the individual at high risk has been vaccinated.
# Health care and other providers in facilities and community settings
This group includes HCWs, regular visitors, emergency response workers, and others who have contact with residents of continuing care or long-term care facilities or residences, those who provide home care for people at high risk, and students of related health care services. For the purposes of this statement, HCWs include any person, paid or unpaid, who provides services, works, volunteers, or trains in a health care setting.
Influenza immunization provides benefits to HCWs and to the patients for whom they care. NACI considers the receipt of influenza vaccination to be an essential component of the standard of care for all HCWs for the protection of their patients.
Transmission of influenza between infected HCWs and their vulnerable patients results in significant morbidity and mortality. For example, randomized controlled trials (RCTs) conducted in geriatric long-term care settings have demonstrated that vaccination of HCWs is associated with substantial decreases in morbidity (47)(48)(49) and all-cause mortality (46)(47)(48)(49) in the residents. Therefore, HCWs should consider annual influenza vaccination included in their responsibility to provide the highest standard of care. In the absence of contraindications, refusal of HCWs to be vaccinated against influenza implies failure in their duty of care to patients.
As noted in PHAC's Guidance: Infection Prevention and Control Measures for Healthcare Workers in Acute Care and Long-term Care Settings for seasonal influenza, all health care organizations should have a written plan for managing an influenza outbreak in their facilities. Inherent in such plans should be policies and programs to optimize HCW's influenza immunization (51) . As part of outbreak management, the above-mentioned PHAC guidance suggests consideration of chemoprophylaxis for all unvaccinated HCWs, unless contraindications exist. Refer to the Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada) website for guidelines regarding the use of antiviral medications for prophylaxis.
# Contacts of individuals at high risk of influenza complications
Vaccination is recommended for contacts, both adults and children, of individuals at high risk of influenza-related complications or hospitalization (see List 1), whether or not the individual at high risk has been vaccinated. These contacts include: household contacts and care providers of individuals at high risk; household contacts and care providers of infants less than 6 months of age, as these infants are at high risk of complications from influenza but cannot receive influenza vaccine; members of a household expecting a newborn during the influenza season; household contacts and care providers (whether in or out of the home) of children 6-59 months of age, and providers of services within closed or relatively closed settings to people at high risk (e.g., crew on a ship).
# III.3 Others People who provide essential community services
Vaccination for these individuals should be encouraged to minimize the disruption of services and routine activities during annual influenza epidemics. People who provide essential community services, including healthy working adults, should consider annual influenza vaccination, as this intervention has been shown to decrease work absenteeism due to respiratory and related illnesses (44,45,(52)(53)(54) .
People in direct contact with poultry infected with avian influenza during culling operations
# Poultry workers
Although seasonal influenza vaccination will not prevent avian influenza infection, some countries (55) and provinces have recommended influenza vaccination on a yearly basis for poultry workers, based on the rationale that preventing infection with human influenza strains may reduce the theoretical potential for human-avian reassortment of genes, should such workers become co-infected with human and avian influenza viruses (56) .
Therefore, NACI recommends seasonal influenza vaccination for people in direct contact with poultry infected with avian influenza during culling operations, as these individuals may be at increased risk of avian influenza infection because of exposure during the culling operation (57)(58)(59)(60) . Refer to the Statement on Seasonal Influenza Vaccine for 2013-2014 for further information informing this recommendation. Direct contact may be defined as sufficient contact with infected poultry to allow transmission of an avian virus to the exposed person. The relevant individuals include those performing the cull, as well as others who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. It is recommended that biosecurity measures such as personal protective equipment and antivirals be used. Refer to Human Health Issues Related to Avian Influenza in Canada for PHAC recommendations on the management of domestic avian influenza outbreaks.
# Swine workers
NACI has concluded that there is insufficient evidence at this time to recommend routine influenza vaccination specifically for swine workers; however, NACI recommends that influenza vaccination should be offered to anyone 6 months of age and older who do not have contraindications to the vaccine.
Refer to the Statement on Seasonal Influenza Vaccine for 2013-2014 for further information informing this recommendation.
# IV. VACCINE PREPARATIONS AVAILABLE FOR USE IN CANADA: ADDITIONAL INFORMATION
The following sections describe information on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccine by type in two categories: IIV and LAIV. Refer to Appendix A for a summary of the characteristics of specific influenza vaccine products available in Canada for the 2019-2020 season.
NACI acknowledges that evidence related to influenza vaccine performance, particularly with respect to vaccine efficacy and effectiveness, is constantly evolving with advances in research methodology and accumulation of data over many influenza seasons. Therefore, the evidence summarized in this section may not include the latest studies. However, in accordance with usual practice, NACI continues to monitor closely the emerging evidence on the efficacy and effectiveness, immunogenicity, and safety of influenza vaccines to update and to make recommendations when warranted.
# IV.1 Inactivated Influenza vaccine (IIV)
IIVs contain standardized amounts of the HA protein from representative seed strains of the two human influenza A subtypes (H3N2 and H1N1) and either one (for trivalent vaccines) or both (for quadrivalent vaccines) of the two influenza B lineages (Yamagata or Victoria). IIVs currently authorized for use in Canada are a mix of split virus and subunit vaccines, both consisting of disrupted virus particles. Split virus vaccines contain whole inactivated viruses split with detergent, ether, or both, while subunit vaccines are made of purified HA and NA. The amount of NA in the vaccines is not standardized. HA-based serum antibody produced to one influenza A subtype is anticipated to provide little or no protection against strains belonging to the other subtype. The potential for trivalent vaccine to stimulate antibody protection across B lineages requires further evaluation and may be dependent upon factors such as age and prior antigenic experience with the two B lineages (61)(62)(63)(64)(65)(66) .
Because of potential changes in the circulating influenza virus from year to year and waning immunity in vaccine recipients, annual influenza vaccination is recommended. Although NACI is aware of some recent studies that suggest that vaccine induced protection may be greater in individuals who have no recent vaccine history, optimal protection against influenza, season after season, is best achieved through annual influenza vaccination (67,68) . NACI will continue to monitor this issue.
# Immunological considerations related to children
Young children have a high burden of illness and their vaccine-induced immune response is not as robust as older children. However, some studies suggest moderate improvement in antibody response in young children, without an increase in reactogenicity, with the use of a full vaccine dose (0.5 mL) for IIV-SDs (6,7,69) . On the basis of this moderate improvement in antibody response without an increase in reactogenicity, NACI recommends the use of a 0.5 mL dose for all recipients of IIV-SDs, including young children, which is thought to mitigate the reduced immune response observed in the studies with the 0.25 mL dose of IIV-SDs.
# Immunological considerations related to older adults and those with immune compromising conditions
Although the initial antibody response in older adults may be lower to some influenza vaccine components when compared to those in other age groups, a literature review identified no evidence for a subsequent antibody decline that was any more rapid in older adults than in younger age groups (70) .
Influenza vaccination can induce protective antibody levels in a substantial proportion of adults and children with immune compromising conditions, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patients (71)(72)(73)(74) .
Most studies have shown that administration of a second dose of influenza vaccine in the same season to older adults or other individuals who may have an altered immune response does not result in a clinically significant antibody boost (75)(76)(77)(78) .
# Standard-dose trivalent inactivated influenza vaccine (IIV3-SD)
Vaccines currently available for use:
• Agriflu ® (Seqirus) • Fluviral ® (GlaxoSmithKline) • Influvac ® (BGP Pharma ULC, operating as Mylan EPD)
# Efficacy and effectiveness
The NACI Literature Review on Influenza Vaccination in Healthy 5-18-Year-olds found that VE of IIV3-SD against laboratory-confirmed influenza was variable but was most frequently between 65-85% (79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97) . In the NACI literature review on Influenza Vaccine Effectiveness, Immunogenicity, and Safety in Healthy Adults 19-64 Years Old, efficacy against laboratoryconfirmed influenza for IIV3-SD in healthy adults 18-64 years of age ranged widely from as low as 15% to as high as 75%, with the majority of studies estimating efficacy at 50-60%. Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for a more detailed summary of efficacy and effectiveness evidence for IIV3-SD in healthy children 5-18 years of age and healthy adults 19-64 years of age.
In older adults, VE of IIV3-SD is about half of that in healthy adults and varies depending on the outcome measures and the study population (98,99) . Systematic reviews have demonstrated that influenza vaccine decreases the incidence of pneumonia, hospital admissions, and deaths in the elderly (98) and reduces exacerbations in people with chronic obstructive pulmonary disease (100) . The NACI Literature Review on the Comparative Effectiveness and Immunogenicity of Subunit and Split Virus Inactivated Influenza Vaccines in Adults 65 Years of Age and Older found no statistically significant differences in VE of subunit IIV3-SD compared with split virus IIV3-SD in adults 65 years of age and older against infection with any influenza virus strain, or against infection with influenza A(H1N1), A(H3N2), or B virus specifically.
In observational studies, influenza vaccination has been shown to reduce the number of physician visits, hospitalizations, and deaths in adults 18-64 years of age with high-risk medical conditions (101) , hospitalizations for cardiac disease and stroke in adults 65 years of age and older (102) , and hospitalization and deaths in adults 18 years of age and older with diabetes mellitus (103) during influenza epidemics. Observational studies that use non-specific clinical outcomes or that do not take into account differences in functional status or health-related behaviours should be interpreted with caution (104)(105)(106)(107)(108) .
# Immunogenicity
Both humoral and cell-mediated responses are thought to play a role in immunity to influenza. While humoral immunity is thought to play a primary role in protection against infection, cellmediated immunity, notably cytotoxic T lymphocyte responses to internal viral components, is increasingly invoked as important in protecting against severe outcomes of influenza, particularly those associated with subtype HA variations (shift and drift) (109) . The IM administration of IIV3-SD results in the production of circulating immunoglobulin G (IgG) antibodies to the viral HA and NA proteins, as well as a more limited cytotoxic T lymphocyte response.
# Safety
Studies evaluating the safety of IIV3-SDs in healthy children have found a good safety profile with no serious adverse events of note (110) . The most common solicited local reactions are pain and redness at the injection site, while the most common solicited systemic reactions are irritability, malaise, and headache. Mild injection site reactions, primarily soreness at the vaccination site, have been found to occur in 7% or less of healthy children who are less than 3 years of age (111)(112)(113) . Post-vaccination fever may be observed in 12% or less of vaccinated children 1-5 years of age (89,113) .
For adults, IIV3-SDs have been demonstrated to have a good safety profile with acceptable reactogenicity (110) . Common local reactions at injection site include redness, swelling, pain, and induration. These reactions last 2-3 days and rarely interfere with normal activities. Common systemic reactions include headache, malaise, myalgia, fatigue, arthralgia, and fever.
# Adjuvanted trivalent inactivated influenza vaccine (IIV3-Adj)
Vaccines currently available for use:
• Fluad ® (Seqirus) • Fluad Pediatric ® (Seqirus)
# Fluad (adults 65 years of age and older) Efficacy and effectiveness
There is fair evidence that the MF59-adjuvanted Fluad (IIV3-Adj) may be effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to unvaccinated individuals. However, there is insufficient evidence that IIV3-Adj is more effective at reducing the risk of hospitalization for influenza and influenza complications in older adults compared to those who received unadjuvanted subunit IIV3-SD. There remain no efficacy or effectiveness studies that compare IIV3-Adj with IIV3-HD or IIV4-SD. Refer to the NACI Literature Review Update on the Efficacy and Effectiveness of High-Dose and MF59-Adjuvanted Trivalent Inactivated Influenza Vaccines in Adults 65 Years of Age and Older for more information on the efficacy and effectiveness of IIV3-Adj in adults 65 years of age and older.
# Immunogenicity
The mechanism of action of MF59 is not fully determined and has primarily been studied using in vitro and mouse models. From these studies, it appears that MF59 may act differently from aluminum-based adjuvants. These studies show that MF59 acts in the muscle fibres to create a local immune-stimulatory environment at the injection site (114) . MF59 allows for an increased influx of phagocytes (e.g., macrophages, monocytes) to the site of injection. The recruited phagocytes are further stimulated by MF59, thereby increasing the production of chemokines to attract more innate immune cells and inducing differentiation of monocytes into dendritic cells (115,116) . MF59 further facilitates the internalization of antigen by these dendritic cells (115,117) . The overall higher number of cells available locally increases the likelihood of interaction between an antigen presenting cell and the antigen, leading to more efficient transport of antigen to the lymph nodes, with resulting improved T cell priming (115) .
There is evidence from RCTs that IIV3-Adj elicits non-inferior immune responses compared to the unadjuvanted subunit and split virus IIV3-SDs; however, superiority of IIV3-Adj to these vaccines by pre-defined criteria has not been consistently demonstrated. Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for more information on the immunogenicity of IIV3-Adj in adults 65 years of age and older.
# Safety
IIV3-Adj produces injection site reactions (pain, erythema, and induration) significantly more frequently than IIV3-SD, but they are classified as mild and transient. Systemic reactions (myalgia, headache, fatigue, and malaise) are comparable or more frequent with IIV3-Adj compared to IIV3-SD and are rated as mild to moderate and transient. Serious adverse events were uncommon and were comparable to IIV3-SD. Refer to the Recommendations on the use of MF59-Adjuvanted Trivalent Influenza Vaccine (Fluad ® ): Supplemental Statement of Seasonal Influenza Vaccine for 2011-2012 for additional information on the safety of IIV3-Adj in adults 65 years of age and older.
# Fluad Pediatric (children 6-23 months of age) Efficacy and effectiveness
A pre-licensure efficacy trial in children 6-71 months of age found a higher relative efficacy for IIV-Adj than the unadjuvanted IIV3-SD (118) . However, the findings of this study should be interpreted with caution. The comparator unadjuvanted IIV3 used in this trial was shown, in an unrelated study, to induce a lower immune response compared to another unadjuvanted IIV3-SD. There were concerns raised by a European Medicines Agency inspection about the quality of diagnostic laboratory testing and validity of ascertainment of influenza cases. The study administered 0.25 mL doses of the comparator unadjuvanted IIV3-SD for children less than 36 months of age, which is lower than the dose of 0.5 mL of unadjuvanted IIV3-SD or IIV4-SD that is recommended for this age group in Canada. Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for more information on the efficacy and effectiveness of IIV3-Adj in children.
# Immunogenicity
In children, there is limited but consistent evidence that IIV3-Adj is more immunogenic than IIV3-SD against both influenza A and B (118)(119)(120)(121)(122)(123) . In particular, a single dose of IIV3-Adj is more immunogenic than a single dose of IIV3-SD, and has been shown in one study to produce greater GMTs than 2 doses of IIV3-SD against influenza A (123) . However, similar to IIV3-SD, IIV3-Adj generally induced a weaker hemagglutination-inhibition antibody response against B strains compared to A strains and therefore 2 doses of IIV3-Adj are still necessary to achieve a satisfactory immune response against influenza B. Almost all of the pre-licensure pediatric studies used vaccine formulations of 0.25 mL in children 6-35 months of age, both for IIV3-Adj and the comparator unadjuvanted influenza vaccine (NACI recommends 0.5 mL dosage of IIV3-SD or IIV4-SD for all age groups). There is limited immunogenicity evidence comparing IIV3-Adj at 0.25 mL dose to IIV3-SD or IIV4-SD at 0.5 mL dose in the 6-23 month age group. Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for more information on the immunogenicity of IIV3-Adj in children.
# Safety
The safety data in children are consistent with what is known about IIV3-Adj's safety profile in adults. In pediatric trials, IIV3-Adj was more reactogenic than IIV3-SD, with recipients experiencing 10-15% more solicited local and systemic reactions. However, most reactions were mild and resolved quickly. A dose-ranging study of MF59-adjuvanted and unadjuvanted IIV3 and IIV4 did not find an increased risk of adverse events associated with increased MF59 dose, antigen dose, or the addition of a second B strain; however, the reactogenicity of 15 µg formulations were slightly higher for both adjuvanted and unadjuvanted vaccines compared to the corresponding 7.5 µg formulations (121) .
There are currently no data on the effects of long-term or repeated administration of adjuvanted influenza vaccines in children. The most significant experience with an adjuvanted influenza vaccine in children was the AS03-adjuvanted A(H1N1) pandemic vaccine that has been associated with an increased risk of narcolepsy. A study comparing two AS03-adjuvanted A(H1N1) vaccine products (Pandemrix and Arepanrix) has suggested that the underlying immune mediated mechanism may not be initiated by the adjuvant, but by another component of the vaccine, specifically the A(H1N1) viral antigen (124) . However, the pandemic vaccine was a single strain adjuvanted vaccine administered only during one season, and it is unknown what effects a multi-strain adjuvanted vaccine or an adjuvanted vaccine administered for more than one season may have in young children.
Refer to the NACI Literature Review on Pediatric Fluad ® Influenza Vaccine Use in Children 6-72 Months of Age for additional information on the safety of IIV3-Adj in children.
# High-dose trivalent inactivated influenza vaccine (IIV3-HD)
Vaccine currently available for use:
• Fluzone ® High-Dose (Sanofi Pasteur)
# Efficacy and effectiveness
There is good evidence that Fluzone High-Dose (IIV3-HD) provides superior protection compared with IIV3-SD in adults 65 years of age and older. A few studies found that IIV3-HD may provide greater benefit in the very elderly (e.g., 75 years of age and older) compared to younger elderly (e.g., 65-74 years of age) (125)(126)(127) ; however, additional studies are needed to validate this finding. There remain no efficacy or effectiveness studies that compare IIV3-HD with IIV3-Adj or IIV4-SD.
# Immunogenicity
Five studies compared the rates of seroconversion for study participants receiving IIV3-HD and IIV3-SD among those 65 years of age and older (128)(129)(130)(131)(132)(133) . Rates of seroconversion were found to be about 19% higher (ranging from 8-39%) for those receiving the higher dose vaccine across all three vaccine strains. Similarly, rates of seroconversion were higher for those receiving the high-compared to standard-dose vaccines for participants 75 years of age and older and for a cohort of participants with underlying cardiopulmonary disease.
Eight studies reported higher rates of seroprotection for older adults receiving IIV3-HD compared to those vaccinated with IIV3-SD (128)(129)(130)(131)(132)(133)(134)(135) . Seroprotection was significantly higher for all 3 strains in the vaccine in three of five studies assessing significance. There were different results in the remaining studies. In the study by Couch et al., seroprotection was higher only against A(H1N1), possibly attributed to the fact that 78% of participants were vaccinated against the same influenza strains within 6 months prior to the study (129) . In Nace et al., seroprotection was higher against A(H3N2) and B but not A(H1N1); this finding may be attributed to strain circulation during the study that made it difficult to assess seroprotection against this subtype (133) . Geometric mean titre ratios (GMTR) of participants' responses to high-versus standard-dose influenza vaccines were reported in several studies and were calculated for those that provided group-specific, post-vaccination titres for each of the vaccines (128)(129)(130)(131)(132)134,135) . Seroresponse to the B strains in the vaccines was about 1.5 times greater (1.3-1.7) in the IIV3-HD recipients than the IIV3-SD recipients. The GMTR of the A strains was about 1.8 times higher for those receiving IIV3-HD compared to IIV3-SD, ranging from 1.6-2.3.
# Safety
IIV3-HD has been observed to produce a higher rate of some systemic reactions than IIV3-SD. Studies have reported higher rates of malaise, myalgia, and moderate to severe fever. Most systemic reactions were mild and resolved within 3 days. Serious adverse events were rare and similar in frequency between standard-dose and high-dose vaccines. Refer to NACI's A Review of the Literature of High Dose Seasonal Influenza Vaccine for Adults 65 Years and Older for details.
# Standard-dose quadrivalent inactivated influenza vaccine (IIV4-SD)
Vaccines currently available for use:
• Afluria ® Tetra (Seqirus) • Flulaval ® Tetra (GlaxoSmithKline) • Fluzone ® Quadrivalent (Sanofi Pasteur)
# Efficacy and effectiveness
In the NACI Literature Review on Quadrivalent Influenza Vaccines, only one study was identified that measured IIV4-SD efficacy. In that study, efficacy was estimated at 59% in children 3-8 years of age, in comparison to children who received hepatitis A vaccine (136) . No literature was found in this review on efficacy or effectiveness directly comparing trivalent and quadrivalent formulations.
# Immunogenicity
In this same review of the literature, NACI reviewed the immunogenicity data for IIV4-SD produced by manufacturers who supplied influenza vaccine in Canada at the time of the literature review: AstraZeneca, GlaxoSmithKline, and Sanofi Pasteur. The results of phase II and III trials that compared trivalent formulations to quadrivalent formulations generally showed non-inferiority of the quadrivalent products for the A(H3N2), A(H1N1), and B strain contained in the trivalent formulations. As expected, these studies showed that the immune response to the B strain that was not in the trivalent formulation was better in subjects who received the quadrivalent vaccine, which contained the additional B strain. These findings were consistent across age groups. Refer to the Literature Review on Quadrivalent Influenza Vaccines for additional details.
In the phase III trials, recipients of the trivalent formulations showed, to a lesser degree, some immune response to the B strain not contained in the trivalent formulation. In one study of adults, both the trivalent and quadrivalent vaccines met all the Committee for Medicinal Products for Human Use (CHMP) and Centre for Biologics Evaluation and Research (CBER) criteria for evaluation of influenza vaccine immunogenicity, including those for the B strain not in the trivalent vaccine.
In all other studies, the trivalent vaccine failed at least one of the criteria for seroprotection or seroconversion for the missing B strain. It has been hypothesized that there is some level of cross-reactivity between B strains. The degree of cross protection against infection with one lineage provided by immunization against the other lineage is uncertain (137) .
# Safety
As IIV4-SD has higher antigenic content than IIV3-SD, increased reactogenicity may be a concern for the quadrivalent vaccine. However, pre-licensure clinical trials (refer to Literature Review on Quadrivalent Influenza Vaccines) and post-marketing surveillance showed that IIV4-SD had a similar safety profile to IIV3-SD (138) .
# IV.2 Live Attenuated Influenza Vaccine (LAIV)
LAIV contains standardized quantities of FFU of live attenuated influenza virus reassortants. The virus strains in LAIV are cold-adapted and temperature sensitive, so they replicate in the nasal mucosa rather than the lower respiratory tract, and they are attenuated, so they do not produce ILI. There have been no reported or documented cases, and no theoretical or scientific basis to suggest transmission of vaccine virus would occur to the individual administering LAIV. As a live replicating whole virus formulation administered intranasally, it elicits mucosal immunity, which may more closely mimic natural infection.
Vaccine currently available for use:
• FluMist ® Quadrivalent (AstraZeneca)
# Efficacy and effectiveness
After careful review of the available Canadian and international LAIV VE data over many influenza seasons, NACI concluded that the current evidence is consistent with LAIV's providing comparable protection against influenza to that afforded by IIV and does not support a recommendation for the preferential use of LAIV in children 2-17 years of age.
Observational studies from the United States of America found low effectiveness of LAIV against circulating post-2009 pandemic A(H1N1), or A(H1N1)pdm09, in 2013-2014 and 2015-2016; however, reduced LAIV effectiveness was not observed in Canada or any other countries that have investigated the issue.
Manufacturer investigation identified potential reduced replicative fitness of the A(H1N1)pdm09like LAIV viruses in the nasal mucosa from the two affected A(H1N1)-dominant seasons compared to pre-2009 pandemic influenza A(H1N1) LAIV viruses as contributing to the poor LAIV effectiveness against circulating A(H1N1) (139) . This finding led to the manufacturer replacing the A(H1N1)pdm09 component of LAIV with a new strain. In adults, studies have found IIV-SD to be similarly or more efficacious or effective compared with LAIV.
Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for detailed information supporting this recommendation.
# Immunogenicity
LAIV, which is administered by the intranasal route, is thought to result in an immune response that mimics that induced by natural infection with wild-type viruses, with the development of both mucosal and systemic immunity. Local mucosal antibodies protect the upper respiratory tract and may be more important for protection than serum antibody.
Studies have demonstrated that the presence of a hemagglutination-inhibition antibody response after the administration of LAIV3 is predictive of protection. However, efficacy studies have shown protection in the absence of a significant antibody response as well (140) . In these studies, LAIV3 has generally been shown to be equally, if not more, immunogenic compared to IIV3-SD for all 3 strains in children, whereas IIV3-SD was typically more immunogenic in adults than LAIV3. Greater rates of seroconversion to LAIV3 occurred in baseline seronegative individuals compared to baseline seropositive individuals in both pediatric and adult populations, because pre-existing immunity may interfere with response to a live vaccine. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for further details regarding the immunogenicity of LAIV3.
LAIV4 has shown non-inferiority based on immunogenicity compared to LAIV3 in both children and adults. The immune response to the B strain found only in the quadrivalent formulation was better in children who received the quadrivalent vaccine (141)(142)(143) .
# Safety
The most common adverse events experienced by recipients of LAIV3 are nasal congestion and runny nose, which are also reported for LAIV4. In a large efficacy trial, rates of wheezing were statistically higher among children 6-23 months of age for LAIV3 compared to IIV3-SD (140) . This finding is expected to be the same for recipients of LAIV4; however, pre-licensure clinical studies for LAIV4 were conducted in adults and children 2 years of age and older.
Studies on LAIV3 have shown that vaccine virus can be recovered by nasal swab in children and adults following immunization (i.e., "shedding"). The frequency of shedding decreases with increasing age and time since vaccination. Shedding is generally below the levels needed to transmit infection, although in rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated people. Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for more information on LAIV and viral shedding.
# IV.3 Schedule
The first time that children 6 months to less than 9 years of age receive seasonal influenza immunization, a two-dose schedule is required to achieve protection (144)(145)(146) . Several studies have looked at whether these two initial doses need to be given in the same season (63,64,147) . Englund et al. reported similar immunogenicity in children 6-23 months of age whether 2 doses were given in the same or separate seasons when there was no change, or only minor vaccine strain change, in vaccine formulation between seasons (63,64) . However, seroprotection rates to the B component were considerably reduced in the subsequent season when there was a major B lineage change, suggesting that the major change in B virus lineage reduced the priming benefit of previous vaccination (62,64) . Issues related to effective prime-boost when there is a major change in influenza B lineage across sequential seasons require further evaluation (148) .
Because children 6-23 months of age are less likely to have had prior priming exposure to an influenza virus, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children in this age group.
# IV.4 Simultaneous Administration with Other Vaccines
In general, NACI recommends that two live parenteral vaccines be administered either on the same day or at least 4 weeks apart (149) . This recommendation is based largely on a single study from 1965 that demonstrated immune interference between smallpox vaccine and measles vaccine administered 9-15 days apart. Subsequent studies have revealed conflicting results on immune interference between live vaccines (150)(151)(152)(153) .
No studies were found on potential immune interference between LAIV and other live attenuated vaccines (oral or parenteral) administered within 4 weeks. A few studies on concomitant administration of LAIV3 with MMR, varicella, and oral polio vaccines did not find evidence of clinically significant immune interference (8)(9)(10) . One study reported a statistically significant but not clinically meaningful decrease in seroresponse rates to rubella antigen when administered concomitantly with LAIV.
In theory, the administration of two live vaccines sequentially within less than 4 weeks could reduce the efficacy of the second vaccine. Possible immune mechanisms include: the inhibitory and immunomodulatory effects of systemic and locally produced cytokines on B-and T-cell response and viral replication; immunosuppression induced by certain viruses (such as measles); and direct viral interference as a result of competition for a common niche. Mucosal vaccines may have less impact on a parenteral vaccine and vice versa. The immune response with a mucosal vaccine may be compartmentalized to the mucosa while that to a parenteral vaccine is systemic. It is likely that there is some interaction between the systemic and mucosal compartments; however, the extent to which this interaction occurs is not known.
Given the lack of data for immune interference, based on expert opinion, NACI recommends that LAIV can be given together with or at any time before or after the administration of any other live attenuated or inactivated vaccine. NACI recognizes that some vaccine providers may choose to give LAIV and other live vaccines simultaneously or separated by at least 4 weeks as a professional preference. Alternatively, an inactivated influenza vaccine may be given.
# IV.5 Additional Vaccine Safety Considerations
Influenza vaccine is safe and well tolerated. Contraindications, precautions, and common adverse events are described in Section II. Additional information regarding egg-allergic individuals and GBS is provided below.
# Egg-allergic individuals
After careful review of clinical and post-licensure safety data, NACI has concluded that eggallergic individuals may be vaccinated against influenza using any appropriate product, including LAIV, without prior influenza vaccine skin test and with the full dose, irrespective of a past severe reaction to egg and without any particular consideration, including vaccination setting. The amount of trace ovalbumin allowed in influenza vaccines that are authorized for use in Canada is associated with a low risk of adverse events. The observation period post-vaccination is as recommended in Vaccine Safety in Part 2 of the CIG. As with all vaccine administration, vaccine providers should be prepared with the necessary equipment, knowledge, and skills to respond to a vaccine emergency at all times.
Refer to the Statement on Seasonal Influenza Vaccine for 2018-2019 for safety data supporting this recommendation for IIV and LAIV.
# Guillain-Barré syndrome
In a review of studies conducted between 1976 and 2005, the United States Institute of Medicine concluded that the 1976 "swine flu" vaccine was associated with an elevated risk of GBS. However, evidence was inadequate to accept or to reject a causal relation between GBS in adults and seasonal influenza vaccination (154) .
The attributable risk of GBS in the period following seasonal and monovalent 2009 pandemic influenza vaccination is about one excess case per million vaccinations (155,156) . In a selfcontrolled study that explored the risk of GBS after seasonal influenza vaccination and after influenza health care encounters (a proxy for influenza illness), the attributable risks were 1.03 GBS admissions per million vaccinations compared with 17.2 GBS admissions per million influenza-coded health care encounters (156) .
This finding shows that both influenza vaccination and influenza illness are associated with small attributable risks of GBS, but the risk of GBS associated with influenza illness is notably higher than with influenza vaccination. The self-controlled study also found that the risk of GBS after vaccination was highest during weeks 2-4, whereas for influenza illness, the risk was greatest within the first week after a health care encounter and decreased thereafter, but remained significantly elevated for up to 4 weeks. The risk of GBS associated with influenza vaccination must be balanced against the risk of GBS associated with influenza infection itself and all the other benefits of influenza vaccination (157)(158)(159)(160) .
# V. CHOICE OF SEASONAL INFLUENZA VACCINE: ADDITIONAL INFORMATION
With the recent availability of a number of new influenza vaccines, some of which are designed to enhance immunogenicity in specific age groups, the choice of product is now more complex. Section II.5 summarizes NACI's recommendations on the choice of currently available influenza vaccines. This section provides more details for these recommendations.
# V.1 Children
# Burden of disease in children
The proportion of disease burden due to influenza B infection is higher in children compared to other age groups. Canadian surveillance data from 2001-2002 to 2012-2013 has shown that influenza B strains accounted for 17% of laboratory-confirmed tests for influenza. Children less than 24 months of age comprise approximately 2% of the Canadian population (161) . (162) .
The IMPACT study also found that the proportion of deaths attributable to influenza was significantly greater for influenza B (1.1%) than influenza A (0.4%). The proportion of hospitalizations due to influenza B relative to all influenza hospitalizations has been generally similar to the proportion of influenza B detections relative to all influenza infections in the general population during the same time period. Additional information can be found in the Statement on Seasonal Influenza Vaccine for 2014-2015. Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that a quadrivalent influenza vaccine should be used. If a quadrivalent vaccine is not available, any of the available trivalent vaccines should be used.
There is insufficient evidence to make comparative recommendations on the use of IIV3-Adj over IIV3-SD.
Children 2-17 years of age Three types of influenza vaccine are available for use in children 2-17 years of age: IIV3-SD, IIV4-SD, and LAIV4.
Given the burden of influenza B disease in children and the potential for lineage mismatch between the predominant circulating strain of influenza B and the strain in a trivalent vaccine, NACI recommends that either IIV4-SD or LAIV4 should be used in children without contraindications. If IIV4-SD or LAIV4 is not available, IIV3-SD should be used.
The current evidence does not support a recommendation for the preferential use of LAIV in children and adolescents 2-17 years of age. Refer to the NACI Statement on Seasonal Influenza Vaccine for 2018-2019 for information supporting this recommendation.
# Children 2-17 years of age with chronic health conditions
NACI recommends that any age-appropriate influenza vaccine (IIV or LAIV) may be considered for children 2-17 years of age with chronic health conditions, with the exception of those with severe asthma (as defined as currently on oral or high-dose inhaled glucocorticosteroids), those with medically attended wheezing in the 7 days prior to vaccination, and those with immune compromising conditions, all of whom should receive IIV. If IIV is used, NACI recommends that a quadrivalent vaccine should be used. If a quadrivalent vaccine is not available, a trivalent vaccine should be used. NACI recommends that LAIV may be given to children with stable, non-severe asthma and children with cystic fibrosis who are not treated with immunosuppressive drugs, such as prolonged systemic corticosteroids.
Refer to the NACI Recommendations on the Use of Live, Attenuated Influenza Vaccine (FluMist ® ): Supplemental Statement on Seasonal Influenza Vaccine for 2011-2012 for additional information supporting these recommendations.
# Summary of vaccine characteristics for decision making
IIV (IIV3-SD and IIV4-SD) and LAIV (LAIV4) are authorized for use in Canada for children 2-17 years of age. The comparison of the vaccine characteristics of IIV and LAIV, in Table 3 below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program.
# Efficacy and effectiveness
There was early evidence of superior efficacy of LAIV3 compared with IIV3-SD in children less than 6 years of age from RCTs, with weaker evidence of superior efficacy in older children. However, later postmarketing and surveillance studies across multiple influenza seasons found comparable protection against influenza for LAIV and IIV, with findings of reduced effectiveness against A(H1N1) in some studies.
Like IIV4-SD, LAIV4 is expected to provide additional protection against the influenza B strain not contained in IIV3-SD.
# Immunogenicity
LAIV3 has been shown to be as immunogenic as IIV3-SD, depending on age, with LAIV4 being non-inferior to LAIV3.
# Safety
Rhinitis (runny nose) and nasal congestion are more common with LAIV. Clinical studies and post-marketing studies showed a similar safety profile to IIV.
Contraindications There are vaccine contraindications specific to LAIV. LAIV is contraindicated for children with severe asthma, medically attended wheezing in the 7 days prior to vaccination, and immune compromising conditions, as well as those currently receiving aspirin or aspirincontaining therapy.
# Administration
Delivery of LAIV as a nasal spray may be preferable for children who are averse to receiving the vaccine by needle injection.
Abbreviations: IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; LAIV3: trivalent live attenuated influenza vaccine; LAIV4: quadrivalent live attenuated influenza vaccine.
# V.2 Adults
# Burden of disease in adults
A study focusing on estimates of deaths associated with influenza in the United States of America has established that the average annual rate of influenza-associated deaths for adults aged 65 years of age and older was 17.0 deaths per 100,000 (range: 2.4-36.7) (163) . The study also states that deaths among persons 65 years of age and older accounted for 87.9% of the overall estimated average annual influenza-associated deaths with underlying pneumonia and influenza causes.
When influenza-related deaths were estimated using underlying respiratory and circulatory causes, these estimates increased to 66.1 deaths per 100,000 (range: 8.0-121.1) and 89.4%, respectively. This study described a wide variation in the estimated number of deaths from season to season, which was closely related to the particular influenza virus types and subtypes in circulation.
Estimates presented in the study of yearly influenza-associated deaths with underlying pneumonia and influenza causes reveal a large difference between influenza type A and B with a calculated median of greater than 6,000 deaths associated with influenza type A and half of that number for influenza type B (approximately 3,360) for persons 65 years of age and older.
During the 22 seasons in which influenza A(H3N2) was the prominent strain, the average influenza-associated mortality rates were 2.7 times higher than for the nine seasons that it was not (all age groups combined), and on average, there were about 37% more annual influenzaassociated deaths, regardless of the underlying medical cause. A higher risk of hospitalization and death was also reported by Cromer et al. in adults 65 years of age and older, compared to younger adults in their assessment of the burden of influenza in England by age and clinical risk group (164) .
Canadian surveillance data show that hospitalization rates among adults 65 years of age and older were higher during the 2014-2015 season compared to the previous five influenza seasons and also compared to the 2012-2013 season when A(H3N2) also predominated; 2014-2015 was a season in which A(H3N2) circulation predominated and in which there was a vaccine mismatch with the circulating A(H3N2) strain.
Similar to the hospitalization rates, death rates among seniors were highest in the 2014-2015 season compared to the previous five seasons and compared to the previous A(H3N2) season in 2012-2013. Death rates among other age groups were similar to or lower than the previous five influenza seasons. Laboratory detections over this same time period showed that influenza seasons in which influenza subtype A(H3N2) predominated, disproportionally affected adults 65 years of age and older, while seasons with greater A(H1N1) detections resulted in a higher prevalence of positive cases in younger age groups. NACI recommends that any of the available influenza vaccines should be used.
# Adults 65 years of age and older
Four types of influenza vaccine are available for use in adults 65 years of age and older: IIV3-SD, IIV3-Adj, IIV3-HD, and IIV4-SD.
# Recommendation for individual-level decision making
NACI concludes that, given the burden of disease associated with influenza A(H3N2) and the good evidence of better efficacy compared to IIV3-SD in this age group, when available, IIV3-HD should be used over IIV3-SD.
There is insufficient evidence to make comparative recommendations on the use of IIV3-Adj or IIV4-SD over IIV3-SD or among IIV3-Adj, IIV3-HD, and IIV4-SD.
# Recommendation for public health program-level decision making
NACI recommends that any of the available influenza vaccines should be used.
IIV3-HD is expected to provide superior protection compared to IIV3-SD; however, with costeffectiveness assessments having been outside the scope of the evidence review and without data on the relative efficacy and effectiveness between IIV3-HD, IIV3-Adj, and IIV4-SD, there is insufficient evidence to make a comparative recommendation on the use of these vaccines at the programmatic level.
# Summary of vaccine characteristics for decision making
There are four types of inactivated influenza vaccines (IIV3-SD, IIV3-Adj, IIV3-HD, and IIV4-SD) authorized for use in Canada for adults 65 years of age and older. The comparison of vaccine characteristics across vaccine types, in Table 4 below, may be considered in making a decision on the preferred vaccine option(s) for use by an individual or a public health program. Due to a lack of available data directly comparing the performance of IIV3-Adj, IIV3-HD, and IIV4-SD, considerations for these vaccines in Table 4 are compared to IIV3-SD for which comparative data on efficacy, effectiveness, and/or immunogenicity with each of IIV3-Adj, IIV3-HD, and IIV4-SD are available. Higher rate of some systemic reactions than IIV3-SD; most systemic reactions were mild and transient.
Serious adverse events were rare and similar in frequency to IIV3-SD.
Pre-licensure clinical trials and postmarketing surveillance showed a similar safety profile to IIV3.
Abbreviations: IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine.
* NACI has not assessed the comparative cost-effectiveness of available influenza vaccine types for adults 65 years of age and older. ** The burden of influenza A(H3N2) disease is higher in adults 65 years of age and older compared to younger age groups. *** Influenza vaccines are contraindicated in people who have had an anaphylactic reaction to any of the vaccine components, with the exception of egg. Please note that not all vaccines listed contain the same components.
# 48
Adults with chronic health conditions NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to adults with chronic health conditions identified in List 1, including those with immune compromising conditions.
Pregnant women NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to pregnant women.
Due to a lack of safety data at this time, LAIV should not be administered to pregnant women due to the theoretical risk to the fetus from administering a live virus vaccine. LAIV can be administered to breastfeeding women.
Health care workers NACI recommends that any age-appropriate IIV, but not LAIV, should be offered to HCWs.
Comparative studies in healthy adults have found IIV to be similarly or more efficacious or effective compared with LAIV (140) . In addition, as a precautionary measure, LAIV recipients should avoid close association with people with severe immune compromising conditions (e.g., bone marrow transplant recipients requiring isolation) for at least 2 weeks following vaccination, because of the theoretical risk for transmitting a vaccine virus and causing infection. Abbreviations: FFU: fluorescent focus units; HA: hemagglutinin; IIV3-Adj: adjuvanted trivalent inactivated influenza vaccine; IIV3-HD: high-dose trivalent inactivated influenza vaccine; IIV3-SD: standard-dose trivalent inactivated influenza vaccine; IIV4-SD: standard-dose quadrivalent inactivated influenza vaccine; IM: intramuscular; LAIV4: quadrivalent live attenuated influenza vaccine; NA: neuraminidase.
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Purpose The neoadjuvant treatment of breast cancer (NABC) is a rapidly changing area that benefits from guidelines integrating evidence with expert consensus to help direct practice. This can optimize patient outcomes by ensuring the appropriate use of evolving neoadjuvant principles. Methods An expert panel formulated evidence-based practice recommendations spanning the entire neoadjuvant breast cancer treatment journey. These were sent for practice-based consensus across Canada using the modified Delphi methodology, through a secure online survey. Final recommendations were graded using the GRADE criteria for guidelines. The evidence was reviewed over the course of guideline development to ensure recommendations remained aligned with current relevant data. Results Response rate to the online survey was almost 30%; representation was achieved from various medical specialties from both community and academic centres in various Canadian provinces. Two rounds of consensus were required to achieve 80% or higher consensus on 59 final statements. Five additional statements were added to reflect updated evidence but not sent for consensus. Conclusions Key highlights of this comprehensive Canadian guideline on NABC include the use of neoadjuvant therapy for early stage triple negative and HER2 positive breast cancer, with subsequent adjuvant treatments for patients with residual disease. The use of molecular signatures, other targeted adjuvant therapies, and optimal response-based local regional management remain actively evolving areas. Many statements had evolving or limited data but still achieved high consensus, demonstrating the utility of such a guideline in helping to unify practice while further evidence evolves in this important area of breast cancer management.# Background
Breast cancer is the most commonly diagnosed malignancy globally, with 2.3 million new cases in 2020 . Outcomes have generally improved particularly in higher income nations, including Canada . This is largely attributed to better screening, improved local therapies, and advances in systemic treatment. In addition, a further appreciation of the breast cancer subtypes and associated disparate biology has facilitated several new approaches to multidisciplinary care that have changed the paradigm of breast cancer management . In particular, practice-changing data available in the last several years has resulted in an increased momentum for the pre-operative, or neoadjuvant chemotherapy (NAC) approach to breast cancer treatment .
A Canadian national consortium for the neoadjuvant treatment of breast cancer (NABC) has existed since 2010. The most recent meeting of this group of national multidisciplinary experts was in May 2019 (Ontario, Canada). This group assembles national multidisciplinary experts in breast cancer to discuss and disseminate emerging evidence-based guidance across the country, and in particular focus on areas that have incomplete evidence and require expert opinion to help direct practice. Various members of this group have previously published meeting reports and one expert consensus guideline, with a significant focus on the utility of NAC for locally advanced breast cancer (LABC) . However, over the last few years, research has increasingly demonstrated the important prognostic and predictive implications of treating certain subtypes of early breast cancer (HER2 positive and triple negative) with NAC , irrespective of upfront clinical stage or operability. The routine use of NAC for early stage breast cancer that is operable on presentation is a paradigm shift of great importance, with significant therapeutic and resource implications . Rapidly evolving evidence, the paucity of long-term data in some studies, the use of variable patient endpoints, and drug funding disparities within the country, can create some uncertainty in therapeutic approaches, but also opportunities for ongoing clinical trials . Considering all this, there is an ongoing need for expert opinion to help consolidate the approach to NABC patient management. This is paramount to achieving the best possible uniform outcomes for Canadian breast cancer patients, particularly considering the publicly funded healthcare landscape. International breast oncology guidelines often embed the use of NAC within larger documents pertaining to breast cancer management . In addition, some of the NAC recommendations are resource and practice-setting specific; there also remains some debate around the impact of certain research findings on clinical care (example using pathologic complete response rate as a practice-changing endpoint). Finally, most guidelines, including the recently published American Society of Clinical Oncology (ASCO) document, focus on systemic therapy alone , and do not include the subsequent implications of systemic therapy on surgical and radiation therapy decision-making. We, therefore, developed a contemporary, evidence-based Canadian National Consensus on the Neoadjuvant Treatment of Breast Cancer, using validated consensus methodology. This is meant to capture the most up-to-date evidence on optimal patient management throughout the entire treatment journey, while aligning multidisciplinary expert opinion with practice-based consensus from clinicians across the country.
Guideline type: Evidence Based Consensus. Intended users: Practitioners who treat invasive breast cancer (pathology, radiology, surgery, medical oncology, radiation oncology, and other involved health professions.)
Applicable resource setting: Upper middle to high income nations with access to advanced screening, diagnostic, pathologic, surgical, radiation, and systemic therapy options.
# Methods
# Expert guideline panel
An expert guideline steering committee was established at the most recent Canadian National NABC Consortium meeting (May 2019, Ontario, Canada). The committee was comprised of academic and clinical experts in breast cancer management in the following specialties: medical oncology, surgical oncology, radiation oncology, breast radiology and anatomic pathology. All committee experts practice in academic cancer centres for more than 5 years, treat more than 100 unique breast cancer patients per year, and have demonstrated research and academic impact in NABC (peer-reviewed publications, research grants/projects, clinical trials involvement, and/or academic meeting presentations.) Representation from multiple Canadian provinces was sought.
# Systematic evidence review
A systematic review of the literature was performed. As management for the neoadjuvant treatment of locally advanced breast cancer and general treatment principles of early breast cancer are well-established , the focus of the review was to update established principles of NABC care and highlight areas of new or evolving evidence that in particular would benefit from consensus to help improve practice. The overall focus was defined as the comprehensive management of breast cancer with a neoadjuvant therapy approach, including specific attention to the domains of multi-disciplinary assessment, diagnosis, monitoring, systemic therapy and local treatment. To maintain scope and feasibility, a single database search (PUBMED) was performed with the following parameters: invasive breast cancer, neoadjuvant, limited to phase 3 or 4 studies, meta-analysis, systematic review, or guidelines published in the English language. To focus mainly on new developments in this area, the search was limited to the past 5 years (initially October 2015 to October 2020 inclusive); the search was then repeated for November 2020 to May 2021 prior to manuscript preparation, to ensure no new relevant evidence had been published (Fig. 1). In December 2020, July 2021, October 2021, and December 2021, a targeted online gray literature search was completed to review any updated evidence as presented at four high impact oncology meetings (San Antonio Breast Cancer Symposium 2020 and 2021, American Society of Clinical Oncology 2021, European Society of Medical Oncology 2021), and any new published guidelines. The guideline panel decided it was important to capture any relevant new evidence with a select few additional recommendations, to ensure the guideline was most up-to-date. It was decided a priori that if the new evidence did not change the relevance or accuracy of existing recommendations, or greatly change the guideline's scope or impact, these few select recommendations would not be sent for consensus to prevent delays in final guideline submission.
# Consensus statements and consensus process
The steering committee developed recommendations for consensus based on the evidence review and discussion of important principles of NABC care, as established during and since the last Canadian NABC consensus statement in 2015 . Discussions were held virtually (telephone), and via email correspondence. The statements were further reviewed by five additional clinical experts in breast surgical, radiation, and medical oncology; these expert reviewers were identified from past Canadian NABC Consortium involvement. Representation from multiple provinces was again ensured.
The Modified-Delphi approach is well recognized as a robust consensus methodology, particularly for consensus development in healthcare . This anonymous, survey-based consensus guideline model has several advantages compared to more traditional expert-based or nominal group methods; the latter rely solely on the opinions of a select group of individuals, and can be more subject to bias Fig. 1 Literature search consort diagram. There were 78 studies included for analysis after applying the inclusion and exclusion criteria or the influence of the most vocal members of a guideline committee. Using the modified-Delphi approach, final statements were emailed to potential physician respondents using a secure online survey platform (Survey Monkey Inc., San Mateo, California, USA). Potential respondents were identified as being probable breast cancer clinicians by national or provincial medical society membership, provincial cancer centre affiliation, description of medical practice as available in public domain (example: institutional websites), recommendation by invited colleagues, and/or previous attendance at Canadian National NABC Consortium meetings. Invited participants were instructed only to respond if they had enough clinical expertise and experience in the neoadjuvant treatment of breast cancer to have an opinion. To achieve a broad practice-based consensus on expert recommendations, the guideline committee preferred not to restrict responses by years of practice or number of patients, and assumed respondents would only engage in the survey if they felt comfortable with the subject matter. Invitation to participate in the consensus process was carried out using email addresses for these individuals, as available in the public domain or through personal solicitation from the steering committee, or as shared by invited colleagues. Given the focus of this guideline was an practice-based physician consensus, other health care disciplines, and patient representatives were not included in the statement development or consensus process itself. Widespread physician representation was targeted, including multidisciplinary providers in both academic and community centers and in all Canadian provinces with comprehensive cancer programs.
Responses were anonymous; only respondent demographics including discipline, geographic area of practice, and years in practice were collected. Respondents were asked to indicate agreement, disagreement, or neutrality (i.e., "no opinion") to each statement. Given that multiple oncology specialties were involved, respondents were asked to indicate "no opinion" only if the statement was outside of their area of direct practice and not because they had no opinion about a statement related to their specialty. Reminders were sent twice over an 8-week period. Respondents were required to provide detailed qualitative feedback regarding statements they disagreed with. Specifically, respondents were instructed that if they did not agree with a statement in its entirety, to indicate disagreement, and provide detailed feedback regarding the elements they did not agree with. As per Modified-Delphi process, statements that did not achieve consensus were reviewed by the steering committee and modified based on the qualitative feedback as collected by the survey. These statements were emailed for a second round of survey; this was emailed to the same participants. Participants were instructed to respond only if they had responded to the first survey; one reminder was sent over 6 weeks. A third round was planned if required (Fig. 2).
# Consensus analysis
Agreement statistics were calculated for each statement based on the total number of responses. The denominator for each statement (N, Agree + Disagree) was calculated as the sum of respondents who agreed and disagreed. Blank responses and those who indicated "no opinion" were excluded from the total number of responses for each question. The numerator (n, Agree) corresponded to the number of respondents who indicated "agree" for each statement. The proportion (n/N) was converted to a percent value (%) to determine the consensus value. A threshold value was determined a priori; consensus was defined as statements with 80% or more of respondents in agreement; statements with consensus > 79.5% were rounded up to 80%. Statements with less than an 80% (i.e., ≤ 79.5%) agreement level were marked for modification in the next round of survey, as per Modified Delphi methodology. Qualitative feedback was collected from respondents who indicated disagreement with particular statements; this feedback was utilized to modify statements that did not achieve consensus with the initial round.
# Grading of recommendations
The final statements were ranked using the GRADE recommendations for guidelines (Strong or Conditional) , with consideration of the four domains within the framework for a recommendation's direction and strength, which include: estimates of effect for desirable and undesirable outcomes of interest, confidence in the estimates of effect, estimates of values and preferences, and resource use . In considering this framework, recommendations were generally considered strong if they were based on positive data and had level 1 or 2 evidence as per the GRADE framework for ranking evidence , and met the threshold for consensus. If a recommendation was lacking updated level 1-2 evidence in the last 5 years (acknowledging the review was limited to this timeframe), was deemed imperative to patient care and received a very high level of consensus (> 89%), it was also rated as strong. Recommendations deemed less impactful to patient care, with level 3 or 4 evidence, with preliminary (short term) level 1 or 2 evidence, high resource implications/lack of public funding, or with no published evidence and consensus < 90%, were marked as conditional. The term conditional was preferred over "weak" to indicate these statements may have evolving data thatmay strengthen the recommendation over time) and/or the statement may still be impactful for patient care, particularly in certain contexts. Available evidence was linked to recommendations in the "Grading" column (Tables 1 and 2). As the consensus statements may have been based on several sources of evidence with varying strengths, and to illustrate the grading of recommendations was not based on the strength of evidence alone (as discussed above), formal grading of the evidence was not integrated into the guideline table. Finally, additional statements added by the panel (Table 3) were all graded as "conditional" to reflect that they were not sent for consensus.
# Engagement of further stakeholders
The final guideline was reviewed by a pharmacist, breast cancer patient representative, and a neoadjuvant nurse navigator, all affiliated with the Sunnybrook Health Sciences Centre. Their feedback on the premise of the guideline, agreement with recommendations, and on implementation was sought.
# Results
A total of 47 recommendations were initially created by the steering committee and integrated into a consensus survey. Email invitations to complete the survey were sent to 391 clinicians in October 2020. There were 109 participants who completed the survey, for a response rate of 28%. Surgical oncology represented the largest respondent group (41/109; 37.6%), followed by medical oncology (29/109; 26.61%) and radiation oncology (21/109; 19.27%) (Fig. 3). Respondents were predominantly within their mid-career level of practice. Geographical representation was achieved from across several Canadian provinces, although the majority of respondents were located in central Canada (66.0% Ontario and Quebec), and at academic health institutions (77.0%). A summary of all respondent profiles is presented in Fig. 3. F.10 Regional radiation for patients after NAC who have positive lymph nodes on surgical pathology (regardless of upfront nodal status): Patients with 4 or more residual positive lymph nodes at the time of surgery should be offered local-regional radiotherapy Patients with 1-3 residual positive lymph nodes should also be strongly considered for local-regional radiotherapy. There is a lack of clear evidence of the benefit of localregional radiotherapy for these patients after NAC and BCS F.11 Regional radiation for patients with clinically positive nodes prior to NAC: Patients who have cN2-3 at presentation, or multiple high-risk features (age, tumor size, LVI, grade, ER-negative/HER2 positive receptor status, location) should be considered for localregional radiation following NAC, irrespective of response on surgical pathology. Patients with initial N1 disease should also be considered for local-regional radiation, regardless of response to NAC Those with suspicious but indeterminate N1 disease prior to NAC, and negative nodal dissection at surgery (sentinel or axillary) can be considered for regional radiation on a case-by-case basis F.12 Treatment of N0 disease after NAC is controversial. Those patients with no residual nodal disease should have a discussion regarding benefits of regional radiotherapy based on presence of high-risk primary tumor features, nodal disease at presentation, and extent of response in lymph nodes and breast to NAC. A comment on fibrous scarring in the lymph nodes on final surgical pathology can be used as a marker of NAC effect, and potential targeting for regional radiation Ongoing trials seek to better define the role of regional RT for N0 disease after NAC, and to assess the benefit of local-regional radiation in patients with in-breast pCR but nodepositive disease after NAC F.13 Post-Mastectomy Radiation Therapy (PMRT): Patients with primary tumors with multiple high-risk features and N0 disease at surgery should also be considered for either localregional radiotherapy or chest wall radiotherapy. Factors such as primary tumor size, grade, lymphovascular invasion (LVI), age, tumor location and margin status should be considered. Regional/nodal radiation should be considered in patients following mastectomy who have residual nodal disease following NAC: patients with 4 or more residual positive lymph nodes at the time of surgery should be offered local-regional RT. Patients with 1-3 residual positive lymph nodes should also be strongly considered for localregional radiation. Patients with cN2-3 disease at presentation should be offered localregional radiation after mastectomy, regardless of response to NAC. Patients with N1 disease at presentation should also be considered for local-regional radiation, regardless of NAC response. Recommendations with results in bold did NOT meet the pre-specified threshold for consensus in Round 1 (>79%); these recommendations were modified and sent for a second round of consensus Neoadjuvant therapy patient selection B.6-R NAC can be offered primarily- for tumor down staging, to select patients who are eligible for breast conservation (considering tumor focality, tumor to breast size ratio, and implications for radiation/reconstruction). The likelihood of tumor response based on biomarkers (example: lower chance in ER positive, HER2 negative) should be considered, in addition to the risk of over-treatment with chemotherapy in certain patients *Added Note-Clarification of the term "primary": in select patients NAC may be offered for down-staging of the tumour as the "primary" goal, however in other patients, NAC is recommended beyond the goal of potentially decreasing clinical tumour burden (example: for HER2 + /triple negative phenotypes The lack of data in this realm should be noted, as well as the implications for potentially requiring further treatment post-operatively for residual disease, and eligibility criteria for these additional therapies (example: adjuvant TDM-1 data is in HER-2 positive patients with 6 or more cycles of NAC.)Refer to section on additional adjuvant therapies 29/36 80.56 Conditional D.3-R.1 Pathologic complete response (pCR) has been established as a meaningful prognostic surrogate for particular subtypes of breast cancer, particularly triple negative and ER-negative, HER-2 positive (with the use of anti-HER2 therapy.) Additional systemic therapies improve outcomes for triple negative and HER-2 positive cancers that have residual disease (lack of pCR) after NAC. Therefore, improving pCR rates means less patients with these subtypes may require additional systemic therapy after surgery. Considering these principles; regarding targeted therapies during NAC: a. Trastuzumab should be given during the taxane portion of NAC for HER-2 positive breast cancers
# Consensus agreement: round 1
During the first survey round, 89.4% of questions (42/47) achieved 80% or greater consensus (agreement). A summary of all statements with the levels of consensus is presented in Table 1. Consensus was not reached for five statements under the following domains: patient selection, neoadjuvant systemic therapy, and local-regional management after neoadjuvant systemic therapy. The five statements that did not receive 80% agreement were modified based on qualitative feedback from the survey. These five statements were restructured into 12 statements and sent for a second round of survey in December 2020. One additional new statement was integrated into the second survey to encompass new data regarding adjuvant therapy that became available as part of the targeted gray literature search in at that time.
# Consensus agreement: round 2
In the second round, there were 81 respondents (81/109; 74.3% of respondents from round 1). A summary of the modified statements in round 2 is outlined in Table 2. All of the modified statements reached ≥ 80% consensus. The new statement on adjuvant therapy achieved consensus. A third
D.3-R.4
Regarding targeted therapies during NAC: d. There is conflicting evidence regarding the addition of a platinum to the taxanecontaining portion of a third-generation NAC regimen; however, if accessible and tolerable, a platinum agent can be considered for triple negative breast cancers, in order to potentially improve PCR. There is evidence that BRCA-associated tumors may not benefit from the addition of a platinum, and therefore ideal patient selection without the knowledge of BRCA-status may be challenging. There is data to support platinums for NAC as an anthracycline-sparing approach. Access remains an issue in many Canadian regions. The addition of a platinum agent to a taxane can also be considered if suboptimal or progressive disease is observed in triple negative tumors during the anthracycline portion of NAC D.5-R.1 For patients in whom tumor progression on NAC is treated with radiation, the addition of a radio-sensitizing systemic agent is reasonable to enhance radiotherapy response, with the primary goal of achieving tumor respectability. There is some practice-based data available for the use of weekly platinum agents with radiation for the treatment of triple negative tumors progressing on NAC. This approach can be considered for eligible patients (considering the balance with modestly increased toxicities)
39/49 79.59 Conditional Local-regional management after neoadjuvant systemic therapy F.4-R.1 Patients with initial N1 disease can be considered for (targeted) sentinel lymph node biopsy if: Patients are clinically (by physical exam) node negative prior to definitive surgery, AND dual tracer is used, AND At least 3 sentinel lymph nodes are removed. At institutions where lymph nodes are clipped at diagnosis, it is recommended that they are localized at surgery, and excised along with the sentinel nodes. Pathologic nodal assessment with immunohistochemistry should be available. Patients should be counseled that the risk of false negatives is low with a sentinel-lymph node approach that meets the criteria above, but that long term outcomes are still uncertain. Multi-disciplinary discussion with a radiation oncologist prior to finalizing the axillary surgical approach (as with the primary breast tumor) is also encouraged *Added notes were not integrated into the consensus statements, and were included to provide further context and clarity after manuscript review round of survey was therefore not required, given the second round achieved complete consensus on this new statement, and all revised statements.
# Systematic review
There were 389 citations found on systematic review; 311 were excluded based on abstract review; criteria are shown in Fig. 1. There were many early phase studies, and those focused on biomarker assessment, a rapidly evolving area of research in the neoadjuvant realm. As much of this data is exploratory or early, these studies were excluded. There were also many studies evaluating imaging response modalities for neoadjuvant therapy; some of these were included and matched to the statement regarding their investigational use.
In general, studies that had negative results or did not meet primary efficacy endpoints, or with early phase data only, or therapies that had subsequent or conflicting data demonstrating a lack of meaningful impact on patient care, were excluded. The 78 included citations were fully reviewed and matched with guideline statements. For ease of readability and clarity, detailed descriptions of the evidence were not included in the recommendation table itself. Some recommendations did not have associated citations, as they were based on data published before the systematic review timeframe.
# Further evidence review and additional statements
Targeted gray literature review did not demonstrate any impact on the accuracy or relevance of existing consensus statements. However, five additional recommendations were created by the expert guideline panel to reflect important areas of practice deemed not to be captured in the initial or revised statements This included statements on sentinel lymph node biopsy for N0 disease , nabpaclitaxel for neoadjuvant therapy , and two additional adjuvant therapies, neratinib and olaparib . Finally, the rapidly evolving impact of molecular gene profiling on NABC was decided to be more clearly addressed established in the adjuvant setting for ER positive, HER2 negative breast cancers that are lymph node negative and 1-3 node positive. These tools can help select patients that may or may not benefit from cytotoxic chemotherapy in addition to adjuvant endocrine therapy. The utility of these assays in lymph node positive cancers is best established for post-menopausal patients. The pre-operative use of these tools on ER positive, HER2 negative core biopsies remains an evolving area of investigation and practice. Clinicians may consider using these tests, if available, as an approach to better define N0 or N1 ER positive HER2 negative cancers at the time of diagnosis, as high molecular risk that may benefit from NAC, versus lower risk that may benefit from upfront surgery. The impact of clinical nodal status at the time of diagnosis, and menopausal status should be taken into account in these circumstances, as well as consideration that the utility of these tests is currently best established in the adjuvant setting where pathologic stage without the impact of NAC is known. Multi-disciplinary discussion on how to integrate the results of these tests in the pre-operative setting is encouraged (in particular discussion between surgeons and medical oncologists.) It should be noted for clinicians and patients that prospective data validating this approach is still accumulating, and access to these tests for this purpose is currently heterogeneous after final external review. The five additional statements are presented in Table 3. Footnotes were included for a few consensus recommendations to clarify concepts as suggested by external review.
# Additional stakeholder feedback
The nursing, patient, and pharmacist feedback sought demonstrated agreement with the recommendations overall, and in particular with the multi-disciplinary approach to NAC care. Suggestions to disseminate the guideline in patient, nursing, and pharmacy forums were made.
# Discussion
There was a high level of agreement on 59 final statements encompassing the complex, multidisciplinary care pathway of neoadjuvant breast cancer patients. Five additional statements were not sent for consensus but were integrated to reflect the most up-to-date evidence pertaining to NABC at the time of manuscript preparation. Important highlights of this guideline include the recommendation to use neoadjuvant systemic therapy for early (operable) stage HER-2 positive and triple negative breast cancer, and the subsequent use of additional adjuvant therapies for those patients with residual disease after definitive surgery. In addition, this guideline demonstrates the importance of multi-disciplinary collaboration throughout the patient care journey. Finally, this consensus guideline demonstrates a balance between improving patient outcomes in an evidence-based manner while seeking to minimize toxicities, with a focus on individualized decision making, including clinical trial enrollment, particularly where evidence is less robust or still accumulating. This is particularly relevant for local-regional treatment approaches where evidence continues to accumulate from ongoing studies.
# Assessment of resource implications
Given the broad scope of this guideline, including many treatment modalities, formal assessment of cost-effectiveness for individual therapies was outside the scope of this guideline. The committee acknowledged that most of the recommendations were applicable to High-middle and High income countries. Due to the robust health technology assessment for cancer drug funding recommendations nationally (pan-Canadian Oncology Drug Review through CADTH) , provincially funded systemic therapies for cancer generally have a cost-effectiveness backing within the Canadian healthcare landscape. Therefore, Health Canada approved agents that do not have wide-spread public funding or remain under evaluation (such as pertuzumab) were acknowledged within the recommendations as potentially having resource constraints at this current time. Corresponding statements suggested that accessibility and resources should be considered in particular for these drugs.
# Limitations
Limitations of this guideline include only a 29% response rate to the consensus survey, and potential sampling and non-response bias. Primarily academic physicians responded to the survey, as such, the opinion of breast cancer clinicians in community practice settings may be under-represented. In addition, medical oncologists and surgeons comprised the largest group of respondents, and the opinion of other specialties may not completely be captured. There were also approximately 25% of initial participants who did not respond to the second round of survey, potentially impacting the results. However, this is unlikely, given the high levels of initial consensus on these statements with the first round (range 66-79%). Patient and other health care professionals were not engaged in the initial development of recommendations; their feedback was only sought on the final guideline and implementation plan. Five additional statements were created but not sent for consensus to prevent delay on the timely dissemination of this guideline; however, they are unlikely to impact on the scope and relevance of the guideline in general.
# Summary and knowledge dissemination plan
This work represents an updated Canadian National Consensus on the Neoadjuvant treatment of breast cancer, across all parts of the therapeutic patient journey. A systematic review of recent literature and formal grading of recommendations was also achieved. The evidence was reviewed several times during guideline preparation, ensuring the most updated data was incorporated in a meaningful manner. The neoadjuvant treatment of breast cancer is a rapidly evolving area of clinical and academic interest; data can change quickly and uptake in clinical settings can falter based on sub-optimal knowledge dissemination or hesitancy to change practice. We believe our approach demonstrates Canadian consensus on key areas of neoadjuvant care, integrating available evidence, expert opinion, and practice-based consensus. We believe this guideline can help optimize patient outcomes across the country, by synthesizing the evidence into comprehensive recommendations for clinical care. Furthermore, the presence of national practice guidelines may help to foster clinical and policy change within healthcare organizations and health networks, with the hope of achieving uniformity of practice and thus patient outcomes. Given the importance of ensuring patient management is aligned with best practice, and to help optimize the use of resources and expertise in this area, we hope to achieve broad dissemination of this consensus guideline. A particular strength of this work is the inclusion of all elements of the patient treatment journey, formal grading of recommendations, and also achieving high levels of consensus, particularly in areas where evidence is lacking or evolving. This may help implementation and uptake of practice elements that can standardize Canadian breast cancer care as the neoadjuvant landscape continues to rapidly evolve. This guideline will be disseminated at the next Canadian National NABC Consensus meeting (planned for mid-2022), and ideally at national and international academic forums. There is also much interest in this document from national, provincial and hospital-based cancer programs in Canada to help guide local practice and resource allocation. We hope this guideline will be a strong addition to the published literature in this important area.
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Purpose The neoadjuvant treatment of breast cancer (NABC) is a rapidly changing area that benefits from guidelines integrating evidence with expert consensus to help direct practice. This can optimize patient outcomes by ensuring the appropriate use of evolving neoadjuvant principles. Methods An expert panel formulated evidence-based practice recommendations spanning the entire neoadjuvant breast cancer treatment journey. These were sent for practice-based consensus across Canada using the modified Delphi methodology, through a secure online survey. Final recommendations were graded using the GRADE criteria for guidelines. The evidence was reviewed over the course of guideline development to ensure recommendations remained aligned with current relevant data. Results Response rate to the online survey was almost 30%; representation was achieved from various medical specialties from both community and academic centres in various Canadian provinces. Two rounds of consensus were required to achieve 80% or higher consensus on 59 final statements. Five additional statements were added to reflect updated evidence but not sent for consensus. Conclusions Key highlights of this comprehensive Canadian guideline on NABC include the use of neoadjuvant therapy for early stage triple negative and HER2 positive breast cancer, with subsequent adjuvant treatments for patients with residual disease. The use of molecular signatures, other targeted adjuvant therapies, and optimal response-based local regional management remain actively evolving areas. Many statements had evolving or limited data but still achieved high consensus, demonstrating the utility of such a guideline in helping to unify practice while further evidence evolves in this important area of breast cancer management.# Background
Breast cancer is the most commonly diagnosed malignancy globally, with 2.3 million new cases in 2020 [1]. Outcomes have generally improved particularly in higher income nations, including Canada [2]. This is largely attributed to better screening, improved local therapies, and advances in systemic treatment. In addition, a further appreciation of the breast cancer subtypes and associated disparate biology has facilitated several new approaches to multidisciplinary care that have changed the paradigm of breast cancer management [3]. In particular, practice-changing data available in the last several years has resulted in an increased momentum for the pre-operative, or neoadjuvant chemotherapy (NAC) approach to breast cancer treatment [4][5][6][7][8].
A Canadian national consortium for the neoadjuvant treatment of breast cancer (NABC) has existed since 2010. The most recent meeting of this group of national multidisciplinary experts was in May 2019 (Ontario, Canada). This group assembles national multidisciplinary experts in breast cancer to discuss and disseminate emerging evidence-based guidance across the country, and in particular focus on areas that have incomplete evidence and require expert opinion to help direct practice. Various members of this group have previously published meeting reports and one expert consensus guideline, with a significant focus on the utility of NAC for locally advanced breast cancer (LABC) [4][5][6]. However, over the last few years, research has increasingly demonstrated the important prognostic and predictive implications of treating certain subtypes of early breast cancer (HER2 positive and triple negative) with NAC [3], irrespective of upfront clinical stage or operability. The routine use of NAC for early stage breast cancer that is operable on presentation is a paradigm shift of great importance, with significant therapeutic and resource implications [7,8]. Rapidly evolving evidence, the paucity of long-term data in some studies, the use of variable patient endpoints, and drug funding disparities within the country, can create some uncertainty in therapeutic approaches, but also opportunities for ongoing clinical trials [9]. Considering all this, there is an ongoing need for expert opinion to help consolidate the approach to NABC patient management. This is paramount to achieving the best possible uniform outcomes for Canadian breast cancer patients, particularly considering the publicly funded healthcare landscape. International breast oncology guidelines often embed the use of NAC within larger documents pertaining to breast cancer management [10]. In addition, some of the NAC recommendations are resource and practice-setting specific; there also remains some debate around the impact of certain research findings on clinical care (example using pathologic complete response rate as a practice-changing endpoint). Finally, most guidelines, including the recently published American Society of Clinical Oncology (ASCO) document, focus on systemic therapy alone [11], and do not include the subsequent implications of systemic therapy on surgical and radiation therapy decision-making. We, therefore, developed a contemporary, evidence-based Canadian National Consensus on the Neoadjuvant Treatment of Breast Cancer, using validated consensus methodology. This is meant to capture the most up-to-date evidence on optimal patient management throughout the entire treatment journey, while aligning multidisciplinary expert opinion with practice-based consensus from clinicians across the country.
Guideline type: Evidence Based Consensus. Intended users: Practitioners who treat invasive breast cancer (pathology, radiology, surgery, medical oncology, radiation oncology, and other involved health professions.)
Applicable resource setting: Upper middle to high income nations with access to advanced screening, diagnostic, pathologic, surgical, radiation, and systemic therapy options.
# Methods
# Expert guideline panel
An expert guideline steering committee was established at the most recent Canadian National NABC Consortium meeting (May 2019, Ontario, Canada). The committee was comprised of academic and clinical experts in breast cancer management in the following specialties: medical oncology, surgical oncology, radiation oncology, breast radiology and anatomic pathology. All committee experts practice in academic cancer centres for more than 5 years, treat more than 100 unique breast cancer patients per year, and have demonstrated research and academic impact in NABC (peer-reviewed publications, research grants/projects, clinical trials involvement, and/or academic meeting presentations.) Representation from multiple Canadian provinces was sought.
# Systematic evidence review
A systematic review of the literature was performed. As management for the neoadjuvant treatment of locally advanced breast cancer and general treatment principles of early breast cancer are well-established [5,10,11], the focus of the review was to update established principles of NABC care and highlight areas of new or evolving evidence that in particular would benefit from consensus to help improve practice. The overall focus was defined as the comprehensive management of breast cancer with a neoadjuvant therapy approach, including specific attention to the domains of multi-disciplinary assessment, diagnosis, monitoring, systemic therapy and local treatment. To maintain scope and feasibility, a single database search (PUBMED) was performed with the following parameters: invasive breast cancer, neoadjuvant, limited to phase 3 or 4 studies, meta-analysis, systematic review, or guidelines published in the English language. To focus mainly on new developments in this area, the search was limited to the past 5 years (initially October 2015 to October 2020 inclusive); the search was then repeated for November 2020 to May 2021 prior to manuscript preparation, to ensure no new relevant evidence had been published (Fig. 1). In December 2020, July 2021, October 2021, and December 2021, a targeted online gray literature search was completed to review any updated evidence as presented at four high impact oncology meetings (San Antonio Breast Cancer Symposium 2020 and 2021, American Society of Clinical Oncology 2021, European Society of Medical Oncology 2021), and any new published guidelines. The guideline panel decided it was important to capture any relevant new evidence with a select few additional recommendations, to ensure the guideline was most up-to-date. It was decided a priori that if the new evidence did not change the relevance or accuracy of existing recommendations, or greatly change the guideline's scope or impact, these few select recommendations would not be sent for consensus to prevent delays in final guideline submission.
# Consensus statements and consensus process
The steering committee developed recommendations for consensus based on the evidence review and discussion of important principles of NABC care, as established during and since the last Canadian NABC consensus statement in 2015 [5]. Discussions were held virtually (telephone), and via email correspondence. The statements were further reviewed by five additional clinical experts in breast surgical, radiation, and medical oncology; these expert reviewers were identified from past Canadian NABC Consortium involvement. Representation from multiple provinces was again ensured.
The Modified-Delphi approach is well recognized as a robust consensus methodology, particularly for consensus development in healthcare [12,13]. This anonymous, survey-based consensus guideline model has several advantages compared to more traditional expert-based or nominal group methods; the latter rely solely on the opinions of a select group of individuals, and can be more subject to bias Fig. 1 Literature search consort diagram. There were 78 studies included for analysis after applying the inclusion and exclusion criteria or the influence of the most vocal members of a guideline committee. Using the modified-Delphi approach, final statements were emailed to potential physician respondents using a secure online survey platform (Survey Monkey Inc., San Mateo, California, USA). Potential respondents were identified as being probable breast cancer clinicians by national or provincial medical society membership, provincial cancer centre affiliation, description of medical practice as available in public domain (example: institutional websites), recommendation by invited colleagues, and/or previous attendance at Canadian National NABC Consortium meetings. Invited participants were instructed only to respond if they had enough clinical expertise and experience in the neoadjuvant treatment of breast cancer to have an opinion. To achieve a broad practice-based consensus on expert recommendations, the guideline committee preferred not to restrict responses by years of practice or number of patients, and assumed respondents would only engage in the survey if they felt comfortable with the subject matter. Invitation to participate in the consensus process was carried out using email addresses for these individuals, as available in the public domain or through personal solicitation from the steering committee, or as shared by invited colleagues. Given the focus of this guideline was an practice-based physician consensus, other health care disciplines, and patient representatives were not included in the statement development or consensus process itself. Widespread physician representation was targeted, including multidisciplinary providers in both academic and community centers and in all Canadian provinces with comprehensive cancer programs.
Responses were anonymous; only respondent demographics including discipline, geographic area of practice, and years in practice were collected. Respondents were asked to indicate agreement, disagreement, or neutrality (i.e., "no opinion") to each statement. Given that multiple oncology specialties were involved, respondents were asked to indicate "no opinion" only if the statement was outside of their area of direct practice and not because they had no opinion about a statement related to their specialty. Reminders were sent twice over an 8-week period. Respondents were required to provide detailed qualitative feedback regarding statements they disagreed with. Specifically, respondents were instructed that if they did not agree with a statement in its entirety, to indicate disagreement, and provide detailed feedback regarding the elements they did not agree with. As per Modified-Delphi process, statements that did not achieve consensus were reviewed by the steering committee and modified based on the qualitative feedback as collected by the survey. These statements were emailed for a second round of survey; this was emailed to the same participants. Participants were instructed to respond only if they had responded to the first survey; one reminder was sent over 6 weeks. A third round was planned if required (Fig. 2).
# Consensus analysis
Agreement statistics were calculated for each statement based on the total number of responses. The denominator for each statement (N, Agree + Disagree) was calculated as the sum of respondents who agreed and disagreed. Blank responses and those who indicated "no opinion" were excluded from the total number of responses for each question. The numerator (n, Agree) corresponded to the number of respondents who indicated "agree" for each statement. The proportion (n/N) was converted to a percent value (%) to determine the consensus value. A threshold value was determined a priori; consensus was defined as statements with 80% or more of respondents in agreement; statements with consensus > 79.5% were rounded up to 80%. Statements with less than an 80% (i.e., ≤ 79.5%) agreement level were marked for modification in the next round of survey, as per Modified Delphi methodology. Qualitative feedback was collected from respondents who indicated disagreement with particular statements; this feedback was utilized to modify statements that did not achieve consensus with the initial round.
# Grading of recommendations
The final statements were ranked using the GRADE recommendations for guidelines (Strong or Conditional) [14], with consideration of the four domains within the framework for a recommendation's direction and strength, which include: estimates of effect for desirable and undesirable outcomes of interest, confidence in the estimates of effect, estimates of values and preferences, and resource use [15]. In considering this framework, recommendations were generally considered strong if they were based on positive data and had level 1 or 2 evidence as per the GRADE framework for ranking evidence [14], and met the threshold for consensus. If a recommendation was lacking updated level 1-2 evidence in the last 5 years (acknowledging the review was limited to this timeframe), was deemed imperative to patient care and received a very high level of consensus (> 89%), it was also rated as strong. Recommendations deemed less impactful to patient care, with level 3 or 4 evidence, with preliminary (short term) level 1 or 2 evidence, high resource implications/lack of public funding, or with no published evidence and consensus < 90%, were marked as conditional. The term conditional was preferred over "weak" to indicate these statements may have evolving data thatmay strengthen the recommendation over time) and/or the statement may still be impactful for patient care, particularly in certain contexts. Available evidence was linked to recommendations in the "Grading" column (Tables 1 and 2). As the consensus statements may have been based on several sources of evidence with varying strengths, and to illustrate the grading of recommendations was not based on the strength of evidence alone (as discussed above), formal grading of the evidence was not integrated into the guideline table. Finally, additional statements added by the panel (Table 3) were all graded as "conditional" to reflect that they were not sent for consensus.
# Engagement of further stakeholders
The final guideline was reviewed by a pharmacist, breast cancer patient representative, and a neoadjuvant nurse navigator, all affiliated with the Sunnybrook Health Sciences Centre. Their feedback on the premise of the guideline, agreement with recommendations, and on implementation was sought.
# Results
A total of 47 recommendations were initially created by the steering committee and integrated into a consensus survey. Email invitations to complete the survey were sent to 391 clinicians in October 2020. There were 109 participants who completed the survey, for a response rate of 28%. Surgical oncology represented the largest respondent group (41/109; 37.6%), followed by medical oncology (29/109; 26.61%) and radiation oncology (21/109; 19.27%) (Fig. 3). Respondents were predominantly within their mid-career level of practice. Geographical representation was achieved from across several Canadian provinces, although the majority of respondents were located in central Canada (66.0% Ontario and Quebec), and at academic health institutions (77.0%). A summary of all respondent profiles is presented in Fig. 3. F.10 Regional radiation for patients after NAC who have positive lymph nodes on surgical pathology (regardless of upfront nodal status): Patients with 4 or more residual positive lymph nodes at the time of surgery should be offered local-regional radiotherapy Patients with 1-3 residual positive lymph nodes should also be strongly considered for local-regional radiotherapy. There is a lack of clear evidence of the benefit of localregional radiotherapy for these patients after NAC and BCS F.11 Regional radiation for patients with clinically positive nodes prior to NAC: Patients who have cN2-3 at presentation, or multiple high-risk features (age, tumor size, LVI, grade, ER-negative/HER2 positive receptor status, location) should be considered for localregional radiation following NAC, irrespective of response on surgical pathology. Patients with initial N1 disease should also be considered for local-regional radiation, regardless of response to NAC Those with suspicious but indeterminate N1 disease prior to NAC, and negative nodal dissection at surgery (sentinel or axillary) can be considered for regional radiation on a case-by-case basis F.12 Treatment of N0 disease after NAC is controversial. Those patients with no residual nodal disease should have a discussion regarding benefits of regional radiotherapy based on presence of high-risk primary tumor features, nodal disease at presentation, and extent of response in lymph nodes and breast to NAC. A comment on fibrous scarring in the lymph nodes on final surgical pathology can be used as a marker of NAC effect, and potential targeting for regional radiation Ongoing trials seek to better define the role of regional RT for N0 disease after NAC, and to assess the benefit of local-regional radiation in patients with in-breast pCR but nodepositive disease after NAC F.13 Post-Mastectomy Radiation Therapy (PMRT): Patients with primary tumors with multiple high-risk features and N0 disease at surgery should also be considered for either localregional radiotherapy or chest wall radiotherapy. Factors such as primary tumor size, grade, lymphovascular invasion (LVI), age, tumor location and margin status should be considered. Regional/nodal radiation should be considered in patients following mastectomy who have residual nodal disease following NAC: patients with 4 or more residual positive lymph nodes at the time of surgery should be offered local-regional RT. Patients with 1-3 residual positive lymph nodes should also be strongly considered for localregional radiation. Patients with cN2-3 disease at presentation should be offered localregional radiation after mastectomy, regardless of response to NAC. Patients with N1 disease at presentation should also be considered for local-regional radiation, regardless of NAC response. Recommendations with results in bold did NOT meet the pre-specified threshold for consensus in Round 1 (>79%); these recommendations were modified and sent for a second round of consensus Neoadjuvant therapy patient selection B.6-R NAC can be offered primarily* for tumor down staging, to select patients who are eligible for breast conservation (considering tumor focality, tumor to breast size ratio, and implications for radiation/reconstruction). The likelihood of tumor response based on biomarkers (example: lower chance in ER positive, HER2 negative) should be considered, in addition to the risk of over-treatment with chemotherapy in certain patients *Added Note-Clarification of the term "primary": in select patients NAC may be offered for down-staging of the tumour as the "primary" goal, however in other patients, NAC is recommended beyond the goal of potentially decreasing clinical tumour burden (example: for HER2 + /triple negative phenotypes The lack of data in this realm should be noted, as well as the implications for potentially requiring further treatment post-operatively for residual disease, and eligibility criteria for these additional therapies (example: adjuvant TDM-1 data is in HER-2 positive patients with 6 or more cycles of NAC.)Refer to section on additional adjuvant therapies 29/36 80.56 Conditional D.3-R.1 Pathologic complete response (pCR) has been established as a meaningful prognostic surrogate for particular subtypes of breast cancer, particularly triple negative and ER-negative, HER-2 positive (with the use of anti-HER2 therapy.) Additional systemic therapies improve outcomes for triple negative and HER-2 positive cancers that have residual disease (lack of pCR) after NAC. Therefore, improving pCR rates means less patients with these subtypes may require additional systemic therapy after surgery. Considering these principles; regarding targeted therapies during NAC: a. Trastuzumab should be given during the taxane portion of NAC for HER-2 positive breast cancers
# Consensus agreement: round 1
During the first survey round, 89.4% of questions (42/47) achieved 80% or greater consensus (agreement). A summary of all statements with the levels of consensus is presented in Table 1. Consensus was not reached for five statements under the following domains: patient selection, neoadjuvant systemic therapy, and local-regional management after neoadjuvant systemic therapy. The five statements that did not receive 80% agreement were modified based on qualitative feedback from the survey. These five statements were restructured into 12 statements and sent for a second round of survey in December 2020. One additional new statement was integrated into the second survey to encompass new data regarding adjuvant therapy that became available as part of the targeted gray literature search in at that time.
# Consensus agreement: round 2
In the second round, there were 81 respondents (81/109; 74.3% of respondents from round 1). A summary of the modified statements in round 2 is outlined in Table 2. All of the modified statements reached ≥ 80% consensus. The new statement on adjuvant therapy achieved consensus. A third
D.3-R.4
Regarding targeted therapies during NAC: d. There is conflicting evidence regarding the addition of a platinum to the taxanecontaining portion of a third-generation NAC regimen; however, if accessible and tolerable, a platinum agent can be considered for triple negative breast cancers, in order to potentially improve PCR. There is evidence that BRCA-associated tumors may not benefit from the addition of a platinum, and therefore ideal patient selection without the knowledge of BRCA-status may be challenging. There is data to support platinums for NAC as an anthracycline-sparing approach. Access remains an issue in many Canadian regions. The addition of a platinum agent to a taxane can also be considered if suboptimal or progressive disease is observed in triple negative tumors during the anthracycline portion of NAC D.5-R.1 For patients in whom tumor progression on NAC is treated with radiation, the addition of a radio-sensitizing systemic agent is reasonable to enhance radiotherapy response, with the primary goal of achieving tumor respectability. There is some practice-based data available for the use of weekly platinum agents with radiation for the treatment of triple negative tumors progressing on NAC. This approach can be considered for eligible patients (considering the balance with modestly increased toxicities)
39/49 79.59 Conditional Local-regional management after neoadjuvant systemic therapy F.4-R.1 Patients with initial N1 disease can be considered for (targeted) sentinel lymph node biopsy if: Patients are clinically (by physical exam) node negative prior to definitive surgery, AND dual tracer is used, AND At least 3 sentinel lymph nodes are removed. At institutions where lymph nodes are clipped at diagnosis, it is recommended that they are localized at surgery, and excised along with the sentinel nodes. Pathologic nodal assessment with immunohistochemistry should be available. Patients should be counseled that the risk of false negatives is low with a sentinel-lymph node approach that meets the criteria above, but that long term outcomes are still uncertain. Multi-disciplinary discussion with a radiation oncologist prior to finalizing the axillary surgical approach (as with the primary breast tumor) is also encouraged *Added notes were not integrated into the consensus statements, and were included to provide further context and clarity after manuscript review round of survey was therefore not required, given the second round achieved complete consensus on this new statement, and all revised statements.
# Systematic review
There were 389 citations found on systematic review; 311 were excluded based on abstract review; criteria are shown in Fig. 1. There were many early phase studies, and those focused on biomarker assessment, a rapidly evolving area of research in the neoadjuvant realm. As much of this data is exploratory or early, these studies were excluded. There were also many studies evaluating imaging response modalities for neoadjuvant therapy; some of these were included and matched to the statement regarding their investigational use.
In general, studies that had negative results or did not meet primary efficacy endpoints, or with early phase data only, or therapies that had subsequent or conflicting data demonstrating a lack of meaningful impact on patient care, were excluded. The 78 included citations were fully reviewed and matched with guideline statements. For ease of readability and clarity, detailed descriptions of the evidence were not included in the recommendation table itself. Some recommendations did not have associated citations, as they were based on data published before the systematic review timeframe.
# Further evidence review and additional statements
Targeted gray literature review did not demonstrate any impact on the accuracy or relevance of existing consensus statements. However, five additional recommendations were created by the expert guideline panel to reflect important areas of practice deemed not to be captured in the initial or revised statements This included statements on sentinel lymph node biopsy for N0 disease [16], nabpaclitaxel for neoadjuvant therapy [17,18], and two additional adjuvant therapies, neratinib [19] and olaparib [20]. Finally, the rapidly evolving impact of molecular gene profiling on NABC was decided to be more clearly addressed established in the adjuvant setting for ER positive, HER2 negative breast cancers that are lymph node negative and 1-3 node positive. These tools can help select patients that may or may not benefit from cytotoxic chemotherapy in addition to adjuvant endocrine therapy. The utility of these assays in lymph node positive cancers is best established for post-menopausal patients. The pre-operative use of these tools on ER positive, HER2 negative core biopsies remains an evolving area of investigation and practice. Clinicians may consider using these tests, if available, as an approach to better define N0 or N1 ER positive HER2 negative cancers at the time of diagnosis, as high molecular risk that may benefit from NAC, versus lower risk that may benefit from upfront surgery. The impact of clinical nodal status at the time of diagnosis, and menopausal status should be taken into account in these circumstances, as well as consideration that the utility of these tests is currently best established in the adjuvant setting where pathologic stage without the impact of NAC is known. Multi-disciplinary discussion on how to integrate the results of these tests in the pre-operative setting is encouraged (in particular discussion between surgeons and medical oncologists.) It should be noted for clinicians and patients that prospective data validating this approach is still accumulating, and access to these tests for this purpose is currently heterogeneous after final external review. The five additional statements are presented in Table 3. Footnotes were included for a few consensus recommendations to clarify concepts as suggested by external review.
# Additional stakeholder feedback
The nursing, patient, and pharmacist feedback sought demonstrated agreement with the recommendations overall, and in particular with the multi-disciplinary approach to NAC care. Suggestions to disseminate the guideline in patient, nursing, and pharmacy forums were made.
# Discussion
There was a high level of agreement on 59 final statements encompassing the complex, multidisciplinary care pathway of neoadjuvant breast cancer patients. Five additional statements were not sent for consensus but were integrated to reflect the most up-to-date evidence pertaining to NABC at the time of manuscript preparation. Important highlights of this guideline include the recommendation to use neoadjuvant systemic therapy for early (operable) stage HER-2 positive and triple negative breast cancer, and the subsequent use of additional adjuvant therapies for those patients with residual disease after definitive surgery. In addition, this guideline demonstrates the importance of multi-disciplinary collaboration throughout the patient care journey. Finally, this consensus guideline demonstrates a balance between improving patient outcomes in an evidence-based manner while seeking to minimize toxicities, with a focus on individualized decision making, including clinical trial enrollment, particularly where evidence is less robust or still accumulating. This is particularly relevant for local-regional treatment approaches where evidence continues to accumulate from ongoing studies.
# Assessment of resource implications
Given the broad scope of this guideline, including many treatment modalities, formal assessment of cost-effectiveness for individual therapies was outside the scope of this guideline. The committee acknowledged that most of the recommendations were applicable to High-middle and High income countries. Due to the robust health technology assessment for cancer drug funding recommendations nationally (pan-Canadian Oncology Drug Review through CADTH) [21], provincially funded systemic therapies for cancer generally have a cost-effectiveness backing within the Canadian healthcare landscape. Therefore, Health Canada approved agents that do not have wide-spread public funding or remain under evaluation (such as pertuzumab) were acknowledged within the recommendations as potentially having resource constraints at this current time. Corresponding statements suggested that accessibility and resources should be considered in particular for these drugs.
# Limitations
Limitations of this guideline include only a 29% response rate to the consensus survey, and potential sampling and non-response bias. Primarily academic physicians responded to the survey, as such, the opinion of breast cancer clinicians in community practice settings may be under-represented. In addition, medical oncologists and surgeons comprised the largest group of respondents, and the opinion of other specialties may not completely be captured. There were also approximately 25% of initial participants who did not respond to the second round of survey, potentially impacting the results. However, this is unlikely, given the high levels of initial consensus on these statements with the first round (range 66-79%). Patient and other health care professionals were not engaged in the initial development of recommendations; their feedback was only sought on the final guideline and implementation plan. Five additional statements were created but not sent for consensus to prevent delay on the timely dissemination of this guideline; however, they are unlikely to impact on the scope and relevance of the guideline in general.
# Summary and knowledge dissemination plan
This work represents an updated Canadian National Consensus on the Neoadjuvant treatment of breast cancer, across all parts of the therapeutic patient journey. A systematic review of recent literature and formal grading of recommendations was also achieved. The evidence was reviewed several times during guideline preparation, ensuring the most updated data was incorporated in a meaningful manner. The neoadjuvant treatment of breast cancer is a rapidly evolving area of clinical and academic interest; data can change quickly and uptake in clinical settings can falter based on sub-optimal knowledge dissemination or hesitancy to change practice. We believe our approach demonstrates Canadian consensus on key areas of neoadjuvant care, integrating available evidence, expert opinion, and practice-based consensus. We believe this guideline can help optimize patient outcomes across the country, by synthesizing the evidence into comprehensive recommendations for clinical care. Furthermore, the presence of national practice guidelines may help to foster clinical and policy change within healthcare organizations and health networks, with the hope of achieving uniformity of practice and thus patient outcomes. Given the importance of ensuring patient management is aligned with best practice, and to help optimize the use of resources and expertise in this area, we hope to achieve broad dissemination of this consensus guideline. A particular strength of this work is the inclusion of all elements of the patient treatment journey, formal grading of recommendations, and also achieving high levels of consensus, particularly in areas where evidence is lacking or evolving. This may help implementation and uptake of practice elements that can standardize Canadian breast cancer care as the neoadjuvant landscape continues to rapidly evolve. This guideline will be disseminated at the next Canadian National NABC Consensus meeting (planned for mid-2022), and ideally at national and international academic forums. There is also much interest in this document from national, provincial and hospital-based cancer programs in Canada to help guide local practice and resource allocation. We hope this guideline will be a strong addition to the published literature in this important area.
#
Acknowledgements Ivan Tyono (pharmacist), Althea Van Massop (nurse navigator), Shelyna Khalfan (patient).
#
Funding Existing academic funds of primary author.
# Data availability Not applicable.
Code availability Not applicable.
# Declarations
Conflicts of Interest Primary Authors: SG-advisory board (Roche, Novartis, Lilly, Pfizer, Exact Science, and Agendia). External Reviewer: JFB-speaking honoraria (Roche, Novartis, Genomic Health, Pfizer, Allergan and Merck), consultant (Roche), Grants (Roche, Novartis, Pfzier, Abbvie), advisory board (Roche, Genomic Health, Nanostring Technologies, Pfizer, Lilly, Novartis and Merck). None of these COI were deemed impactful on the development or review of specific guideline recommendations.
# Ethical approval Not applicable.
Research involving humans and animal participants Not applicable.
# Informed consent Not applicable.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
# Authors and Affiliations
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l'iode-123 IOFLUPANE peut apporter des informations importantes. Cette investigation en médecine nucléaire est recommandée dans les situations suivantes : 1) Antécédents qui pourraient être compatibles avec des tremblements essentiels (Parkinsonisme versus tremblement essentiel). 2) Signes légers ou subtils de Parkinsonisme (Parkinsonisme versus variante de la normale).
3) Antécédents d'exposition prolongée à un agent bloquant les récepteurs de la dopamine (Parkinsonisme versus induction médicamenteuse. 4) Manifestations inhabituelles ou variables à l'examen (Parkinsonisme versus parkinsonisme fonctionnel. 5) Dystonie proéminente (Parkinsonisme versus tremblements dystoniques. 6) Suspicion de Parkinsonisme superposé (par exemple bradycardie faciale) chez des personnes connues comme porteuses de maladie neurologique affectant le système moteur (myélopathie, accident vasculo-cérébral, maladie neuromusculaire, etc.). 7) Autres manifestations atypiques (mauvaise réponse à la Lévodopa, absence de progression de la maladie, apparition en très jeune âge, etc.).
# LES SEULES CONTRE-INDICATIONS INCLUENT :
- Grossesse.
- Incapacité à coopérer avec l'examen d'imagerie cérébrale.
- Hypersensibilité connue à la substance active ou à l'un des ses éléments. Une allergie à l'iode n'est pas une contre-indication absolue.
# CONTRE-INDICATION RELATIVE:
- L'allaitement maternel Lors de la préparation du patient, l'obtention des antécédents et de s'assurer que le patient ne prend pas d'agents perturbateurs sont de première importance. De plus, une sélection adéquate des paramètres d'acquisition de l'examen et le positionnement du patient sont des éléments essentiels pour l'obtention d'un examen diagnostique valable.
Le rapport final doit fournir une impression globale d'une scintigraphie Normale ou Anormale. L'interprétation peut inclure à la fois une évaluation qualitative et des analyses semi-quantitatives par les médecins formés pour interpréter ces scintigraphies.
Le médecin référent peut alors utiliser les résultats de la scintigraphie à l'iode-123 IOFLUPANE pour gérer au mieux la condition du patient.
# INTRODUCTION
The Canadian Association of Nuclear Medicine (CANM) strives for excellence in the practice of diagnostic and therapeutic nuclear medicine by promoting the continued professional competence of nuclear medicine specialists, establishing guidelines of clinical practice, and encouraging biomedical research. We work with all professionals in nuclear medicine to ensure that Canadians have access to the highest quality nuclear medicine services.
These practice guidelines have been developed with input from clinician experts in movement disorders as well as neuroimaging through a consensus process and have been extensively reviewed and approved by the CANM Board of Directors. They are proposed as a reference tool to clinicians dealing with patients with movement disorders to help provide appropriate care. They are not considered to be inflexible rules or requirements of practice. The final decision regarding the ordering and use of any procedure or course of action is made by the clinician based on the situation and the clinician's judgement. These guidelines are intended for clinicians as well as nuclear medicine physicians to aid in understanding the test, provide guidance with appropriate ordering as well as for interpretation and reporting.
Clinical diagnosis of Parkinsonism is straightforward and arrived at based on clinical observations without the use of additional tests in the vast majority of cases. However, for incomplete syndromes, or an overlap between multiple concurrent conditions especially in early stage presentation, utilizing imaging of the dopamine transport system provides an improvement in diagnostic accuracy. 1,2,3 N-v-fluoropropyl-2b-carbomethoxy-3b-(4-123I-iodo-phenyl) nortropane (123I-ioflupane) is a molecular imaging agent used to demonstrate the location and concentration of cell membrane dopamine transporters (DaTs) located on axon terminals of nigral dopaminergic projection neurons. It has shown efficacy for detecting degeneration of the dopaminergic nigro-striatal pathway, allowing better separation of patients with essential tremor from those with Parkinsonian syndromes, as well as differentiating between some causes of Parkinsonism (e.g. functional/psychogenic or iatrogenic forms).
This document provides information and guidance for the indications, technical aspects, interpretation, and reporting of DaT single photon emissions computed tomography (SPECT) scans with 123I-ioflupane. These have been developed using the previous work of the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging. 4,5,6
# INDICATIONS
Making a diagnosis of idiopathic Parkinson's disease (PD) generally relies on the identification of cardinal motor signs and the absence of features indicative of another disease with the support of levodopa responsiveness. In the vast majority of cases, the diagnosis of PD can be made based entirely on the clinical assessment. Up until 2015, the most widely accepted clinical criteria for PD diagnosis was the UK Brain bank criteria. 6 In 2015, the International Parkinson and Movement Disorder Society published new guidelines that have been implemented in the 2 nd edition of the Canadian Guideline for PD. 7,8 The clinical observations useful in the diagnosis of PD can however be inaccurate even in the hands of experienced neurologists, particularly early in the course of the disease. Large clinicopathological series estimate that 10-25% of patients with a clinical diagnosis of established PD will have an alternative diagnosis at autopsy. 6,9,10,11 This underscores the important role of ancillary tests in the diagnostic workup of select patients with Parkinsonism.
In cases of diagnostic uncertainty, DaT scanning can be considered as an aid to the clinical diagnosis 3 . Abnormal uptake of -FP-CIT has consistently been shown across studies to have extremely high sensitivity and specificity in cases of neurodegenerative parkinsonism associated with loss of nigrostriatal dopamine neurons. 12,13,14,15,16,17 Clinical follow-up is the reference standard in most of these studies but is only a surrogate of the gold standard, which is the autopsy-proven definitive diagnosis. However, DaT imaging has been shown to be very accurate in the early prediction of the final clinical diagnosis obtained after long term follow-up. Importantly, DaT scanning is not helpful in differentiating between neurodegenerative parkinsonian disorders. 17b,17c DaT scanning has been shown to have a substantial impact on management and confidence of diagnosis in select patients (Table 1). Indications for testing may include: 3,5,18,19 1) history or examination features that could be compatible with essential tremor (i.e. PD vs. ET) 2) mild or subtle signs of parkinsonism (i.e. PD vs. normal variant)
3) a history of prolonged exposure to a dopamine receptor blocking agent (i.e. PD vs. drug-induced parkinsonism) 4) distractible or variable features on exam (ie. PD vs. functional parkinsonism) 5) prominent dystonia (i.e. PD vs. dystonic tremor) 6) suspected superimposed parkinsonism (e.g. facial bradykinesia) in persons with a known neurologic disease affecting the motor system (myelopathy, stroke, neuromuscular disease, etc.) 7) other atypical signs (poor response to levodopa, lack of disease progression, very young onset, etc.)
Of note, there does not appear to be a diagnostic benefit to repeat scanning after a period of time if the initial scan is normal. 20
# Abnormal striatal uptake of -FP-CIT Normal striatal uptake of -FP-CIT
# Variable findings
DaT imaging is a reliable surrogate of nigro-striatal degeneration and some conditions (PD in particular) are always associated with it, thus explaining the diagnostic role of SPECT scans with 123 I-ioflupane. In some condition however, the impairment of the nigro-striatal fiber is variable and so is the striatal uptake.
'Vascular parkinsonism' has undergone a drastic nosologic revision in recent years and it is now acknowledged that it is often an overdiagnosed condition in patients with degenerative diseases also featuring vascular changes of the white matter (the so-called "pseudovascular parkinsonism"). 22 In some cases of pseudovascular parkinsonism a more diffuse and symmetrical reduction of uptake is observed 23 often with irregularities in the profile of the putamen. In "definite" vascular parkinsonism there is an ischemic or hemorrhagic stroke involving the substantia nigra and/or nigrostriatal pathway and DaT imaging is positive. Most of these cases are unilateral parkinsonism. By contrast, DaT is normal in "vascular pseudoparkinsonism" (e.g., akinetic mutism resulting from bilateral mesial frontal strokes or apathetic depression from bilateral striatal lacunar strokes). 24 Cortico-basal syndrome (CBS) is the most challenging movement disorder from a diagnostic standpoint as its underlying pathology is cortico-basal degeneration only in a minority of cases (other being caused by progressive supranuclear palsy (PSP), Alzheimer or even prion pathology). Not surprisingly DaT imaging is variable depending on the underlying pathology, with some cases showing normal uptake. 25 A similar scenario is seen in orthostatic tremor (OT), in which an abnormal DaT is supposed to be found in the so-called 'plus' forms (as opposed to primary or secondary forms), occurring when OT is associated with PD or other cases of degenerative parkinsonism. 26 Likewise, primary progressive freezing of gait may herald many different degenerative processes and an abnormal DaT is seen in cases caused by PSP pathology while a normal uptake is more often seen in cases evolving towards CBS or motor neuron diseases. 27 Holmes tremor is another heterogenous condition supposedly caused by a strategic (usually vascular) lesion involving both the nigro-striatal system and the cerebello-thalamic fibers. However, due to the variability of lesions, a normal DaT study is still possible (e.g. in case of lesions not involving the midbrain). 28 Many other conditions are associated with variable involvement of the nigra which therefore present with different DaT imaging appearances (e.g. Huntington disease) and in some cases an improvement of the uptake has been reported following treatment, such as in Normal Pressure Hydrocephalus (NPH). Not many papers have explored the role of DaT imaging in NPH but the following scenarios can be hypothesized: 1) an abnormal uptake in patients with co-existing PD or other degenerative conditions involving the pars compacta of the substantia nigra, 2) an abnormal uptake in patients mistakenly diagnosed with NPH while having PD or other degenerative conditions involving the pars compacta of the substantia nigra, 3) a normal uptake (e.g. in the so-called "pseudovascular pseudoparkinsonism" 29 , and 4) an abnormal uptake caused by the mechanical compression of the fiber reaching the putamen.
# The role of DaT imaging in research
DaT imaging has different roles in research protocols, some of which is still not fully explored but at least 5 principal applications can be listed here:
- DaT imaging as a biomarker to assess PD progression, for example, in the Parkinson Progression Marker Initiative funded by the Michael J Fox Foundation 30 2. Study of the regional differences in uptake to understand different PD presentations 3. Use of DaT imaging as endophenotype in populations at risk of developing PD, such as carriers of genetic mutation 31 or patients with REM sleep behavioral disorder 4. DaT scanning can be used as a marker of the protective effect of surgical 32 or pharmacological treatment. 33 As for the last point, it should be emphasized that the DaT expression is influenced by factors other than number of dopaminergic neurons (e.g. up or downregulation influenced by drugs), thus its role in proving a disease modifying effect is object of debate.
# CONTRAINDICATIONS
Absolute:
- Pregnancy.
- Inability to cooperate with brain imaging.
- Known hypersensitivity to the active substance or to any of its excipients. An iodine allergy is, however, not an absolute contraindication to receiving this radiotracer.
# Relative:
Breastfeeding. If possible, consider delaying the examination until breastfeeding has ceased. It is unknown if ioflupane is secreted in human milk, therefore, if administration is considered necessary, breast-feeding should be interrupted for a minimum of 1 day and up to 6 days. 34,35,36
# REQUEST/REQUISITION SUGGESTED FORMAT
The suggested format for the requisition is to have boxes to allow the referring clinician to provide the following information:
# PATIENT PREPARATION
Prior to arrival, medications that may alter tracer binding should be stopped, if possible, for at least 5 halflives (see Table 2 for medications, durations to be held, and effect on imaging). The decision to withdraw medications should be made by the specialist caring for the patient after weighing benefits and risks. 71 5 days (24 hrs) = increase binding, = decrease binding, = no effect, NDRI = norepinephrine-dopamine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitors, SNRIs = Serotonin-norepinephrine reuptake inhibitors, MAO-B = monoamine oxidase-B, COMT = catechol-O-methyltransferase, DAT = dopamine transporter. T = theoretical, H = human data, A = animal data., CR = case report At least 1 hour prior to radiotracer injection, a single 400mg dose of potassium perchlorate or 100mg equivalent of iodide in Lugol's solution should be administered to reduce exposure of the thyroid to free 123 I. This is not mandatory as the radiation dose expected to the thyroid gland would be very low and it may be avoided if patients are known to have sensitivities. A dim or quiet environment is not necessary for the uptake period.
# IMAGING
Set Up and Positioning 2.5 or 5-mL solution containing 185 or 370MBq of 123 I-ioflupane is administered intravenously as a slow bolus over roughly 20 s followed by a saline flush. 3 Binding of the radiotracer is stable between 3 and 6 hours after injection, at which point SPECT imaging can be acquired. It is encouraged that each centre optimize reproducibility and reduce variability by maintaining the same interval. 56,72,73 Voiding is recommended prior to scanning to avoid interruptions and frequently after imaging to reduce radiation exposure. All eyeglasses, earrings, hair clips, combs or hearing aids should be removed if possible. 74 The patient should be supine with the head straight (chin in neutral position and vertical canthomeatal line) and instructed to remain still during the image acquisition. Reducing head tilt is desirable but should not jeopardize patient comfort as images can be reoriented following acquisition. The corpus striatum(caudate nucleus and putamen) and occiput are required in the field of view. A case by case strategic decision should be considered in patients with L-DOPA induced dyskinesias as whether to hold the drug. Patients with severe tremor should likely be scanned under the effect of the therapy but this noted in the report. Although rarely of use, restraint devices can be utilized to minimize movement. If movement is an issue, short-acting benzodiazepine sedation does not affect image quality and can be used if agreed upon by the patient or patient's legal representative, referring physician and the patient has arranged appropriate transport following the exam. 35
# Equipment & Image Acquisition
Detector: Multiple detector or dedicated SPECT camera are strongly preferred over single headed cameras due to shortened scan time to achieve adequate counts at the routine doses administered for data acquisition. 35 The field of view should include the entire brain and the smallest possible, safe rotation radius should be used (typically 11-15cm). 35 Collimator: Low Energy High Resolution (LEHR) parallel-hole collimation is adequate, but, if available, fan-beam collimators may be preferred for improved resolution at the cost of count rate capability. Photopeak: The photopeak should be 159keV +/-10%. Additional energy windows can be used for scatter correction. Matrix: A 128 x 128 matrix is recommended. Acquisition pixel size should be one-third to one-half of the expected resolution. Hardware zoom may be necessary to achieve an appropriate pixel size of 3.5-4.5mm. Slices should be 1 pixel thick. Angular Sampling, Scan Time and Total Detected Events: 3-degree angular sampling for 360 degrees of coverage (180 degrees for each head in a dual head camera) is recommended, although continuous rotation may also be used. The number of seconds per position depends on the sensitivity of the system, but usually 30-40s are required. A minimum of 1.5 million total counts should be collected for optimal images if scatter correction is applied (otherwise >3 million). Total acquisition time will vary according to camera specifications, but is often between 30-45 minutes. Consider segmenting data acquisition into multiple sequential acquisitions which may permit exclusion of data with artefacts (i.e. exclude segments with movement artifact). Image Processing: Projection data in cine mode and sinograms should be displayed to assess scan quality of data, patient motion, and artifacts. Rescanning will be required for large movements, but motion correction can be applied to correct for minor movements. Iterative reconstruction is preferred but filtered back projection is adequate. The entire brain volume should be reconstructed at the highest pixel resolution (i.e. one-pixel slice thickness). A low-pass filter (i.e. Butterworth) is recommended and should preserve the linearity of the count rate response. Other filters may introduce artifact and are not recommended for general use. All 3 dimensions should be filtered either by 2D prefiltering of the projection data or by applying a 3D postfilter to the reconstructed data.
Attenuation correction is recommended. Attenuation maps can be measured from a sequentially or simultaneously acquired CT or transmission scan or calculated according to the Chang technique (broad beam linear correction coefficient for 123 I: = 0.11cm -1 ). Variance may occur with fan-beam collimators and accuracy should be verified with an appropriate phantom. Images are reconstructed into slices in 3 standard planes (axial, coronal, sagittal). Transverse slices should be parallel to a standard, reproducible anatomic orientation, such as the anterior commissure-posterior commissure line. Correct reorientation aids visual assessment and is crucial for quantitative assessments.
Quantification assesses the ratio of activity in a structure/region of interest to activity in a reference region (generally striatum or striatal subregions compared to the occipital area (or possibly cerebellum)). Regions/volumes of interest may be drawn manually, using automated systems or voxel-based mathematical systems. For both manual and automated semiquantification, the left and right striatum as well as the caudate and putamen should be quantified separately.
# INTERPRETATION
In general, visual assessment of the images is sufficient to make an accurate diagnosis when the uptake is clearly abnormal. However, the addition of semiquantification has been shown to allow readers with limited experience in the interpretation of DaT imaging to perform as well as more experienced readers. The addition of semiquantification and comparison to age matched normal values has also been shown to increase reader confidence in the interpretation of DaT imaging.
The images should be viewed using appropriate computer software, which allows for adjustment of the alignment, colour table, background subtraction or contrast. It is recommended that readers become familiar with one color scale to allow for consistency in interpretation between studies.
Visual interpretation should begin by assessing the quality of the images. Alignment of the head should be checked, as a misalignment could result in artificial asymmetry and a misinterpretation of the images. The raw images of the SPECT scan should be viewed in the cine mode or sinogram mode to assess for movement or other technical artifacts. If applicable, the possible affect of any medications known to interfere with 123I-ioflupane striatal binding should be considered. Using a fixed set of reference images at all levels (Normal to severe decrease) can aid in providing a qualitative assessment of uptake.
The striata should be assessed for their shape, extent, symmetry and intensity. On axial images in a normal study the striata will be symmetric with well defined borders and have a comma or crescent shape. Abnormal studies are characterized by decreased intensity of the striatum on one or both sides, as well as decrease in size to a circle or oval shape.
The head of the caudate and the putamen should have high contrast to the background in patients of all ages and for all colour scales. With normal aging, some decrease in striatal binding occurs in both the caudate and putamen and should be recognized to avoid overinterpretation. Activity in the head of the caudate should be compared to activity in the putamen, as when abnormal, the putamen is usually more severely affected than the caudate nucleus, especially in iPD. In a normal healthy patient, the striata should be fairly symmetric although mild asymmetry may be seen. In the disease state, abnormalities usually first become visible in the putamen contralateral to the neurological signs. Some common patterns can be seen on visual interpretation. In Parkinson's disease, there is usually a decrease in activity in the dorsal putamen contralateral to the neurological signs and this progresses anteriorly ipsilaterally over time. In contrast, in atypical Parkinson's syndromes the abnormalities tend to be more symmetric and involve more of the caudate.
In cases of vascular parkinsonism, striatal uptake is usually normal or only slightly decreased except in cases of striatal infarcts. An infarct usually appears as a punched out defect when compared to the neurodegenerative syndrome abnormalities described above.
Correlation with available CT or MRI studies of the brain should occur and may provide additional information that could aid in accurate interpretation of studies, in particular by showing anatomic lesions that may alter the appearance of the striatal structures.
# QUANTITATIVE ANALYSES
Quantification with use of validated age-matched reference values may be helpful to accurately interpret DaT imaging. Further benefits of quantification include earlier detection of disease, the ability to objectively assess loss of presynaptic dopaminergic neurons over subsequent studies and providing useful data for research and multicenter studies.
There is no universally accepted cut-off value for normal or abnormal, as quantitative data can be affected by the camera system, calibration, image acquisition protocol, post-acquisition processing including corrections and quantification protocol. Quantitative data needs to be compared to a suitable database of reference values, ideally age-matched. To use quantification, each site needs to determine a reference range by scanning a population of healthy controls or alternatively calibrate its procedure with a site that has a reference database. Cross-calibration can be done by establishing the relationship between measured uptake ratio and true activity using an anthropomorphic phantom filled with different concentrations of activity and comparing to the same done at another site.
Quantification is subject to interobserver variability especially for inexperienced readers, which may be secondary to differences in reorientation of the head and errors in placement of the reference regions of interest. However, this can be overcome with the use of automated systems to analyze volumes of interest.
For manual quantification, standardized alignment of the head should be used and the sum of at least 3 consecutive slices with standardized region of interests of at least twice the full width and half maximum represents the minimum requirement of tissue volume sampling. A consistent number of slices should be used. For automated quantification, a 3D volume of interest is preferred but the placement of the region of interest should be checked visually. Quantitative data can be reported as striatal binding expressed as percentage of normal binding for agematched reference uptake.
# REPORT
The report should include the usual demographic information used in imaging reports at the imaging site for example the patient's name, date of birth and hospital identification number. The name of the referring physician and date of the scan should also be included.
# a) History
The provided clinical history should be included in the report, including the type, duration and side of neurological symptoms and any relevant past medical history.
State whether the patient is on any drugs known to interfere with 123I-ioflupane binding, and if so which drugs.
If sedation was used, state the dosage, route and timing in relation to the scan.
# b) Technique
State the injected dose the radiopharmaceutical, the elapsed time between the injection of the radiopharmaceutical and image acquisition. c) Findings Describe any factors that limit image quality, such as patient motion.
Describe the visual interpretation of striatal binding as normal or abnormal. If abnormal, report the location and severity of reduced striatal binding. For severity of reduced binding descriptions such as mild, moderate and severe are suggested. If relevant, compare the findings with any previous 123I-ioflupane studies for the patient. Correlate with previous 18 F-FDG PET, CT or MRI studies of the brain, as applicable.
If semiquantitative analysis was performed, report the values and reference range. An age matched reference range is preferred.
# d) Impression
State overall impression of scan as Normal or Abnormal.
An abnormal study indicates that a presynaptic striatal dopaminergic terminals deficit is present and can be seen in conditions such as PD, PSP, multiple system atrophy, and dementia with Lewy bodies. The reporting physician should avoid referring to a clear diagnosis for example, PD, as these remain a clinical diagnosis for which. DATscan provides supportive information. If required to clarify the diagnosis, further studies such as 18F-FDG PET may be recommended.
|
#
l'iode-123 IOFLUPANE peut apporter des informations importantes. Cette investigation en médecine nucléaire est recommandée dans les situations suivantes : 1) Antécédents qui pourraient être compatibles avec des tremblements essentiels (Parkinsonisme versus tremblement essentiel). 2) Signes légers ou subtils de Parkinsonisme (Parkinsonisme versus variante de la normale).
3) Antécédents d'exposition prolongée à un agent bloquant les récepteurs de la dopamine (Parkinsonisme versus induction médicamenteuse. 4) Manifestations inhabituelles ou variables à l'examen (Parkinsonisme versus parkinsonisme fonctionnel. 5) Dystonie proéminente (Parkinsonisme versus tremblements dystoniques. 6) Suspicion de Parkinsonisme superposé (par exemple bradycardie faciale) chez des personnes connues comme porteuses de maladie neurologique affectant le système moteur (myélopathie, accident vasculo-cérébral, maladie neuromusculaire, etc.). 7) Autres manifestations atypiques (mauvaise réponse à la Lévodopa, absence de progression de la maladie, apparition en très jeune âge, etc.).
# LES SEULES CONTRE-INDICATIONS INCLUENT :
1. Grossesse.
2. Incapacité à coopérer avec l'examen d'imagerie cérébrale.
3. Hypersensibilité connue à la substance active ou à l'un des ses éléments. Une allergie à l'iode n'est pas une contre-indication absolue.
# CONTRE-INDICATION RELATIVE:
1. L'allaitement maternel Lors de la préparation du patient, l'obtention des antécédents et de s'assurer que le patient ne prend pas d'agents perturbateurs sont de première importance. De plus, une sélection adéquate des paramètres d'acquisition de l'examen et le positionnement du patient sont des éléments essentiels pour l'obtention d'un examen diagnostique valable.
Le rapport final doit fournir une impression globale d'une scintigraphie Normale ou Anormale. L'interprétation peut inclure à la fois une évaluation qualitative et des analyses semi-quantitatives par les médecins formés pour interpréter ces scintigraphies.
Le médecin référent peut alors utiliser les résultats de la scintigraphie à l'iode-123 IOFLUPANE pour gérer au mieux la condition du patient.
# INTRODUCTION
The Canadian Association of Nuclear Medicine (CANM) strives for excellence in the practice of diagnostic and therapeutic nuclear medicine by promoting the continued professional competence of nuclear medicine specialists, establishing guidelines of clinical practice, and encouraging biomedical research. We work with all professionals in nuclear medicine to ensure that Canadians have access to the highest quality nuclear medicine services.
These practice guidelines have been developed with input from clinician experts in movement disorders as well as neuroimaging through a consensus process and have been extensively reviewed and approved by the CANM Board of Directors. They are proposed as a reference tool to clinicians dealing with patients with movement disorders to help provide appropriate care. They are not considered to be inflexible rules or requirements of practice. The final decision regarding the ordering and use of any procedure or course of action is made by the clinician based on the situation and the clinician's judgement. These guidelines are intended for clinicians as well as nuclear medicine physicians to aid in understanding the test, provide guidance with appropriate ordering as well as for interpretation and reporting.
Clinical diagnosis of Parkinsonism is straightforward and arrived at based on clinical observations without the use of additional tests in the vast majority of cases. However, for incomplete syndromes, or an overlap between multiple concurrent conditions especially in early stage presentation, utilizing imaging of the dopamine transport system provides an improvement in diagnostic accuracy. 1,2,3 N-v-fluoropropyl-2b-carbomethoxy-3b-(4-123I-iodo-phenyl) nortropane (123I-ioflupane) is a molecular imaging agent used to demonstrate the location and concentration of cell membrane dopamine transporters (DaTs) located on axon terminals of nigral dopaminergic projection neurons. It has shown efficacy for detecting degeneration of the dopaminergic nigro-striatal pathway, allowing better separation of patients with essential tremor from those with Parkinsonian syndromes, as well as differentiating between some causes of Parkinsonism (e.g. functional/psychogenic or iatrogenic forms).
This document provides information and guidance for the indications, technical aspects, interpretation, and reporting of DaT single photon emissions computed tomography (SPECT) scans with 123I-ioflupane. These have been developed using the previous work of the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging. 4,5,6
# INDICATIONS
Making a diagnosis of idiopathic Parkinson's disease (PD) generally relies on the identification of cardinal motor signs and the absence of features indicative of another disease with the support of levodopa responsiveness. In the vast majority of cases, the diagnosis of PD can be made based entirely on the clinical assessment. Up until 2015, the most widely accepted clinical criteria for PD diagnosis was the UK Brain bank criteria. 6 In 2015, the International Parkinson and Movement Disorder Society published new guidelines that have been implemented in the 2 nd edition of the Canadian Guideline for PD. 7,8 The clinical observations useful in the diagnosis of PD can however be inaccurate even in the hands of experienced neurologists, particularly early in the course of the disease. Large clinicopathological series estimate that 10-25% of patients with a clinical diagnosis of established PD will have an alternative diagnosis at autopsy. 6,9,10,11 This underscores the important role of ancillary tests in the diagnostic workup of select patients with Parkinsonism.
In cases of diagnostic uncertainty, DaT scanning can be considered as an aid to the clinical diagnosis 3 . Abnormal uptake of [123I]-FP-CIT has consistently been shown across studies to have extremely high sensitivity and specificity in cases of neurodegenerative parkinsonism associated with loss of nigrostriatal dopamine neurons. 12,13,14,15,16,17 Clinical follow-up is the reference standard in most of these studies but is only a surrogate of the gold standard, which is the autopsy-proven definitive diagnosis. However, DaT imaging has been shown to be very accurate in the early prediction of the final clinical diagnosis obtained after long term follow-up. Importantly, DaT scanning is not helpful in differentiating between neurodegenerative parkinsonian disorders. 17b,17c DaT scanning has been shown to have a substantial impact on management and confidence of diagnosis in select patients (Table 1). Indications for testing may include: 3,5,18,19 1) history or examination features that could be compatible with essential tremor (i.e. PD vs. ET) 2) mild or subtle signs of parkinsonism (i.e. PD vs. normal variant)
3) a history of prolonged exposure to a dopamine receptor blocking agent (i.e. PD vs. drug-induced parkinsonism) 4) distractible or variable features on exam (ie. PD vs. functional parkinsonism) 5) prominent dystonia (i.e. PD vs. dystonic tremor) 6) suspected superimposed parkinsonism (e.g. facial bradykinesia) in persons with a known neurologic disease affecting the motor system (myelopathy, stroke, neuromuscular disease, etc.) 7) other atypical signs (poor response to levodopa, lack of disease progression, very young onset, etc.)
Of note, there does not appear to be a diagnostic benefit to repeat scanning after a period of time if the initial scan is normal. 20
# Abnormal striatal uptake of [123I]-FP-CIT Normal striatal uptake of [123I]-FP-CIT
# Variable findings
DaT imaging is a reliable surrogate of nigro-striatal degeneration and some conditions (PD in particular) are always associated with it, thus explaining the diagnostic role of SPECT scans with 123 I-ioflupane. In some condition however, the impairment of the nigro-striatal fiber is variable and so is the striatal uptake.
'Vascular parkinsonism' has undergone a drastic nosologic revision in recent years and it is now acknowledged that it is often an overdiagnosed condition in patients with degenerative diseases also featuring vascular changes of the white matter (the so-called "pseudovascular parkinsonism"). 22 In some cases of pseudovascular parkinsonism a more diffuse and symmetrical reduction of uptake is observed 23 often with irregularities in the profile of the putamen. In "definite" vascular parkinsonism there is an ischemic or hemorrhagic stroke involving the substantia nigra and/or nigrostriatal pathway and DaT imaging is positive. Most of these cases are unilateral parkinsonism. By contrast, DaT is normal in "vascular pseudoparkinsonism" (e.g., akinetic mutism resulting from bilateral mesial frontal strokes or apathetic depression from bilateral striatal lacunar strokes). 24 Cortico-basal syndrome (CBS) is the most challenging movement disorder from a diagnostic standpoint as its underlying pathology is cortico-basal degeneration only in a minority of cases (other being caused by progressive supranuclear palsy (PSP), Alzheimer or even prion pathology). Not surprisingly DaT imaging is variable depending on the underlying pathology, with some cases showing normal uptake. 25 A similar scenario is seen in orthostatic tremor (OT), in which an abnormal DaT is supposed to be found in the so-called 'plus' forms (as opposed to primary or secondary forms), occurring when OT is associated with PD or other cases of degenerative parkinsonism. 26 Likewise, primary progressive freezing of gait may herald many different degenerative processes and an abnormal DaT is seen in cases caused by PSP pathology while a normal uptake is more often seen in cases evolving towards CBS or motor neuron diseases. 27 Holmes tremor is another heterogenous condition supposedly caused by a strategic (usually vascular) lesion involving both the nigro-striatal system and the cerebello-thalamic fibers. However, due to the variability of lesions, a normal DaT study is still possible (e.g. in case of lesions not involving the midbrain). 28 Many other conditions are associated with variable involvement of the nigra which therefore present with different DaT imaging appearances (e.g. Huntington disease) and in some cases an improvement of the uptake has been reported following treatment, such as in Normal Pressure Hydrocephalus (NPH). Not many papers have explored the role of DaT imaging in NPH but the following scenarios can be hypothesized: 1) an abnormal uptake in patients with co-existing PD or other degenerative conditions involving the pars compacta of the substantia nigra, 2) an abnormal uptake in patients mistakenly diagnosed with NPH while having PD or other degenerative conditions involving the pars compacta of the substantia nigra, 3) a normal uptake (e.g. in the so-called "pseudovascular pseudoparkinsonism" 29 , and 4) an abnormal uptake caused by the mechanical compression of the fiber reaching the putamen.
# The role of DaT imaging in research
DaT imaging has different roles in research protocols, some of which is still not fully explored but at least 5 principal applications can be listed here:
1. DaT imaging as a biomarker to assess PD progression, for example, in the Parkinson Progression Marker Initiative funded by the Michael J Fox Foundation 30 2. Study of the regional differences in uptake to understand different PD presentations 3. Use of DaT imaging as endophenotype in populations at risk of developing PD, such as carriers of genetic mutation 31 or patients with REM sleep behavioral disorder 4. DaT scanning can be used as a marker of the protective effect of surgical 32 or pharmacological treatment. 33 As for the last point, it should be emphasized that the DaT expression is influenced by factors other than number of dopaminergic neurons (e.g. up or downregulation influenced by drugs), thus its role in proving a disease modifying effect is object of debate.
# CONTRAINDICATIONS
Absolute:
1. Pregnancy.
2. Inability to cooperate with brain imaging.
3. Known hypersensitivity to the active substance or to any of its excipients. An iodine allergy is, however, not an absolute contraindication to receiving this radiotracer.
# Relative:
Breastfeeding. If possible, consider delaying the examination until breastfeeding has ceased. It is unknown if ioflupane is secreted in human milk, therefore, if administration is considered necessary, breast-feeding should be interrupted for a minimum of 1 day and up to 6 days. 34,35,36
# REQUEST/REQUISITION SUGGESTED FORMAT
The suggested format for the requisition is to have boxes to allow the referring clinician to provide the following information:
# PATIENT PREPARATION
Prior to arrival, medications that may alter tracer binding should be stopped, if possible, for at least 5 halflives (see Table 2 for medications, durations to be held, and effect on imaging). The decision to withdraw medications should be made by the specialist caring for the patient after weighing benefits and risks. 71 5 days (24 hrs) = increase binding, = decrease binding, = no effect, NDRI = norepinephrine-dopamine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitors, SNRIs = Serotonin-norepinephrine reuptake inhibitors, MAO-B = monoamine oxidase-B, COMT = catechol-O-methyltransferase, DAT = dopamine transporter. T = theoretical, H = human data, A = animal data., CR = case report At least 1 hour prior to radiotracer injection, a single 400mg dose of potassium perchlorate or 100mg equivalent of iodide in Lugol's solution should be administered to reduce exposure of the thyroid to free 123 I. This is not mandatory as the radiation dose expected to the thyroid gland would be very low and it may be avoided if patients are known to have sensitivities. A dim or quiet environment is not necessary for the uptake period.
# IMAGING
Set Up and Positioning 2.5 or 5-mL solution containing 185 or 370MBq of 123 I-ioflupane is administered intravenously as a slow bolus over roughly 20 s followed by a saline flush. 3 Binding of the radiotracer is stable between 3 and 6 hours after injection, at which point SPECT imaging can be acquired. It is encouraged that each centre optimize reproducibility and reduce variability by maintaining the same interval. 56,72,73 Voiding is recommended prior to scanning to avoid interruptions and frequently after imaging to reduce radiation exposure. All eyeglasses, earrings, hair clips, combs or hearing aids should be removed if possible. 74 The patient should be supine with the head straight (chin in neutral position and vertical canthomeatal line) and instructed to remain still during the image acquisition. Reducing head tilt is desirable but should not jeopardize patient comfort as images can be reoriented following acquisition. The corpus striatum(caudate nucleus and putamen) and occiput are required in the field of view. A case by case strategic decision should be considered in patients with L-DOPA induced dyskinesias as whether to hold the drug. Patients with severe tremor should likely be scanned under the effect of the therapy but this noted in the report. Although rarely of use, restraint devices can be utilized to minimize movement. If movement is an issue, short-acting benzodiazepine sedation does not affect image quality and can be used if agreed upon by the patient or patient's legal representative, referring physician and the patient has arranged appropriate transport following the exam. 35
# Equipment & Image Acquisition
Detector: Multiple detector or dedicated SPECT camera are strongly preferred over single headed cameras due to shortened scan time to achieve adequate counts at the routine doses administered for data acquisition. 35 The field of view should include the entire brain and the smallest possible, safe rotation radius should be used (typically 11-15cm). 35 Collimator: Low Energy High Resolution (LEHR) parallel-hole collimation is adequate, but, if available, fan-beam collimators may be preferred for improved resolution at the cost of count rate capability. Photopeak: The photopeak should be 159keV +/-10%. Additional energy windows can be used for scatter correction. Matrix: A 128 x 128 matrix is recommended. Acquisition pixel size should be one-third to one-half of the expected resolution. Hardware zoom may be necessary to achieve an appropriate pixel size of 3.5-4.5mm. Slices should be 1 pixel thick. Angular Sampling, Scan Time and Total Detected Events: 3-degree angular sampling for 360 degrees of coverage (180 degrees for each head in a dual head camera) is recommended, although continuous rotation may also be used. The number of seconds per position depends on the sensitivity of the system, but usually 30-40s are required. A minimum of 1.5 million total counts should be collected for optimal images if scatter correction is applied (otherwise >3 million). Total acquisition time will vary according to camera specifications, but is often between 30-45 minutes. Consider segmenting data acquisition into multiple sequential acquisitions which may permit exclusion of data with artefacts (i.e. exclude segments with movement artifact). Image Processing: Projection data in cine mode and sinograms should be displayed to assess scan quality of data, patient motion, and artifacts. Rescanning will be required for large movements, but motion correction can be applied to correct for minor movements. Iterative reconstruction is preferred but filtered back projection is adequate. The entire brain volume should be reconstructed at the highest pixel resolution (i.e. one-pixel slice thickness). A low-pass filter (i.e. Butterworth) is recommended and should preserve the linearity of the count rate response. Other filters may introduce artifact and are not recommended for general use. All 3 dimensions should be filtered either by 2D prefiltering of the projection data or by applying a 3D postfilter to the reconstructed data.
Attenuation correction is recommended. Attenuation maps can be measured from a sequentially or simultaneously acquired CT or transmission scan or calculated according to the Chang technique (broad beam linear correction coefficient for 123 I: = 0.11cm -1 ). Variance may occur with fan-beam collimators and accuracy should be verified with an appropriate phantom. Images are reconstructed into slices in 3 standard planes (axial, coronal, sagittal). Transverse slices should be parallel to a standard, reproducible anatomic orientation, such as the anterior commissure-posterior commissure line. Correct reorientation aids visual assessment and is crucial for quantitative assessments.
Quantification assesses the ratio of activity in a structure/region of interest to activity in a reference region (generally striatum or striatal subregions compared to the occipital area (or possibly cerebellum)). Regions/volumes of interest may be drawn manually, using automated systems or voxel-based mathematical systems. For both manual and automated semiquantification, the left and right striatum as well as the caudate and putamen should be quantified separately.
# INTERPRETATION
In general, visual assessment of the images is sufficient to make an accurate diagnosis when the uptake is clearly abnormal. However, the addition of semiquantification has been shown to allow readers with limited experience in the interpretation of DaT imaging to perform as well as more experienced readers. The addition of semiquantification and comparison to age matched normal values has also been shown to increase reader confidence in the interpretation of DaT imaging.
The images should be viewed using appropriate computer software, which allows for adjustment of the alignment, colour table, background subtraction or contrast. It is recommended that readers become familiar with one color scale to allow for consistency in interpretation between studies.
Visual interpretation should begin by assessing the quality of the images. Alignment of the head should be checked, as a misalignment could result in artificial asymmetry and a misinterpretation of the images. The raw images of the SPECT scan should be viewed in the cine mode or sinogram mode to assess for movement or other technical artifacts. If applicable, the possible affect of any medications known to interfere with 123I-ioflupane striatal binding should be considered. Using a fixed set of reference images at all levels (Normal to severe decrease) can aid in providing a qualitative assessment of uptake.
The striata should be assessed for their shape, extent, symmetry and intensity. On axial images in a normal study the striata will be symmetric with well defined borders and have a comma or crescent shape. Abnormal studies are characterized by decreased intensity of the striatum on one or both sides, as well as decrease in size to a circle or oval shape.
The head of the caudate and the putamen should have high contrast to the background in patients of all ages and for all colour scales. With normal aging, some decrease in striatal binding occurs in both the caudate and putamen and should be recognized to avoid overinterpretation. Activity in the head of the caudate should be compared to activity in the putamen, as when abnormal, the putamen is usually more severely affected than the caudate nucleus, especially in iPD. In a normal healthy patient, the striata should be fairly symmetric although mild asymmetry may be seen. In the disease state, abnormalities usually first become visible in the putamen contralateral to the neurological signs. Some common patterns can be seen on visual interpretation. In Parkinson's disease, there is usually a decrease in activity in the dorsal putamen contralateral to the neurological signs and this progresses anteriorly ipsilaterally over time. In contrast, in atypical Parkinson's syndromes the abnormalities tend to be more symmetric and involve more of the caudate.
In cases of vascular parkinsonism, striatal uptake is usually normal or only slightly decreased except in cases of striatal infarcts. An infarct usually appears as a punched out defect when compared to the neurodegenerative syndrome abnormalities described above.
Correlation with available CT or MRI studies of the brain should occur and may provide additional information that could aid in accurate interpretation of studies, in particular by showing anatomic lesions that may alter the appearance of the striatal structures.
# QUANTITATIVE ANALYSES
Quantification with use of validated age-matched reference values may be helpful to accurately interpret DaT imaging. Further benefits of quantification include earlier detection of disease, the ability to objectively assess loss of presynaptic dopaminergic neurons over subsequent studies and providing useful data for research and multicenter studies.
There is no universally accepted cut-off value for normal or abnormal, as quantitative data can be affected by the camera system, calibration, image acquisition protocol, post-acquisition processing including corrections and quantification protocol. Quantitative data needs to be compared to a suitable database of reference values, ideally age-matched. To use quantification, each site needs to determine a reference range by scanning a population of healthy controls or alternatively calibrate its procedure with a site that has a reference database. Cross-calibration can be done by establishing the relationship between measured uptake ratio and true activity using an anthropomorphic phantom filled with different concentrations of activity and comparing to the same done at another site.
Quantification is subject to interobserver variability especially for inexperienced readers, which may be secondary to differences in reorientation of the head and errors in placement of the reference regions of interest. However, this can be overcome with the use of automated systems to analyze volumes of interest.
For manual quantification, standardized alignment of the head should be used and the sum of at least 3 consecutive slices with standardized region of interests of at least twice the full width and half maximum represents the minimum requirement of tissue volume sampling. A consistent number of slices should be used. For automated quantification, a 3D volume of interest is preferred but the placement of the region of interest should be checked visually. Quantitative data can be reported as striatal binding expressed as percentage of normal binding for agematched reference uptake.
# REPORT
The report should include the usual demographic information used in imaging reports at the imaging site for example the patient's name, date of birth and hospital identification number. The name of the referring physician and date of the scan should also be included.
# a) History
The provided clinical history should be included in the report, including the type, duration and side of neurological symptoms and any relevant past medical history.
State whether the patient is on any drugs known to interfere with 123I-ioflupane binding, and if so which drugs.
If sedation was used, state the dosage, route and timing in relation to the scan.
# b) Technique
State the injected dose the radiopharmaceutical, the elapsed time between the injection of the radiopharmaceutical and image acquisition. c) Findings Describe any factors that limit image quality, such as patient motion.
Describe the visual interpretation of striatal binding as normal or abnormal. If abnormal, report the location and severity of reduced striatal binding. For severity of reduced binding descriptions such as mild, moderate and severe are suggested. If relevant, compare the findings with any previous 123I-ioflupane studies for the patient. Correlate with previous 18 F-FDG PET, CT or MRI studies of the brain, as applicable.
If semiquantitative analysis was performed, report the values and reference range. An age matched reference range is preferred.
# d) Impression
State overall impression of scan as Normal or Abnormal.
An abnormal study indicates that a presynaptic striatal dopaminergic terminals deficit is present and can be seen in conditions such as PD, PSP, multiple system atrophy, and dementia with Lewy bodies. The reporting physician should avoid referring to a clear diagnosis for example, PD, as these remain a clinical diagnosis for which. DATscan provides supportive information. If required to clarify the diagnosis, further studies such as 18F-FDG PET may be recommended.
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The COVID-19 therapy Paxlovid® consists of the antiviral medication nirmatrelvir co-packaged with the pharmacokinetic enhancer ("booster") ritonavir, taken as a twice daily, oral, five-day treatment course, with dosage adjustment required for renal impairment (see prescribing information). 1,2 Nirmatrelvir/ritonavir treatment is initiated as soon as possible following a positive SARS-CoV-2 test result. Eligibility criteria for nirmatrelvir/ritonavir vary between Canadian provinces and will likely evolve over time. Also, eligibility in British Columbia may be expanded as drug supply increases. Therefore, prescribers are strongly encouraged to refer to current nirmatrelvir/ritonavir prescribing information and local guidelines for treatment eligibility and general contraindications/precautions.#
Theoretical risk of HIV-1 drug resistance mutations in persons with undiagnosed or untreated HIV 1 - Nirmatrelvir/ritonavir prescribing information cautions that, because ritonavir has antiretroviral activity, persons with undiagnosed or uncontrolled HIV-1 infection might be at risk for developing drug resistance mutations to HIV protease inhibitors.
- Given the low dose of ritonavir and the short-duration treatment course of nirmatrelvir/ritonavir for COVID-19, the risk of emergent HIV drug resistance mutations in the presence of uncontrolled HIV infection is low. If nirmatrelvir/ritonavir is clinically indicated for COVID-19, do not delay treatment initiation while awaiting HIV-related test results. If there is a suspicion of undiagnosed/ untreated HIV infection, follow up with diagnostic screening and/or (re-)engagement with HIV care as soon as possible.
- HIV infected individuals who are diagnosed with COVID-19, and who meet current COVID-19 Therapeutics Committee (CTC) eligibility criteria for nirmatrelvir/ritonavir should be considered eligible to receive nirmatrelvir/ritonavir therapy, regardless of ARV treatment status, viral load level, or CD4 cell count. (/ treatments)
# General drug interaction considerations: 1-4
Nirmatrelvir/ritonavir has the potential to have numerous clinically important drug interactions, largely related to the ritonavir component (strong CYP3A inhibitor). Healthcare providers are advised to conduct a detailed medication review (PharmaNet review and medication history including prescription and nonprescription medication use -of note, PharmaNet captures most but not all the antiretroviral prescriptions in British Columbia) and check for drug interactions using a current drug interaction resource, such as University of Liverpool COVID-19 Drug Interactions /, which is current and considers drug interactions in the context of the short treatment duration of nirmatrelvir/ ritonavir.
# Co-administration with Antiretroviral therapy (ART) or Pre-exposure prophylaxis (PrEP) medications
The combination of nirmatrelvir/ritonavir with antiretroviral HIV medications has not been evaluated in clinical studies, and there is limited clinical experience. Prescribers are encouraged to individualize riskbenefit assessment, considering potential drug interactions, comorbidities (including kidney disease), and risk factors for severe COVID-19 disease.
In general, ART or PrEP may be continued without interruption during nirmatrelvir/ritonavir therapy. Specific clinical scenarios include:
- ART regimen includes the "booster" ritonavir or cobicistat: 1,3,4 Paxlovid® prescribing information recommends taking nirmatrelvir/ritonavir in addition to the usual ART regimen, without dose adjustment (i.e. short-term additive doses of "booster" components).
- The additive ritonavir and/or cobicistat doses from combined ART and COVID-19 treatments may be associated with short-term increased side effects such as gastrointestinal upset.
- ART regimen or PrEP medication includes tenofovir alafenamide: 3,4 No dose adjustment of tenofovir alafenamide (TAF) is required. Continue the usual ART or PrEP medication schedule.
- Ritonavir inhibits the transporter P-gp and may increase the absorption of tenofovir from the gut, increasing tenofovir levels. Although TAF prescribing information recommends a 10 mg daily dose when co-administered with ritonavir, persons whose ART or PrEP regimen includes TAF 25 mg daily do NOT require TAF dose adjustment during short-term nirmatrelvir/ritonavir therapy.4
- ART regimen includes hepatic (CYP3A) enzyme-inducing antiretrovirals: 3,4 Nirmatrelvir/ritonavir may be given together with efavirenz or nevirapine without dose adjustment.
- The antiretrovirals nevirapine and efavirenz are moderate inducers of CYP3A4 and could potentially decrease levels of nirmatrelvir/ritonavir. Although co-administration has not been studied, drug interaction resources 3,4 suggest the Paxlovid® 100 mg twice daily ritonavir dose likely offsets a potential decrease in ritonavir levels secondary to efavirenz or nevirapine CYP3A induction.3 4. ART regimen includes maraviroc: For ART regimens including ritonavir or cobicistat, the usual maraviroc dose is 150 mg twice daily. Persons whose current maraviroc dose is a total of 300 mg daily should continue their usual dose during nirmatrelvir/ritonavir therapy.
- Persons taking an unboosted ART regimen with a total maraviroc dose >300 mg daily should continue their usual dose. If significant maraviroc side effects develop (diarrhea, nausea, headache, hypotension), a temporary maraviroc dose reduction may be considered.4 Consult the HIV care provider/ HIV pharmacist (and continue the usual maraviroc dose while awaiting guidance).
# Resources:
REACH line (Rapid Expert Advice and Consultation for HIV) for healthcare providers 1-800-665-7677 Upon dialing this number, healthcare providers may speak to:
- An HIV Infectious Disease Specialist - A Family Physician who is experienced in HIV management - An HIV-experienced Pharmacist- *For consultation regarding antiretroviral drug interactions with nirmatrelvir/ritonavir in persons receiving HIV treatment or prevention therapies a pharmacist at St. Paul's Hospital Ambulatory Pharmacy may also be reached at: 1-888-511-6222 (Monday to Friday daytime and urgent issues after hours)
The current version of this document is available for download at:
|
The COVID-19 therapy Paxlovid® consists of the antiviral medication nirmatrelvir co-packaged with the pharmacokinetic enhancer ("booster") ritonavir, taken as a twice daily, oral, five-day treatment course, with dosage adjustment required for renal impairment (see prescribing information). 1,2 Nirmatrelvir/ritonavir treatment is initiated as soon as possible following a positive SARS-CoV-2 test result. Eligibility criteria for nirmatrelvir/ritonavir vary between Canadian provinces and will likely evolve over time. Also, eligibility in British Columbia may be expanded as drug supply increases. Therefore, prescribers are strongly encouraged to refer to current nirmatrelvir/ritonavir prescribing information and local guidelines for treatment eligibility and general contraindications/precautions.#
Theoretical risk of HIV-1 drug resistance mutations in persons with undiagnosed or untreated HIV 1 • Nirmatrelvir/ritonavir prescribing information cautions that, because ritonavir has antiretroviral activity, persons with undiagnosed or uncontrolled HIV-1 infection might be at risk for developing drug resistance mutations to HIV protease inhibitors.
• Given the low dose of ritonavir and the short-duration treatment course of nirmatrelvir/ritonavir for COVID-19, the risk of emergent HIV drug resistance mutations in the presence of uncontrolled HIV infection is low. If nirmatrelvir/ritonavir is clinically indicated for COVID-19, do not delay treatment initiation while awaiting HIV-related test results. If there is a suspicion of undiagnosed/ untreated HIV infection, follow up with diagnostic screening and/or (re-)engagement with HIV care as soon as possible.
• HIV infected individuals who are diagnosed with COVID-19, and who meet current COVID-19 Therapeutics Committee (CTC) eligibility criteria for nirmatrelvir/ritonavir should be considered eligible to receive nirmatrelvir/ritonavir therapy, regardless of ARV treatment status, viral load level, or CD4 cell count. (http://www.bccdc.ca/health-professionals/clinical-resources/covid-19-care/clinical-care/ treatments)
# General drug interaction considerations: 1-4
Nirmatrelvir/ritonavir has the potential to have numerous clinically important drug interactions, largely related to the ritonavir component (strong CYP3A inhibitor). Healthcare providers are advised to conduct a detailed medication review (PharmaNet review and medication history including prescription and nonprescription medication use -of note, PharmaNet captures most but not all the antiretroviral prescriptions in British Columbia) and check for drug interactions using a current drug interaction resource, such as University of Liverpool COVID-19 Drug Interactions https://www.covid19-druginteractions.org/, which is current and considers drug interactions in the context of the short treatment duration of nirmatrelvir/ ritonavir.
# Co-administration with Antiretroviral therapy (ART) or Pre-exposure prophylaxis (PrEP) medications
The combination of nirmatrelvir/ritonavir with antiretroviral HIV medications has not been evaluated in clinical studies, and there is limited clinical experience. Prescribers are encouraged to individualize riskbenefit assessment, considering potential drug interactions, comorbidities (including kidney disease), and risk factors for severe COVID-19 disease.
In general, ART or PrEP may be continued without interruption during nirmatrelvir/ritonavir therapy. Specific clinical scenarios include:
1. ART regimen includes the "booster" ritonavir or cobicistat: 1,3,4 Paxlovid® prescribing information recommends taking nirmatrelvir/ritonavir in addition to the usual ART regimen, without dose adjustment (i.e. short-term additive doses of "booster" components).
• The additive ritonavir and/or cobicistat doses from combined ART and COVID-19 treatments may be associated with short-term increased side effects such as gastrointestinal upset.
2. ART regimen or PrEP medication includes tenofovir alafenamide: 3,4 No dose adjustment of tenofovir alafenamide (TAF) is required. Continue the usual ART or PrEP medication schedule.
• Ritonavir inhibits the transporter P-gp and may increase the absorption of tenofovir from the gut, increasing tenofovir levels. Although TAF prescribing information recommends a 10 mg daily dose when co-administered with ritonavir, persons whose ART or PrEP regimen includes TAF 25 mg daily do NOT require TAF dose adjustment during short-term nirmatrelvir/ritonavir therapy.4
3. ART regimen includes hepatic (CYP3A) enzyme-inducing antiretrovirals: 3,4 Nirmatrelvir/ritonavir may be given together with efavirenz or nevirapine without dose adjustment.
• The antiretrovirals nevirapine and efavirenz are moderate inducers of CYP3A4 and could potentially decrease levels of nirmatrelvir/ritonavir. Although co-administration has not been studied, drug interaction resources 3,4 suggest the Paxlovid® 100 mg twice daily ritonavir dose likely offsets a potential decrease in ritonavir levels secondary to efavirenz or nevirapine CYP3A induction.3 4. ART regimen includes maraviroc: [3][4][5] For ART regimens including ritonavir or cobicistat, the usual maraviroc dose is 150 mg twice daily. Persons whose current maraviroc dose is a total of 300 mg daily should continue their usual dose during nirmatrelvir/ritonavir therapy.
• Persons taking an unboosted ART regimen with a total maraviroc dose >300 mg daily should continue their usual dose. If significant maraviroc side effects develop (diarrhea, nausea, headache, hypotension), a temporary maraviroc dose reduction may be considered.4 Consult the HIV care provider/ HIV pharmacist (and continue the usual maraviroc dose while awaiting guidance).
# Resources:
REACH line (Rapid Expert Advice and Consultation for HIV) for healthcare providers 1-800-665-7677 Upon dialing this number, healthcare providers may speak to:
• An HIV Infectious Disease Specialist • A Family Physician who is experienced in HIV management • An HIV-experienced Pharmacist* *For consultation regarding antiretroviral drug interactions with nirmatrelvir/ritonavir in persons receiving HIV treatment or prevention therapies a pharmacist at St. Paul's Hospital Ambulatory Pharmacy may also be reached at: 1-888-511-6222 (Monday to Friday daytime and urgent issues after hours)
The current version of this document is available for download at: http://www.bccfe.ca/publications/centre-documents/bc-cfe-guidelines-use-paxlovid-and-arvs
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# Guideline Resource Unit
# Background
There are two common distinct histologies of esophageal cancer. Chronic gastroesophageal reflux predisposes to Barrett's metaplasia and the development of adenocarcinoma 1 . Typically, it develops within the distal esophagus; in North America, it is now more prevalent than the other histology, squamous cell carcinoma 2 . The recognized risk factors for squamous cell carcinoma include tobacco and alcohol exposure. 3 Guideline Questions
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with esophageal cancer, including both squamous cell and adenocarcinoma. Different principles may apply to pediatric patients.
# Recommendations
Recommended Diagnostic Work-Up
- Esophagogastroduodenoscopy with biopsy establishes the tumour's location (distance from incisors) and histology. - An augmented CT scan of the thorax, abdomen and pelvis also helps to establish the tumour's Guideline Resource Unit location, depth of penetration into the esophageal wall, invasion into adjacent structures, and involvement of regional and non-regional lymph nodes. Metastatic disease confers an incurable situation for which only palliative maneuvers would be appropriate.
- Blood work identifies any end-organ dysfunction that may preclude the safe administration of chemotherapy. - if no metastatic disease is seen on the baseline CT, F-fluorodeoxy-D-glucose (FDG) PET scan can complement an augmented CT scan and help to identify radiologically-occult metastatic disease .
Optional Investigations:
- In the absence of metastatic disease (based upon the above investigations), the following tests may be of additional value if it would influence treatment decisions: o Bronchoscopy if tumor is located at or above the level of the carina. o Endoscopic ultrasound (establishes the depth of penetration into the esophageal wall, invasion into adjacent structures, and involvement of regional and non-regional lymph nodes) for clinically node negative, T1 or T2 tumors. o Pulmonary function testing (required prior to surgical resection and may be necessary prior to chemoradiotherapy). - Bone scans can be done for patients suspected of having bone metastases, CT head or MRI for patients suspected of having brain metastases
# Stage Information
Tumors involving the esophagogastric junction (EGJ) with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal rather than gastric cancers. In contrast, EGJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach cancers (refer to gastric cancer guideline). Guideline Resource Unit Regional- Lymph Node Involvement (N Stage): N0 No regional lymph node involvement N1 Involvement of one or two regional lymph nodes N2 Involvement of three to six regional lymph nodes N3 Involvement of seven or more regional lymph nodes gastric cancer for all other tumours (epicenter in stomach more than 5 cm from the esophagogastric junction and without extension into esophagus).
0 0 0 NA Any Stage 0 is 0 NA Stage IA 0 0 1 1 Any Stage IA 1a 0 1 1a 0 0 X Any 1a 0 X Stage IB 1a 0 0 2-3 Any Stage IB 1a 0 2 1b 0 0 1-3 Any 1b 0 1-2 1b 0 0 X Any 1b 0 X 2 0 0 1 Any Stage IC 1 0 3 Stage IIA 2 0 0 2-3 Any 2 0 1-2 2 0 0 X Any Stage IIA 2 0 3 3 0 0 Any L 2 0 X 3 0 0 1 U/M Stage IIB 1 1 Any Stage IIB 3 0 0 2-3 U/M 3 0 Any 3 0 0 X Any Stage IIIA 1 2 Any 3 0 0 Any X 2 1
# Goals of Therapy
To render the patient free of disease, to relieve symptoms (e.g.: dysphagia), and to improve or prolong survival, if possible.
Guideline Resource Unit Recommendations 14 :
- Complete the work-up (as described above).
- For patients who do not have metastatic disease: o Early referral to a surgeon trained in esophageal surgery is important to assess for resectability. o Patients should be referred for a multidisciplinary discussion including radiation oncologists and medical oncologists prior to surgery for patients with resectable disease. - Assess the degree of dysphagia and consult with a dietician to optimize the patient's nutritional status. Consider placement of a nasogastic (NG) feeding tube. If the NG feeding tube insertion is technically difficult, placement should be performed radiographically. - In a curative situation, avoid placement of an endoluminal stent as it increases the complication and mortality rate with radical chemoradiotherapy 15 . - Patients who receive preoperative chemoRT should have a CT scan prior to surgery. In certain cases, FDG-PET can provide an assessment of response but should only be done if clinically warranted . - There is limited data to support the use of imaging after definitive chemoRT or after surgical resection for non-metastatic patients, however, individualized discussion regarding imaging after definitive chemoRT or after surgical resection for non-metastatic patients may be appropriate in select clinical cases. - For patients on palliative systemic treatment, CT chest, abdomen, and pelvis should be done every 2-3 months depending on the clinical situation. - Consider treatment on a clinical trial, if available. - Multidisciplinary discussion regarding chemoRT vs chemotherapy recommended For gastric cancers, refer to the Gastric Cancer Guidelines. For more details, refer to table 2. Note: EGJ was redefined in the AJCC 8th edition: adenocarcinomas with epicenters no more than 2cm into the gastric cardia are staged as esophageal adenocarcinomas, and those extending further are staged as stomach cancers. 55 Table 3. Curative therapy recommendations for patients with esophageal cancer.
# Stage Recommendations TisN0 or T1aN0 Disease
Endoscopic Therapy for Superficial Cancers: - Endoscopic mucosal resection (EMR) 22, , submucosal dissection (ESD) and various ablation techniques (e.g.: photo-dynamic therapy 23 , argon plasma coagulation, radiofrequency ablation 24 , cryotherapy) can preserve the integrity of the esophagus and provide a potentially curative option for superficial cancers. - Provided careful endoscopic surveillance can be performed, consider for patients with favorable mucosal tumours- who are interested in an esophagus-sparing approach or who are elderly, with multiple comorbidities, or otherwise high surgical risk. *Note: Favorable mucosal tumours include non-invasive (in situ) lesions or disease that invades into the mucosa (but not submucosa). Invasion into deepest third of submucosa 49%
Esophagectomy:
- Resect disease if both technically and medically feasible. Aim to achieve an "R0"resection (no gross or microscopic residual tumour). - Post-operative morbidity and survival are significantly better when surgery is completed in an experienced centre 25 . T1bN0 Disease
# Preferred
# Esophagectomy:
- Esophagectomy is the preferred treatment choice for fit patients with superficial esophageal cancers invading the submucosa.
# Alternate
Endoscopic therapy:
- For most patients with favorable intramucosal tumors, who are interested in an esophagus-sparing approach or are older with multiple comorbidities or are otherwise high surgical risk are candidates for endoscopic resection rather than surgical resection.
- If a patient is not medically operable, declines surgery, or is not a candidate for EMR/ESD, refer to 17 . This protocol improves the R0 resection rate (92% versus 69%) and overall survival (HR 0.657, CI95% 0.495-0.871, p = 0.003) when compared to surgery alone. It prolongs median survival from 24.0 months to 49.4 months and increases the one-, two-, three-, and five-year survival rates from 70% to 82%, 50% to 67%, 44% to 58%, and 34% to 47% respectively. It offers a pCR rate of 23%. 75% of the patients enrolled had adenocarcinoma. About 25% of patients had disease at the esophagogastric junction. - Aim to achieve an "R0"resection (no gross or microscopic residual tumour).
- Post-operative morbidity and survival are significantly better when surgery is completed in an experienced centre 25 .
# Post-operative Adjuvant Therapy:
The Checkmate 577 trial randomized patients who received preoperative CROSS chemoradiotherapy followed by surgery with residual pathological disease (> ypT1 and/or >ypN1) to nivolumab (240 mg/m 2 IV q 2 weekly for up to 1 year) or placebo.
- Note that esophagectomy alone is an option in low risk cT2N0 patients. 56
# Preferred
# Alternate
# Guideline Resource Unit
Disease free survival (DFS) was significantly improved in the nivolumab group compared to the placebo (median 22.4 months versus 11.0 months, HR 0.69, 95% CI 0.56-0.86, p=0.003). 48 Nivolumab is not currently funded for this indication in Alberta.
- No randomized trial (and at least two meta-analyses 26,27 has demonstrated a survival advantage for preoperative chemoradiotherapy over chemotherapy alone - One network meta-analysis concluded that there is a survival benefit for neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy 28 .
# Alternatives for patients not candidates for FLOT
- MAGIC: When compared to surgery alone in patients with good performance status (ECOG ≤1) and T2-4N0-3M0 adenocarcinoma of the distal third of the esophagus, gastro-esophageal junction, or stomach, peri-operative chemotherapy improves the five-year progression-free (HR 0.66, CI95% 0.53-0.81, p < 0.001) and overall survival (from 23.0% to 36.3%, HR 0.74, CI95% 0.59-0.93, p = 0.008 19 ).
- Pre-Operative Phase: Three three-week cycles of Epirubicin 50 mg/m 2 and Cisplatin 60 mg/m 2 IV on day one plus a continuous intravenous infusion of 5-Fluorouracil 200 mg/m 2 /day over twenty-one days.
# Chemotherapy
- Operative Phase: Perform surgical resection with oncologic principles.
- Post-Operative Phase: As described in the pre-operative phase (above). Alternative for patients not candidates for epirubicin (MAGIC): cisplatin 5FU has been evaluated in patients with operable adenocarcinoma of the esophagus and gastroesophageal junction - The FFCD trial six peri-operative cycles of Cisplatin and infusional fluorouracil improves the five-year disease-free survival (34% versus 19%, HR 0.65, CI95% 0.48-0.89, p = 0.003), overall survival (38% versus 24%, HR 0.69, CI95% 0.50-0.95, p = 0.02), and rate of curative resection (84% versus 73%, p = 0.04) compared to surgery alone. Chemotherapy was given every 4 weeks and was comprised of cisplatin 100 mg/m 2 IV on day one plus 5-Fluorouracil 800 mg/m 2 /day over days one through five days, every 28 days 29 . - The OE5 trial randomized patients to 4 cycles of ECX or 2 cycles of cisplatin and infusional fluorouracil prior to surgery. The pathological complete response rate was higher in the ECX arm compared to cisplatin/fluoruracil (11% vs 3%). However, there was no significant difference in overall survival (23.4 months vs 26.1 months, HR 0.90 0.77-1.05, p = 0.19) 21 - These regimens require placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port. - For patients in whom it is not possible to resect disease due to medical or technical issues, refer to Table 3 Guideline Resource Unit
# Preferred Recommendation
In whom it is not possible to resect disease due to medical or technical issues: Primary ('Definitive') Chemoradiotherapy: - The two treatment options are: - Preferred: Deliver 5,000 cGy in twenty-five fractions over five weeks plus Oxaliplatin 85 mg/mg 2 IV and Leucovorin 200 mg/m 2 IV followed by 5-Fluorouracil 400 mg/m 2 IV bolus followed by 5-Fluorouracil 800 mg/m 2 /day over days one and two on weeks one, three, five, seven, nine, and eleven. This regimen is associated with less mucositis, alopecia, and renal toxicity plus numerically fewer toxic and sudden deaths but without a difference in overall survival, progression-free survival, and pCR rate 30 . (Level 1 evidence) - Alternatively deliver 5,000 cGy in twenty-five fractions over five weeks plus Cisplatin 75 mg/m 2 IV over one hour and 5-Fluorouracil 4,000 mg/m 2 IV over ninetysix hours on weeks one, five, eight, and eleven. This protocol offers an five-year overall survival rate of 27% (compared to 0% for radiotherapy alone) 31 . Note: 82% of the patients enrolled had squamous cell carcinoma of the esophagus. - These regimens require placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port.
# Alternate
Radiotherapy Alone:
- Consider for patients who decline chemotherapy or in whom chemotherapy is deemed unsafe.
# Guideline Resource Unit
# Recommendations for Incurable Situations
Provide palliative maneuvers to maintain and/or improve quality of life:
- Relieve pain, bleeding, and/or dysphagia with radiotherapy (30 Gy in 10 fractions is preferred, alternatively 40 Gy in 15 fractions or 50 Gy in 20 fractions). 2. Consider placement of an endoluminal stent 32,33 or photodynamic therapy 34 to relieve dysphagia. 3. Patients with advanced esophageal cancer who have a self expanding metal stent inserted for the primary management of dysphagia do not gain additional benefit from concurrent palliative radiotherapy (Level 1 evidence). Palliative radiotherapy may be indicated for bleeding. 49 4. Consider palliative chemotherapy to control disease and prolong survival in patients with a satisfactory performance status (ECOG ≤ 2) 35-41 5. Consider treatment on a clinical trial if available. 6. Consider early referral to palliative care. (Symptom management guidelines can be found here). 7. Refer to dieticians and consider psychosocial referral. Early interdisciplinary care with the addition of psychologists and dieticians improved survival compared to standard oncology care in phase III trial of untreated patients with metastatic upper GI cancers (median overall survival 14.8 months vs 11.9 months, HR 0.68; 95% CI 0.51-0.9,; = 0.021). 58
# Metastatic Adenocarcinoma of the Esophagus or Gastroesophageal Junction
Many phase III clinical trials for metastatic gastric cancer also included patients with adenocarcinoma of the gastroesophageal junction. By extrapolation, patients with metastatic adenocarcinoma of the esophagus and gastroesophageal junction are treated as per metastatic gastric cancers. .
Evaluation of HER2 protein expression via immunohistochemistry or in situ hybridization is recommended to select patients with metastastic esophageal/gastroesophageal adenocarcinoma for trastuzumab based treatment 42 .
# Metastatic Squamous Cell Cancer of the Esophagus
There is limited data to guide systemic therapy for metastatic squamous cell cancer of the esophagus. The combination of a platinum with a fluoropyrimidine is the preferred first line regimen 42,43 .
- The benefit was seen in all patients, but primarily driven by the patients with squamous cell cancer. 50 Pembrolizumab is not currently funded for this indication in Alberta.
# Guideline Resource Unit
Second Line Therapy 47 The ATTRACTION-3 study randomized patients with advanced esophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy to nivolumab versus chemotherapy of physician's choice (paclitaxel 100 mg/m2 q week for 6 weeks followed by 1 week off) or docetaxel (75 mg/m2 q3 weeks). Overall survival was significantly improved in the nivolumab group compared to chemotherapy (median 10.9 months versus 8.4 months, HR 0.77, 95% CI 0.62-0.96; p=0.019). There was no significant difference in progression free survival for nivolumab versus chemotherapy (median 1.7 months versus 3.4 months, HR 108, 95% CI 087-1 34). The prespecified interaction analysis indicated no significant interaction of treatment effect by PD-L1 status. Nivolumab is not currently available on the Alberta CancerCare Drug Benefit List.
Taxane based chemotherapy would be a reasonable alternative option and is available through the Alberta CancerCare Drug Benefit List.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta GI Tumour Team. Members of the Alberta GI Tumour Team include surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta GI Tumour Team, external participants identified by the Working Group Lead, and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
|
# Guideline Resource Unit
# Background
There are two common distinct histologies of esophageal cancer. Chronic gastroesophageal reflux predisposes to Barrett's metaplasia and the development of adenocarcinoma 1 . Typically, it develops within the distal esophagus; in North America, it is now more prevalent than the other histology, squamous cell carcinoma 2 . The recognized risk factors for squamous cell carcinoma include tobacco and alcohol exposure. 3 Guideline Questions
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with esophageal cancer, including both squamous cell and adenocarcinoma. Different principles may apply to pediatric patients.
# Recommendations
Recommended Diagnostic Work-Up
• Esophagogastroduodenoscopy with biopsy establishes the tumour's location (distance from incisors) and histology. • An augmented CT scan of the thorax, abdomen and pelvis also helps to establish the tumour's Guideline Resource Unit location, depth of penetration into the esophageal wall, invasion into adjacent structures, and involvement of regional and non-regional lymph nodes. Metastatic disease confers an incurable situation for which only palliative maneuvers would be appropriate.
• Blood work identifies any end-organ dysfunction that may preclude the safe administration of chemotherapy. • if no metastatic disease is seen on the baseline CT, F-fluorodeoxy-D-glucose (FDG) PET scan can complement an augmented CT scan and help to identify radiologically-occult metastatic disease [4][5][6] .
Optional Investigations:
• In the absence of metastatic disease (based upon the above investigations), the following tests may be of additional value if it would influence treatment decisions: o Bronchoscopy if tumor is located at or above the level of the carina. [51][52][53] o Endoscopic ultrasound (establishes the depth of penetration into the esophageal wall, invasion into adjacent structures, and involvement of regional and non-regional lymph nodes) for clinically node negative, T1 or T2 tumors. [51][52][53][54] o Pulmonary function testing (required prior to surgical resection and may be necessary prior to chemoradiotherapy). • Bone scans can be done for patients suspected of having bone metastases, CT head or MRI for patients suspected of having brain metastases
# Stage Information
Tumors involving the esophagogastric junction (EGJ) with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal rather than gastric cancers. In contrast, EGJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach cancers (refer to gastric cancer guideline). Guideline Resource Unit Regional* Lymph Node Involvement (N Stage): N0 No regional lymph node involvement N1 Involvement of one or two regional lymph nodes N2 Involvement of three to six regional lymph nodes N3 Involvement of seven or more regional lymph nodes gastric cancer for all other tumours (epicenter in stomach more than 5 cm from the esophagogastric junction and without extension into esophagus).
0 0 0 NA Any Stage 0 is 0 NA Stage IA 0 0 1 1 Any Stage IA 1a 0 1 1a 0 0 X Any 1a 0 X Stage IB 1a 0 0 2-3 Any Stage IB 1a 0 2 1b 0 0 1-3 Any 1b 0 1-2 1b 0 0 X Any 1b 0 X 2 0 0 1 Any Stage IC 1 0 3 Stage IIA 2 0 0 2-3 Any 2 0 1-2 2 0 0 X Any Stage IIA 2 0 3 3 0 0 Any L 2 0 X 3 0 0 1 U/M Stage IIB 1 1 Any Stage IIB 3 0 0 2-3 U/M 3 0 Any 3 0 0 X Any Stage IIIA 1 2 Any 3 0 0 Any X 2 1
# Goals of Therapy
To render the patient free of disease, to relieve symptoms (e.g.: dysphagia), and to improve or prolong survival, if possible.
Guideline Resource Unit Recommendations 14 :
• Complete the work-up (as described above).
• For patients who do not have metastatic disease: o Early referral to a surgeon trained in esophageal surgery is important to assess for resectability. o Patients should be referred for a multidisciplinary discussion including radiation oncologists and medical oncologists prior to surgery for patients with resectable disease. • Assess the degree of dysphagia and consult with a dietician to optimize the patient's nutritional status. Consider placement of a nasogastic (NG) feeding tube. If the NG feeding tube insertion is technically difficult, placement should be performed radiographically. • In a curative situation, avoid placement of an endoluminal stent as it increases the complication and mortality rate with radical chemoradiotherapy 15 . • Patients who receive preoperative chemoRT should have a CT scan prior to surgery. In certain cases, FDG-PET can provide an assessment of response but should only be done if clinically warranted [7][8][9][10][11][12] . • There is limited data to support the use of imaging after definitive chemoRT or after surgical resection for non-metastatic patients, however, individualized discussion regarding imaging after definitive chemoRT or after surgical resection for non-metastatic patients may be appropriate in select clinical cases. • For patients on palliative systemic treatment, CT chest, abdomen, and pelvis should be done every 2-3 months depending on the clinical situation. • Consider treatment on a clinical trial, if available. * Multidisciplinary discussion regarding chemoRT vs chemotherapy recommended For gastric cancers, refer to the Gastric Cancer Guidelines. For more details, refer to table 2. Note: EGJ was redefined in the AJCC 8th edition: adenocarcinomas with epicenters no more than 2cm into the gastric cardia are staged as esophageal adenocarcinomas, and those extending further are staged as stomach cancers. 55 Table 3. Curative therapy recommendations for patients with esophageal cancer.
# Stage Recommendations TisN0 or T1aN0 Disease
Endoscopic Therapy for Superficial Cancers: • Endoscopic mucosal resection (EMR) 22, , submucosal dissection (ESD) and various ablation techniques (e.g.: photo-dynamic therapy 23 , argon plasma coagulation, radiofrequency ablation 24 , cryotherapy) can preserve the integrity of the esophagus and provide a potentially curative option for superficial cancers. • Provided careful endoscopic surveillance can be performed, consider for patients with favorable mucosal tumours* who are interested in an esophagus-sparing approach or who are elderly, with multiple comorbidities, or otherwise high surgical risk. *Note: Favorable mucosal tumours include non-invasive (in situ) lesions or disease that invades into the mucosa (but not submucosa). Invasion into deepest third of submucosa 49%
Esophagectomy:
• Resect disease if both technically and medically feasible. Aim to achieve an "R0"resection (no gross or microscopic residual tumour). • Post-operative morbidity and survival are significantly better when surgery is completed in an experienced centre 25 . T1bN0 Disease
# Preferred
# Esophagectomy:
• Esophagectomy is the preferred treatment choice for fit patients with superficial esophageal cancers invading the submucosa.
# Alternate
Endoscopic therapy:
• For most patients with favorable intramucosal tumors, who are interested in an esophagus-sparing approach or are older with multiple comorbidities or are otherwise high surgical risk are candidates for endoscopic resection rather than surgical resection.
• If a patient is not medically operable, declines surgery, or is not a candidate for EMR/ESD, refer to 17 . This protocol improves the R0 resection rate (92% versus 69%) and overall survival (HR 0.657, CI95% 0.495-0.871, p = 0.003) when compared to surgery alone. It prolongs median survival from 24.0 months to 49.4 months and increases the one-, two-, three-, and five-year survival rates from 70% to 82%, 50% to 67%, 44% to 58%, and 34% to 47% respectively. It offers a pCR rate of 23%. 75% of the patients enrolled had adenocarcinoma. About 25% of patients had disease at the esophagogastric junction. • Aim to achieve an "R0"resection (no gross or microscopic residual tumour).
• Post-operative morbidity and survival are significantly better when surgery is completed in an experienced centre 25 .
# •Post-operative Adjuvant Therapy:
The Checkmate 577 trial randomized patients who received preoperative CROSS chemoradiotherapy followed by surgery with residual pathological disease (> ypT1 and/or >ypN1) to nivolumab (240 mg/m 2 IV q 2 weekly for up to 1 year) or placebo.
* Note that esophagectomy alone is an option in low risk cT2N0 patients. 56
# Preferred
# Alternate
# Guideline Resource Unit
Disease free survival (DFS) was significantly improved in the nivolumab group compared to the placebo (median 22.4 months versus 11.0 months, HR 0.69, 95% CI 0.56-0.86, p=0.003). 48 Nivolumab is not currently funded for this indication in Alberta.
• No randomized trial (and at least two meta-analyses 26,27 has demonstrated a survival advantage for preoperative chemoradiotherapy over chemotherapy alone • One network meta-analysis concluded that there is a survival benefit for neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy 28 .
o
# Alternatives for patients not candidates for FLOT
• MAGIC: When compared to surgery alone in patients with good performance status (ECOG ≤1) and T2-4N0-3M0 adenocarcinoma of the distal third of the esophagus, gastro-esophageal junction, or stomach, peri-operative chemotherapy improves the five-year progression-free (HR 0.66, CI95% 0.53-0.81, p < 0.001) and overall survival (from 23.0% to 36.3%, HR 0.74, CI95% 0.59-0.93, p = 0.008 19 ).
• Pre-Operative Phase: Three three-week cycles of Epirubicin 50 mg/m 2 and Cisplatin 60 mg/m 2 IV on day one plus a continuous intravenous infusion of 5-Fluorouracil 200 mg/m 2 /day over twenty-one days.
# Chemotherapy
• Operative Phase: Perform surgical resection with oncologic principles.
• Post-Operative Phase: As described in the pre-operative phase (above). Alternative for patients not candidates for epirubicin (MAGIC): cisplatin 5FU has been evaluated in patients with operable adenocarcinoma of the esophagus and gastroesophageal junction • The FFCD trial six peri-operative cycles of Cisplatin and infusional fluorouracil improves the five-year disease-free survival (34% versus 19%, HR 0.65, CI95% 0.48-0.89, p = 0.003), overall survival (38% versus 24%, HR 0.69, CI95% 0.50-0.95, p = 0.02), and rate of curative resection (84% versus 73%, p = 0.04) compared to surgery alone. Chemotherapy was given every 4 weeks and was comprised of cisplatin 100 mg/m 2 IV on day one plus 5-Fluorouracil 800 mg/m 2 /day over days one through five days, every 28 days 29 . • The OE5 trial randomized patients to 4 cycles of ECX or 2 cycles of cisplatin and infusional fluorouracil prior to surgery. The pathological complete response rate was higher in the ECX arm compared to cisplatin/fluoruracil (11% vs 3%). However, there was no significant difference in overall survival (23.4 months vs 26.1 months, HR 0.90 0.77-1.05, p = 0.19) 21 • These regimens require placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port. • For patients in whom it is not possible to resect disease due to medical or technical issues, refer to Table 3 Guideline Resource Unit
# Preferred Recommendation
In whom it is not possible to resect disease due to medical or technical issues: Primary ('Definitive') Chemoradiotherapy: • The two treatment options are: • Preferred: Deliver 5,000 cGy in twenty-five fractions over five weeks plus Oxaliplatin 85 mg/mg 2 IV and Leucovorin 200 mg/m 2 IV followed by 5-Fluorouracil 400 mg/m 2 IV bolus followed by 5-Fluorouracil 800 mg/m 2 /day over days one and two on weeks one, three, five, seven, nine, and eleven. This regimen is associated with less mucositis, alopecia, and renal toxicity plus numerically fewer toxic and sudden deaths but without a difference in overall survival, progression-free survival, and pCR rate 30 . (Level 1 evidence) • Alternatively deliver 5,000 cGy in twenty-five fractions over five weeks plus Cisplatin 75 mg/m 2 IV over one hour and 5-Fluorouracil 4,000 mg/m 2 IV over ninetysix hours on weeks one, five, eight, and eleven. This protocol offers an five-year overall survival rate of 27% (compared to 0% for radiotherapy alone) 31 . Note: 82% of the patients enrolled had squamous cell carcinoma of the esophagus. • These regimens require placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port.
# Alternate
Radiotherapy Alone:
• Consider for patients who decline chemotherapy or in whom chemotherapy is deemed unsafe.
# Guideline Resource Unit
# Recommendations for Incurable Situations
Provide palliative maneuvers to maintain and/or improve quality of life:
1. Relieve pain, bleeding, and/or dysphagia with radiotherapy (30 Gy in 10 fractions is preferred, alternatively 40 Gy in 15 fractions or 50 Gy in 20 fractions). 2. Consider placement of an endoluminal stent 32,33 or photodynamic therapy 34 to relieve dysphagia. 3. Patients with advanced esophageal cancer who have a self expanding metal stent inserted for the primary management of dysphagia do not gain additional benefit from concurrent palliative radiotherapy (Level 1 evidence). Palliative radiotherapy may be indicated for bleeding. 49 4. Consider palliative chemotherapy to control disease and prolong survival in patients with a satisfactory performance status (ECOG ≤ 2) 35-41 5. Consider treatment on a clinical trial if available. 6. Consider early referral to palliative care. (Symptom management guidelines can be found here). 7. Refer to dieticians and consider psychosocial referral. Early interdisciplinary care with the addition of psychologists and dieticians improved survival compared to standard oncology care in phase III trial of untreated patients with metastatic upper GI cancers (median overall survival 14.8 months vs 11.9 months, HR 0.68; 95% CI 0.51-0.9,; = 0.021). 58
# Metastatic Adenocarcinoma of the Esophagus or Gastroesophageal Junction
Many phase III clinical trials for metastatic gastric cancer also included patients with adenocarcinoma of the gastroesophageal junction. By extrapolation, patients with metastatic adenocarcinoma of the esophagus and gastroesophageal junction are treated as per metastatic gastric cancers. [Link to Gastric Guideline].
Evaluation of HER2 protein expression via immunohistochemistry or in situ hybridization is recommended to select patients with metastastic esophageal/gastroesophageal adenocarcinoma for trastuzumab based treatment 42 .
# Metastatic Squamous Cell Cancer of the Esophagus
There is limited data to guide systemic therapy for metastatic squamous cell cancer of the esophagus. The combination of a platinum with a fluoropyrimidine is the preferred first line regimen 42,43 .
• The benefit was seen in all patients, but primarily driven by the patients with squamous cell cancer. 50 Pembrolizumab is not currently funded for this indication in Alberta.
# Guideline Resource Unit
Second Line Therapy 47 The ATTRACTION-3 study randomized patients with advanced esophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy to nivolumab versus chemotherapy of physician's choice (paclitaxel 100 mg/m2 q week for 6 weeks followed by 1 week off) or docetaxel (75 mg/m2 q3 weeks). Overall survival was significantly improved in the nivolumab group compared to chemotherapy (median 10.9 months versus 8.4 months, HR 0.77, 95% CI 0.62-0.96; p=0.019). There was no significant difference in progression free survival for nivolumab versus chemotherapy (median 1.7 months versus 3.4 months, HR 1•08, 95% CI 0•87-1 •34). The prespecified interaction analysis indicated no significant interaction of treatment effect by PD-L1 status. Nivolumab is not currently available on the Alberta CancerCare Drug Benefit List.
Taxane based chemotherapy would be a reasonable alternative option and is available through the Alberta CancerCare Drug Benefit List.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta GI Tumour Team. Members of the Alberta GI Tumour Team include surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta GI Tumour Team, external participants identified by the Working Group Lead, and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial GI Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2021) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for noncommercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-ncnd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of Cancer Care Alberta's evidence-based clinical practice guidelines and supporting materials comes from the Cancer Care Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Rachid Mohamed has nothing to disclose. Dr. Diane Severin has nothing to disclose. Dr. Colin Schieman has nothing to disclose. Dr. Patricia Tang reports personal fees from Celgene, Genomic Health International, Amgen, Merck, Taiho Pharmaceutical, AstraZeneca, Pfizer, and Novartis.
Derek Tilley has nothing to disclose. Dr. Clarence Wong reports grants from Alberta Innovates, personal fees from Allergan, personal fees from Medtronic, personal fees from Takeda, personal fees from Pendopharm, grants from Somagen, outside the submitted work.
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9 Lignes directrices pour l'exercice de l'anesthésie dans les lieux isolés 9.1 Soins anesthésiques dispensés dans un établissement médical/chirurgical/dentaire non hospitalier 9.2 Soins anesthésiques dispensés hors de la salle d'opération dans un hôpital ou un établissement non hospitalier Annexe 1: Association canadienne de normalisation -Normes concernant le matériel Annexe 2: Classification de l'état de santé des patients, selon l'American Society of Anesthesiologists Annexe 3: Liste de vérification préanesthésique Annexe 4: Lignes directrices, normes et autres énoncés officiels disponibles sur l'internet Annexe 5: Exposé de principe sur les assistants en anesthésie : Un exposé de principe officiel de la Société canadienne des anesthésiologistes Annexe 6: Sédation procédurale : exposé de principe de la Société canadienne des anesthésiologistes#
How does this statement differ from the 2020 Guidelines?
- Several important content changes have been made and they are highlighted in bold in the text. Some of the more important changes include:
- Additional recommendations related to anesthesia medication safety and error prevention, under section 3.1 Responsibilities of the Healthcare Facility, that expand on recommendations introduced in the 2020 Revised Edition that were specific to safety and diversion prevention for controlled medications (e.g., opioids).
- The addition of brain natriuretic peptide (BNP/NT-pro BNP) as a preoperative investigation to be considered for patients with, or at risk for, significant cardiovascular disease.
- A revision to section 4.2 Fasting Guidelines to clarify the role of H2 receptor blockers in the management of patients presenting for Cesarean delivery (see accompanying editorial).
- An entirely new section 5.7 Patient Positioning to address the critical importance of meticulous planning, execution, and rechecking of positioning for patient safety.
- A minor but important change related to the requirements for documentation of initial vital signs in PACU necessitated by the expanding implementation of Anesthesia Information Management Systems.
- The recommendation that, during patient transport to and in the PACU, if patients with in situ endotracheal tubes require supplemental oxygen, that it should only be administered utilizing devices approved for that application to reduce the risk barotrauma.
- Extensive revision to section 9.0, now called Guidelines for Practice of Anesthesia in Remote Locations, addressing the delivery of anesthesia care in remote locations both within and outside of a hospital facility. An important recommendation is that anesthesia staff should have appropriately trained anesthesia support personnel (e.g., an anesthesia assistant) present or immediately available to assist them.
- Appendix 1: Canadian Standards Association-Standards for Equipment - Appendix 5: Position Paper on Anesthesia Assistants has been significantly revised in cooperation with the CAS Committee on the Anesthesia Care Team and is available as electronic supplementary material.
Comment cet énoncé diffère-t-il des Lignes directrices de 2020? Plusieurs modifications importantes ont été apportées au contenu; elles sont surlignées en gras dans le texte. Parmi les modifications les plus importantes, citons :
- Des recommandations supplémentaires concernant l'innocuité et la prévention des erreurs des médicaments anesthésiques, sous la section 3.1 Responsabilite´s de l'e´tablissement de sante´, qui approfondissent les recommandations introduites dans l'É dition révisée de 2020 spécifiques à l'innocuité et à la prévention du détournement des substances contrôlées (par ex. les opioïdes).
- L'ajout du peptide cérébral natriurétique (BNP/NT-pro BNP) parmi les examens préopératoires à envisager chez les patients atteints ou courant un risque d'être atteints de maladie cardiovasculaire significative.
- Une révision de la section 4.2 Lignes directrices concernant le jeuˆne afin de clarifier le rôle des antagonistes des récepteurs H2 dans la prise en charge des patientes devant subir un accouchement par césarienne (voir l'éditorial associé).
- Une toute nouvelle section 5.7 Positionnement du patient afin de souligner l'importance cruciale de la planification, de l'exécution et de la vérification méticuleuses du positionnement pour la sécurité des patients.
- Une modification mineure mais importante liée aux exigences de documentation des signes vitaux initiaux en salle de réveil nécessaires en raison de l'utilisation toujours plus répandue des Systèmes électroniques de gestion de l'information en anesthésie.
- La recommandation selon laquelle, pendant le transfert des patients et dans la salle de réveil, lorsqu'un patient chez qui un tube endotrachéal est installé nécessite de l'oxygène supplémentaire, l'administration ne devrait se faire qu'à l'aide de dispositifs approuvés pour cette application afin de réduire le risque de barotraumatisme.
- Une révision approfondie de la section 9.0, désormais intitulée Lignes directrices pour l'exercice de l'anesthe´sie dans les lieux isole´s, abordant la fourniture de soins anesthésiques dans les lieux isolés tant au sein d'un établissement hospitalier que hors d'un milieu hospitalier. Une recommandation importante touche au fait que le personnel d'anesthésie devrait disposer de personnel de soutien en anesthésie ayant reçu une formation adéquate (par ex., un assistant en anesthésie) présent ou immédiatement disponible pour l'assister.
- Annexe 1 : Association canadienne de normalisation -Normes concernant le matériel - L'Annexe 5 : Expose´de principe sur les assistants en anesthe´sie a été révisée de fond en comble en coopération avec le Comité sur les équipes de soin en anesthésie de la SCA et est disponible sous forme de matériel électronique supplémentaire
# Table des matières
# Préambule
Overview The Guidelines to the Practice of Anesthesia Revised Edition 2021 (the Guidelines) were prepared by the Canadian Anesthesiologists' Society (CAS), which reserves the right to determine their publication and distribution. The Guidelines are subject to revision and updated versions are published annually. The Guidelines to the Practice of Anesthesia Revised Edition 2021 supersedes all previously published versions of this document. Although the CAS encourages Canadian anesthesiologists to adhere to its practice guidelines to ensure high-quality patient care, the CAS cannot guarantee any specific patient outcome. Anesthesiologists should exercise their own professional judgement in determining the proper course of action for any patient's circumstances. The CAS assumes no responsibility or liability for any error or omission arising from the use of any information contained in its Guidelines to the Practice of Anesthesia.
# Preamble
Anesthesiology is a dynamic specialty of medicine that fosters continuous improvements in anesthetic care for patients undergoing surgical and obstetric procedures in Canada. This document is reviewed annually and revised periodically.
The following recommendations are aimed at providing basic guidelines to anesthetic practice. They are intended as a framework for reasonable and acceptable patient care and should be interpreted as such to allow for some degree of flexibility in different circumstances. Each section of the Guidelines is subject to revision as warranted by the evolution of technology and practice.
# Basic Principles
In this document, the term anesthesiologist is used to designate all licensed medical practitioners with privileges to administer anesthetics. An anesthetic is the deliberate performance of any procedure to render a patient temporarily insensitive to pain or to the external environment so that a diagnostic or therapeutic procedure can be performed.
These Guidelines are intended to apply to all anesthesiologists in Canada. The independent practice of anesthesia is a specialized field of medicine, and as such, it should be practiced by physicians with appropriate training in anesthesia. The only route to specialist recognition in anesthesia in Canada is through the certification process of the Royal College of Physicians and Surgeons of Canada. The Canadian Anesthesiologists' Society (CAS) acknowledges the fact that remote communities often lack the population base to support a specialist Can J Anesth/J Can Anesth (2021) 68:92-129 ? Text approved by CAS Board for 2021 Edition.
Texte approuvé par le CA de la SCApour l'édition 2021.
Electronic supplementary material The online version of this article () contains supplementary material, which is available to authorized users. anesthesiology practice.
In these communities, appropriately trained family physicians may be required to provide anesthesia services. In communities with the clinical volume to support full-time anesthesiologists, fellowship-certified anesthesiologists should provide these services. All anesthesiologists must continue their education in the practice of anesthesia, pain management, perioperative care, and resuscitation and participate in a structured maintenance of competence program (e.g., Royal College MOC).
# Organization of Anesthetic Services
The department of anesthesia should be properly organized, directed, and integrated with other departments in the organization or facility, and it should include all facility staff members who provide anesthetic services to patients for surgical, obstetric, diagnostic, and therapeutic purposes.
The department should be staffed appropriately, bearing in mind the scope and nature of the services it provides, and it should strive to ensure that these services are available as required by the healthcare facility.
The chief of the department should be a physician who has obtained certification or appropriate training in anesthesia. This individual should be appointed in the same manner as other chiefs of clinical departments and should be a member of the senior medical administrative bodies for the facility.
# Responsibilities of the Chief of Anesthesia
- To be aware of the current CAS Guidelines to the Practice of Anesthesia, the requirements of the Canadian Council on Health Services Accreditation, and the requirements of the provincial licensing authority as they relate to anesthesia; 2. To ensure that written policies with respect to the practice of anesthesia are established and enforced; 3. To evaluate the qualifications and abilities of the physicians providing anesthetic care as well as other health professionals providing ancillary care-this includes, but is not restricted to, recommending clinical privileges for physicians with anesthetic responsibilities and annually reviewing these privileges; 4. To employ a systematic approach for monitoring the quality of anesthetic care provided by members of the department of anesthesia throughout the healthcare facility; Monitoring quality of care may include, but need not be restricted to, the use of chart audits, clinical indicator and outcome monitoring, adverse event reporting systems, morbidity and mortality conferences, and critical incident case reviews. The extent of quality improvement activities will vary depending on the departmental and health facility resources available to the chief. For effective quality improvement, it is strongly encouraged that all department members should actively participate in any such activities. 5. To ensure that records are kept for all anesthetic procedures-these records should allow for evaluation of all anesthetic care in the facility; 6. To carry out such other duties as the governing body of the facility may delegate to ensure safe anesthetic care; 7. To promote institutional compliance with applicable Canadian Standards Association (CSA) Standards (Appendix 1); and 8. To coordinate liaison between the departments of anesthesiology, biomedical engineering, and information management services. Special areas of anesthetic care may have specific concerns. The department of anesthesia in each institution may determine privileges in pediatric anesthesia according to the pediatric population it serves, the child's age, the presence of comorbidities, the physician's specific training and experience in pediatric anesthesia, and the complexity of the procedure involved.
# Privileges in Anesthesia
Physicians with anesthetic privileges should possess the knowledge and technical and non-technical skills necessary for the practice of anesthesia.
Knowledge and technical skills include the ability: - To provide preanesthetic evaluation of the patient and determine the appropriate anesthetic management; - To render the patient insensible to pain for the performance of diagnostic and therapeutic procedures, surgical operations, and obstetric procedures; - To monitor and support the vital organ systems during the perioperative period;
- To provide immediate postanesthetic management of the patient; - To provide resuscitation and intensive care when indicated; and - To provide relief from acute and chronic pain. Nontechnical skills include: - Task management: planning and preparing, prioritizing, providing and maintaining standards, and identifying and utilizing resources; - Teamwork: coordinating activities with team members, exchanging information, using authority and assertiveness, assessing capabilities, supporting others, and supporting the World Health Organization Surgical Safety Checklist; - Situational awareness: anticipating, gathering information, recognizing, and understanding, and;
- Decision-making: identifying options, balancing risks and selecting options, and re-evaluating.
# Fitness to Practice
The provision of anesthesia care requires anesthesiologists to have a high level of expertise, sound judgment, and the ability to recognize and respond to changing clinical situations despite sometimes adverse personal physical circumstances. Anesthesia departments must recognize that fit anesthesia practitioners provide optimal patient care. Anesthesia departments are therefore obligated to develop policies that ensure, as far as possible, that practitioners are healthy and fit to undertake their duties of practice.
A variety of factors impair health and fitness for duty, including adverse physical conditions, mental impairment, and fatigue. All these factors impair fitness and the ability to recognize and respond appropriately to often rapidly changing clinical circumstances. Many studies have shown that fatigue impairs judgement and psychomotor performance in a manner similar to drugs or alcohol. Shifting circadian rhythms, aging, and lack of sleep reinforce such problems; a fatigue-induced lack of recognition of these problems can compound the potential for errors in such circumstances. Physical impairment, illness, and severe stress can have similar detrimental effects on performance.
Anesthesia departments and individual anesthesiologists have a responsibility to organize their working duties such that illness and fatigue do not regularly affect clinical duties. Individual rosters must allow adequate rest between working shifts, and daily rosters should allow appropriate breaks for physiological needs, nutrition, and mental fitness. Operating room scheduling should avoid requiring anesthesiologists to undertake non-emergency procedures during unfavourable hours.
No specific prescription for working shifts and daily rosters can be appropriate for every working situation. Large departments have flexibility to incorporate short shifts and individual leave, while small departments may not have such freedom. Nevertheless, this important area of professional practice must receive ongoing consideration and attention.
# Residents
Residents in anesthesia are registered medical practitioners who participate in the provision of anesthesia services both inside and outside the operating room as part of their training. The Royal College of Physicians and Surgeons of Canada and provincial and local regulatory authorities require that a responsible attending staff anesthesiologist must supervise all resident activities. The degree of this supervision must consider the condition of each patient, the nature of the anesthetic service, and the experience and capabilities of the resident (increasing professional responsibility). At the discretion of the supervising staff anesthesiologist, residents may provide a range of anesthetic care with minimal supervision. In all cases, the supervising attending anesthesiologist must remain readily available to give advice or assist the resident with urgent or routine patient care. Whether supervision is direct or indirect, close communication between the resident and the responsible supervising staff anesthesiologist is essential for safe patient care. Each anesthesia department teaching anesthesia residents should have policies regarding the activities and supervision of residents.
# Ancillary Personnel
The healthcare facility must ensure that ancillary personnel are available as assistants to the anesthesiologist. Such assistants must be available at all times and places where anesthetic services are provided. Ancillary personnel should have the competencies to meet the specific needs of subspecialty areas of anesthesia, reflecting on the need for specific skills in areas such as specialty pediatric anesthesia.
It is recommended that facilities have a formally designated anesthesia assistant with specific training in anesthesia assistance. The department of anesthesia and the appropriate administrative bodies must approve the scope of practice for anesthesia assistants working in a specific institution. Furthermore, anesthesia assistants like other employed health professionals, must be covered by the facility's liability insurance. Duties and tasks delegated to anesthesia assistants must be consistent with existing governmental regulations, the policies and guidelines established by professional regulatory agencies, and the policies of the local facility.
An institution without formal anesthesia assistants must provide other paramedical personnel to assist the anesthesiologist. The tasks that these assistants may perform must be clearly defined. An anesthesiologist must only delegate or assign those tasks for which such personnel have approval or accreditation.
# Anesthetic Equipment and Anesthetizing Location
An anesthetic must be administered in an appropriate facility. All necessary equipment, including emergency equipment, life support systems, medications, and supplies must be readily available. It is strongly recommended that a cognitive aid manual be made available at all anesthetizing locations in support of the management of critical perioperative emergencies. The contents of the manual should be regularly reviewed, updated as required, and periodically practiced as a team.
The healthcare facility, in consultation with the department of anesthesia, is responsible for the design and maintenance of preoperative, postoperative, and anesthetizing locations, as well as the purchase, maintenance, and disposal of anesthetic and ancillary equipment and supplies. The Canadian Standards Association (CSA) and other standards development organizations have published standards and guidance documents for the design, construction, and renovation of healthcare facilities and for the risk management, basic safety, and essential performance of medical equipment (Appendix 1).
# Responsibilities of the Healthcare Facility
The healthcare facility must ensure that: 1. The operating rooms, anesthetizing locations, and perioperative care locations comply with at least the minimum design and construction requirements of the national, provincial, and local building, plumbing, electrical, HVAC (heating, ventilation, and air conditioning), fire, and security codes at the time of construction or renovation. 2. Medical gas and vacuum systems, waste anesthetic gas scavenging systems, terminal units, head walls, low pressure connecting assemblies, and pressure regulators meet the requirements of the CSA and are certified by a CSA-approved testing agency. 3. Oxygen concentrators that comply with CSA requirements are an acceptable substitute for bulk oxygen supply systems. When such concentrators are installed, users must be aware that:
a. The facility medical oxygen supply may deliver a fraction of inspired oxygen (FiO 2 ) that varies from 0.93 to 0.99; b. Oxygen analyzers must be calibrated against 100% O 2 (FiO 2 0.99) and room air or equivalent (FiO 2 0.21); c. The use of low-flow (less than one litre total fresh gas flow) anesthetic techniques may result in the accumulation of inert gas (argon) and the dilution of nitrous oxide and oxygen in the circuit.
There is compliance with all safety regulations and best practice with respect to the storage, preparation, identification, labelling, disposal, and use of medical gases, medications, and related materials.
a. General medication safety recommendations include, but need not be restricted to:
- Identifying an anesthesia department lead designated to cooperate with pharmacy to promote medication safety best practice. In recognition of the increased risk of medication errors related to medication brand substitutions and look-alike packaging, departments and pharmacies should consider strategies to reduce this risk.
- Requesting that pharmacy staff notify anesthesia staff, with as much notice as possible, of upcoming medication supplier, packaging, or concentration changes such that anesthesia staff can be alerted. - Standardization of drug trays across all locations and during product transitions. Medications with different supplier brands and packaging for a medication should not be mixed in the same anesthesia cart. - Medication substitutions, particularly of a different concentration, should be labelled with highly visible warning labels when any new medication is introduced. - Look-alike medications should be physically separated in the anesthesia carts as much as is possible and identified with warning labels. - Cautioning physicians and technical support staff that replacement of unopened medications back into anesthesia carts is risky because medication may be put in the incorrect location.
- Reporting any medication-related adverse events through local adverse event reporting systems or CAIRS or both.
b. Through cooperation between the departments of anesthesia and pharmacy, there are policies developed and enforced for the safe handling, storage, and disposal of controlled medications (e.g., opioids) in the operating rooms and postanesthesia care unit (PACU) that are consistent with the law, with any regulatory authority requirements, and established best practice principles. The goals of such policies should be to limit access of unauthorized personnel to controlled medications to minimize the risk of controlled medication diversion, and to establish robust documentation procedures that can be audited, while also protecting patient safety by still permitting anesthesia providers immediate access to any medications required for patient care.
Best practice principles support a variety of specific strategies to achieve these goals. The CAS does not endorse any one specific strategy or policy but strongly recommends that all available options be considered. Robust systems and procedures must be implemented. Due consideration should be given to any limitation in resources available to implement specific security systems and procedures within a facility, particularly for smaller facilities.
Recommendations include, but need not be restricted to: - Storing controlled substances in a secure lockable safe or locked drawer when the OR is unattended by anesthesia personnel (e.g., between cases). - Never leaving controlled substances (including those drawn up into syringes or bags) unattended in any location. - Emptying the contents of syringes and bags containing controlled substances before disposal. - Adopting disposal and/or destruction systems to dispose of controlled substance waste. - Consideration of a requirement that controlled substance waste be returned to the pharmacy and be subjected to random analysis. - Periodic audits of a healthcare provider's controlled substance utilization records and their anesthesia records. - Consideration of the implementation of automated anesthesia cabinets or automated medication dispensing cabinets (e.g. PyxisTM)
The operating room, labour and delivery, postanesthesia care unit (PACU), and regional block areas, for example, should all be recognized as high risk areas for controlled medication diversion and therefore must be subject to heightened security, surveillance, and auditing.
- If general anesthesia is provided using an electronic anesthetic system (gas machine), it must comply with CAN/CSA-C22. Anesthesia providers must ensure that potentially infectious materials or agents are not transferred from one patient to another. Special attention in this regard should be given to syringes, infusion pump administration sets, and multi-dose drug vials.
Training on the safe use of all anesthesia equipment should be provided to all anesthesia department members prior to use. Attendance at these sessions should be documented. These training sessions should be repeated as necessary for new or established department members.
# Waste Gases
# The Preanesthetic Period
The department of anesthesia should establish policies regarding preanesthetic assessment.
The primary goal of preanesthetic assessment is to obtain the information required to plan anesthetic management. Accordingly, a physician who is knowledgeable about anesthetic management for the proposed diagnostic or therapeutic procedure should document all aspects of the patient's medical and surgical history, findings on physical examination, and laboratory investigations that are relevant to anesthetic management. The patient's history should include past and current medical problems, current and recent drug therapy, unusual reactions or responses to drugs, and any problems or complications associated with previous anesthetics. A family history of adverse reactions associated with anesthesia should also be obtained. Information about the anesthetic that the patient considers relevant should also be documented. An American Society of Anesthesiologists physical status classification (Appendix 2) should be recorded for each patient.
In appropriate cases, the availability of an ''Advance Care Plan'' (representation agreement, advanced directive, ''living will'', ''do not resuscitate'' directive, etc.) should be ascertained, and its applicability to the proposed intervention should be determined and documented on the anesthetic assessment record.
The surgeon may request consultation with an anesthesiologist. Medical consultations should be obtained when indicated.
Preoperative anesthetic assessment or consultation may take place in an outpatient clinic before admission for the operative procedure. Indications for pre-admission assessment include the presence of significant medical problems (comorbidities), the nature of the proposed diagnostic or therapeutic procedure, and patient request. A parent/guardian must be present if the patient is a child or not competent to provide informed consent. All patients should be informed that arrangements will be made to meet with an anesthesiologist if they wish to discuss anesthetic management before admission to the facility. The preoperative assessment clinic should also allow nursing and other healthcare personnel to assess the patient. The attending anesthesiologist is responsible for performing a final preanesthetic assessment in the immediate preoperative period.
# Preoperative Testing
Laboratory testing should not be performed on a routine basis but should be obtained only when results will change perioperative management. Laboratory investigations should be performed when indicated by the patient's medical status, drug therapy, and the nature of the proposed procedure.
Routine
# Partial thromboplastin time/ international normalized ratio
May be considered:
- with conditions or medications associated with impaired coagulation (e.g., liver disease, malnutrition), history of excessive bleeding, or a family history of heritable coagulopathies
- for patients on oral or parenteral anticoagulant therapy.
# TEST INDICATIONS
Electrolytes May be considered:
- with known or compelling findings in favour of hypertension, congestive heart failure, chronic renal failure, complicated diabetes, liver disease, pituitary-adrenal disease, malnutrition
- for patients taking diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and other therapy affecting electrolytes.
Creatinine and estimated glomerular filtration rate (eGFR) May be considered:
- as above for electrolytes, also with advanced age and for patients taking medications potentially affecting renal function
- for patients receiving direct oral anticoagulants
- as required for calculating perioperative risk indices
- eGFR is recommended to assist with renal outcome prediction.
Fasting glucose level May be considered:
- for diabetics, preoperatively on day of surgery to guide glycemic control
- for patients on glucocorticoid therapy
- as screening for body mass index [ 40 or a very high risk of diabetes based on signs and symptoms.
# Hemoglobin A1c
- May be considered for known diabetics as early as possible before surgery (ideally at time of surgical referral) if results would change management.
# Pregnancy testing Based on specific institutional guidelines
- Should be offered to women of childbearing age based on any reasonable likelihood of pregnancy, on the reliability of menstrual history, and if the results will cancel or change the procedure or the anesthetic management.
- Point of care urine or blood testing capability is ideal and is therefore recommended.
# Electrocardiography
- May be considered for patients with known or suspected coronary heart disease, significant arrhythmia, peripheral vascular disease, or other significant structural heart disease.
- May be considered in the absence of symptoms or known cardiovascular disease in patients having high-risk surgery in the presence of clinical risk factors (e.g., Revised Cardiac Risk Index (RCRI) or American College of Surgeons (ACS) Surgical Risk Calculator).
Brain natriuretic peptide (BNP or NT-pro BNP)
May be considered if:
- age ‡ 65 yr,
- age 45-65 yr with significant cardiac disease,
- Revised Cardiac Risk Index score ‡ 1.
# Chest radiograph
- Not recommended for asymptomatic patients in routine preoperative assessment unless part of a surgical or oncological workup unrelated to perioperative risk assessment.
- May be considered for patients with acute or chronic cardiopulmonary disease based on history and physical exam if it will change management.
# Fasting Policies
Fasting policies should vary to account for age and preexisting medical conditions and should apply to all forms of anesthesia, including procedural sedation (see Appendix 6). 1 Emergent or urgent procedures should be undertaken after considering the risk of delaying surgery vs the risk of aspiration of gastric contents. The type and amount of food ingested should be considered in determining the duration of fasting. Before elective procedures, the minimum duration of fasting should be:
- Eight hours after a large meal of solids particularly containing protein (e.g., meat) or fatty foods - Six hours after a light meal (e.g., non-fatty meal such as toast) - Six hours after ingestion of infant formula, non-human milk, or expressed breast milk fortified with additions - Four hours after ingestion of breast milk - Two hours after ingestion of clear fluids for adults - One hour after ingestion of clear fluids for infants and children Unless contraindicated, adults and children should be encouraged to drink clear fluids (including water, pulp-free juice, complex carbohydrate beverages, and black tea or coffee up to two hours before elective surgery. Pediatric patients should also be encouraged to consume clear fluids, as defined, up to one hour before elective procedures.
Conditions that delay gastric emptying require individual patient assessment. These guidelines may be modified at the discretion of the physician.
Premedication, when indicated, should be ordered by the anesthesiologist. Orders should be specific as to dose, time, and route of administration.
An H2 receptor antagonist (oral or intravenous) is recommended for all women presenting for Cesarean delivery.
Thirty mL of oral sodium citrate (0.3 molar) is recommended prior to an emergent Cesarean delivery if general anesthesia is planned. See Section 7.3 for fasting guidelines specific to patients in active labour.
# Additional Regulations
Provincial legislation or facility bylaws may dictate additional regulations governing the conduct of anesthesia.
# The Anesthetic Period
# Preparation for Anesthesia
Before beginning anesthesia, the anesthesiologist must ensure that 1. An explanation of the planned anesthetic procedure, including recognized risks and alternative techniques, has been provided and documented; 2. An adequate review of the patient's condition has been performed; 3. All equipment that is expected to be required is available and in working order, including the equipment required for supporting core temperature management (patient core temperature 36-37°C); 4. A reserve source of oxygen under pressure is available; 5. All drugs and agents that are expected to be required are correctly identified-user-applied drug labels should conform to the CSA Standard CAN/CSA-Z264.3-98 (R2005) (Appendix 1); 6. If Luer neuraxial connectors are used, both sides of all Luer connections must be labelled. Consideration should be given to the use of neuraxial connectors complying with ISO 80369-6:2016-small bore connectors for neuraxial application (e.g., NRFitÒ connectors) subject to availability from equipment suppliers; and 7. The manufacturers' recommendations concerning the use, handling, and disposal of anesthetic equipment and supplies have been considered.
# Airway Management
Airway management, particularly of the difficult airway, contributes to a significant proportion of anesthesia related morbidity and mortality.
The appropriate management of those patients who have a predicted, or an unanticipated difficult intubation, a failed airway, where bag-mask ventilation or supraglottic device placement may be difficult, or who require a surgical airway is critical for patient safety. This includes, but need not be restricted to, adequate airway assessment, equipment (e.g., difficult airway carts, videolaryngoscopes, bronchoscopes), training and simulation, support personnel and the use of protocols and cognitive aids to optimize difficult airway management. The CAS does not endorse any one specific protocol, algorithm, or cognitive aid for difficult and failed airway management but strongly recommends that readers refer to Appendix 4 for up to date publications related to this topic.
# Delegation of Patient Care
The anesthesiologist's primary responsibility is to the patient receiving care. The anesthesiologist or an anesthesia assistant supervised by the anesthesiologist must remain with the patient at all times throughout the conduct of all general and major regional, anesthetics and for procedural sedation until the patient is transferred to the care of personnel in an appropriate care unit.
If the attending anesthesiologist leaves the operating room temporarily, he/she must delegate care of the patient to another anesthesiologist, a resident in anesthesia, or an anesthesia assistant. When the attending anesthesiologist delegates care to a resident in anesthesia or an anesthesia assistant, the attending anesthesiologist remains responsible for the anesthetic management of the patient. Before delegating care of the patient to an anesthesia assistant, the anesthesiologist must ensure that the patient's condition is stable and that the anesthesia assistant is familiar with the operative procedure and the operating room environment and equipment. The attending anesthesiologist must remain immediately available when care is delegated to an anesthesia assistant.
An anesthesiologist may briefly delegate routine care of a stable patient to a competent person who is not an anesthesia assistant only under the most exceptional circumstances, e.g., to provide life-saving emergency care to another patient. That person's only responsibility would be to monitor the patient during the anesthesiologist's absence and to keep the anesthesiologist informed until he/ she returns. In this situation, the anesthesiologist remains responsible for the care of the patient and must inform the operating room team.
An intraoperative handover of care between two anesthesiologists should be documented in the anesthesia record and follow a structured protocol.
It is unacceptable for one anesthesiologist to simultaneously administer general anesthesia, major regional anesthesia (spinal, epidural, or other), or deep procedural sedation (see Appendix 6) 1 for concurrent diagnostic or therapeutic procedures on more than one patient. Nevertheless, it may be appropriate in specific circumstances for one anesthesiologist to supervise more than one patient where only minimal to moderate sedation is administered, provided an appropriately trained, qualified, and accredited individual approved by the department of anesthesiology, and the healthcare institution is in constant attendance with each patient receiving care. In an obstetric unit, however, it is acceptable to supervise more than one patient receiving regional analgesia for labour. Due care must be taken to ensure that a suitably trained person adequately observes each patient following an established protocol. When an anesthesiologist is providing anesthetic care for an obstetric delivery, a second appropriately trained person should be available to provide neonatal resuscitation.
It is unacceptable for a single physician to administer an anesthetic, including deep procedural sedation, and simultaneously perform a diagnostic or therapeutic procedure, except for procedures done with only infiltration of local anesthetic and/or minimal sedation.
# Patient Monitoring
The only indispensable monitor is the presence, at all times, of a physician or an anesthesia assistant who is under the immediate supervision of an anesthesiologist and has appropriate training and experience. Mechanical and electronic monitors are, at best, aids to vigilance. Such devices assist the anesthesiologist to ensure the integrity of the vital organs and, in particular, the adequacy of tissue perfusion and oxygenation. Monitoring equipment must be used as intended by the manufacturer and approved by Health Canada for the specific application.
The healthcare facility is responsible for the provision and maintenance of monitoring equipment that meets current published equipment standards.
The chief of anesthesia is responsible for advising the healthcare facility regarding the procurement of monitoring equipment and for establishing policies for monitoring to help ensure patient safety.
The anesthesiologist is responsible for monitoring the patient receiving care and for ensuring that appropriate monitoring equipment is available and working correctly. A preanesthetic checklist (Appendix 3 or equivalent) must be completed prior to initiation of anesthesia.
Cautious dosing, vigilant monitoring, and the appropriate reversal of neuromuscular blocking drugs are all essential for patient safety. Neuromuscular monitoring must be utilized when neuromuscular blocking agents are administered.
Monitoring guidelines for standard patient care apply to all patients receiving general anesthesia, regional anesthesia, or procedural sedation.
# Required Monitoring Equipment
Monitoring equipment is classified as follows:
- Required: These monitors must be in continuous use throughout the administration of all anesthetics. - Exclusively available for each patient: These monitors must be available at each anesthetic work station so that they can be used with no delay. - Immediately available: These monitors must be available to facilitate their use without undue delay.
The following monitoring equipment is required: - Pulse oximeter;
- Apparatus to measure blood pressure, either directly or noninvasively; - Electrocardiography; - Neuromuscular blockade monitor when neuromuscular blocking drugs are used; - Capnography for general anesthesia and to assess the adequacy of ventilation for moderate or deep procedural sedation; and - Agent-specific anesthetic gas monitor, when inhalational anesthetic agents are used.
The following monitoring equipment must be exclusively available for each patient:
- Apparatus to measure temperature; - Stethoscope; - Appropriate lighting to visualize an exposed portion of the patient.
The following monitoring equipment must be immediately available: - Spirometer to measure tidal volume; - Manometer to measure endotracheal tube cuff pressure.
- Equipment for invasive hemodynamic monitoring if indicated (e.g., arterial, central venous).
The anesthesiologist must remain constantly vigilant, understanding that brief interruptions in continuous monitoring may be unavoidable and there are certain circumstances in which a monitor may fail.
Audible and visual alarms for oximetry and capnography should not be indefinitely disabled during the conduct of an anesthetic except during unusual circumstances. The variable pitch, pulse tone, and lowthreshold alarm of the pulse oximeter and the capnograph apnea alarm must give an audible and visual warning.
# Perioperative Temperature Management
Monitoring patient core temperature is strongly recommended during cases of general and neuraxial regional anesthesia lasting 30 min or longer. In the absence of surgical or patient indications for intraoperative hypothermia, active patient warming systems, control of the operating room ambient temperature, and other methods, should be used to target a central core temperature of 36-37°C.
# Patient Positioning
Patient positioning for procedures requiring anesthesia is an operating room team responsibility and demands a high level of attention to avoid complications. It is recognized, however, that positioning-related complications can still occur despite best practice and vigilance. Risks related to patient positioning will vary and depend on the type and duration of surgery, the specific position utilized, and patient factors such as BMI and other comorbidities. Therefore, the considerations and planning for positioning best practice should be discussed by the surgical team ideally before anesthesia induction, for example during part 1 of the Surgical Safety Checklist. All members of the team, including the anesthesiologist, should be encouraged to voice concerns related to any aspect of positioning (e.g., specific risk factors and availability, condition and appropriateness of OR tables and other positioning equipment), and strategies to mitigate these risks should be considered. Patient positioning should be documented and also rechecked regularly by the anesthesiologist to be sure positioning conditions remain ideal. Patients should be informed preoperatively of any specific risks that may be associated with the position planned for their procedure.
# Records
All monitored physiologic variables should be charted at intervals appropriate to the clinical circumstances. Heart rate and blood pressure should be recorded at least every five minutes. Oxygen saturation must be monitored continuously and should be recorded at frequent intervals, at a minimum of every five minutes, for all patients. End-tidal carbon dioxide concentration must be monitored continuously and recorded at frequent intervals if the trachea is intubated or a supraglottic device is in situ. Reasons for deviation from these charting guidelines should be documented in the anesthetic record. Monitors, equipment, and techniques, as well as time, dose, and route of all drugs and intravenous fluids should be recorded. All other relevant intraoperative anesthesia care and events, including unexpected or adverse events, should also be recorded.
The patient health record should include the patient's level of consciousness, heart rate, blood pressure, oxygen saturation, and respiratory rate as first determined in the PACU. These recommendations apply to both manually created (handwritten) and electronic anesthesia information management system (AIMS) created anesthesia records. At present, there are no practice standards for what additional data (e.g., gas analysis, ventilator, and respiratory data) that can potentially be collected by an AIMS charting system should become part of a patient's permanent health record.
AIMS have been shown to have potential benefits over handwritten records in several key areas, including improved legibility, precision and reliability of anesthesia records, providing searchable data for quality improvement, outcome and performance reporting and translational research, enhanced medication safety and tracking and real-time clinical decision support for users. The anesthesia patient safety literature supports the use of AIMS. Importantly, AIMS maintain a longitudinal patient database so historical patient encounters should be easily retrievable for review and this should be considered an important feature of any system. The CAS does not promote or endorse any one specific vendor or product but acknowledges that there may be potential benefits of a well designed and implemented AIMS over manually charted records where facility and anesthesia department resources permit the consideration of an AIMS. Ideally it should be implemented and supported in cooperation with the facility information technology department including communication with other facility electronic patient databases wherever possible.
6 The Postanesthetic Period
# Recovery Facility
A PACU must be available in any facility that provides anesthetic services. Administrative policies to coordinate medical and nursing care responsibilities must be enforced in accordance with facility bylaws.
The department of anesthesia should have overall medical administrative responsibility for the PACU. There should be a PACU policy manual approved by appropriate medical, nursing, and administrative authorities.
The anesthesiologist should accompany the patient to the PACU, communicate necessary information to the PACU nurse(s) as part of a structured handover of care protocol, and write appropriate orders. Continuous monitoring of patients is recommended during the perioperative period appropriate to the clinical situation. If clinically indicated, supplemental oxygen, portable pulse oximetry, and other appropriate monitoring devices should be applied during transport to the PACU or intensive care unit. If supplemental oxygen is applied during transport or in PACU to patients who are intubated it is strongly recommended that it only be provided using devices approved for that specific application to minimize any risk of barotrauma. The anesthesiologist should delegate care to the PACU nurse only when assured that nursing staff may safely observe and care for the patient. The anesthesiologist or designated alternate is responsible for providing anesthetic-related care in the PACU. Discharge from the PACU is the responsibility of the anesthesiologist; this responsibility may be delegated in accordance with facility policy.
Supplemental oxygen and suction must be available for every patient in the PACU. Emergency equipment for airway management, resuscitation, and life support must be available in the PACU. Equipment for management of the difficult airway must be immediately available to the PACU. The monitoring used in the PACU should be appropriate to the patient's condition, and a full range of monitoring devices should be available. Monitor alarms should be enabled with alarm settings appropriate to the condition and age of the patient. The use of continuous pulse oximetry is required in the initial phase of recovery. Capnography is required for intubated and deeply sedated patients and is recommended for unconscious patients with in situ supraglottic airway devices. An apnea monitor is recommended for preterm infants with a gestational age of less than 50 weeks.
An accurate record of the immediate recovery period must be maintained. This must include a record of vital signs together with other aspects of treatment and observation. The recovery record must form a part of the permanent medical record. Any complications that bear any relation to the anesthetic should be recorded either on the recovery record or on the progress notes on the patient's chart.
In some circumstances, it may be considered acceptable to transfer a patient directly to other care units or to bypass the PACU if the appropriate level of care is available in another unit in the facility and the suitability of the patient for this transfer is documented on the anesthetic record.
# Discharge of Patients After Day Surgery
Discharge of patients after day surgery must utilize a formal care plan approved by the institution and be documented in the patient care notes. Patients should meet the facility discharge to home criteria using a validated assessment tool. (e.g., Post Anesthetic Discharge Scoring System). Specific written instructions should include management of pain and postoperative complications, and both routine and emergency follow-up. The patient should be advised regarding the additive effects of alcohol and other sedative drugs, the danger of driving or operating other hazardous machinery during the postoperative period (most commonly 24 hr postoperatively), and the necessity for attention by a competent adult during the postoperative period (most commonly 24 hr postoperatively).
7 Guidelines for Obstetric Regional Analgesia Anesthesia services for parturients include obstetric analgesia for labour-for both uncomplicated and complicated deliveries-or for operative deliveries. All guidelines regarding provision of anesthesia for other diagnostic or therapeutic procedures also apply to the provision of obstetric anesthesia. The guidelines in this section pertain to epidural and spinal analgesia during labour. The term ''regional analgesia'' includes epidural, spinal, and combined spinal-epidural analgesia.
These guidelines are reviewed annually by the Obstetric Anesthesia Section of CAS and updated as indicated. Each facility may choose to develop additional guidelines or policies for specific situations in which obstetric regional analgesia is provided.
Under the direction of an anesthesiologist, some aspects of monitoring and management of obstetric regional analgesia may be delegated to other healthcare personnel. Each facility should ensure that such other personnel receive the same training, certification, continuing education, and recertification in obstetric regional analgesia.
# Initiation of Obstetric Regional Analgesia
Before introducing obstetric regional analgesia, the facility should have appropriate monitoring protocols in place. These protocols should outline the types of monitoring required and the frequency of monitoring. In addition, they should clearly state how to manage common problems and emergencies and indicate whom to contact if assistance is required.
- Obstetric regional analgesia should be provided only by physicians with training, facility privileges, and licence to provide these services. This includes trainees with appropriate supervision. 2. Regional analgesia should be initiated and maintained only in locations where appropriate resuscitation equipment and drugs are immediately available. 3. Informed consent should be obtained and documented in the medical record. 4. Intravenous access must be established before initiating regional analgesia, and it should be maintained throughout the administration of regional analgesia. 5. The anesthesiologist should be immediately available until analgesia is established and the patient's vital signs are stable. When initial and top-up bolus epidural local anesthetics are administered, the anesthesiologist must be immediately available to intervene appropriately recognizing that these techniques can cause immediate life-threatening complications.
Individual departments of anesthesiology should establish their own policies regarding the appropriate availability of an anesthesiologist to manage the potential complications of regional analgesia for labour and delivery.
Safety systems must be in place to secure epidural local anesthetic mixtures and supplies containing controlled substances (e.g., opioids) to minimize the risk of diversion.
# Oral Intake During Labour
Gastric emptying of solids is delayed during labour and opioid analgesics may further delay gastric emptying.
Therefore, parturients should generally be discouraged from ingesting solid foods when in active labour. In contrast to solid food, clear fluids are emptied relatively rapidly from the stomach during labour. Therefore, in general, women should be permitted clear fluids as desired during active labour. Individual facilities should develop protocols regarding the intake of solids and clear fluids by women in active labour.
# Guidelines for Acute Pain Management Using Neuraxial Analgesia
When neuraxial analgesia is managed by anesthesiologists, the incidence of side effects is no higher than when alternative techniques of pain management are used. Accordingly, when its use is appropriate, neuraxial analgesia should be managed by anesthesiologists.
For the purposes of these guidelines, neuraxial analgesia is defined as intrathecal or epidural administration of opioids and/or local anesthetics for treatment of postoperative pain or other acute pain problems. These guidelines are to provide anesthesiologists with the principles of management to maximize the benefit-risk ratio of providing neuraxial analgesia.
# Administrative and Educational Policies
The department of anesthesia should establish an acute pain service that is responsible for: 1. Developing policies and procedures for neuraxial analgesia. - Assessment and management of hypotension in patients receiving neuraxial analgesia; and - Signs and symptoms of the rare but catastrophic complications of epidural hematoma or abscess.
# Policies for Drug Administration
Each facility should use a limited number of standard solutions. A preprinted order sheet listing the standard solutions for the facility is strongly recommended. Before any solution that is not standard in the facility is dispensed, the anesthesiologist should verify the order with nursing and pharmacy personnel and discuss its indications and all concerns relating to its use with the nurses responsible for administering the drug and monitoring the patient.
The risk of errors due to incorrect route of drug injection must be minimized. For continuous infusions or PCEA, the use of unique tamper-proof pumps that are distinct from the pumps used for intravenous fluid or drug administration is strongly recommended. The tubing between neuraxial analgesia infusion pumps and catheters should not have ports that could permit unintentional injection of intravenous drugs (see section 5.1-6).
Preparation of solutions should follow a standardized procedure. All analgesic drug solutions should be labeled with the composition of the solution (opioid, local anesthetic, or both) and its intended route of administration. For epidural administration, this should include the date and time of preparation and the name of the individual who prepared it.
# Patient Monitoring and Management of Adverse Events
Patients receiving neuraxial analgesia should be in a room equipped with oxygen and suction. Resuscitation drugs and equipment must be immediately available. Before initiating neuraxial analgesia, intravenous access must be secured, and after discontinuing neuraxial analgesia, intravenous access must be maintained for the expected duration of drug effects. Epidural catheter dressings should permit examination for catheter movement and daily inspection of the catheter entry site for any signs of infection.
Standardized policies for patient management should be established. The parameters to be assessed, frequency of assessments, documentation, and procedures for management of complications should be specified. Adequate nursing personnel must be available to assess and manage patients receiving neuraxial analgesia. Monitoring should continue after discontinuation of neuraxial analgesia until its effects have dissipated.
An anesthesiologist must be readily available to advise nursing personnel on such issues as dose titration and management of adverse effects. Each facility with an acute pain service should ensure that an anesthesiologist is available to attend directly to patients receiving neuraxial analgesia within an appropriate time depending on the clinical situation. Each facility should also specify procedures for emergent management of any lifethreatening complications.
Other drugs, particularly benzodiazepines or parenteral opioids, may cause severe respiratory depression in patients receiving neuraxial analgesia. For this reason, other physicians should not order sedatives or analgesics for any patient receiving neuraxial analgesia. The acute pain service should direct analgesic and sedative therapy until the effects of neuraxial analgesia have dissipated.
# Epidurals and Anticoagulation
Patients with epidural catheters may receive prophylactic low-dose anticoagulant therapy if appropriate precautions are taken:
- To minimize the risk of epidural hematoma, catheter insertion and removal and the timing of anticoagulant administration must be coordinated so that no clinically significant anticoagulant effect is present at these times. - Use of nonsteroidal anti-inflammatory drugs in patients receiving neuraxial analgesia is appropriate, but concurrent administration of these drugs or other antiplatelet medication and an anticoagulant may increase the risk of epidural hematoma.
- Where neuraxial analgesia is used for prolonged postoperative pain management, every effort should be made to avoid lower extremity motor blockade. - Nursing staff should be aware of the signs and symptoms of epidural hematoma. Any change in neurologic status or new-onset back pain must be investigated immediately.
If full anticoagulation is indicated in a patient with an epidural catheter, the anesthesiologist should be consulted so that catheter removal and initiation of alternative analgesic management are accomplished before anticoagulation.
# Guidelines for the Practice of Anesthesia in Remote Locations
The basic principles, training requirements, techniques, equipment, and medications used for the practice of anesthesia in remote locations are as outlined in other sections of these Guidelines. They apply equally to anesthesia care, including procedural sedation (see Appendix 6) delivered by anesthesiologists in any operating room or out-of-operating room locations both within a hospital facility and outside of a hospital facility (e.g., offices, clinics).
9.1 Anesthesia Care delivered in a Non-Hospital Medical/Surgical/Dental Facility
# Patient Selection
The physical status of patients should be classified using the American Society of Anesthesiologists physical status (ASA) score. Typically, only patients with ASA classifications of I and II should be considered for procedures. Patients with ASA III classification may be accepted under certain circumstances but only at the discretion of the attending anesthesiologist. Caution should be exercised when booking patients with a known difficult airway.
# Preoperative Considerations
The patient must have had a recent and documented health history, physical examination including an airway examination, and any appropriate laboratory investigations. This may be carried out by another physician (e.g., proceduralist) but it is strongly recommended that there be a screening process that is developed and supported by the anesthesia leadershipproviding services. The duration of fasting should be consistent with section 4.2 Fasting Guidelines.
# Conduct of Anesthesia
The anesthetic and recovery facilities must conform to facility standards established by the CSA (see Appendix 1) and all CAS guidelines established for patient care. The patient should be discharged home from the facility using a validated scoring system for fitness to discharge (e.g., Post Anesthetic Discharge Scoring System).
Patients should be provided with written instructions for the preoperative and postoperative periods. The demand for the delivery of anesthesia care services outside of an operating room (e.g., endoscopy, interventional radiology, cardiac catheterization) is growing because of technological advances and the growth in the availability of less invasive, yet potentially painful, procedures. The delivery of anesthesia care in these remote procedural units can present unique challenges to the anesthesia care team (e.g., patients may have an ASA status of III-IV and have significant comorbidities) and they may be some distance from the operating rooms and support staff or outside of a hospital facility. Procedural units where anesthesiologists have been asked to provide care should comply with the same CSA standards (Appendix 1), equipment guidelines (see section 3.0), and general CAS guidelines as an operating room to the greatest extent possible. This includes, but need not be restricted to, patient selection and assessment, preprocedural testing, fasting guidelines, equipment and electrical outlets, oxygen and suction, ventilation and scavenging if inhalational agents will be utilized, medications and equipment required for resuscitation, patient monitoring, the recovery facility and anesthesia support personnel. Any location outside of an operating room where anesthesiologists provide care must be approved by the anesthesia leadership of the facility. Appropriately trained and experienced anesthesia support personnel, for example an Anesthesia Assistant (see section 2.5) or other staff with experience supporting anesthesia should be present or immediately available to assist the anesthesiologist in remote locations. It is not appropriate to rely solely on procedural unit staff to support anesthesia unless they have had training and experience in the direct support of the delivery of anesthesia care and are approved by anesthesia leadership. There must be reliable two-way communication available to call for assistance and support of the anesthesia provider as it may be required. Les recommandations suivantes ont pour objectif de proposer des lignes directrices de base touchant l'exercice de l'anesthésie. Leur but est de constituer un cadre pour la prestation de soins aux patients qui soient raisonnables et acceptables, et c'est ainsi qu'elles devraient être interprétées, ce qui permet une certaine flexibilité selon les circonstances. Chaque partie du Guide peut faire l'objet de révision au besoin, selon l'évolution de la technologie et de la pratique.
# Principes de base
Dans le présent document, le mot anesthésiologiste est utilisé pour désigner toute personne qui a un permis d'exercer la médecine avec privilège d'administrer l'anesthésie. L'anesthésie est la réalisation délibérée de toute intervention visant à rendre un patient temporairement insensible à la douleur ou à l'environnement externe dans le but d'exécuter une intervention diagnostique ou thérapeutique.
Le présent Guide s'adresse à tous les anesthésiologistes du Canada. L'exercice indépendant de l'anesthésie est une spécialité médicale et, à ce titre, elle doit être exercée par des médecins ayant une formation appropriée en anesthésie. Le processus de certification du Collège royal des médecins et chirurgiens du Canada constitue la seule voie de reconnaissance comme spécialiste en anesthésie au Canada.
La Société canadienne des anesthésiologistes (SCA) reconnâıt que la population dans les collectivités éloignées n'est souvent pas suffisamment nombreuse pour justifier une pratique d'anesthésiologie spécialisée. Dans ces collectivités, des médecins de famille ayant reçu une formation adéquate pourraient être appelés à dispenser les services d'anesthésie. Dans les communautés ou' le volume clinique est suffisamment important pour justifier l'emploi d'anesthésiologistes à temps plein, des anesthésiologistes ayant complété leur spécialisation devraient offrir ces services. Tous les anesthésiologistes doivent poursuivre une formation continue dans la pratique de l'anesthésie, de la prise en charge de la douleur, des soins périopératoires et de la réanimation, et participer à un programme structuré de maintien des compétences (par ex., MDC du Collège royal).
# Organisation des services d'anesthésie
Le département d'anesthésie devrait être organisé, dirigé et intégré de façon appropriée aux autres départements de l'organisme ou de l'établissement, et devrait regrouper tous les membres du personnel de l'établissement qui assurent des soins anesthésiques aux patients, aussi bien à des fins chirurgicales, obstétricales, diagnostiques ou thérapeutiques.
Compte tenu de l'ampleur et de la nature des services offerts, le département devrait comporter le personnel nécessaire et s'efforcer d'assurer que ces services soient disponibles comme l'établissement de soins de santé le requiert.
Le chef du département devrait être un médecin certifié en anesthésie ou encore possédant une formation adéquate en anesthésie. Cette personne devrait être nommée de la même manière que les autres chefs de départements cliniques et devrait faire partie des entités administratives médicales supérieures de l'établissement. Aucune recommandation spécifique concernant les quarts de travail et la liste de garde quotidienne ne peut être adaptée à toutes les situations de travail. Les grands départements disposent de la flexibilité nécessaire à intégrer des quarts de travail courts et des congés personnels, alors que les départements plus petits pourraient ne pas jouir de cette liberté. Toutefois, ce domaine important de l'exercice professionnel doit faire l'objet d'une attention et d'une considération constantes.
# Résidents
Les résidents en anesthésie sont des médecins autorisés qui participent à la prestation des soins anesthésiques tant en salle d'opération qu'à l'extérieur de celle-ci dans le cadre de leur formation. Le Collège royal des médecins et chirurgiens du Canada et les organismes de règlementation provinciaux et locaux exigent qu'un anesthésiologiste responsable supervise toutes les activités des résidents. Le degré de supervision doit prendre en considération l'état de chaque patient, la nature des soins anesthésiques, ainsi que l'expérience et les capacités du résident (responsabilité professionnelle croissante). A' la discrétion de l'anesthésiologiste superviseur, les résidents peuvent fournir une gamme de soins anesthésiques sous un minimum de supervision. Dans tous les cas, l'anesthésiologiste superviseur doit demeurer promptement disponible afin de prodiguer des conseils ou d'assister le résident lors de soins urgents ou de routine. Que la supervision soit directe ou indirecte, une communication étroite entre le résident et l'anesthésiologiste superviseur est essentielle pour garantir des soins sécuritaires aux patients. Chaque département d'anesthésie qui enseigne aux résidents en anesthésie doit avoir des politiques en place concernant les activités et la supervision des résidents. 2.7 Personnel de soutien L'établissement de soins de santé doit s'assurer de la disponibilité de personnel de soutien pour remplir un rôle d'assistance auprès de l'anesthésiologiste. Cette assistance doit être disponible en tout temps et en tout lieu ou' des services d'anesthésie sont offerts. Le personnel de soutien doit posséder les compétences nécessaires à répondre aux besoins spécifiques des domaines de surspécialité de l'anesthésie, ce qui se répercute sur le besoin de compétences spécifiques dans des domaines tels que l'anesthésie spécialisée en pédiatrie.
On recommande aux établissements de disposer d'un assistant en anesthésie formellement désigné qui aura reçu une formation spécifique en assistance en anesthésie. Le département d'anesthésie et les autorités administratives compétentes doivent approuver l'étendue des tâches des assistants en anesthésie travaillant dans un établissement en particulier. En outre, les assistants en anesthésie, tout comme les autres professionnels de la santé employés par l'établissement, doivent être protégés par l'assuranceresponsabilité de l'établissement. Les responsabilités et les tâches déléguées aux assistants en anesthésie doivent être conformes aux règlements gouvernementaux en vigueur, aux politiques et lignes directrices édictées par les organismes de règlementation de la profession, et aux politiques de l'établissement local.
Un établissement ne disposant pas d'assistants en anesthésie en bonne et due forme doit mettre à disposition de l'anesthésiologiste du personnel paramédical afin de l'assister. Les tâches incombant à ces assistants doivent être clairement définies. Un anesthésiologiste ne doit leur déléguer ou impartir que les tâches pour lesquelles ils ont été autorisés ou approuvés.
3 Matériel d'anesthésie et lieux convenant à l'anesthésie L'anesthésie doit se pratiquer dans un établissement adapté. Tout le matériel nécessaire, y compris le matériel d'urgence, les systèmes de soutien des fonctions vitales, les médicaments et les autres fournitures, doit être à portée de main. Il est fortement recommandé qu'un manuel de listes de contrôle et d'aides cognitives soit disponible dans tous les lieux où l'anesthésie est pratiquée afin de soutenir la prise en charge des urgences périopératoires critiques. Le contenu de ce manuel devrait être révisé et mis à jour régulièrement selon les besoins et répété de façon périodique en équipe.
L'établissement de soins de santé, en consultation avec le département d'anesthésie, est responsable de l'aménagement et de l'entretien des lieux servant aux soins préopératoires, postopératoires et anesthésiques, ainsi que de l'achat, de l'entretien et du traitement après utilisation du matériel et des fournitures servant à l'anesthésie et aux autres fonctions connexes. L'Association canadienne de normalisation (CSA) et d'autres organismes d'élaboration de normes ont publié des normes et des recommandations se rapportant à la conception, la construction et la rénovation des établissements de santé, ainsi que concernant la gestion du risque, la sécurité de base et les performances essentielles du matériel médical (Annexe 1).
# Responsabilités de l'établissement de santé
Il incombe à l'établissement de soins de santé de veiller à l'application des mesures suivantes :
# La période préanesthésique
Le département d'anesthésie devrait formuler les politiques concernant l'évaluation préanesthésique. Le principal objet de l'évaluation préanesthésique est d'obtenir les renseignements requis pour planifier la prise en charge anesthésique. Par conséquent, un médecin bien informé quant à la prise en charge anesthésique pour la procédure diagnostique ou thérapeutique proposée devrait documenter tous les aspects des antécédents médicochirurgicaux du patient, le bilan de l'examen physique et les résultats des analyses de laboratoire pertinents à la prise en charge anesthésique. Les antécédents du patient devraient inclure les problèmes médicaux passés et actuels, la prise de médicaments récente et actuelle, les réactions ou réponses inhabituelles aux médicaments et tous les problèmes et complications associés aux anesthésies administrées antérieurement. Il y a lieu de connâıtre également les antécédents familiaux de réactions indésirables associées à l'anesthésie. Tout renseignement concernant l'anesthésie que le patient juge pertinent de signaler devrait également être noté. Il convient enfin d'inscrire au dossier médical de chaque patient le code de classification de l'American Society of Anesthesiologists (Annexe 2).
Dans les cas adaptés, la disponibilité d'un « Plan de soins avancés » (accord de représentation, directive préalable, « testament biologique », directive « ne pas réanimer », etc.) doit être vérifiée et son applicabilité à l'intervention proposée déterminée et documentée au dossier d'évaluation anesthésique.
Le chirurgien peut solliciter une consultation avec un anesthésiologiste. Les consultations médicales devraient être obtenues lorsque cela est indiqué.
Le bilan ou la consultation anesthésique préopératoire peut avoir lieu en clinique externe avant l'admission pour l'opération. Les indications concernant l'évaluation préalable à l'admission comprennent l'existence de problèmes médicaux importants (comorbidités), la nature de la procédure diagnostique ou thérapeutique proposée, et la demande du patient. La présence d'un parent/tuteur légal est nécessaire si le patient est un enfant ou n'est pas apte à fournir un consentement éclairé. Tous les patients devraient être informés que des dispositions seront prises pour rencontrer un anesthésiologiste s'ils souhaitent s'entretenir de leur prise en charge anesthésique avant leur admission à l'établissement. La clinique d'évaluation préopératoire devrait également permettre au personnel infirmier et aux autres membres du personnel de santé d'évaluer le patient. L'anesthésiologiste en charge du patient est responsable de l'évaluation préanesthésique finale durant la période préopératoire immédiate.
# Examens préopératoires
Les examens de laboratoire ne devraient pas être réalisés sur une base régulière mais uniquement lorsque les résultats modifieront la prise en charge périopératoire. Les analyses de laboratoire devraient être réalisées lorsque l'état du patient, le traitement médicamenteux et la nature de l'intervention proposée les justifient. Les tests sanguins de laboratoire, les électrocardiogrammes et les radiographies du poumon de routine ne sont pas recommandés chez les patients asymptomatiques subissant une chirurgie à faible risque.
# Dépistage d'hématies falciformes avec
- Devrait être proposé consultation aux patients présentant un risque élevé en raison de leur origine ethnique.
# Temps de thromboplastine partielle/rapport international normalisé
Peut être envisagé :
- Avec les affections ou médicaments associés à une altération de la coagulation (p. ex., maladies hépatiques, malnutrition), antécédents de saignements excessifs, ou antécédents familiaux de coagulopathies transmissibles.
- Pour les patients recevant un traitement anticoagulant par voie orale ou parentérale.
# Taux d'électrolytes
Peut être envisagé :
- Si connu pour ou avec des constatations connues ou convaincantes en faveur des pathologies suivantes : hypertension, insuffisance cardiaque congestive, insuffisance rénale chronique, diabète avec complications, maladie hépatique, trouble hypophysaire, atteinte de l'axe hypophyso-adrénalien, malnutrition.
- chez des patients recevant des diurétiques, des inhibiteurs de l'enzyme de conversion de l'angiotensine, des bloqueurs du récepteur de l'angiotensine et d'autres traitements affectant les électrolytes.
Créatinine et débit de filtration glomérulaire estimé (DFGe/ eGFR)
Peut être envisagé :
- Comme ci-dessus pour les électrolytes, également avec un âge avancé et chez les patients prenant des médicaments affectant potentiellement la fonction rénale.
- Pour les patients recevant des anticoagulants directs par voie orale.
- Si nécessaire pour calculer les indices de risque périopératoire.
- Le DFGe est recommandé pour contribuer à la prédiction de l'évolution de la fonction rénale.
# TEST INDICATIONS
Glycémie à jeun Peut être envisagé :
- Chez les diabétiques, en préopératoire, le jour de la chirurgie pour guider le contrôle glycémique.
- Pour les patients recevant un traitement avec glucocorticöıdes.
- A' titre de dépistage chez les patients ayant un IMC [ 40 ou un risque très élevé de diabète en fonction de signes et symptômes.
# Hémoglobine A1c
- Peut être envisagé chez les diabétiques connus, le plus tôt possible avant la chirurgie (de préférence, sitôt le patient adressé au chirurgien) si les résultats sont susceptibles de modifier la prise en charge du patient.
Test de grossesse En fonction des lignes directrices propres à l'établissement
- Devrait être proposé aux femmes en âge de procréer en fonction de la probabilité raisonnable de grossesse, de la fiabilité de l'historique des menstruations et si le résultat est susceptible d'annuler ou modifier la procédure ou la prise en charge de l'anesthésie.
- La possibilité d'effectuer un test urinaire ou sanguin au point de service est l'idéal et donc recommandée.
# É lectrocardiogramme
- Peut être envisagé chez les patients avec une coronaropathie, une arythmie significative, une maladie vasculaire périphérique ou toute autre cardiopathie importante connue ou soupçonnée.
- Peut être envisagé en l'absence de symptômes ou de maladie cardiovasculaire connue chez les patients devant subir une chirurgie à risque intermédiaire ou élevée en présence de facteurs de risque cliniques (par ex. Index de risque cardiaque révisé (RCRI), ou Calculateur de risque chirurgical de l'American College of Surgeons).
Le peptide cérébral natriurétique (BNP ou NT-pro BNP) peut être envisagé si :
- le patient est âgé ‡ 65 ans,
- le patient est âgé de 45-65 ans et a une condition cardiaque significative,
- le patient a un score à l'Index cardiaque de risque révisé ‡ 1.
É chocardiographie au repos - Peut être envisagée si l'évaluation clinique suggère une anomalie intracardiaque obstructive sévère et non diagnostiquée, une cardiomyopathie ou une hypertension pulmonaire sévère.
# TEST INDICATIONS
Radiographie pulmonaire - Non recommandée chez les patients asymptomatiques dans le cadre de l'évaluation préopératoire de routine, à moins que cet examen ne fasse partie d'un bilan chirurgical ou oncologique non lié à l'évaluation du risque périopératoire.
- Peut être envisagée chez les patients souffrant de maladie cardiopulmonaire aiguë ou chronique en fonction de leurs antécédents et de l'examen physique, si cela modifiera la prise en charge.
# Lignes directrices concernant le jeûne
Les règles concernant le jeûne devraient varier en fonction de l'âge du patient et de ses antécédents médicaux et s'appliquer à toutes les formes d'anesthésie, incluant la sédation procédurale (voir Annexe 6). 1 Les interventions très urgentes ou urgentes doivent être réalisées après avoir examiné les risques qu'entrâınerait leur report comparativement au risque d'aspiration du contenu de l'estomac. Le type et la quantité de nourriture absorbée doivent être pris en considération pour déterminer la durée du jeûne. Avant une intervention non urgente, la durée minimale du jeûne devait être de :
- Huit heures après un repas copieux comportant des aliments solides, particulièrement s'il contenait des protéines (par ex. de la viande) ou des aliments gras; - Six heures après un repas léger (par ex. repas faible en gras tel une tartine); - Six heures après l'ingestion de lait maternisé, de lait non humain ou de lait maternel tiré et fortifié avec des adjuvants; - Quatre heures après l'ingestion de lait maternel;
- Deux heures après l'ingestion de liquides clairs pour un adulte; - Une heure après l'ingestion de liquides clairs pour les nourrissons ou les enfants.
Sauf contre-indication, il convient d'encourager les adultes et les enfants à boire des liquides clairs (eau, jus sans pulpe, boissons à base de sucres complexes et thé ou café noir) jusqu'à deux heures avant une chirurgie non urgente. Les patients pédiatriques devraient également être encouragés à boire des liquides clairs, tels que définis, jusqu'à une heure avant une chirurgie non urgente.
Les conditions retardant la vidange gastrique nécessitent une évaluation au cas par cas du patient. Ces recommandations peuvent être modifiées à la discrétion du médecin.
Lorsqu'elle est indiquée, la prémédication devrait être ordonnée par l'anesthésiologiste. Les ordonnances doivent spécifier la dose, le moment et la voie d'administration.
Un antagoniste des récepteurs H2 (par voie orale ou intraveineuse) est recommandé pour toutes les femmes devant subir un accouchement par césarienne.
Trente (30) mL de citrate de sodium (0,3 molaire) sont recommandés avant un accouchement par césarienne urgent si l'on planifie une anesthésie générale.
Voir la Section 7.3 pour les recommandations de jeûne spécifiques aux patientes en travail actif.
# Règlementations supplémentaires
Des lois provinciales ou la règlementation de l'établissement pourraient prescrire d'autres directives régissant l'administration de l'anesthésie.
5 La période anesthésique
# Préparation à l'anesthésie
Avant le début de l'anesthésie, l'anesthésiologiste doit s'assurer que 1. La procédure anesthésique prévue a été expliquée au patient, y compris les risques reconnus et les techniques alternatives, et on a documenté cette explication; 2. Une évaluation adaptée de l'état du patient a été réalisée; 3. Tout le matériel qu'on prévoit nécessaire est accessible et en bon état de fonctionnement, y compris le matériel nécessaire au maintien de la température centrale (température centrale du patient 36-37°C); 4. On a accès à une source de réserve d'oxygène sous pression; 5. Tous les médicaments et agents qu'on prévoit nécessaires sont correctement identifiés -les étiquettes de médicament apposées par l'usager doivent être conformes à la norme de la CSA CAN/ CSA -Z264.3-98 (R2005) (Annexe 1); 6. Si des connecteurs Luer neuraxiaux sont utilisés, les deux côtés des raccords Luer doivent être étiquetés. Il faut envisager l'utilisation de connecteurs neuraxiaux conformes à la norme ISO 80369-6:2016connecteurs de petit diamètre interne pour application neuraxiale (raccords NRFitÒ) en fonction des disponibilités des fournisseurs de matériel; et 7. On a tenu compte des indications du fabricant quant à l'utilisation, à la manipulation et à la disposition de l'équipement et du matériel d'anesthésie.
# Prise en charge des voies aériennes
La prise en charge des voies aériennes, particulièrement en cas de voies aériennes difficiles, contribue significativement à la morbidité et à la mortalité liées à l'anesthésie.
Une prise en charge adaptée des patients dont l'intubation est difficile, de manière prévue ou imprévue, chez lesquels l'intubation a échoué, lorsqu'une ventilation au masque ou le positionnement d'un dispositif supraglottique pourrait être difficile, ou qui nécessitent des voies aériennes chirurgicales, est essentielle à la sécurité des patients. Cette prise en charge comprend, sans nécessairement s'y limiter, une évaluation adaptée des voies aériennes, du matériel (par ex. chariots pour les voies aériennes difficiles, vidéolaryngoscopes, bronchoscopes), une formation et des exercices de simulation appropriés, du personnel de soutien et le recours aux protocoles et listes de contrôle adéquats afin de prendre en charge au mieux des voies aériennes difficiles. La SCA ne recommande pas un protocole, un algorithme ou une liste de contrôle en particulier pour la prise en charge des voies aériennes difficiles ou lors d'un échec d'intubation, mais elle encourage fortement les lecteurs à se référer à l'Annexe 4 pour accéder aux publications les plus récentes sur le sujet.
# Délégation des soins aux patients
L'anesthésiologiste est avant tout responsable du patient qu'il a sous ses soins. L'anesthésiologiste ou un assistant en anesthésie supervisé par l'anesthésiologiste doit demeurer constamment aux côtés du patient pour toute la durée d'une anesthésie générale, régionale majeure et intraveineuse monitorée, jusqu'à ce que le patient ait été confié aux soins du personnel de l'unité de soins compétente.
Si l'anesthésiologiste traitant quitte temporairement la salle d'opération, il doit confier les soins du patient à un autre anesthésiologiste, à un résident en anesthésie ou à un assistant en anesthésie. Lorsque l'anesthésiologiste traitant délègue les soins à un résident en anesthésie ou à un assistant en anesthésie, il demeure responsable de la prise en charge anesthésique du patient. Avant de déléguer les soins du patient à un assistant en anesthésie, l'anesthésiologiste doit s'assurer que l'état du patient est stable et que l'assistant en anesthésie est familier avec l'intervention chirurgicale ainsi qu'avec l'environnement et le matériel de la salle d'opération. L'anesthésiologiste traitant doit demeurer immédiatement disponible lorsque les soins sont délégués à un assistant en anesthésie.
Un anesthésiologiste peut brièvement confier les soins courants d'un patient dont l'état est stable à une personne compétente qui n'est pas un assistant en anesthésie qu'en cas de circonstances particulièrement exceptionnelles, pour se porter par exemple au secours d'un autre patient dont la vie est en danger. L'unique responsabilité de cette personne devrait être de surveiller le patient en l'absence de l'anesthésiologiste et de tenir l'anesthésiologiste informé jusqu'à son retour. Dans de telles circonstances, l'anesthésiologiste demeure responsable des soins prodigués au patient et se doit de tenir l'équipe de la salle d'opération au courant.
Le transfert peropératoire des soins entre deux anesthésiologistes doit être noté au dossier d'anesthésie et se conformer à un protocole structuré.
Il est inacceptable qu'un anesthésiologiste administre simultanément une anesthésie générale, une anesthésie régionale majeure (rachidienne, péridurale ou autre) ou une sédation procédurale profonde (voir Annexe 6) 1 pour des interventions diagnostiques ou thérapeutiques concomitantes pratiquées sur plus d'un patient à la fois. Toutefois, il peut être admis, dans des circonstances particulières, qu'un anesthésiologiste supervise plus d'un patient chez lequel une sédation minime à modérée est administrée, à condition qu'un individu ayant reçu une formation adéquate, qualifié, accrédité et approuvé par le service d'anesthésiologie et l'établissement de santé, soit constamment présent auprès de chaque patient recevant des soins. Il sera par contre admis, dans un service d'obstétrique, de surveiller simultanément plus d'une patiente à laquelle est administrée une analgésie régionale pour le travail. Chaque parturiente devra cependant être surveillée adéquatement par une personne compétente, suivant un protocole établi. Lorsqu'un anesthésiologiste dispense des soins anesthésiques en vue d'un accouchement, une deuxième personne dûment formée doit se tenir prête à intervenir pour pratiquer la réanimation néonatale.
Il est inacceptable qu'un seul médecin administre une anesthésie y compris la sédation procédurale profonde simultanément à la réalisation d'une procédure diagnostique ou thérapeutique, exception faite des interventions réalisées par seule infiltration d'anesthésiques locaux et/ou une sédation minimale.
# Monitorage du patient
Le seul moniteur indispensable est la présence, à tous les instants, d'un médecin ou d'un assistant en anesthésie placé sous la supervision immédiate d'un anesthésiologiste et détenant la formation et l'expérience appropriées. Les moniteurs mécaniques et électroniques ne sont, au mieux, que des aides à la vigilance. Ces appareils aident l'anesthésiologiste à s'assurer de l'intégrité des organes vitaux et, en particulier, de la perfusion et de l'oxygénation satisfaisantes des tissus. Le matériel de monitorage doit être utilisé comme prévu par le fabricant et approuvé par Santé Canada pour l'application spécifique.
Il incombe à l'établissement de soins de santé de fournir et d'entretenir un équipement de monitorage qui respecte les normes en vigueur.
Il incombe au chef du département d'anesthésie de conseiller l'établissement de soins de santé au sujet de l'acquisition de l'équipement de monitorage et d'établir les normes de monitorage qui aideront à assurer la sécurité du patient.
Il incombe à l'anesthésiologiste de monitorer le patient qui est sous ses soins et de s'assurer que l'équipement de monitorage approprié soit disponible et fonctionne correctement. Une feuille de vérification préanesthésique (Annexe 3 ou équivalent) doit être remplie avant l'amorce de l'anesthésie.
Une posologie prudente, un monitorage vigilant et la neutralisation adéquate des bloqueurs neuromusculaires sont des éléments essentiels à la sécurité des patients. Un monitorage neuromusculaire doit être utilisé lors de l'administration de bloqueurs neuromusculaires. Les directives de monitorage pour les soins standard aux patients s'appliquent à tous les patients recevant une anesthésie générale, une anesthésie régionale ou une sédation intraveineuse.
# Matériel de monitorage requis
Le matériel de monitorage est catégorisé comme suit : - Requis : Ces moniteurs doivent être utilisés sans interruption pendant toute la durée de l'administration de toute anesthésie. - Accessible en exclusivité pour chaque patient : Ces moniteurs doivent être accessibles à chaque poste de travail d'anesthésie, de sorte qu'ils puissent être utilisés sans délai. - À portée immédiate : Ces moniteurs doivent être accessibles afin de faciliter leur utilisation sans délai indu.
Le matériel de monitorage suivant est requis : - Un saturomètre; - Un appareil permettant de mesurer la tension artérielle, directement ou sans effraction; - Un électrocardiographe; - Un moniteur de bloc neuromusculaire lors de l'utilisation de bloqueurs neuromusculaires;
- Un capnographe, pour l'anesthésie générale et pour évaluer le caractère adéquat de la ventilation pour une sédation modérée ou une sédation procédurale profonde; et - Un moniteur de gaz anesthésiques spécifique à l'agent, lorsque des agents anesthésiques par inhalation sont utilisés.
Le matériel de monitorage suivant doit être accessible en exclusivité pour chaque patient :
- Un appareil pour mesurer la température;
- Un stimulateur des nerfs périphériques, lors de l'utilisation de bloqueurs neuromusculaires; - Un stéthoscope -précordial, oesophagien ou paratrachéal; et - Un éclairage suffisant pour visualiser une partie exposée du patient.
Le matériel de monitorage suivant sera à portée immédiate :
- Un spiromètre pour mesurer le volume respiratoire;
- Un manomètre pour mesurer la pression du ballonnet du tube endotrachéal. - Le matériel pour un monitorage hémodynamique invasif si indiqué (p. ex., ligne artérielle, cathéter veineux central).
L'anesthésiologiste doit demeurer vigilant en tout temps, étant conscient que de brèves interruptions du monitorage continu peuvent être inévitables et que, dans certaines circonstances, un moniteur pourrait faire défaut. Les alarmes audibles et visuelles du saturomètre et du capnographe ne devraient pas être désactivées indéfiniment pendant le déroulement d'une anesthésie, sauf en cas de circonstances inhabituelles. L'alarme à tonalité variable, celle des pulsations cardiaques et l'alarme de seuil inférieur du saturomètre ainsi que l'alarme d'apnée du capnographe doivent émettre un signal audible et visible.
# Dossiers
Toutes les variables physiologiques monitorées doivent être enregistrées à intervalles réguliers en fonction des circonstances cliniques. La fréquence cardiaque et la tension artérielle doivent être enregistrées au minimum toutes les cinq minutes. La saturation en oxygène doit être monitorée en continu et devrait être enregistrée à intervalles fréquents, au minimum toutes les cinq minutes, chez tous les patients. La concentration en dioxyde de carbone (PCO2) télé-expiratoire doit être monitorée en continu et enregistrée à intervalles fréquents en cas d'intubation trachéale ou si un dispositif supraglottique est en place. On doit documenter au dossier anesthésique toute raison pour laquelle on déroge à ces directives de tenue de dossier. Les types de moniteurs, le matériel et les techniques, ainsi que l'heure, la posologie et la voie d'administration de tout médicament et liquide devraient être notés. Tous les autres soins et événements anesthésiques peropératoires pertinents, y compris les événements imprévus ou indésirables, devraient également être enregistrés.
Le dossier de santé du patient doit inclure le niveau de conscience du patient, sa fréquence cardiaque, sa tension artérielle, sa saturation en oxygène et sa fréquence respiratoire tels que mesurés à l'arrivée en salle de réveil. Ces recommandations s'appliquent tant aux dossiers anesthésiques manuscrits qu'à ceux créés via des systèmes électroniques de gestion de l'information en anesthésie (SGIA). À l'heure actuelle, il n'existe aucune norme de pratique indiquant quelles données supplémentaires (par ex. données d'analyse de gaz, de ventilation et respiratoires) potentiellement récoltées par un système de dossier de SGIA devraient faire partie du dossier de santé permanent d'un patient.
Il a été démontré que les SGIA pouvaient avoir des avantages potentiels par rapport aux dossiers rédigés à la main dans plusieurs domaines clés, notamment en augmentant la lisibilité, la précision et la fiabilité des dossiers anesthésiques, en créant des données interrogeables favorisant l'amélioration de la qualité, la communication des résultats et de la performance, la recherche translationnelle, une meilleure innocuité et un meilleur suivi des médicaments, ainsi qu'un suivi et un soutien à la décision clinique en temps réel pour les utilisateurs. La littérature sur la sécurité des patients en anesthésie appuie l'utilisation des SGIA. Il est important de mentionner que les SGIA permettent de créer une base de données de patients longitudinale, de telle manière que les antécédents anesthésiques importants des patients soient facilement trouvables si l'on veut les passer en revue, ce qui devrait être considéré comme une propriété importante pour tout système. La SCA ne promeut ni n'endosse un fournisseur ou un produit en particulier, mais elle reconnâıt les avantages potentiels d'un SGIA bien conçu et mis en oeuvre par rapport à des dossiers complétés manuellement là ou' les ressources institutionnelles et du département d'anesthésie permettent d'envisager l'implantation d'un SGIA. Dans l'idéal, ce système devrait être mis en oeuvre et géré en coopération avec le département des technologies de l'information de l'établissement, et devrait permettre la communication avec les autres bases de données électroniques de patients de l'établissement dans la mesure du possible.
6 La période postanesthésique 6.1 La salle de réveil Une salle de réveil doit être disponible dans tout établissement offrant des services anesthésiques. Des politiques administratives conformes aux règlements de l'établissement devront être appliquées de façon à coordonner les responsabilités des soins médicaux et infirmiers.
Le département d'anesthésie devrait endosser l'ensemble de la responsabilité administrative médicale pour la salle de réveil. Il devrait exister un manuel des politiques de la salle de réveil approuvé par les autorités médicales, infirmières et administratives compétentes.
L'anesthésiologiste devrait accompagner le patient en salle de réveil, transmettre les renseignements nécessaires au personnel infirmier de la salle de réveil dans le cadre d'un transfert structuré du protocole de soins, et rédiger les ordonnances nécessaires. Le monitorage continu des patients est recommandé pendant la phase périopératoire en fonction de la situation clinique. Si cliniquement indiqué, de l'oxygène supplémentaire, une oxymétrie de pouls portable et d'autres dispositifs de monitorage adaptés doivent être utilisés pendant le transfert vers la salle de réveil ou l'USI. Si de l'oxygène supplémentaire est administré à des patients intubés pendant le transport ou en salle de réveil, afin de minimiser tout risque de barotraumatisme, il est fortement recommandé de ne le fournir qu'avec des dispositifs approuvés pour cette application spécifique. L'anesthésiologiste ne devrait déléguer les soins du patient à l'infirmier ou l'infirmière de la salle de réveil que lorsqu'il est assuré que le personnel infirmier pourra adéquatement observer et prendre soin du patient. L'anesthésiologiste ou un anesthésiologiste remplaçant désigné est responsable des soins postanesthésiques en salle de réveil. Le congé de la salle de réveil est sous la responsabilité de l'anesthésiologiste; cette responsabilité peut être déléguée en accord avec les politiques de l'établissement.
Une source d'oxygène d'appoint et une succion doivent être disponibles pour chaque patient en salle de réveil. Le matériel d'urgence nécessaire à la prise en charge des voies aériennes, la réanimation et au support vital doit être disponible en salle de réveil. Le matériel pour la prise en charge de voies aériennes difficiles doit être à portée immédiate en salle de réveil. Le monitorage utilisé en salle de réveil doit être adapté à l'état du patient et un éventail complet d'appareils de monitorage doit être disponible. Les alarmes des moniteurs doivent être en fonction, avec des paramètres d'alarme adaptés à l'état et à l'âge du patient. L'utilisation continue d'un saturomètre est requise pendant la phase initiale de récupération. Un capnographe est requis pour les patients intubés ou sous sédation profonde et est recommandé pour les patients inconscients ayant des dispositifs supraglottiques in situ dans les voies aériennes. Un moniteur d'apnée est recommandé chez les nourrissons prématurés et ayant un âge gestationnel de moins de 50 semaines.
Un dossier détaillé de la période immédiate de réveil doit être tenu. Celui-ci doit inclure un enregistrement des signes vitaux ainsi que des autres aspects du traitement et de l'observation. Cette feuille d'observation fait partie du dossier médical permanent. Toute complication ayant un lien avec l'anesthésie doit être notée sur la feuille de la salle de réveil ou dans les notes d'évolution du dossier du patient. Dans certaines situations, il peut être acceptable de transférer un patient directement vers d'autres unités de soins ou de passer outre la salle de réveil si un niveau de soins adapté est disponible dans une autre unité de l'établissement et s'il est noté au dossier anesthésique que le patient est jugé apte à ce transfert.
# Congé des patients après chirurgie d'un jour
Le congé des patients après une chirurgie ambulatoire doit se faire en utilisant un plan formel de soins approuvé par l'institution et documenté dans les notes de soins prodigués aux patients. Les patients doivent satisfaire les critères de congé au domicile en utilisant un outil d'évaluation validé (p. ex., le système de cotation de congé post-anesthésie ). La prise en charge de la douleur et des complications postopératoires, ainsi que le suivi de routine et d'urgence, doivent tous faire l'objet d'instructions écrites spécifiques. Le patient doit être averti au sujet des synergies additives qu'il existe entre l'alcool et d'autres sédatifs, du danger de conduire ou d'utiliser des machines dangereuses dans la période postopératoire (dans la plupart des cas durant les 24 heures suivant l'opération), et de la nécessité d'attention de la part d'un adulte compétent dans la période postopératoire (dans la plupart des cas durant les 24 heures suivant l'opération).
# Lignes directrices pour l'analgésie régionale en obstétrique
Les services d'anesthésie destinés aux parturientes comprennent l'analgésie obstétricale pour le travailpour l'accouchement avec ou sans complication -ou pour les césariennes. Toutes les directives visant l'anesthésie administrée pour toute autre intervention diagnostique ou thérapeutique s'appliquent également à l'anesthésie obstétricale. Les directives de la présente section portent sur l'analgésie péridurale et la rachianesthésie pendant le travail. L'expression « analgésie régionale » désigne l'analgésie péridurale, la rachianesthésie et la combinaison des deux.
Ces directives sont passées en revue chaque année par la Section d'anesthésie obstétricale de la SCA et mises à jour au besoin. Chaque établissement peut décider d'élaborer des directives ou politiques supplémentaires pour des situations spécifiques dans lesquelles une analgésie régionale obstétricale est dispensée.
Sous la direction d'un anesthésiologiste, certains aspects du monitorage et de la prise en charge de l'analgésie régionale obstétricale peuvent être délégués à d'autres membres du personnel de santé. Chaque établissement doit s'assurer que ces personnes reçoivent les mêmes formation, certification, formation continue et recertification en analgésie régionale en obstétrique. Chaque département d'anesthésiologie devrait établir ses propres politiques concernant la disponibilité jugée adaptée d'un anesthésiologiste pour prendre en charge les complications potentielles liées à l'analgésie régionale pour le travail obstétrical et l'accouchement.
Des systèmes de sécurité doivent exister pour protéger les mélanges d'anesthésiques locaux périduraux contenant des substances contrôlées (par ex. des opiöıdes) de façon à minimiser les risques de détournement.
# Absorption orale pendant le travail
La vidange gastrique des aliments solides est retardée pendant le travail, et les analgésiques opiöıdes peuvent la retarder encore davantage. Par conséquent, on devrait généralement décourager les parturientes d'ingérer des aliments solides pendant le travail actif. Contrairement aux aliments solides, les liquides clairs sont éliminés relativement rapidement de l'estomac pendant le travail. Ainsi, en règle générale, on devrait permettre aux parturientes d'ingérer des liquides clairs comme elles le souhaitent pendant le travail actif. Chaque établissement devrait élaborer des protocoles concernant l'absorption d'aliments solides et de liquides clairs par les femmes en travail actif.
8 Lignes directrices pour la prise en charge de la douleur aiguë à l'aide de l'analgésie neuraxiale Lorsque l'analgésie neuraxiale est prise en charge par des anesthésiologistes, l'incidence d'effets secondaires n'est pas plus élevée que lorsque des techniques alternatives de prise en charge de la douleur sont utilisées. En conséquence, lorsque son utilisation est indiquée, l'analgésie neuraxiale devrait être prise en charge par les anesthésiologistes.
Aux fins de ce guide, l'analgésie neuraxiale se définit comme l'administration intrathécale ou péridurale d'opiöıdes et/ou d'anesthésiques locaux en vue du traitement de la douleur postopératoire ou d'autres problèmes de douleur aiguë. Ce guide vise à fournir aux anesthésiologistes les principes de prise en charge afin que l'analgésie neuraxiale soit pratiquée de manière à en maximiser les avantages et en minimiser les risques. Le risque d'erreurs attribuables à une voie impropre d'injection du médicament doit être minimisé. Pour des perfusions continues ou une APCP, l'emploi de pompes inviolables distinctes de celles utilisées pour l'administration de solutés ou de médicaments est vivement recommandé. La tubulure entre les pompes de perfusion de l'analgésie neuraxiale et les cathéters ne devrait comporter aucun orifice susceptible de permettre une injection non intentionnelle de médicaments intraveineux.
La préparation des solutions devrait suivre une procédure standardisée. Toutes les solutions analgésiques devraient porter une étiquette indiquant la composition de la solution (opiöıde, anesthésique local, ou les deux) ainsi que la voie d'administration appropriée. Dans le cas d'une administration péridurale, cela doit inclure la date et l'heure de la préparation ainsi que le nom de la personne l'ayant préparée.
# Monitorage des patients et prise en charge des évènements indésirables
Les patients auxquels est administrée une analgésie neuraxiale devraient être placés dans une chambre équipée d'oxygène et de succion. Des médicaments et du matériel de réanimation doivent être à portée immédiate. L'accès intraveineux doit être établi avant d'amorcer l'analgésie neuraxiale et, après cessation de l'analgésie neuraxiale, maintenu pendant toute la durée prévue des effets médicamenteux.
Le pansement qui maintient en place le cathéter péridural doit permettre l'examen du cathéter pour détecter tout mouvement et permettre l'inspection quotidienne du point d'entrée afin de déceler tout signe d'infection.
L'adoption de politiques standardisées au chapitre de la prise en charge des patients est préconisée. Les paramètres qu'il convient d'évaluer, la fréquence des évaluations, la documentation et les procédures de prise en charge des complications devraient être précisés. Un personnel de soins infirmiers en nombre suffisant doit être présent pour évaluer et prendre en charge les patients recevant une analgésie neuraxiale. Le monitorage devrait se poursuivre après cessation de l'analgésie neuraxiale jusqu'à ce que ses effets se soient dissipés.
Un anesthésiologiste doit être immédiatement disponible afin de conseiller le personnel infirmier sur des aspects tels que le titrage de la dose et la prise en charge des effets indésirables. Chaque établissement doté d'un service de traitement de la douleur aiguë doit veiller à ce qu'un anesthésiologiste soit disponible pour s'occuper directement des patients recevant une analgésie neuraxiale dans un délai approprié en fonction de la situation clinique. Chaque établissement devrait également déterminer les procédures en vue d'une prise en charge urgente de toute complication menaçant le pronostic vital. D'autres médicaments, notamment les benzodiazépines ou les opiöıdes parentéraux, peuvent causer une dépression respiratoire majeure chez les patients recevant une analgésie neuraxiale. Pour cette raison, les autres médecins ne devraient pas prescrire de sédatifs ou d'analgésiques à tout patient recevant une analgésie neuraxiale. Le service de traitement de la douleur aiguë devrait demeurer en charge de la thérapeutique analgésique et sédative jusqu'à dissipation des effets de l'analgésie neuraxiale. 9 Lignes directrices pour l'exercice de l'anesthésie dans les lieux isolés Les principes fondamentaux, les exigences de formation, les techniques, le matériel et les médicaments utilisés pour la pratique de l'anesthésie dans les lieux isolés ont été documentés dans d'autres sections de ce Guide. Ils s'appliquent également aux soins anesthésiques, notamment à la sédation consciente (voir Annexe 6) dispensée par un anesthésiologiste dans toute salle d'opération ou emplacement hors de la salle d'opération, tant à l'intérieur d'un établissement hospitalier qu'à l'extérieur (par ex. bureaux, cliniques). 9.1 Soins anesthésiques dispensés dans un établissement médical/chirurgical/dentaire non hospitalier
# Se´lection des patients
Le statut physique des patients devrait être catégorisé selon le score de l'American Society of Anesthesiologists (ASA). D'une manière générale, seuls les patients des classes ASA I et II devraient être retenus pour subir une intervention. Les patients de statut ASA III pourraient être acceptés sous certaines conditions, mais seulement à la discrétion de l'anesthésiologiste en charge. Il faut faire preuve de prudence lors de la sélection de patients présentant des voies aériennes difficiles connues.
# Conside´rations pre´ope´ratoires
Une histoire de cas et un examen physique récents, incluant un examen des voies aériennes, devraient paraître au dossier du patient, ainsi que les résultats des examens de laboratoire appropriés. Ces examens peuvent être exécutés par un autre médecin (par ex. un 'procéduraliste', soit un médecin/chirurgien compétent pour réaliser des interventions diagnostiques ou thérapeutiques), mais l'existence d'un processus de sélection mis au point et endossé par les services anesthésiques est fortement recommandée. La durée du jeû ne devrait être conforme à la section 4.2 Lignes directrices concernant le jeuˆne.
# Conduite de l'anesthe´sie
Les installations des salles d'anesthésie et de réveil doivent être conformes aux normes hospitalières établies par la CSA (voir Annexe 1) et à toutes les lignes directrices de la SCA établies pour les soins aux patients. Le patient devrait recevoir son congé de l'hôpital pour rentrer à la maison en utilisant un système de notation validé évaluant son aptitude au congé (par. ex. Système de cotation de congé postanesthésique). Les patients devraient recevoir des instructions écrites concernant les périodes préopératoire et postopératoire. 9.2 Soins anesthésiques dispensés hors de la salle d'opération dans un hôpital ou un établissement non hospitalier En raison des avancées technologiques et de la plus grande disponibilité d'interventions moins invasives mais potentiellement douloureuses, la demande pour la fourniture de soins anesthésiques à l'extérieur de la salle d'opération (par ex., endoscopie, radiologie interventionnelle, cathétérisation cardiaque) croît. La fourniture de soins anesthésiques dans ces unités interventionnelles éloignées peut s'accompagner de défis particuliers pour l'équipe de soins anesthésiques (p. ex., les patients pourraient avoir un statut ASA III-IV et d'importantes comorbidités), et ces unités pourraient se trouver à une certaine distance des salles d'opération et du personnel de soutien, voire à l'extérieur d'un établissement hospitalier. Les unités d'intervention dans lesquelles les anesthésiologistes sont appelés à fournir des soins devraient se conformer, dans la mesure du possible, aux mêmes normes de la CSA (Annexe 1), lignes directrices concernant le matériel d'anesthésie (voir section 3.0), et lignes directrices générales de la SCA qu'une salle d'opération. Cela comprend, sans s'y limiter, la sélection et l'évaluation des patients, les examens pré-procéduraux, les lignes directrices concernant le jeû ne, le matériel et les prises électriques, l'oxygène et la succion, la ventilation et l'évacuation des agents volatils si utilisés, les médicaments et le matériel nécessaires à la réanimation, le monitorage du patient, les installations de rétablissement et le personnel de soutien en anesthésie. Tout lieu où des anesthésiologistes fournissent des soins en dehors d'une salle d'opération doit être approuvé par la direction de l'anesthésie dans l'établissement. Du personnel de soutien en anesthésie adéquatement formé et expérimenté, par exemple un assistant en anesthésie (voir section 2.5) ou d'autres personnes ayant de l'expérience dans le soutien en anesthésie, devrait être présent ou immédiatement disponible pour assister l'anesthésiologiste dans les lieux isolés. Il ne convient pas de dépendre exclusivement du personnel de l'unité chirurgicale pour soutenir l'anesthésie, à moins que ce personnel ne soit formé et ait de l'expérience dans le soutien direct de la fourniture de soins anesthésiques et qu'il ait reçu l'aval de la direction de l'anesthésie. Une communication bidirectionnelle fiable doit être disponible pour que le prestataire d'anesthésie ait accès à de l'aide et du soutien si nécessaire.
Remerciements Nous tenons à remercier les anciens membres du Comité des normes de pratique de l'anesthésie qui ont apporté leurs contributions à des versions antérieures de ce Guide. Le Comité tient à remercier since'rement le Dr Hilary P. Grocott pour son aide majeure pendant son mandat en tant que rédacteur en chef du JCA.
Conflits d'intérêts Tous les auteurs de cet article font partie du Comité des normes de la Société canadienne des anesthésiologistes (SCA). Aucun des auteurs n'a un quelconque intérêt financier ou commercial lié aux sociétés ou fabricants d'appareils médicaux dont il est fait mention dans cet article ou dans les annexes associées. Dr Gregory Dobson est président du Comité des normes de la SCA. Annexe 4: Lignes directrices, normes et autres énoncés officiels disponibles sur l'internet L'Annexe 4 (disponible au : / Guide-d-exercice) offre une liste non exhaustive de sites contenant des déclarations officielles promulguées par d'autres associations médicales au Canada et ailleurs dans le monde. Cette liste est fournie aux membres de la SCA uniquement à des fins pratiques. La SCA n'est pas responsable de l'exactitude, de la mise à jour ou de la fiabilité du contenu de ces sites. La SCA n'offre aucune garantie à cet effet. Elle se dégage de toute responsabilité concernant l'information trouvée par le biais de ces liens et n'endosse pas nécessairement ces sites ou leur contenu. Cette liste contient l'adresse de sites qui sera mise à jour de façon périodique.
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9 Lignes directrices pour l'exercice de l'anesthésie dans les lieux isolés 9.1 Soins anesthésiques dispensés dans un établissement médical/chirurgical/dentaire non hospitalier 9.2 Soins anesthésiques dispensés hors de la salle d'opération dans un hôpital ou un établissement non hospitalier Annexe 1: Association canadienne de normalisation -Normes concernant le matériel Annexe 2: Classification de l'état de santé des patients, selon l'American Society of Anesthesiologists Annexe 3: Liste de vérification préanesthésique Annexe 4: Lignes directrices, normes et autres énoncés officiels disponibles sur l'internet Annexe 5: Exposé de principe sur les assistants en anesthésie : Un exposé de principe officiel de la Société canadienne des anesthésiologistes Annexe 6: Sédation procédurale : exposé de principe de la Société canadienne des anesthésiologistes#
How does this statement differ from the 2020 Guidelines?
• Several important content changes have been made and they are highlighted in bold in the text. Some of the more important changes include:
• Additional recommendations related to anesthesia medication safety and error prevention, under section 3.1 Responsibilities of the Healthcare Facility, that expand on recommendations introduced in the 2020 Revised Edition that were specific to safety and diversion prevention for controlled medications (e.g., opioids).
• The addition of brain natriuretic peptide (BNP/NT-pro BNP) as a preoperative investigation to be considered for patients with, or at risk for, significant cardiovascular disease.
• A revision to section 4.2 Fasting Guidelines to clarify the role of H2 receptor blockers in the management of patients presenting for Cesarean delivery (see accompanying editorial).
• An entirely new section 5.7 Patient Positioning to address the critical importance of meticulous planning, execution, and rechecking of positioning for patient safety.
• A minor but important change related to the requirements for documentation of initial vital signs in PACU necessitated by the expanding implementation of Anesthesia Information Management Systems.
• The recommendation that, during patient transport to and in the PACU, if patients with in situ endotracheal tubes require supplemental oxygen, that it should only be administered utilizing devices approved for that application to reduce the risk barotrauma.
• Extensive revision to section 9.0, now called Guidelines for Practice of Anesthesia in Remote Locations, addressing the delivery of anesthesia care in remote locations both within and outside of a hospital facility. An important recommendation is that anesthesia staff should have appropriately trained anesthesia support personnel (e.g., an anesthesia assistant) present or immediately available to assist them.
• Appendix 1: Canadian Standards Association-Standards for Equipment • Appendix 5: Position Paper on Anesthesia Assistants has been significantly revised in cooperation with the CAS Committee on the Anesthesia Care Team and is available as electronic supplementary material.
Comment cet énoncé diffère-t-il des Lignes directrices de 2020? Plusieurs modifications importantes ont été apportées au contenu; elles sont surlignées en gras dans le texte. Parmi les modifications les plus importantes, citons :
• Des recommandations supplémentaires concernant l'innocuité et la prévention des erreurs des médicaments anesthésiques, sous la section 3.1 Responsabilite´s de l'e´tablissement de sante´, qui approfondissent les recommandations introduites dans l'É dition révisée de 2020 spécifiques à l'innocuité et à la prévention du détournement des substances contrôlées (par ex. les opioïdes).
• L'ajout du peptide cérébral natriurétique (BNP/NT-pro BNP) parmi les examens préopératoires à envisager chez les patients atteints ou courant un risque d'être atteints de maladie cardiovasculaire significative.
• Une révision de la section 4.2 Lignes directrices concernant le jeuˆne afin de clarifier le rôle des antagonistes des récepteurs H2 dans la prise en charge des patientes devant subir un accouchement par césarienne (voir l'éditorial associé).
• Une toute nouvelle section 5.7 Positionnement du patient afin de souligner l'importance cruciale de la planification, de l'exécution et de la vérification méticuleuses du positionnement pour la sécurité des patients.
• Une modification mineure mais importante liée aux exigences de documentation des signes vitaux initiaux en salle de réveil nécessaires en raison de l'utilisation toujours plus répandue des Systèmes électroniques de gestion de l'information en anesthésie.
• La recommandation selon laquelle, pendant le transfert des patients et dans la salle de réveil, lorsqu'un patient chez qui un tube endotrachéal est installé nécessite de l'oxygène supplémentaire, l'administration ne devrait se faire qu'à l'aide de dispositifs approuvés pour cette application afin de réduire le risque de barotraumatisme.
• Une révision approfondie de la section 9.0, désormais intitulée Lignes directrices pour l'exercice de l'anesthe´sie dans les lieux isole´s, abordant la fourniture de soins anesthésiques dans les lieux isolés tant au sein d'un établissement hospitalier que hors d'un milieu hospitalier. Une recommandation importante touche au fait que le personnel d'anesthésie devrait disposer de personnel de soutien en anesthésie ayant reçu une formation adéquate (par ex., un assistant en anesthésie) présent ou immédiatement disponible pour l'assister.
• Annexe 1 : Association canadienne de normalisation -Normes concernant le matériel • L'Annexe 5 : Expose´de principe sur les assistants en anesthe´sie a été révisée de fond en comble en coopération avec le Comité sur les équipes de soin en anesthésie de la SCA et est disponible sous forme de matériel électronique supplémentaire
# Table des matières
# Préambule
Overview The Guidelines to the Practice of Anesthesia Revised Edition 2021 (the Guidelines) were prepared by the Canadian Anesthesiologists' Society (CAS), which reserves the right to determine their publication and distribution. The Guidelines are subject to revision and updated versions are published annually. The Guidelines to the Practice of Anesthesia Revised Edition 2021 supersedes all previously published versions of this document. Although the CAS encourages Canadian anesthesiologists to adhere to its practice guidelines to ensure high-quality patient care, the CAS cannot guarantee any specific patient outcome. Anesthesiologists should exercise their own professional judgement in determining the proper course of action for any patient's circumstances. The CAS assumes no responsibility or liability for any error or omission arising from the use of any information contained in its Guidelines to the Practice of Anesthesia.
# Preamble
Anesthesiology is a dynamic specialty of medicine that fosters continuous improvements in anesthetic care for patients undergoing surgical and obstetric procedures in Canada. This document is reviewed annually and revised periodically.
The following recommendations are aimed at providing basic guidelines to anesthetic practice. They are intended as a framework for reasonable and acceptable patient care and should be interpreted as such to allow for some degree of flexibility in different circumstances. Each section of the Guidelines is subject to revision as warranted by the evolution of technology and practice.
# Basic Principles
In this document, the term anesthesiologist is used to designate all licensed medical practitioners with privileges to administer anesthetics. An anesthetic is the deliberate performance of any procedure to render a patient temporarily insensitive to pain or to the external environment so that a diagnostic or therapeutic procedure can be performed.
These Guidelines are intended to apply to all anesthesiologists in Canada. The independent practice of anesthesia is a specialized field of medicine, and as such, it should be practiced by physicians with appropriate training in anesthesia. The only route to specialist recognition in anesthesia in Canada is through the certification process of the Royal College of Physicians and Surgeons of Canada. The Canadian Anesthesiologists' Society (CAS) acknowledges the fact that remote communities often lack the population base to support a specialist Can J Anesth/J Can Anesth (2021) 68:92-129 https://doi.org/10.1007/s12630-020-01842-x ? Text approved by CAS Board for 2021 Edition.
Texte approuvé par le CA de la SCApour l'édition 2021.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12630-020-01842-x) contains supplementary material, which is available to authorized users. anesthesiology practice.
In these communities, appropriately trained family physicians may be required to provide anesthesia services. In communities with the clinical volume to support full-time anesthesiologists, fellowship-certified anesthesiologists should provide these services. All anesthesiologists must continue their education in the practice of anesthesia, pain management, perioperative care, and resuscitation and participate in a structured maintenance of competence program (e.g., Royal College MOC).
# Organization of Anesthetic Services
The department of anesthesia should be properly organized, directed, and integrated with other departments in the organization or facility, and it should include all facility staff members who provide anesthetic services to patients for surgical, obstetric, diagnostic, and therapeutic purposes.
The department should be staffed appropriately, bearing in mind the scope and nature of the services it provides, and it should strive to ensure that these services are available as required by the healthcare facility.
The chief of the department should be a physician who has obtained certification or appropriate training in anesthesia. This individual should be appointed in the same manner as other chiefs of clinical departments and should be a member of the senior medical administrative bodies for the facility.
# Responsibilities of the Chief of Anesthesia
1. To be aware of the current CAS Guidelines to the Practice of Anesthesia, the requirements of the Canadian Council on Health Services Accreditation, and the requirements of the provincial licensing authority as they relate to anesthesia; 2. To ensure that written policies with respect to the practice of anesthesia are established and enforced; 3. To evaluate the qualifications and abilities of the physicians providing anesthetic care as well as other health professionals providing ancillary care-this includes, but is not restricted to, recommending clinical privileges for physicians with anesthetic responsibilities and annually reviewing these privileges; 4. To employ a systematic approach for monitoring the quality of anesthetic care provided by members of the department of anesthesia throughout the healthcare facility; Monitoring quality of care may include, but need not be restricted to, the use of chart audits, clinical indicator and outcome monitoring, adverse event reporting systems, morbidity and mortality conferences, and critical incident case reviews. The extent of quality improvement activities will vary depending on the departmental and health facility resources available to the chief. For effective quality improvement, it is strongly encouraged that all department members should actively participate in any such activities. 5. To ensure that records are kept for all anesthetic procedures-these records should allow for evaluation of all anesthetic care in the facility; 6. To carry out such other duties as the governing body of the facility may delegate to ensure safe anesthetic care; 7. To promote institutional compliance with applicable Canadian Standards Association (CSA) Standards (Appendix 1); and 8. To coordinate liaison between the departments of anesthesiology, biomedical engineering, and information management services. Special areas of anesthetic care may have specific concerns. The department of anesthesia in each institution may determine privileges in pediatric anesthesia according to the pediatric population it serves, the child's age, the presence of comorbidities, the physician's specific training and experience in pediatric anesthesia, and the complexity of the procedure involved.
# Privileges in Anesthesia
Physicians with anesthetic privileges should possess the knowledge and technical and non-technical skills necessary for the practice of anesthesia.
Knowledge and technical skills include the ability: • To provide preanesthetic evaluation of the patient and determine the appropriate anesthetic management; • To render the patient insensible to pain for the performance of diagnostic and therapeutic procedures, surgical operations, and obstetric procedures; • To monitor and support the vital organ systems during the perioperative period;
• To provide immediate postanesthetic management of the patient; • To provide resuscitation and intensive care when indicated; and • To provide relief from acute and chronic pain. Nontechnical skills include: • Task management: planning and preparing, prioritizing, providing and maintaining standards, and identifying and utilizing resources; • Teamwork: coordinating activities with team members, exchanging information, using authority and assertiveness, assessing capabilities, supporting others, and supporting the World Health Organization Surgical Safety Checklist; • Situational awareness: anticipating, gathering information, recognizing, and understanding, and;
• Decision-making: identifying options, balancing risks and selecting options, and re-evaluating.
# Fitness to Practice
The provision of anesthesia care requires anesthesiologists to have a high level of expertise, sound judgment, and the ability to recognize and respond to changing clinical situations despite sometimes adverse personal physical circumstances. Anesthesia departments must recognize that fit anesthesia practitioners provide optimal patient care. Anesthesia departments are therefore obligated to develop policies that ensure, as far as possible, that practitioners are healthy and fit to undertake their duties of practice.
A variety of factors impair health and fitness for duty, including adverse physical conditions, mental impairment, and fatigue. All these factors impair fitness and the ability to recognize and respond appropriately to often rapidly changing clinical circumstances. Many studies have shown that fatigue impairs judgement and psychomotor performance in a manner similar to drugs or alcohol. Shifting circadian rhythms, aging, and lack of sleep reinforce such problems; a fatigue-induced lack of recognition of these problems can compound the potential for errors in such circumstances. Physical impairment, illness, and severe stress can have similar detrimental effects on performance.
Anesthesia departments and individual anesthesiologists have a responsibility to organize their working duties such that illness and fatigue do not regularly affect clinical duties. Individual rosters must allow adequate rest between working shifts, and daily rosters should allow appropriate breaks for physiological needs, nutrition, and mental fitness. Operating room scheduling should avoid requiring anesthesiologists to undertake non-emergency procedures during unfavourable hours.
No specific prescription for working shifts and daily rosters can be appropriate for every working situation. Large departments have flexibility to incorporate short shifts and individual leave, while small departments may not have such freedom. Nevertheless, this important area of professional practice must receive ongoing consideration and attention.
# Residents
Residents in anesthesia are registered medical practitioners who participate in the provision of anesthesia services both inside and outside the operating room as part of their training. The Royal College of Physicians and Surgeons of Canada and provincial and local regulatory authorities require that a responsible attending staff anesthesiologist must supervise all resident activities. The degree of this supervision must consider the condition of each patient, the nature of the anesthetic service, and the experience and capabilities of the resident (increasing professional responsibility). At the discretion of the supervising staff anesthesiologist, residents may provide a range of anesthetic care with minimal supervision. In all cases, the supervising attending anesthesiologist must remain readily available to give advice or assist the resident with urgent or routine patient care. Whether supervision is direct or indirect, close communication between the resident and the responsible supervising staff anesthesiologist is essential for safe patient care. Each anesthesia department teaching anesthesia residents should have policies regarding the activities and supervision of residents.
# Ancillary Personnel
The healthcare facility must ensure that ancillary personnel are available as assistants to the anesthesiologist. Such assistants must be available at all times and places where anesthetic services are provided. Ancillary personnel should have the competencies to meet the specific needs of subspecialty areas of anesthesia, reflecting on the need for specific skills in areas such as specialty pediatric anesthesia.
It is recommended that facilities have a formally designated anesthesia assistant with specific training in anesthesia assistance. The department of anesthesia and the appropriate administrative bodies must approve the scope of practice for anesthesia assistants working in a specific institution. Furthermore, anesthesia assistants like other employed health professionals, must be covered by the facility's liability insurance. Duties and tasks delegated to anesthesia assistants must be consistent with existing governmental regulations, the policies and guidelines established by professional regulatory agencies, and the policies of the local facility.
An institution without formal anesthesia assistants must provide other paramedical personnel to assist the anesthesiologist. The tasks that these assistants may perform must be clearly defined. An anesthesiologist must only delegate or assign those tasks for which such personnel have approval or accreditation.
# Anesthetic Equipment and Anesthetizing Location
An anesthetic must be administered in an appropriate facility. All necessary equipment, including emergency equipment, life support systems, medications, and supplies must be readily available. It is strongly recommended that a cognitive aid manual be made available at all anesthetizing locations in support of the management of critical perioperative emergencies. The contents of the manual should be regularly reviewed, updated as required, and periodically practiced as a team.
The healthcare facility, in consultation with the department of anesthesia, is responsible for the design and maintenance of preoperative, postoperative, and anesthetizing locations, as well as the purchase, maintenance, and disposal of anesthetic and ancillary equipment and supplies. The Canadian Standards Association (CSA) and other standards development organizations have published standards and guidance documents for the design, construction, and renovation of healthcare facilities and for the risk management, basic safety, and essential performance of medical equipment (Appendix 1).
# Responsibilities of the Healthcare Facility
The healthcare facility must ensure that: 1. The operating rooms, anesthetizing locations, and perioperative care locations comply with at least the minimum design and construction requirements of the national, provincial, and local building, plumbing, electrical, HVAC (heating, ventilation, and air conditioning), fire, and security codes at the time of construction or renovation. 2. Medical gas and vacuum systems, waste anesthetic gas scavenging systems, terminal units, head walls, low pressure connecting assemblies, and pressure regulators meet the requirements of the CSA and are certified by a CSA-approved testing agency. 3. Oxygen concentrators that comply with CSA requirements are an acceptable substitute for bulk oxygen supply systems. When such concentrators are installed, users must be aware that:
a. The facility medical oxygen supply may deliver a fraction of inspired oxygen (FiO 2 ) that varies from 0.93 to 0.99; b. Oxygen analyzers must be calibrated against 100% O 2 (FiO 2 0.99) and room air or equivalent (FiO 2 0.21); c. The use of low-flow (less than one litre total fresh gas flow) anesthetic techniques may result in the accumulation of inert gas (argon) and the dilution of nitrous oxide and oxygen in the circuit.
# 4.
There is compliance with all safety regulations and best practice with respect to the storage, preparation, identification, labelling, disposal, and use of medical gases, medications, and related materials.
a. General medication safety recommendations include, but need not be restricted to:
• Identifying an anesthesia department lead designated to cooperate with pharmacy to promote medication safety best practice. In recognition of the increased risk of medication errors related to medication brand substitutions and look-alike packaging, departments and pharmacies should consider strategies to reduce this risk.
• Requesting that pharmacy staff notify anesthesia staff, with as much notice as possible, of upcoming medication supplier, packaging, or concentration changes such that anesthesia staff can be alerted. • Standardization of drug trays across all locations and during product transitions. Medications with different supplier brands and packaging for a medication should not be mixed in the same anesthesia cart. • Medication substitutions, particularly of a different concentration, should be labelled with highly visible warning labels when any new medication is introduced. • Look-alike medications should be physically separated in the anesthesia carts as much as is possible and identified with warning labels. • Cautioning physicians and technical support staff that replacement of unopened medications back into anesthesia carts is risky because medication may be put in the incorrect location.
• Reporting any medication-related adverse events through local adverse event reporting systems or CAIRS or both.
b. Through cooperation between the departments of anesthesia and pharmacy, there are policies developed and enforced for the safe handling, storage, and disposal of controlled medications (e.g., opioids) in the operating rooms and postanesthesia care unit (PACU) that are consistent with the law, with any regulatory authority requirements, and established best practice principles. The goals of such policies should be to limit access of unauthorized personnel to controlled medications to minimize the risk of controlled medication diversion, and to establish robust documentation procedures that can be audited, while also protecting patient safety by still permitting anesthesia providers immediate access to any medications required for patient care.
Best practice principles support a variety of specific strategies to achieve these goals. The CAS does not endorse any one specific strategy or policy but strongly recommends that all available options be considered. Robust systems and procedures must be implemented. Due consideration should be given to any limitation in resources available to implement specific security systems and procedures within a facility, particularly for smaller facilities.
Recommendations include, but need not be restricted to: • Storing controlled substances in a secure lockable safe or locked drawer when the OR is unattended by anesthesia personnel (e.g., between cases). • Never leaving controlled substances (including those drawn up into syringes or bags) unattended in any location. • Emptying the contents of syringes and bags containing controlled substances before disposal. • Adopting disposal and/or destruction systems to dispose of controlled substance waste. • Consideration of a requirement that controlled substance waste be returned to the pharmacy and be subjected to random analysis. • Periodic audits of a healthcare provider's controlled substance utilization records and their anesthesia records. • Consideration of the implementation of automated anesthesia cabinets or automated medication dispensing cabinets (e.g. PyxisTM)
The operating room, labour and delivery, postanesthesia care unit (PACU), and regional block areas, for example, should all be recognized as high risk areas for controlled medication diversion and therefore must be subject to heightened security, surveillance, and auditing.
5. If general anesthesia is provided using an electronic anesthetic system (gas machine), it must comply with CAN/CSA-C22. Anesthesia providers must ensure that potentially infectious materials or agents are not transferred from one patient to another. Special attention in this regard should be given to syringes, infusion pump administration sets, and multi-dose drug vials.
Training on the safe use of all anesthesia equipment should be provided to all anesthesia department members prior to use. Attendance at these sessions should be documented. These training sessions should be repeated as necessary for new or established department members.
# Waste Gases
# The Preanesthetic Period
The department of anesthesia should establish policies regarding preanesthetic assessment.
The primary goal of preanesthetic assessment is to obtain the information required to plan anesthetic management. Accordingly, a physician who is knowledgeable about anesthetic management for the proposed diagnostic or therapeutic procedure should document all aspects of the patient's medical and surgical history, findings on physical examination, and laboratory investigations that are relevant to anesthetic management. The patient's history should include past and current medical problems, current and recent drug therapy, unusual reactions or responses to drugs, and any problems or complications associated with previous anesthetics. A family history of adverse reactions associated with anesthesia should also be obtained. Information about the anesthetic that the patient considers relevant should also be documented. An American Society of Anesthesiologists physical status classification (Appendix 2) should be recorded for each patient.
In appropriate cases, the availability of an ''Advance Care Plan'' (representation agreement, advanced directive, ''living will'', ''do not resuscitate'' directive, etc.) should be ascertained, and its applicability to the proposed intervention should be determined and documented on the anesthetic assessment record.
The surgeon may request consultation with an anesthesiologist. Medical consultations should be obtained when indicated.
Preoperative anesthetic assessment or consultation may take place in an outpatient clinic before admission for the operative procedure. Indications for pre-admission assessment include the presence of significant medical problems (comorbidities), the nature of the proposed diagnostic or therapeutic procedure, and patient request. A parent/guardian must be present if the patient is a child or not competent to provide informed consent. All patients should be informed that arrangements will be made to meet with an anesthesiologist if they wish to discuss anesthetic management before admission to the facility. The preoperative assessment clinic should also allow nursing and other healthcare personnel to assess the patient. The attending anesthesiologist is responsible for performing a final preanesthetic assessment in the immediate preoperative period.
# Preoperative Testing
Laboratory testing should not be performed on a routine basis but should be obtained only when results will change perioperative management. Laboratory investigations should be performed when indicated by the patient's medical status, drug therapy, and the nature of the proposed procedure.
Routine
# Partial thromboplastin time/ international normalized ratio
May be considered:
• with conditions or medications associated with impaired coagulation (e.g., liver disease, malnutrition), history of excessive bleeding, or a family history of heritable coagulopathies
• for patients on oral or parenteral anticoagulant therapy.
# TEST INDICATIONS
Electrolytes May be considered:
• with known or compelling findings in favour of hypertension, congestive heart failure, chronic renal failure, complicated diabetes, liver disease, pituitary-adrenal disease, malnutrition
• for patients taking diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and other therapy affecting electrolytes.
Creatinine and estimated glomerular filtration rate (eGFR) May be considered:
• as above for electrolytes, also with advanced age and for patients taking medications potentially affecting renal function
• for patients receiving direct oral anticoagulants
• as required for calculating perioperative risk indices
• eGFR is recommended to assist with renal outcome prediction.
Fasting glucose level May be considered:
• for diabetics, preoperatively on day of surgery to guide glycemic control
• for patients on glucocorticoid therapy
• as screening for body mass index [ 40 or a very high risk of diabetes based on signs and symptoms.
# Hemoglobin A1c
• May be considered for known diabetics as early as possible before surgery (ideally at time of surgical referral) if results would change management.
# Pregnancy testing Based on specific institutional guidelines
• Should be offered to women of childbearing age based on any reasonable likelihood of pregnancy, on the reliability of menstrual history, and if the results will cancel or change the procedure or the anesthetic management.
• Point of care urine or blood testing capability is ideal and is therefore recommended.
# Electrocardiography
• May be considered for patients with known or suspected coronary heart disease, significant arrhythmia, peripheral vascular disease, or other significant structural heart disease.
• May be considered in the absence of symptoms or known cardiovascular disease in patients having high-risk surgery in the presence of clinical risk factors (e.g., Revised Cardiac Risk Index (RCRI) or American College of Surgeons (ACS) Surgical Risk Calculator).
Brain natriuretic peptide (BNP or NT-pro BNP)
May be considered if:
• age ‡ 65 yr,
• age 45-65 yr with significant cardiac disease,
• Revised Cardiac Risk Index score ‡ 1.
# Chest radiograph
• Not recommended for asymptomatic patients in routine preoperative assessment unless part of a surgical or oncological workup unrelated to perioperative risk assessment.
• May be considered for patients with acute or chronic cardiopulmonary disease based on history and physical exam if it will change management.
# Fasting Policies
Fasting policies should vary to account for age and preexisting medical conditions and should apply to all forms of anesthesia, including procedural sedation (see Appendix 6). 1 Emergent or urgent procedures should be undertaken after considering the risk of delaying surgery vs the risk of aspiration of gastric contents. The type and amount of food ingested should be considered in determining the duration of fasting. Before elective procedures, the minimum duration of fasting should be:
• Eight hours after a large meal of solids particularly containing protein (e.g., meat) or fatty foods • Six hours after a light meal (e.g., non-fatty meal such as toast) • Six hours after ingestion of infant formula, non-human milk, or expressed breast milk fortified with additions • Four hours after ingestion of breast milk • Two hours after ingestion of clear fluids for adults • One hour after ingestion of clear fluids for infants and children Unless contraindicated, adults and children should be encouraged to drink clear fluids (including water, pulp-free juice, complex carbohydrate beverages, and black tea or coffee up to two hours before elective surgery. Pediatric patients should also be encouraged to consume clear fluids, as defined, up to one hour before elective procedures.
Conditions that delay gastric emptying require individual patient assessment. These guidelines may be modified at the discretion of the physician.
Premedication, when indicated, should be ordered by the anesthesiologist. Orders should be specific as to dose, time, and route of administration.
An H2 receptor antagonist (oral or intravenous) is recommended for all women presenting for Cesarean delivery.
Thirty mL of oral sodium citrate (0.3 molar) is recommended prior to an emergent Cesarean delivery if general anesthesia is planned. See Section 7.3 for fasting guidelines specific to patients in active labour.
# Additional Regulations
Provincial legislation or facility bylaws may dictate additional regulations governing the conduct of anesthesia.
# The Anesthetic Period
# Preparation for Anesthesia
Before beginning anesthesia, the anesthesiologist must ensure that 1. An explanation of the planned anesthetic procedure, including recognized risks and alternative techniques, has been provided and documented; 2. An adequate review of the patient's condition has been performed; 3. All equipment that is expected to be required is available and in working order, including the equipment required for supporting core temperature management (patient core temperature 36-37°C); 4. A reserve source of oxygen under pressure is available; 5. All drugs and agents that are expected to be required are correctly identified-user-applied drug labels should conform to the CSA Standard CAN/CSA-Z264.3-98 (R2005) (Appendix 1); 6. If Luer neuraxial connectors are used, both sides of all Luer connections must be labelled. Consideration should be given to the use of neuraxial connectors complying with ISO 80369-6:2016-small bore connectors for neuraxial application (e.g., NRFitÒ connectors) subject to availability from equipment suppliers; and 7. The manufacturers' recommendations concerning the use, handling, and disposal of anesthetic equipment and supplies have been considered.
# Airway Management
Airway management, particularly of the difficult airway, contributes to a significant proportion of anesthesia related morbidity and mortality.
The appropriate management of those patients who have a predicted, or an unanticipated difficult intubation, a failed airway, where bag-mask ventilation or supraglottic device placement may be difficult, or who require a surgical airway is critical for patient safety. This includes, but need not be restricted to, adequate airway assessment, equipment (e.g., difficult airway carts, videolaryngoscopes, bronchoscopes), training and simulation, support personnel and the use of protocols and cognitive aids to optimize difficult airway management. The CAS does not endorse any one specific protocol, algorithm, or cognitive aid for difficult and failed airway management but strongly recommends that readers refer to Appendix 4 for up to date publications related to this topic.
# Delegation of Patient Care
The anesthesiologist's primary responsibility is to the patient receiving care. The anesthesiologist or an anesthesia assistant supervised by the anesthesiologist must remain with the patient at all times throughout the conduct of all general and major regional, anesthetics and for procedural sedation until the patient is transferred to the care of personnel in an appropriate care unit.
If the attending anesthesiologist leaves the operating room temporarily, he/she must delegate care of the patient to another anesthesiologist, a resident in anesthesia, or an anesthesia assistant. When the attending anesthesiologist delegates care to a resident in anesthesia or an anesthesia assistant, the attending anesthesiologist remains responsible for the anesthetic management of the patient. Before delegating care of the patient to an anesthesia assistant, the anesthesiologist must ensure that the patient's condition is stable and that the anesthesia assistant is familiar with the operative procedure and the operating room environment and equipment. The attending anesthesiologist must remain immediately available when care is delegated to an anesthesia assistant.
An anesthesiologist may briefly delegate routine care of a stable patient to a competent person who is not an anesthesia assistant only under the most exceptional circumstances, e.g., to provide life-saving emergency care to another patient. That person's only responsibility would be to monitor the patient during the anesthesiologist's absence and to keep the anesthesiologist informed until he/ she returns. In this situation, the anesthesiologist remains responsible for the care of the patient and must inform the operating room team.
An intraoperative handover of care between two anesthesiologists should be documented in the anesthesia record and follow a structured protocol.
It is unacceptable for one anesthesiologist to simultaneously administer general anesthesia, major regional anesthesia (spinal, epidural, or other), or deep procedural sedation (see Appendix 6) 1 for concurrent diagnostic or therapeutic procedures on more than one patient. Nevertheless, it may be appropriate in specific circumstances for one anesthesiologist to supervise more than one patient where only minimal to moderate sedation is administered, provided an appropriately trained, qualified, and accredited individual approved by the department of anesthesiology, and the healthcare institution is in constant attendance with each patient receiving care. In an obstetric unit, however, it is acceptable to supervise more than one patient receiving regional analgesia for labour. Due care must be taken to ensure that a suitably trained person adequately observes each patient following an established protocol. When an anesthesiologist is providing anesthetic care for an obstetric delivery, a second appropriately trained person should be available to provide neonatal resuscitation.
It is unacceptable for a single physician to administer an anesthetic, including deep procedural sedation, and simultaneously perform a diagnostic or therapeutic procedure, except for procedures done with only infiltration of local anesthetic and/or minimal sedation.
# Patient Monitoring
The only indispensable monitor is the presence, at all times, of a physician or an anesthesia assistant who is under the immediate supervision of an anesthesiologist and has appropriate training and experience. Mechanical and electronic monitors are, at best, aids to vigilance. Such devices assist the anesthesiologist to ensure the integrity of the vital organs and, in particular, the adequacy of tissue perfusion and oxygenation. Monitoring equipment must be used as intended by the manufacturer and approved by Health Canada for the specific application.
The healthcare facility is responsible for the provision and maintenance of monitoring equipment that meets current published equipment standards.
The chief of anesthesia is responsible for advising the healthcare facility regarding the procurement of monitoring equipment and for establishing policies for monitoring to help ensure patient safety.
The anesthesiologist is responsible for monitoring the patient receiving care and for ensuring that appropriate monitoring equipment is available and working correctly. A preanesthetic checklist (Appendix 3 or equivalent) must be completed prior to initiation of anesthesia.
Cautious dosing, vigilant monitoring, and the appropriate reversal of neuromuscular blocking drugs are all essential for patient safety. Neuromuscular monitoring must be utilized when neuromuscular blocking agents are administered.
Monitoring guidelines for standard patient care apply to all patients receiving general anesthesia, regional anesthesia, or procedural sedation.
# Required Monitoring Equipment
Monitoring equipment is classified as follows:
• Required: These monitors must be in continuous use throughout the administration of all anesthetics. • Exclusively available for each patient: These monitors must be available at each anesthetic work station so that they can be used with no delay. • Immediately available: These monitors must be available to facilitate their use without undue delay.
The following monitoring equipment is required: • Pulse oximeter;
• Apparatus to measure blood pressure, either directly or noninvasively; • Electrocardiography; • Neuromuscular blockade monitor when neuromuscular blocking drugs are used; • Capnography for general anesthesia and to assess the adequacy of ventilation for moderate or deep procedural sedation; and • Agent-specific anesthetic gas monitor, when inhalational anesthetic agents are used.
The following monitoring equipment must be exclusively available for each patient:
• Apparatus to measure temperature; • Stethoscope; • Appropriate lighting to visualize an exposed portion of the patient.
The following monitoring equipment must be immediately available: • Spirometer to measure tidal volume; • Manometer to measure endotracheal tube cuff pressure.
• Equipment for invasive hemodynamic monitoring if indicated (e.g., arterial, central venous).
The anesthesiologist must remain constantly vigilant, understanding that brief interruptions in continuous monitoring may be unavoidable and there are certain circumstances in which a monitor may fail.
Audible and visual alarms for oximetry and capnography should not be indefinitely disabled during the conduct of an anesthetic except during unusual circumstances. The variable pitch, pulse tone, and lowthreshold alarm of the pulse oximeter and the capnograph apnea alarm must give an audible and visual warning.
# Perioperative Temperature Management
Monitoring patient core temperature is strongly recommended during cases of general and neuraxial regional anesthesia lasting 30 min or longer. In the absence of surgical or patient indications for intraoperative hypothermia, active patient warming systems, control of the operating room ambient temperature, and other methods, should be used to target a central core temperature of 36-37°C.
# Patient Positioning
Patient positioning for procedures requiring anesthesia is an operating room team responsibility and demands a high level of attention to avoid complications. It is recognized, however, that positioning-related complications can still occur despite best practice and vigilance. Risks related to patient positioning will vary and depend on the type and duration of surgery, the specific position utilized, and patient factors such as BMI and other comorbidities. Therefore, the considerations and planning for positioning best practice should be discussed by the surgical team ideally before anesthesia induction, for example during part 1 of the Surgical Safety Checklist. All members of the team, including the anesthesiologist, should be encouraged to voice concerns related to any aspect of positioning (e.g., specific risk factors and availability, condition and appropriateness of OR tables and other positioning equipment), and strategies to mitigate these risks should be considered. Patient positioning should be documented and also rechecked regularly by the anesthesiologist to be sure positioning conditions remain ideal. Patients should be informed preoperatively of any specific risks that may be associated with the position planned for their procedure.
# Records
All monitored physiologic variables should be charted at intervals appropriate to the clinical circumstances. Heart rate and blood pressure should be recorded at least every five minutes. Oxygen saturation must be monitored continuously and should be recorded at frequent intervals, at a minimum of every five minutes, for all patients. End-tidal carbon dioxide concentration must be monitored continuously and recorded at frequent intervals if the trachea is intubated or a supraglottic device is in situ. Reasons for deviation from these charting guidelines should be documented in the anesthetic record. Monitors, equipment, and techniques, as well as time, dose, and route of all drugs and intravenous fluids should be recorded. All other relevant intraoperative anesthesia care and events, including unexpected or adverse events, should also be recorded.
The patient health record should include the patient's level of consciousness, heart rate, blood pressure, oxygen saturation, and respiratory rate as first determined in the PACU. These recommendations apply to both manually created (handwritten) and electronic anesthesia information management system (AIMS) created anesthesia records. At present, there are no practice standards for what additional data (e.g., gas analysis, ventilator, and respiratory data) that can potentially be collected by an AIMS charting system should become part of a patient's permanent health record.
AIMS have been shown to have potential benefits over handwritten records in several key areas, including improved legibility, precision and reliability of anesthesia records, providing searchable data for quality improvement, outcome and performance reporting and translational research, enhanced medication safety and tracking and real-time clinical decision support for users. The anesthesia patient safety literature supports the use of AIMS. Importantly, AIMS maintain a longitudinal patient database so historical patient encounters should be easily retrievable for review and this should be considered an important feature of any system. The CAS does not promote or endorse any one specific vendor or product but acknowledges that there may be potential benefits of a well designed and implemented AIMS over manually charted records where facility and anesthesia department resources permit the consideration of an AIMS. Ideally it should be implemented and supported in cooperation with the facility information technology department including communication with other facility electronic patient databases wherever possible.
6 The Postanesthetic Period
# Recovery Facility
A PACU must be available in any facility that provides anesthetic services. Administrative policies to coordinate medical and nursing care responsibilities must be enforced in accordance with facility bylaws.
The department of anesthesia should have overall medical administrative responsibility for the PACU. There should be a PACU policy manual approved by appropriate medical, nursing, and administrative authorities.
The anesthesiologist should accompany the patient to the PACU, communicate necessary information to the PACU nurse(s) as part of a structured handover of care protocol, and write appropriate orders. Continuous monitoring of patients is recommended during the perioperative period appropriate to the clinical situation. If clinically indicated, supplemental oxygen, portable pulse oximetry, and other appropriate monitoring devices should be applied during transport to the PACU or intensive care unit. If supplemental oxygen is applied during transport or in PACU to patients who are intubated it is strongly recommended that it only be provided using devices approved for that specific application to minimize any risk of barotrauma. The anesthesiologist should delegate care to the PACU nurse only when assured that nursing staff may safely observe and care for the patient. The anesthesiologist or designated alternate is responsible for providing anesthetic-related care in the PACU. Discharge from the PACU is the responsibility of the anesthesiologist; this responsibility may be delegated in accordance with facility policy.
Supplemental oxygen and suction must be available for every patient in the PACU. Emergency equipment for airway management, resuscitation, and life support must be available in the PACU. Equipment for management of the difficult airway must be immediately available to the PACU. The monitoring used in the PACU should be appropriate to the patient's condition, and a full range of monitoring devices should be available. Monitor alarms should be enabled with alarm settings appropriate to the condition and age of the patient. The use of continuous pulse oximetry is required in the initial phase of recovery. Capnography is required for intubated and deeply sedated patients and is recommended for unconscious patients with in situ supraglottic airway devices. An apnea monitor is recommended for preterm infants with a gestational age of less than 50 weeks.
An accurate record of the immediate recovery period must be maintained. This must include a record of vital signs together with other aspects of treatment and observation. The recovery record must form a part of the permanent medical record. Any complications that bear any relation to the anesthetic should be recorded either on the recovery record or on the progress notes on the patient's chart.
In some circumstances, it may be considered acceptable to transfer a patient directly to other care units or to bypass the PACU if the appropriate level of care is available in another unit in the facility and the suitability of the patient for this transfer is documented on the anesthetic record.
# Discharge of Patients After Day Surgery
Discharge of patients after day surgery must utilize a formal care plan approved by the institution and be documented in the patient care notes. Patients should meet the facility discharge to home criteria using a validated assessment tool. (e.g., Post Anesthetic Discharge Scoring System). Specific written instructions should include management of pain and postoperative complications, and both routine and emergency follow-up. The patient should be advised regarding the additive effects of alcohol and other sedative drugs, the danger of driving or operating other hazardous machinery during the postoperative period (most commonly 24 hr postoperatively), and the necessity for attention by a competent adult during the postoperative period (most commonly 24 hr postoperatively).
7 Guidelines for Obstetric Regional Analgesia Anesthesia services for parturients include obstetric analgesia for labour-for both uncomplicated and complicated deliveries-or for operative deliveries. All guidelines regarding provision of anesthesia for other diagnostic or therapeutic procedures also apply to the provision of obstetric anesthesia. The guidelines in this section pertain to epidural and spinal analgesia during labour. The term ''regional analgesia'' includes epidural, spinal, and combined spinal-epidural analgesia.
These guidelines are reviewed annually by the Obstetric Anesthesia Section of CAS and updated as indicated. Each facility may choose to develop additional guidelines or policies for specific situations in which obstetric regional analgesia is provided.
Under the direction of an anesthesiologist, some aspects of monitoring and management of obstetric regional analgesia may be delegated to other healthcare personnel. Each facility should ensure that such other personnel receive the same training, certification, continuing education, and recertification in obstetric regional analgesia.
# Initiation of Obstetric Regional Analgesia
Before introducing obstetric regional analgesia, the facility should have appropriate monitoring protocols in place. These protocols should outline the types of monitoring required and the frequency of monitoring. In addition, they should clearly state how to manage common problems and emergencies and indicate whom to contact if assistance is required.
1. Obstetric regional analgesia should be provided only by physicians with training, facility privileges, and licence to provide these services. This includes trainees with appropriate supervision. 2. Regional analgesia should be initiated and maintained only in locations where appropriate resuscitation equipment and drugs are immediately available. 3. Informed consent should be obtained and documented in the medical record. 4. Intravenous access must be established before initiating regional analgesia, and it should be maintained throughout the administration of regional analgesia. 5. The anesthesiologist should be immediately available until analgesia is established and the patient's vital signs are stable. When initial and top-up bolus epidural local anesthetics are administered, the anesthesiologist must be immediately available to intervene appropriately recognizing that these techniques can cause immediate life-threatening complications.
Individual departments of anesthesiology should establish their own policies regarding the appropriate availability of an anesthesiologist to manage the potential complications of regional analgesia for labour and delivery.
Safety systems must be in place to secure epidural local anesthetic mixtures and supplies containing controlled substances (e.g., opioids) to minimize the risk of diversion.
# Oral Intake During Labour
Gastric emptying of solids is delayed during labour and opioid analgesics may further delay gastric emptying.
Therefore, parturients should generally be discouraged from ingesting solid foods when in active labour. In contrast to solid food, clear fluids are emptied relatively rapidly from the stomach during labour. Therefore, in general, women should be permitted clear fluids as desired during active labour. Individual facilities should develop protocols regarding the intake of solids and clear fluids by women in active labour.
# Guidelines for Acute Pain Management Using Neuraxial Analgesia
When neuraxial analgesia is managed by anesthesiologists, the incidence of side effects is no higher than when alternative techniques of pain management are used. Accordingly, when its use is appropriate, neuraxial analgesia should be managed by anesthesiologists.
For the purposes of these guidelines, neuraxial analgesia is defined as intrathecal or epidural administration of opioids and/or local anesthetics for treatment of postoperative pain or other acute pain problems. These guidelines are to provide anesthesiologists with the principles of management to maximize the benefit-risk ratio of providing neuraxial analgesia.
# Administrative and Educational Policies
The department of anesthesia should establish an acute pain service that is responsible for: 1. Developing policies and procedures for neuraxial analgesia. • Assessment and management of hypotension in patients receiving neuraxial analgesia; and • Signs and symptoms of the rare but catastrophic complications of epidural hematoma or abscess.
# Policies for Drug Administration
Each facility should use a limited number of standard solutions. A preprinted order sheet listing the standard solutions for the facility is strongly recommended. Before any solution that is not standard in the facility is dispensed, the anesthesiologist should verify the order with nursing and pharmacy personnel and discuss its indications and all concerns relating to its use with the nurses responsible for administering the drug and monitoring the patient.
The risk of errors due to incorrect route of drug injection must be minimized. For continuous infusions or PCEA, the use of unique tamper-proof pumps that are distinct from the pumps used for intravenous fluid or drug administration is strongly recommended. The tubing between neuraxial analgesia infusion pumps and catheters should not have ports that could permit unintentional injection of intravenous drugs (see section 5.1-6).
Preparation of solutions should follow a standardized procedure. All analgesic drug solutions should be labeled with the composition of the solution (opioid, local anesthetic, or both) and its intended route of administration. For epidural administration, this should include the date and time of preparation and the name of the individual who prepared it.
# Patient Monitoring and Management of Adverse Events
Patients receiving neuraxial analgesia should be in a room equipped with oxygen and suction. Resuscitation drugs and equipment must be immediately available. Before initiating neuraxial analgesia, intravenous access must be secured, and after discontinuing neuraxial analgesia, intravenous access must be maintained for the expected duration of drug effects. Epidural catheter dressings should permit examination for catheter movement and daily inspection of the catheter entry site for any signs of infection.
Standardized policies for patient management should be established. The parameters to be assessed, frequency of assessments, documentation, and procedures for management of complications should be specified. Adequate nursing personnel must be available to assess and manage patients receiving neuraxial analgesia. Monitoring should continue after discontinuation of neuraxial analgesia until its effects have dissipated.
An anesthesiologist must be readily available to advise nursing personnel on such issues as dose titration and management of adverse effects. Each facility with an acute pain service should ensure that an anesthesiologist is available to attend directly to patients receiving neuraxial analgesia within an appropriate time depending on the clinical situation. Each facility should also specify procedures for emergent management of any lifethreatening complications.
Other drugs, particularly benzodiazepines or parenteral opioids, may cause severe respiratory depression in patients receiving neuraxial analgesia. For this reason, other physicians should not order sedatives or analgesics for any patient receiving neuraxial analgesia. The acute pain service should direct analgesic and sedative therapy until the effects of neuraxial analgesia have dissipated.
# Epidurals and Anticoagulation
Patients with epidural catheters may receive prophylactic low-dose anticoagulant therapy if appropriate precautions are taken:
• To minimize the risk of epidural hematoma, catheter insertion and removal and the timing of anticoagulant administration must be coordinated so that no clinically significant anticoagulant effect is present at these times. • Use of nonsteroidal anti-inflammatory drugs in patients receiving neuraxial analgesia is appropriate, but concurrent administration of these drugs or other antiplatelet medication and an anticoagulant may increase the risk of epidural hematoma.
• Where neuraxial analgesia is used for prolonged postoperative pain management, every effort should be made to avoid lower extremity motor blockade. • Nursing staff should be aware of the signs and symptoms of epidural hematoma. Any change in neurologic status or new-onset back pain must be investigated immediately.
If full anticoagulation is indicated in a patient with an epidural catheter, the anesthesiologist should be consulted so that catheter removal and initiation of alternative analgesic management are accomplished before anticoagulation.
# Guidelines for the Practice of Anesthesia in Remote Locations
The basic principles, training requirements, techniques, equipment, and medications used for the practice of anesthesia in remote locations are as outlined in other sections of these Guidelines. They apply equally to anesthesia care, including procedural sedation (see Appendix 6) delivered by anesthesiologists in any operating room or out-of-operating room locations both within a hospital facility and outside of a hospital facility (e.g., offices, clinics).
9.1 Anesthesia Care delivered in a Non-Hospital Medical/Surgical/Dental Facility
# Patient Selection
The physical status of patients should be classified using the American Society of Anesthesiologists physical status (ASA) score. Typically, only patients with ASA classifications of I and II should be considered for procedures. Patients with ASA III classification may be accepted under certain circumstances but only at the discretion of the attending anesthesiologist. Caution should be exercised when booking patients with a known difficult airway.
# Preoperative Considerations
The patient must have had a recent and documented health history, physical examination including an airway examination, and any appropriate laboratory investigations. This may be carried out by another physician (e.g., proceduralist) but it is strongly recommended that there be a screening process that is developed and supported by the anesthesia leadershipproviding services. The duration of fasting should be consistent with section 4.2 Fasting Guidelines.
# Conduct of Anesthesia
The anesthetic and recovery facilities must conform to facility standards established by the CSA (see Appendix 1) and all CAS guidelines established for patient care. The patient should be discharged home from the facility using a validated scoring system for fitness to discharge (e.g., Post Anesthetic Discharge Scoring System).
Patients should be provided with written instructions for the preoperative and postoperative periods. The demand for the delivery of anesthesia care services outside of an operating room (e.g., endoscopy, interventional radiology, cardiac catheterization) is growing because of technological advances and the growth in the availability of less invasive, yet potentially painful, procedures. The delivery of anesthesia care in these remote procedural units can present unique challenges to the anesthesia care team (e.g., patients may have an ASA status of III-IV and have significant comorbidities) and they may be some distance from the operating rooms and support staff or outside of a hospital facility. Procedural units where anesthesiologists have been asked to provide care should comply with the same CSA standards (Appendix 1), equipment guidelines (see section 3.0), and general CAS guidelines as an operating room to the greatest extent possible. This includes, but need not be restricted to, patient selection and assessment, preprocedural testing, fasting guidelines, equipment and electrical outlets, oxygen and suction, ventilation and scavenging if inhalational agents will be utilized, medications and equipment required for resuscitation, patient monitoring, the recovery facility and anesthesia support personnel. Any location outside of an operating room where anesthesiologists provide care must be approved by the anesthesia leadership of the facility. Appropriately trained and experienced anesthesia support personnel, for example an Anesthesia Assistant (see section 2.5) or other staff with experience supporting anesthesia should be present or immediately available to assist the anesthesiologist in remote locations. It is not appropriate to rely solely on procedural unit staff to support anesthesia unless they have had training and experience in the direct support of the delivery of anesthesia care and are approved by anesthesia leadership. There must be reliable two-way communication available to call for assistance and support of the anesthesia provider as it may be required. Les recommandations suivantes ont pour objectif de proposer des lignes directrices de base touchant l'exercice de l'anesthésie. Leur but est de constituer un cadre pour la prestation de soins aux patients qui soient raisonnables et acceptables, et c'est ainsi qu'elles devraient être interprétées, ce qui permet une certaine flexibilité selon les circonstances. Chaque partie du Guide peut faire l'objet de révision au besoin, selon l'évolution de la technologie et de la pratique.
# Principes de base
Dans le présent document, le mot anesthésiologiste est utilisé pour désigner toute personne qui a un permis d'exercer la médecine avec privilège d'administrer l'anesthésie. L'anesthésie est la réalisation délibérée de toute intervention visant à rendre un patient temporairement insensible à la douleur ou à l'environnement externe dans le but d'exécuter une intervention diagnostique ou thérapeutique.
Le présent Guide s'adresse à tous les anesthésiologistes du Canada. L'exercice indépendant de l'anesthésie est une spécialité médicale et, à ce titre, elle doit être exercée par des médecins ayant une formation appropriée en anesthésie. Le processus de certification du Collège royal des médecins et chirurgiens du Canada constitue la seule voie de reconnaissance comme spécialiste en anesthésie au Canada.
La Société canadienne des anesthésiologistes (SCA) reconnâıt que la population dans les collectivités éloignées n'est souvent pas suffisamment nombreuse pour justifier une pratique d'anesthésiologie spécialisée. Dans ces collectivités, des médecins de famille ayant reçu une formation adéquate pourraient être appelés à dispenser les services d'anesthésie. Dans les communautés ou' le volume clinique est suffisamment important pour justifier l'emploi d'anesthésiologistes à temps plein, des anesthésiologistes ayant complété leur spécialisation devraient offrir ces services. Tous les anesthésiologistes doivent poursuivre une formation continue dans la pratique de l'anesthésie, de la prise en charge de la douleur, des soins périopératoires et de la réanimation, et participer à un programme structuré de maintien des compétences (par ex., MDC du Collège royal).
# Organisation des services d'anesthésie
Le département d'anesthésie devrait être organisé, dirigé et intégré de façon appropriée aux autres départements de l'organisme ou de l'établissement, et devrait regrouper tous les membres du personnel de l'établissement qui assurent des soins anesthésiques aux patients, aussi bien à des fins chirurgicales, obstétricales, diagnostiques ou thérapeutiques.
Compte tenu de l'ampleur et de la nature des services offerts, le département devrait comporter le personnel nécessaire et s'efforcer d'assurer que ces services soient disponibles comme l'établissement de soins de santé le requiert.
Le chef du département devrait être un médecin certifié en anesthésie ou encore possédant une formation adéquate en anesthésie. Cette personne devrait être nommée de la même manière que les autres chefs de départements cliniques et devrait faire partie des entités administratives médicales supérieures de l'établissement. Aucune recommandation spécifique concernant les quarts de travail et la liste de garde quotidienne ne peut être adaptée à toutes les situations de travail. Les grands départements disposent de la flexibilité nécessaire à intégrer des quarts de travail courts et des congés personnels, alors que les départements plus petits pourraient ne pas jouir de cette liberté. Toutefois, ce domaine important de l'exercice professionnel doit faire l'objet d'une attention et d'une considération constantes.
# Résidents
Les résidents en anesthésie sont des médecins autorisés qui participent à la prestation des soins anesthésiques tant en salle d'opération qu'à l'extérieur de celle-ci dans le cadre de leur formation. Le Collège royal des médecins et chirurgiens du Canada et les organismes de règlementation provinciaux et locaux exigent qu'un anesthésiologiste responsable supervise toutes les activités des résidents. Le degré de supervision doit prendre en considération l'état de chaque patient, la nature des soins anesthésiques, ainsi que l'expérience et les capacités du résident (responsabilité professionnelle croissante). A' la discrétion de l'anesthésiologiste superviseur, les résidents peuvent fournir une gamme de soins anesthésiques sous un minimum de supervision. Dans tous les cas, l'anesthésiologiste superviseur doit demeurer promptement disponible afin de prodiguer des conseils ou d'assister le résident lors de soins urgents ou de routine. Que la supervision soit directe ou indirecte, une communication étroite entre le résident et l'anesthésiologiste superviseur est essentielle pour garantir des soins sécuritaires aux patients. Chaque département d'anesthésie qui enseigne aux résidents en anesthésie doit avoir des politiques en place concernant les activités et la supervision des résidents. 2.7 Personnel de soutien L'établissement de soins de santé doit s'assurer de la disponibilité de personnel de soutien pour remplir un rôle d'assistance auprès de l'anesthésiologiste. Cette assistance doit être disponible en tout temps et en tout lieu ou' des services d'anesthésie sont offerts. Le personnel de soutien doit posséder les compétences nécessaires à répondre aux besoins spécifiques des domaines de surspécialité de l'anesthésie, ce qui se répercute sur le besoin de compétences spécifiques dans des domaines tels que l'anesthésie spécialisée en pédiatrie.
On recommande aux établissements de disposer d'un assistant en anesthésie formellement désigné qui aura reçu une formation spécifique en assistance en anesthésie. Le département d'anesthésie et les autorités administratives compétentes doivent approuver l'étendue des tâches des assistants en anesthésie travaillant dans un établissement en particulier. En outre, les assistants en anesthésie, tout comme les autres professionnels de la santé employés par l'établissement, doivent être protégés par l'assuranceresponsabilité de l'établissement. Les responsabilités et les tâches déléguées aux assistants en anesthésie doivent être conformes aux règlements gouvernementaux en vigueur, aux politiques et lignes directrices édictées par les organismes de règlementation de la profession, et aux politiques de l'établissement local.
Un établissement ne disposant pas d'assistants en anesthésie en bonne et due forme doit mettre à disposition de l'anesthésiologiste du personnel paramédical afin de l'assister. Les tâches incombant à ces assistants doivent être clairement définies. Un anesthésiologiste ne doit leur déléguer ou impartir que les tâches pour lesquelles ils ont été autorisés ou approuvés.
3 Matériel d'anesthésie et lieux convenant à l'anesthésie L'anesthésie doit se pratiquer dans un établissement adapté. Tout le matériel nécessaire, y compris le matériel d'urgence, les systèmes de soutien des fonctions vitales, les médicaments et les autres fournitures, doit être à portée de main. Il est fortement recommandé qu'un manuel de listes de contrôle et d'aides cognitives soit disponible dans tous les lieux où l'anesthésie est pratiquée afin de soutenir la prise en charge des urgences périopératoires critiques. Le contenu de ce manuel devrait être révisé et mis à jour régulièrement selon les besoins et répété de façon périodique en équipe.
L'établissement de soins de santé, en consultation avec le département d'anesthésie, est responsable de l'aménagement et de l'entretien des lieux servant aux soins préopératoires, postopératoires et anesthésiques, ainsi que de l'achat, de l'entretien et du traitement après utilisation du matériel et des fournitures servant à l'anesthésie et aux autres fonctions connexes. L'Association canadienne de normalisation (CSA) et d'autres organismes d'élaboration de normes ont publié des normes et des recommandations se rapportant à la conception, la construction et la rénovation des établissements de santé, ainsi que concernant la gestion du risque, la sécurité de base et les performances essentielles du matériel médical (Annexe 1).
# Responsabilités de l'établissement de santé
Il incombe à l'établissement de soins de santé de veiller à l'application des mesures suivantes :
# La période préanesthésique
Le département d'anesthésie devrait formuler les politiques concernant l'évaluation préanesthésique. Le principal objet de l'évaluation préanesthésique est d'obtenir les renseignements requis pour planifier la prise en charge anesthésique. Par conséquent, un médecin bien informé quant à la prise en charge anesthésique pour la procédure diagnostique ou thérapeutique proposée devrait documenter tous les aspects des antécédents médicochirurgicaux du patient, le bilan de l'examen physique et les résultats des analyses de laboratoire pertinents à la prise en charge anesthésique. Les antécédents du patient devraient inclure les problèmes médicaux passés et actuels, la prise de médicaments récente et actuelle, les réactions ou réponses inhabituelles aux médicaments et tous les problèmes et complications associés aux anesthésies administrées antérieurement. Il y a lieu de connâıtre également les antécédents familiaux de réactions indésirables associées à l'anesthésie. Tout renseignement concernant l'anesthésie que le patient juge pertinent de signaler devrait également être noté. Il convient enfin d'inscrire au dossier médical de chaque patient le code de classification de l'American Society of Anesthesiologists (Annexe 2).
Dans les cas adaptés, la disponibilité d'un « Plan de soins avancés » (accord de représentation, directive préalable, « testament biologique », directive « ne pas réanimer », etc.) doit être vérifiée et son applicabilité à l'intervention proposée déterminée et documentée au dossier d'évaluation anesthésique.
Le chirurgien peut solliciter une consultation avec un anesthésiologiste. Les consultations médicales devraient être obtenues lorsque cela est indiqué.
Le bilan ou la consultation anesthésique préopératoire peut avoir lieu en clinique externe avant l'admission pour l'opération. Les indications concernant l'évaluation préalable à l'admission comprennent l'existence de problèmes médicaux importants (comorbidités), la nature de la procédure diagnostique ou thérapeutique proposée, et la demande du patient. La présence d'un parent/tuteur légal est nécessaire si le patient est un enfant ou n'est pas apte à fournir un consentement éclairé. Tous les patients devraient être informés que des dispositions seront prises pour rencontrer un anesthésiologiste s'ils souhaitent s'entretenir de leur prise en charge anesthésique avant leur admission à l'établissement. La clinique d'évaluation préopératoire devrait également permettre au personnel infirmier et aux autres membres du personnel de santé d'évaluer le patient. L'anesthésiologiste en charge du patient est responsable de l'évaluation préanesthésique finale durant la période préopératoire immédiate.
# Examens préopératoires
Les examens de laboratoire ne devraient pas être réalisés sur une base régulière mais uniquement lorsque les résultats modifieront la prise en charge périopératoire. Les analyses de laboratoire devraient être réalisées lorsque l'état du patient, le traitement médicamenteux et la nature de l'intervention proposée les justifient. Les tests sanguins de laboratoire, les électrocardiogrammes et les radiographies du poumon de routine ne sont pas recommandés chez les patients asymptomatiques subissant une chirurgie à faible risque.
# Dépistage d'hématies falciformes avec
• Devrait être proposé consultation aux patients présentant un risque élevé en raison de leur origine ethnique.
# Temps de thromboplastine partielle/rapport international normalisé
Peut être envisagé :
• Avec les affections ou médicaments associés à une altération de la coagulation (p. ex., maladies hépatiques, malnutrition), antécédents de saignements excessifs, ou antécédents familiaux de coagulopathies transmissibles.
• Pour les patients recevant un traitement anticoagulant par voie orale ou parentérale.
# Taux d'électrolytes
Peut être envisagé :
• Si connu pour ou avec des constatations connues ou convaincantes en faveur des pathologies suivantes : hypertension, insuffisance cardiaque congestive, insuffisance rénale chronique, diabète avec complications, maladie hépatique, trouble hypophysaire, atteinte de l'axe hypophyso-adrénalien, malnutrition.
• chez des patients recevant des diurétiques, des inhibiteurs de l'enzyme de conversion de l'angiotensine, des bloqueurs du récepteur de l'angiotensine et d'autres traitements affectant les électrolytes.
Créatinine et débit de filtration glomérulaire estimé (DFGe/ eGFR)
Peut être envisagé :
• Comme ci-dessus pour les électrolytes, également avec un âge avancé et chez les patients prenant des médicaments affectant potentiellement la fonction rénale.
• Pour les patients recevant des anticoagulants directs par voie orale.
• Si nécessaire pour calculer les indices de risque périopératoire.
• Le DFGe est recommandé pour contribuer à la prédiction de l'évolution de la fonction rénale.
# TEST INDICATIONS
Glycémie à jeun Peut être envisagé :
• Chez les diabétiques, en préopératoire, le jour de la chirurgie pour guider le contrôle glycémique.
• Pour les patients recevant un traitement avec glucocorticöıdes.
• A' titre de dépistage chez les patients ayant un IMC [ 40 ou un risque très élevé de diabète en fonction de signes et symptômes.
# Hémoglobine A1c
• Peut être envisagé chez les diabétiques connus, le plus tôt possible avant la chirurgie (de préférence, sitôt le patient adressé au chirurgien) si les résultats sont susceptibles de modifier la prise en charge du patient.
Test de grossesse En fonction des lignes directrices propres à l'établissement
• Devrait être proposé aux femmes en âge de procréer en fonction de la probabilité raisonnable de grossesse, de la fiabilité de l'historique des menstruations et si le résultat est susceptible d'annuler ou modifier la procédure ou la prise en charge de l'anesthésie.
• La possibilité d'effectuer un test urinaire ou sanguin au point de service est l'idéal et donc recommandée.
# É lectrocardiogramme
• Peut être envisagé chez les patients avec une coronaropathie, une arythmie significative, une maladie vasculaire périphérique ou toute autre cardiopathie importante connue ou soupçonnée.
• Peut être envisagé en l'absence de symptômes ou de maladie cardiovasculaire connue chez les patients devant subir une chirurgie à risque intermédiaire ou élevée en présence de facteurs de risque cliniques (par ex. Index de risque cardiaque révisé (RCRI), ou Calculateur de risque chirurgical de l'American College of Surgeons).
Le peptide cérébral natriurétique (BNP ou NT-pro BNP) peut être envisagé si :
• le patient est âgé ‡ 65 ans,
• le patient est âgé de 45-65 ans et a une condition cardiaque significative,
• le patient a un score à l'Index cardiaque de risque révisé ‡ 1.
É chocardiographie au repos • Peut être envisagée si l'évaluation clinique suggère une anomalie intracardiaque obstructive sévère et non diagnostiquée, une cardiomyopathie ou une hypertension pulmonaire sévère.
# TEST INDICATIONS
Radiographie pulmonaire • Non recommandée chez les patients asymptomatiques dans le cadre de l'évaluation préopératoire de routine, à moins que cet examen ne fasse partie d'un bilan chirurgical ou oncologique non lié à l'évaluation du risque périopératoire.
• Peut être envisagée chez les patients souffrant de maladie cardiopulmonaire aiguë ou chronique en fonction de leurs antécédents et de l'examen physique, si cela modifiera la prise en charge.
# Lignes directrices concernant le jeûne
Les règles concernant le jeûne devraient varier en fonction de l'âge du patient et de ses antécédents médicaux et s'appliquer à toutes les formes d'anesthésie, incluant la sédation procédurale (voir Annexe 6). 1 Les interventions très urgentes ou urgentes doivent être réalisées après avoir examiné les risques qu'entrâınerait leur report comparativement au risque d'aspiration du contenu de l'estomac. Le type et la quantité de nourriture absorbée doivent être pris en considération pour déterminer la durée du jeûne. Avant une intervention non urgente, la durée minimale du jeûne devait être de :
• Huit heures après un repas copieux comportant des aliments solides, particulièrement s'il contenait des protéines (par ex. de la viande) ou des aliments gras; • Six heures après un repas léger (par ex. repas faible en gras tel une tartine); • Six heures après l'ingestion de lait maternisé, de lait non humain ou de lait maternel tiré et fortifié avec des adjuvants; • Quatre heures après l'ingestion de lait maternel;
• Deux heures après l'ingestion de liquides clairs pour un adulte; • Une heure après l'ingestion de liquides clairs pour les nourrissons ou les enfants.
Sauf contre-indication, il convient d'encourager les adultes et les enfants à boire des liquides clairs (eau, jus sans pulpe, boissons à base de sucres complexes et thé ou café noir) jusqu'à deux heures avant une chirurgie non urgente. Les patients pédiatriques devraient également être encouragés à boire des liquides clairs, tels que définis, jusqu'à une heure avant une chirurgie non urgente.
Les conditions retardant la vidange gastrique nécessitent une évaluation au cas par cas du patient. Ces recommandations peuvent être modifiées à la discrétion du médecin.
Lorsqu'elle est indiquée, la prémédication devrait être ordonnée par l'anesthésiologiste. Les ordonnances doivent spécifier la dose, le moment et la voie d'administration.
Un antagoniste des récepteurs H2 (par voie orale ou intraveineuse) est recommandé pour toutes les femmes devant subir un accouchement par césarienne.
Trente (30) mL de citrate de sodium (0,3 molaire) sont recommandés avant un accouchement par césarienne urgent si l'on planifie une anesthésie générale.
Voir la Section 7.3 pour les recommandations de jeûne spécifiques aux patientes en travail actif.
# Règlementations supplémentaires
Des lois provinciales ou la règlementation de l'établissement pourraient prescrire d'autres directives régissant l'administration de l'anesthésie.
5 La période anesthésique
# Préparation à l'anesthésie
Avant le début de l'anesthésie, l'anesthésiologiste doit s'assurer que 1. La procédure anesthésique prévue a été expliquée au patient, y compris les risques reconnus et les techniques alternatives, et on a documenté cette explication; 2. Une évaluation adaptée de l'état du patient a été réalisée; 3. Tout le matériel qu'on prévoit nécessaire est accessible et en bon état de fonctionnement, y compris le matériel nécessaire au maintien de la température centrale (température centrale du patient 36-37°C); 4. On a accès à une source de réserve d'oxygène sous pression; 5. Tous les médicaments et agents qu'on prévoit nécessaires sont correctement identifiés -les étiquettes de médicament apposées par l'usager doivent être conformes à la norme de la CSA CAN/ CSA -Z264.3-98 (R2005) (Annexe 1); 6. Si des connecteurs Luer neuraxiaux sont utilisés, les deux côtés des raccords Luer doivent être étiquetés. Il faut envisager l'utilisation de connecteurs neuraxiaux conformes à la norme ISO 80369-6:2016connecteurs de petit diamètre interne pour application neuraxiale (raccords NRFitÒ) en fonction des disponibilités des fournisseurs de matériel; et 7. On a tenu compte des indications du fabricant quant à l'utilisation, à la manipulation et à la disposition de l'équipement et du matériel d'anesthésie.
# Prise en charge des voies aériennes
La prise en charge des voies aériennes, particulièrement en cas de voies aériennes difficiles, contribue significativement à la morbidité et à la mortalité liées à l'anesthésie.
Une prise en charge adaptée des patients dont l'intubation est difficile, de manière prévue ou imprévue, chez lesquels l'intubation a échoué, lorsqu'une ventilation au masque ou le positionnement d'un dispositif supraglottique pourrait être difficile, ou qui nécessitent des voies aériennes chirurgicales, est essentielle à la sécurité des patients. Cette prise en charge comprend, sans nécessairement s'y limiter, une évaluation adaptée des voies aériennes, du matériel (par ex. chariots pour les voies aériennes difficiles, vidéolaryngoscopes, bronchoscopes), une formation et des exercices de simulation appropriés, du personnel de soutien et le recours aux protocoles et listes de contrôle adéquats afin de prendre en charge au mieux des voies aériennes difficiles. La SCA ne recommande pas un protocole, un algorithme ou une liste de contrôle en particulier pour la prise en charge des voies aériennes difficiles ou lors d'un échec d'intubation, mais elle encourage fortement les lecteurs à se référer à l'Annexe 4 pour accéder aux publications les plus récentes sur le sujet.
# Délégation des soins aux patients
L'anesthésiologiste est avant tout responsable du patient qu'il a sous ses soins. L'anesthésiologiste ou un assistant en anesthésie supervisé par l'anesthésiologiste doit demeurer constamment aux côtés du patient pour toute la durée d'une anesthésie générale, régionale majeure et intraveineuse monitorée, jusqu'à ce que le patient ait été confié aux soins du personnel de l'unité de soins compétente.
Si l'anesthésiologiste traitant quitte temporairement la salle d'opération, il doit confier les soins du patient à un autre anesthésiologiste, à un résident en anesthésie ou à un assistant en anesthésie. Lorsque l'anesthésiologiste traitant délègue les soins à un résident en anesthésie ou à un assistant en anesthésie, il demeure responsable de la prise en charge anesthésique du patient. Avant de déléguer les soins du patient à un assistant en anesthésie, l'anesthésiologiste doit s'assurer que l'état du patient est stable et que l'assistant en anesthésie est familier avec l'intervention chirurgicale ainsi qu'avec l'environnement et le matériel de la salle d'opération. L'anesthésiologiste traitant doit demeurer immédiatement disponible lorsque les soins sont délégués à un assistant en anesthésie.
Un anesthésiologiste peut brièvement confier les soins courants d'un patient dont l'état est stable à une personne compétente qui n'est pas un assistant en anesthésie qu'en cas de circonstances particulièrement exceptionnelles, pour se porter par exemple au secours d'un autre patient dont la vie est en danger. L'unique responsabilité de cette personne devrait être de surveiller le patient en l'absence de l'anesthésiologiste et de tenir l'anesthésiologiste informé jusqu'à son retour. Dans de telles circonstances, l'anesthésiologiste demeure responsable des soins prodigués au patient et se doit de tenir l'équipe de la salle d'opération au courant.
Le transfert peropératoire des soins entre deux anesthésiologistes doit être noté au dossier d'anesthésie et se conformer à un protocole structuré.
Il est inacceptable qu'un anesthésiologiste administre simultanément une anesthésie générale, une anesthésie régionale majeure (rachidienne, péridurale ou autre) ou une sédation procédurale profonde (voir Annexe 6) 1 pour des interventions diagnostiques ou thérapeutiques concomitantes pratiquées sur plus d'un patient à la fois. Toutefois, il peut être admis, dans des circonstances particulières, qu'un anesthésiologiste supervise plus d'un patient chez lequel une sédation minime à modérée est administrée, à condition qu'un individu ayant reçu une formation adéquate, qualifié, accrédité et approuvé par le service d'anesthésiologie et l'établissement de santé, soit constamment présent auprès de chaque patient recevant des soins. Il sera par contre admis, dans un service d'obstétrique, de surveiller simultanément plus d'une patiente à laquelle est administrée une analgésie régionale pour le travail. Chaque parturiente devra cependant être surveillée adéquatement par une personne compétente, suivant un protocole établi. Lorsqu'un anesthésiologiste dispense des soins anesthésiques en vue d'un accouchement, une deuxième personne dûment formée doit se tenir prête à intervenir pour pratiquer la réanimation néonatale.
Il est inacceptable qu'un seul médecin administre une anesthésie y compris la sédation procédurale profonde simultanément à la réalisation d'une procédure diagnostique ou thérapeutique, exception faite des interventions réalisées par seule infiltration d'anesthésiques locaux et/ou une sédation minimale.
# Monitorage du patient
Le seul moniteur indispensable est la présence, à tous les instants, d'un médecin ou d'un assistant en anesthésie placé sous la supervision immédiate d'un anesthésiologiste et détenant la formation et l'expérience appropriées. Les moniteurs mécaniques et électroniques ne sont, au mieux, que des aides à la vigilance. Ces appareils aident l'anesthésiologiste à s'assurer de l'intégrité des organes vitaux et, en particulier, de la perfusion et de l'oxygénation satisfaisantes des tissus. Le matériel de monitorage doit être utilisé comme prévu par le fabricant et approuvé par Santé Canada pour l'application spécifique.
Il incombe à l'établissement de soins de santé de fournir et d'entretenir un équipement de monitorage qui respecte les normes en vigueur.
Il incombe au chef du département d'anesthésie de conseiller l'établissement de soins de santé au sujet de l'acquisition de l'équipement de monitorage et d'établir les normes de monitorage qui aideront à assurer la sécurité du patient.
Il incombe à l'anesthésiologiste de monitorer le patient qui est sous ses soins et de s'assurer que l'équipement de monitorage approprié soit disponible et fonctionne correctement. Une feuille de vérification préanesthésique (Annexe 3 ou équivalent) doit être remplie avant l'amorce de l'anesthésie.
Une posologie prudente, un monitorage vigilant et la neutralisation adéquate des bloqueurs neuromusculaires sont des éléments essentiels à la sécurité des patients. Un monitorage neuromusculaire doit être utilisé lors de l'administration de bloqueurs neuromusculaires. Les directives de monitorage pour les soins standard aux patients s'appliquent à tous les patients recevant une anesthésie générale, une anesthésie régionale ou une sédation intraveineuse.
# Matériel de monitorage requis
Le matériel de monitorage est catégorisé comme suit : • Requis : Ces moniteurs doivent être utilisés sans interruption pendant toute la durée de l'administration de toute anesthésie. • Accessible en exclusivité pour chaque patient : Ces moniteurs doivent être accessibles à chaque poste de travail d'anesthésie, de sorte qu'ils puissent être utilisés sans délai. • À portée immédiate : Ces moniteurs doivent être accessibles afin de faciliter leur utilisation sans délai indu.
Le matériel de monitorage suivant est requis : • Un saturomètre; • Un appareil permettant de mesurer la tension artérielle, directement ou sans effraction; • Un électrocardiographe; • Un moniteur de bloc neuromusculaire lors de l'utilisation de bloqueurs neuromusculaires;
• Un capnographe, pour l'anesthésie générale et pour évaluer le caractère adéquat de la ventilation pour une sédation modérée ou une sédation procédurale profonde; et • Un moniteur de gaz anesthésiques spécifique à l'agent, lorsque des agents anesthésiques par inhalation sont utilisés.
Le matériel de monitorage suivant doit être accessible en exclusivité pour chaque patient :
• Un appareil pour mesurer la température;
• Un stimulateur des nerfs périphériques, lors de l'utilisation de bloqueurs neuromusculaires; • Un stéthoscope -précordial, oesophagien ou paratrachéal; et • Un éclairage suffisant pour visualiser une partie exposée du patient.
Le matériel de monitorage suivant sera à portée immédiate :
• Un spiromètre pour mesurer le volume respiratoire;
• Un manomètre pour mesurer la pression du ballonnet du tube endotrachéal. • Le matériel pour un monitorage hémodynamique invasif si indiqué (p. ex., ligne artérielle, cathéter veineux central).
L'anesthésiologiste doit demeurer vigilant en tout temps, étant conscient que de brèves interruptions du monitorage continu peuvent être inévitables et que, dans certaines circonstances, un moniteur pourrait faire défaut. Les alarmes audibles et visuelles du saturomètre et du capnographe ne devraient pas être désactivées indéfiniment pendant le déroulement d'une anesthésie, sauf en cas de circonstances inhabituelles. L'alarme à tonalité variable, celle des pulsations cardiaques et l'alarme de seuil inférieur du saturomètre ainsi que l'alarme d'apnée du capnographe doivent émettre un signal audible et visible.
# Dossiers
Toutes les variables physiologiques monitorées doivent être enregistrées à intervalles réguliers en fonction des circonstances cliniques. La fréquence cardiaque et la tension artérielle doivent être enregistrées au minimum toutes les cinq minutes. La saturation en oxygène doit être monitorée en continu et devrait être enregistrée à intervalles fréquents, au minimum toutes les cinq minutes, chez tous les patients. La concentration en dioxyde de carbone (PCO2) télé-expiratoire doit être monitorée en continu et enregistrée à intervalles fréquents en cas d'intubation trachéale ou si un dispositif supraglottique est en place. On doit documenter au dossier anesthésique toute raison pour laquelle on déroge à ces directives de tenue de dossier. Les types de moniteurs, le matériel et les techniques, ainsi que l'heure, la posologie et la voie d'administration de tout médicament et liquide devraient être notés. Tous les autres soins et événements anesthésiques peropératoires pertinents, y compris les événements imprévus ou indésirables, devraient également être enregistrés.
Le dossier de santé du patient doit inclure le niveau de conscience du patient, sa fréquence cardiaque, sa tension artérielle, sa saturation en oxygène et sa fréquence respiratoire tels que mesurés à l'arrivée en salle de réveil. Ces recommandations s'appliquent tant aux dossiers anesthésiques manuscrits qu'à ceux créés via des systèmes électroniques de gestion de l'information en anesthésie (SGIA). À l'heure actuelle, il n'existe aucune norme de pratique indiquant quelles données supplémentaires (par ex. données d'analyse de gaz, de ventilation et respiratoires) potentiellement récoltées par un système de dossier de SGIA devraient faire partie du dossier de santé permanent d'un patient.
Il a été démontré que les SGIA pouvaient avoir des avantages potentiels par rapport aux dossiers rédigés à la main dans plusieurs domaines clés, notamment en augmentant la lisibilité, la précision et la fiabilité des dossiers anesthésiques, en créant des données interrogeables favorisant l'amélioration de la qualité, la communication des résultats et de la performance, la recherche translationnelle, une meilleure innocuité et un meilleur suivi des médicaments, ainsi qu'un suivi et un soutien à la décision clinique en temps réel pour les utilisateurs. La littérature sur la sécurité des patients en anesthésie appuie l'utilisation des SGIA. Il est important de mentionner que les SGIA permettent de créer une base de données de patients longitudinale, de telle manière que les antécédents anesthésiques importants des patients soient facilement trouvables si l'on veut les passer en revue, ce qui devrait être considéré comme une propriété importante pour tout système. La SCA ne promeut ni n'endosse un fournisseur ou un produit en particulier, mais elle reconnâıt les avantages potentiels d'un SGIA bien conçu et mis en oeuvre par rapport à des dossiers complétés manuellement là ou' les ressources institutionnelles et du département d'anesthésie permettent d'envisager l'implantation d'un SGIA. Dans l'idéal, ce système devrait être mis en oeuvre et géré en coopération avec le département des technologies de l'information de l'établissement, et devrait permettre la communication avec les autres bases de données électroniques de patients de l'établissement dans la mesure du possible.
6 La période postanesthésique 6.1 La salle de réveil Une salle de réveil doit être disponible dans tout établissement offrant des services anesthésiques. Des politiques administratives conformes aux règlements de l'établissement devront être appliquées de façon à coordonner les responsabilités des soins médicaux et infirmiers.
Le département d'anesthésie devrait endosser l'ensemble de la responsabilité administrative médicale pour la salle de réveil. Il devrait exister un manuel des politiques de la salle de réveil approuvé par les autorités médicales, infirmières et administratives compétentes.
L'anesthésiologiste devrait accompagner le patient en salle de réveil, transmettre les renseignements nécessaires au personnel infirmier de la salle de réveil dans le cadre d'un transfert structuré du protocole de soins, et rédiger les ordonnances nécessaires. Le monitorage continu des patients est recommandé pendant la phase périopératoire en fonction de la situation clinique. Si cliniquement indiqué, de l'oxygène supplémentaire, une oxymétrie de pouls portable et d'autres dispositifs de monitorage adaptés doivent être utilisés pendant le transfert vers la salle de réveil ou l'USI. Si de l'oxygène supplémentaire est administré à des patients intubés pendant le transport ou en salle de réveil, afin de minimiser tout risque de barotraumatisme, il est fortement recommandé de ne le fournir qu'avec des dispositifs approuvés pour cette application spécifique. L'anesthésiologiste ne devrait déléguer les soins du patient à l'infirmier ou l'infirmière de la salle de réveil que lorsqu'il est assuré que le personnel infirmier pourra adéquatement observer et prendre soin du patient. L'anesthésiologiste ou un anesthésiologiste remplaçant désigné est responsable des soins postanesthésiques en salle de réveil. Le congé de la salle de réveil est sous la responsabilité de l'anesthésiologiste; cette responsabilité peut être déléguée en accord avec les politiques de l'établissement.
Une source d'oxygène d'appoint et une succion doivent être disponibles pour chaque patient en salle de réveil. Le matériel d'urgence nécessaire à la prise en charge des voies aériennes, la réanimation et au support vital doit être disponible en salle de réveil. Le matériel pour la prise en charge de voies aériennes difficiles doit être à portée immédiate en salle de réveil. Le monitorage utilisé en salle de réveil doit être adapté à l'état du patient et un éventail complet d'appareils de monitorage doit être disponible. Les alarmes des moniteurs doivent être en fonction, avec des paramètres d'alarme adaptés à l'état et à l'âge du patient. L'utilisation continue d'un saturomètre est requise pendant la phase initiale de récupération. Un capnographe est requis pour les patients intubés ou sous sédation profonde et est recommandé pour les patients inconscients ayant des dispositifs supraglottiques in situ dans les voies aériennes. Un moniteur d'apnée est recommandé chez les nourrissons prématurés et ayant un âge gestationnel de moins de 50 semaines.
Un dossier détaillé de la période immédiate de réveil doit être tenu. Celui-ci doit inclure un enregistrement des signes vitaux ainsi que des autres aspects du traitement et de l'observation. Cette feuille d'observation fait partie du dossier médical permanent. Toute complication ayant un lien avec l'anesthésie doit être notée sur la feuille de la salle de réveil ou dans les notes d'évolution du dossier du patient. Dans certaines situations, il peut être acceptable de transférer un patient directement vers d'autres unités de soins ou de passer outre la salle de réveil si un niveau de soins adapté est disponible dans une autre unité de l'établissement et s'il est noté au dossier anesthésique que le patient est jugé apte à ce transfert.
# Congé des patients après chirurgie d'un jour
Le congé des patients après une chirurgie ambulatoire doit se faire en utilisant un plan formel de soins approuvé par l'institution et documenté dans les notes de soins prodigués aux patients. Les patients doivent satisfaire les critères de congé au domicile en utilisant un outil d'évaluation validé (p. ex., le système de cotation de congé post-anesthésie [PADSS]). La prise en charge de la douleur et des complications postopératoires, ainsi que le suivi de routine et d'urgence, doivent tous faire l'objet d'instructions écrites spécifiques. Le patient doit être averti au sujet des synergies additives qu'il existe entre l'alcool et d'autres sédatifs, du danger de conduire ou d'utiliser des machines dangereuses dans la période postopératoire (dans la plupart des cas durant les 24 heures suivant l'opération), et de la nécessité d'attention de la part d'un adulte compétent dans la période postopératoire (dans la plupart des cas durant les 24 heures suivant l'opération).
# Lignes directrices pour l'analgésie régionale en obstétrique
Les services d'anesthésie destinés aux parturientes comprennent l'analgésie obstétricale pour le travailpour l'accouchement avec ou sans complication -ou pour les césariennes. Toutes les directives visant l'anesthésie administrée pour toute autre intervention diagnostique ou thérapeutique s'appliquent également à l'anesthésie obstétricale. Les directives de la présente section portent sur l'analgésie péridurale et la rachianesthésie pendant le travail. L'expression « analgésie régionale » désigne l'analgésie péridurale, la rachianesthésie et la combinaison des deux.
Ces directives sont passées en revue chaque année par la Section d'anesthésie obstétricale de la SCA et mises à jour au besoin. Chaque établissement peut décider d'élaborer des directives ou politiques supplémentaires pour des situations spécifiques dans lesquelles une analgésie régionale obstétricale est dispensée.
Sous la direction d'un anesthésiologiste, certains aspects du monitorage et de la prise en charge de l'analgésie régionale obstétricale peuvent être délégués à d'autres membres du personnel de santé. Chaque établissement doit s'assurer que ces personnes reçoivent les mêmes formation, certification, formation continue et recertification en analgésie régionale en obstétrique. Chaque département d'anesthésiologie devrait établir ses propres politiques concernant la disponibilité jugée adaptée d'un anesthésiologiste pour prendre en charge les complications potentielles liées à l'analgésie régionale pour le travail obstétrical et l'accouchement.
Des systèmes de sécurité doivent exister pour protéger les mélanges d'anesthésiques locaux périduraux contenant des substances contrôlées (par ex. des opiöıdes) de façon à minimiser les risques de détournement.
# Absorption orale pendant le travail
La vidange gastrique des aliments solides est retardée pendant le travail, et les analgésiques opiöıdes peuvent la retarder encore davantage. Par conséquent, on devrait généralement décourager les parturientes d'ingérer des aliments solides pendant le travail actif. Contrairement aux aliments solides, les liquides clairs sont éliminés relativement rapidement de l'estomac pendant le travail. Ainsi, en règle générale, on devrait permettre aux parturientes d'ingérer des liquides clairs comme elles le souhaitent pendant le travail actif. Chaque établissement devrait élaborer des protocoles concernant l'absorption d'aliments solides et de liquides clairs par les femmes en travail actif.
8 Lignes directrices pour la prise en charge de la douleur aiguë à l'aide de l'analgésie neuraxiale Lorsque l'analgésie neuraxiale est prise en charge par des anesthésiologistes, l'incidence d'effets secondaires n'est pas plus élevée que lorsque des techniques alternatives de prise en charge de la douleur sont utilisées. En conséquence, lorsque son utilisation est indiquée, l'analgésie neuraxiale devrait être prise en charge par les anesthésiologistes.
Aux fins de ce guide, l'analgésie neuraxiale se définit comme l'administration intrathécale ou péridurale d'opiöıdes et/ou d'anesthésiques locaux en vue du traitement de la douleur postopératoire ou d'autres problèmes de douleur aiguë. Ce guide vise à fournir aux anesthésiologistes les principes de prise en charge afin que l'analgésie neuraxiale soit pratiquée de manière à en maximiser les avantages et en minimiser les risques. Le risque d'erreurs attribuables à une voie impropre d'injection du médicament doit être minimisé. Pour des perfusions continues ou une APCP, l'emploi de pompes inviolables distinctes de celles utilisées pour l'administration de solutés ou de médicaments est vivement recommandé. La tubulure entre les pompes de perfusion de l'analgésie neuraxiale et les cathéters ne devrait comporter aucun orifice susceptible de permettre une injection non intentionnelle de médicaments intraveineux.
La préparation des solutions devrait suivre une procédure standardisée. Toutes les solutions analgésiques devraient porter une étiquette indiquant la composition de la solution (opiöıde, anesthésique local, ou les deux) ainsi que la voie d'administration appropriée. Dans le cas d'une administration péridurale, cela doit inclure la date et l'heure de la préparation ainsi que le nom de la personne l'ayant préparée.
# Monitorage des patients et prise en charge des évènements indésirables
Les patients auxquels est administrée une analgésie neuraxiale devraient être placés dans une chambre équipée d'oxygène et de succion. Des médicaments et du matériel de réanimation doivent être à portée immédiate. L'accès intraveineux doit être établi avant d'amorcer l'analgésie neuraxiale et, après cessation de l'analgésie neuraxiale, maintenu pendant toute la durée prévue des effets médicamenteux.
Le pansement qui maintient en place le cathéter péridural doit permettre l'examen du cathéter pour détecter tout mouvement et permettre l'inspection quotidienne du point d'entrée afin de déceler tout signe d'infection.
L'adoption de politiques standardisées au chapitre de la prise en charge des patients est préconisée. Les paramètres qu'il convient d'évaluer, la fréquence des évaluations, la documentation et les procédures de prise en charge des complications devraient être précisés. Un personnel de soins infirmiers en nombre suffisant doit être présent pour évaluer et prendre en charge les patients recevant une analgésie neuraxiale. Le monitorage devrait se poursuivre après cessation de l'analgésie neuraxiale jusqu'à ce que ses effets se soient dissipés.
Un anesthésiologiste doit être immédiatement disponible afin de conseiller le personnel infirmier sur des aspects tels que le titrage de la dose et la prise en charge des effets indésirables. Chaque établissement doté d'un service de traitement de la douleur aiguë doit veiller à ce qu'un anesthésiologiste soit disponible pour s'occuper directement des patients recevant une analgésie neuraxiale dans un délai approprié en fonction de la situation clinique. Chaque établissement devrait également déterminer les procédures en vue d'une prise en charge urgente de toute complication menaçant le pronostic vital. D'autres médicaments, notamment les benzodiazépines ou les opiöıdes parentéraux, peuvent causer une dépression respiratoire majeure chez les patients recevant une analgésie neuraxiale. Pour cette raison, les autres médecins ne devraient pas prescrire de sédatifs ou d'analgésiques à tout patient recevant une analgésie neuraxiale. Le service de traitement de la douleur aiguë devrait demeurer en charge de la thérapeutique analgésique et sédative jusqu'à dissipation des effets de l'analgésie neuraxiale. 9 Lignes directrices pour l'exercice de l'anesthésie dans les lieux isolés Les principes fondamentaux, les exigences de formation, les techniques, le matériel et les médicaments utilisés pour la pratique de l'anesthésie dans les lieux isolés ont été documentés dans d'autres sections de ce Guide. Ils s'appliquent également aux soins anesthésiques, notamment à la sédation consciente (voir Annexe 6) dispensée par un anesthésiologiste dans toute salle d'opération ou emplacement hors de la salle d'opération, tant à l'intérieur d'un établissement hospitalier qu'à l'extérieur (par ex. bureaux, cliniques). 9.1 Soins anesthésiques dispensés dans un établissement médical/chirurgical/dentaire non hospitalier
# Se´lection des patients
Le statut physique des patients devrait être catégorisé selon le score de l'American Society of Anesthesiologists (ASA). D'une manière générale, seuls les patients des classes ASA I et II devraient être retenus pour subir une intervention. Les patients de statut ASA III pourraient être acceptés sous certaines conditions, mais seulement à la discrétion de l'anesthésiologiste en charge. Il faut faire preuve de prudence lors de la sélection de patients présentant des voies aériennes difficiles connues.
# Conside´rations pre´ope´ratoires
Une histoire de cas et un examen physique récents, incluant un examen des voies aériennes, devraient paraître au dossier du patient, ainsi que les résultats des examens de laboratoire appropriés. Ces examens peuvent être exécutés par un autre médecin (par ex. un 'procéduraliste', soit un médecin/chirurgien compétent pour réaliser des interventions diagnostiques ou thérapeutiques), mais l'existence d'un processus de sélection mis au point et endossé par les services anesthésiques est fortement recommandée. La durée du jeû ne devrait être conforme à la section 4.2 Lignes directrices concernant le jeuˆne.
# Conduite de l'anesthe´sie
Les installations des salles d'anesthésie et de réveil doivent être conformes aux normes hospitalières établies par la CSA (voir Annexe 1) et à toutes les lignes directrices de la SCA établies pour les soins aux patients. Le patient devrait recevoir son congé de l'hôpital pour rentrer à la maison en utilisant un système de notation validé évaluant son aptitude au congé (par. ex. Système de cotation de congé postanesthésique). Les patients devraient recevoir des instructions écrites concernant les périodes préopératoire et postopératoire. 9.2 Soins anesthésiques dispensés hors de la salle d'opération dans un hôpital ou un établissement non hospitalier En raison des avancées technologiques et de la plus grande disponibilité d'interventions moins invasives mais potentiellement douloureuses, la demande pour la fourniture de soins anesthésiques à l'extérieur de la salle d'opération (par ex., endoscopie, radiologie interventionnelle, cathétérisation cardiaque) croît. La fourniture de soins anesthésiques dans ces unités interventionnelles éloignées peut s'accompagner de défis particuliers pour l'équipe de soins anesthésiques (p. ex., les patients pourraient avoir un statut ASA III-IV et d'importantes comorbidités), et ces unités pourraient se trouver à une certaine distance des salles d'opération et du personnel de soutien, voire à l'extérieur d'un établissement hospitalier. Les unités d'intervention dans lesquelles les anesthésiologistes sont appelés à fournir des soins devraient se conformer, dans la mesure du possible, aux mêmes normes de la CSA (Annexe 1), lignes directrices concernant le matériel d'anesthésie (voir section 3.0), et lignes directrices générales de la SCA qu'une salle d'opération. Cela comprend, sans s'y limiter, la sélection et l'évaluation des patients, les examens pré-procéduraux, les lignes directrices concernant le jeû ne, le matériel et les prises électriques, l'oxygène et la succion, la ventilation et l'évacuation des agents volatils si utilisés, les médicaments et le matériel nécessaires à la réanimation, le monitorage du patient, les installations de rétablissement et le personnel de soutien en anesthésie. Tout lieu où des anesthésiologistes fournissent des soins en dehors d'une salle d'opération doit être approuvé par la direction de l'anesthésie dans l'établissement. Du personnel de soutien en anesthésie adéquatement formé et expérimenté, par exemple un assistant en anesthésie (voir section 2.5) ou d'autres personnes ayant de l'expérience dans le soutien en anesthésie, devrait être présent ou immédiatement disponible pour assister l'anesthésiologiste dans les lieux isolés. Il ne convient pas de dépendre exclusivement du personnel de l'unité chirurgicale pour soutenir l'anesthésie, à moins que ce personnel ne soit formé et ait de l'expérience dans le soutien direct de la fourniture de soins anesthésiques et qu'il ait reçu l'aval de la direction de l'anesthésie. Une communication bidirectionnelle fiable doit être disponible pour que le prestataire d'anesthésie ait accès à de l'aide et du soutien si nécessaire.
Remerciements Nous tenons à remercier les anciens membres du Comité des normes de pratique de l'anesthésie qui ont apporté leurs contributions à des versions antérieures de ce Guide. Le Comité tient à remercier since'rement le Dr Hilary P. Grocott pour son aide majeure pendant son mandat en tant que rédacteur en chef du JCA.
Conflits d'intérêts Tous les auteurs de cet article font partie du Comité des normes de la Société canadienne des anesthésiologistes (SCA). Aucun des auteurs n'a un quelconque intérêt financier ou commercial lié aux sociétés ou fabricants d'appareils médicaux dont il est fait mention dans cet article ou dans les annexes associées. Dr Gregory Dobson est président du Comité des normes de la SCA. Annexe 4: Lignes directrices, normes et autres énoncés officiels disponibles sur l'internet L'Annexe 4 (disponible au : http://www.cas.ca/Francais/ Guide-d-exercice) offre une liste non exhaustive de sites contenant des déclarations officielles promulguées par d'autres associations médicales au Canada et ailleurs dans le monde. Cette liste est fournie aux membres de la SCA uniquement à des fins pratiques. La SCA n'est pas responsable de l'exactitude, de la mise à jour ou de la fiabilité du contenu de ces sites. La SCA n'offre aucune garantie à cet effet. Elle se dégage de toute responsabilité concernant l'information trouvée par le biais de ces liens et n'endosse pas nécessairement ces sites ou leur contenu. Cette liste contient l'adresse de sites qui sera mise à jour de façon périodique.
#
Acknowledgements Contributions to earlier versions of the Guidelines from former members of the Committee on Standards to the Practice of Anesthesia are gratefully acknowledged. The Committee wishes to gratefully acknowledge the tremendous support provided by Dr. Hilary P. Grocott during his term as the CJA Editor-in Chief.
#
Competing interests All authors of this article are members of the Standards Committee of the Canadian Anesthesiologists' Society (CAS). None of the authors have any financial or commercial interest relating to the companies or manufacturers of medical devices referenced either in this article or in the related appendices. Dr. Gregory Dobson is Chair of the Committee on Standards of the CAS.
# Appendix 1: Canadian Standards Association-Standards for Equipment
Available as Electronic Supplementary Material. Appendix 4 (available at: http://www.cas.ca/English/ Guidelines) provides a non-exhaustive list of sites with official statements promulgated by other related medical organizations both in Canada and worldwide. This list is provided solely for the convenience of CAS members. The CAS is not responsible for the accuracy, currency, or reliability of the content. The CAS does not offer any guarantee in this regard. It is not responsible for the information found through these links and does not necessarily endorse the sites or their content. This list includes sites that are updated periodically.
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# THROMBOPROPHYLAXIS: HOSPITALIZED MEDICAL PATIENTS OBJECTIVE:
To review the risk factors for venous thromboembolism (VTE) and bleeding in acutely ill hospitalized medical patients and to recommend thromboprophylaxis options based on the risks of thrombosis and bleeding.
# BACKGROUND:
VTE is a frequent cause of preventable morbidity and mortality in patients hospitalized with medical illness, and 1-3% of patients admitted to hospital will suffer a complication of VTE during hospitalization. Thromboprophylaxis in medically-ill patients has been shown to be safe and effective.
The risk of developing VTE is affected by a patient's underlying medical condition as well as the presence of other co-morbidities. Risk factors for VTE in medically ill patients include: age >70 years, previous VTE, immobility ≥3 days, stroke, acute spinal cord injury, active cancer, known thrombophilia, sepsis, acute inflammatory conditions, acute infectious disease, obesity (body mass index >30), hormone therapy, intensive care unit admission, and respiratory or cardiac failure.
The risk of developing bleeding is significantly increased if the patient has an active gastroduodenal ulcer, previous bleeding (<3 months before hospitalization), advanced age, severe renal failure (creatinine clearance <30 mL/min), hepatic failure, active cancer, low platelet count (<50 × 10 9 /L), or planned surgery in the next 6 to 12 hours. There are few externally validated models for predicting bleeding risk in hospitalized medical patients. One such model is the IMPROVE bleeding risk score.
Decisions regarding anticoagulant thromboprophylaxis in acutely-ill hospitalized medical patients should be made after consideration of risk factors for both VTE and bleeding. A number of scoring systems have been studied to estimate risk of VTE in hospitalized medical patients including the IMPROVE-DD risk score, the Padua Prediction Score, and the GENEVA risk score. Computerized riskassessment tools should be implemented wherever feasible to increase the net clinical benefit from thromboprophylaxis and avoid unnecessary provision of thromboprophylaxis to patients at low risk. From a population perspective, a recent Markov model suggests that prophylaxis was cost-effective for an average medical inpatient with a VTE risk of ≥1.0%.
# OPTIONS FOR THROMBOPROPHYLAXIS:
Acutely ill hospitalized medical patients at increased risk of VTE who are not bleeding or at high risk of bleeding should receive anticoagulant thromboprophylaxis generally with a subcutaneous (SC) low molecular weight heparin (LMWH):
- dalteparin 5,000 units SC daily
- enoxaparin 40 mg SC daily - tinzaparin 4,500 units SC daily - fondaparinux 2.5 mg SC daily Unfractionated heparin (UFH) 5,000 units SC twice daily may also be a consideration. However, LMWH is preferred over UFH because of less frequent dosing and lower risk of heparin-induced thrombocytopenia (HIT).
Acutely ill hospitalized medical patients at low risk of VTE and those who are bleeding or at high risk of bleeding should not receive anticoagulant thromboprophylaxis. In this latter situation, properly measured and fitted elastic compression stockings (ECS) or intermittent pneumatic compression (IPC) devices should be used. When the bleeding risk decreases, one of the anticoagulant thromboprophylaxis options above should be started.
# SPECIAL CONSIDERATIONS:
- Direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban): These agents should generally not be used for prophylaxis in medically ill hospitalized patients, due to a lack of data to date to support their effectiveness and safety in this patient population.
- Duration of prophylaxis: Anticoagulant thromboprophylaxis should generally continue until acute care hospital discharge and not be extended beyond the period of hospitalization.
- Under-and over-weight: Dose reduction should be considered for patients with weight 100 kg. For patients weighing over 120 kg, even higher doses should be considered.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Cancer and Thrombosis - Central Venous Catheter-Related Deep Venous Thrombosis - Unfractionated Heparin, Low Molecular Weight Heparin and Fondaparinux
# Date of Version: 18October2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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# THROMBOPROPHYLAXIS: HOSPITALIZED MEDICAL PATIENTS OBJECTIVE:
To review the risk factors for venous thromboembolism (VTE) and bleeding in acutely ill hospitalized medical patients and to recommend thromboprophylaxis options based on the risks of thrombosis and bleeding.
# BACKGROUND:
VTE is a frequent cause of preventable morbidity and mortality in patients hospitalized with medical illness, and 1-3% of patients admitted to hospital will suffer a complication of VTE during hospitalization. Thromboprophylaxis in medically-ill patients has been shown to be safe and effective.
The risk of developing VTE is affected by a patient's underlying medical condition as well as the presence of other co-morbidities. Risk factors for VTE in medically ill patients include: age >70 years, previous VTE, immobility ≥3 days, stroke, acute spinal cord injury, active cancer, known thrombophilia, sepsis, acute inflammatory conditions, acute infectious disease, obesity (body mass index >30), hormone therapy, intensive care unit admission, and respiratory or cardiac failure.
The risk of developing bleeding is significantly increased if the patient has an active gastroduodenal ulcer, previous bleeding (<3 months before hospitalization), advanced age, severe renal failure (creatinine clearance [CrCl] <30 mL/min), hepatic failure, active cancer, low platelet count (<50 × 10 9 /L), or planned surgery in the next 6 to 12 hours. There are few externally validated models for predicting bleeding risk in hospitalized medical patients. One such model is the IMPROVE bleeding risk score.
Decisions regarding anticoagulant thromboprophylaxis in acutely-ill hospitalized medical patients should be made after consideration of risk factors for both VTE and bleeding. A number of scoring systems have been studied to estimate risk of VTE in hospitalized medical patients including the IMPROVE-DD risk score, the Padua Prediction Score, and the GENEVA risk score. Computerized riskassessment tools should be implemented wherever feasible to increase the net clinical benefit from thromboprophylaxis and avoid unnecessary provision of thromboprophylaxis to patients at low risk. From a population perspective, a recent Markov model suggests that prophylaxis was cost-effective for an average medical inpatient with a VTE risk of ≥1.0%.
# OPTIONS FOR THROMBOPROPHYLAXIS:
Acutely ill hospitalized medical patients at increased risk of VTE who are not bleeding or at high risk of bleeding should receive anticoagulant thromboprophylaxis generally with a subcutaneous (SC) low molecular weight heparin (LMWH):
• dalteparin 5,000 units SC daily
• enoxaparin 40 mg SC daily • tinzaparin 4,500 units SC daily • fondaparinux 2.5 mg SC daily Unfractionated heparin (UFH) 5,000 units SC twice daily may also be a consideration. However, LMWH is preferred over UFH because of less frequent dosing and lower risk of heparin-induced thrombocytopenia (HIT).
Acutely ill hospitalized medical patients at low risk of VTE and those who are bleeding or at high risk of bleeding should not receive anticoagulant thromboprophylaxis. In this latter situation, properly measured and fitted elastic compression stockings (ECS) or intermittent pneumatic compression (IPC) devices should be used. When the bleeding risk decreases, one of the anticoagulant thromboprophylaxis options above should be started.
# SPECIAL CONSIDERATIONS:
• Direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban): These agents should generally not be used for prophylaxis in medically ill hospitalized patients, due to a lack of data to date to support their effectiveness and safety in this patient population.
• Duration of prophylaxis: Anticoagulant thromboprophylaxis should generally continue until acute care hospital discharge and not be extended beyond the period of hospitalization.
• Under-and over-weight: Dose reduction should be considered for patients with weight <40 kg; dose increase should be considered for patients with weight >100 kg. For patients weighing over 120 kg, even higher doses should be considered.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Cancer and Thrombosis • Central Venous Catheter-Related Deep Venous Thrombosis • Unfractionated Heparin, Low Molecular Weight Heparin and Fondaparinux
# Date of Version: 18October2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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gender diverse and non-binary people refers to those who are: 1) Assigned female at birth and have not undergone top surgery (mastectomy); or 2) Assigned male at birth and have been on feminizing hormone therapy for 5 or more years in total. † Cisgender refers to people who have a gender identity that matches the sex they were assigned at birth.To provide updated evidence-based guidance on screening for breast cancer. To help Albertans and their healthcare providers make informed choices about breast cancer screening.Asymptomatic women, transgender, gender diverse, and non-binary people - of all ages Exclusions z Persons with signs and symptoms suggesting breast cancer z Persons currently being treated for breast cancer z Cisgender † men These guidelines have not been updated since the last full update was completed in 2013. Since that time, new evidence has become available and other new guidelines have been published. The updated Alberta Breast Cancer Screening Clinical Practice Guidelines include new recommendations based on this new information.A provincial breast cancer screening clinical practice guideline committee was funded by the Alberta Medical Association's Accelerating Change Transformation Team (ACTT) for guideline review and update. The committee has representation from radiology, family medicine, nursing, medical oncology, public health & preventative medicine, surgery and the public. The topics of special interest (e.g. breast density, higher-than-average risk, tomosynthesis, recommended screening ages, etc.) were reviewed using systematic reviews, expert opinion, Alberta breast cancer screening data and micro-simulation modeling. Following evidence synthesis, committee members developed recommendations through careful consideration of the benefits and harms as well as the strength of the current evidence. A modified Delphi process was used to reach consensus and determine the best option. The guidelines herein represent the collective input of the experts on the committee. As new information becomes available, the balance of benefits and harms may change. As such, recommendations will continue to be updated accordingly.# Background
# RISK FACTORS
Breast cancer is the most common form of cancer in women in Alberta, apart from non-melanoma skin cancer. 6 Approximately 1 in 7 women are expected to be diagnosed with breast cancer during their lifetime, and 1 in 35 will die from the disease. 7 Age and family history are major non-modifiable risk factors. Other non-modifiable risk factors include breast density, certain benign breast conditions (atypical hyperplasia, lobular carcinoma in situ, etc.), several reproductive factors, and a history of chest wall radiation. Modifiable lifestyle factors such as body weight, physical activity, alcohol consumption, and smoking should be addressed in the context of overall wellness and breast cancer risk reduction.
-- 5 - Clinical Practice Guideline 2022
# ABSOLUTE VS RELATIVE RISK
When looking at the impact a risk factor has on breast cancer risk, it is important to remember the difference between absolute risk and relative risk.
Absolute Risk: Looks at the total risk of developing a disease.
For example, if your odds of developing breast cancer are 1 in 7, the risk is about 14%. If a certain risk factor changes the odds to 1 in 6, about 17%, the difference would be 17% -14% = 3%. This means the absolute risk has increased by about 3%.
Relative Risk: Looks at the change in risk as a proportion of the total risk. This can make the impact of a change appear much more significant. 8 Using the previous example, the change in relative risk would be 3% ÷ 14% = 21%. This means the relative risk has increased by about 21%.
Note: To avoid repetition, the type of risk used in this guideline is always relative risk, unless otherwise specified. This is due to the fact that relative risk is generally what is cited in the literature.
# Non-modifiable Risk Factors
# AGE
As people get older, their risk of breast cancer increases (see Table 1).
# AGE GROUP
PROBABILITY
# FAMILY HISTORY
Family History: It is important to assess history of cancer on both sides of the family. Having one or two first degree relatives affected by breast cancer is associated with a lifetime increased incidence of breast cancer of 5.5% and 13.3%, respectively. 10 The increase in relative risk is greater for younger individuals and is greater when the affected relative was diagnosed at a younger age. 10 Known Mutations: BRCA mutations are alterations to genes (mainly BRCA1 and BRCA2 genes) that normally help protect against breast cancer. Mutations to these genes can increase the risk of developing breast cancer. The cumulative lifetime risk of breast cancer is estimated to be 72% for BRCA1 and 69% for BRCA2 carriers, up to the age of 80. 11 The prevalence of BRCA1 and BRCA2 mutations in the general population has not been well established; however, modeling estimates are between 1 in 300 (0.3%) and 1 in 500 (0.2%) depending on ethnicity *. 12 However, approximately only 1 to 2% of breast cancer cases have a BRCA1 or BRCA2 mutation. 13 Both men and women can pass on these gene mutations to their children; transmission is autosomal dominant, so each child has a 50/50 chance of inheriting these gene mutations. It is important to assess history of cancer on both sides of the family.
Aside from BRCA mutations, other genetic syndromes may increase the risk of breast cancer and ovarian cancer. Clinics will consider assessment, counselling, and potential genetic testing for these syndromes, as appropriate. However, there may also be some mutations that increase risk of breast cancer, but whose exact identification is currently unknown and for which genetic testing is not available.
Medical Genetics referral should be made for a patient when they have a personal and/or family history as outlined in Appendix A.
# BREAST DENSITY
Below is a brief overview of breast density. For more information, including printable resources for both patients and healthcare providers, visit screeningforlife.ca/for-health-providers and select either Patient Education Resources (for patients) or Shared Decision Making (for healthcare providers).
Breast density refers to the amount of dense tissue compared to non-dense (fatty) tissue in the breasts. There are four categories of breast density (American College of Radiology categories A-D):
A The breasts are almost entirely fatty.
B There are scattered areas of fibroglandular density.
C The breasts are heterogeneously dense, which may obscure small masses.
D The breasts are extremely dense, which lowers the sensitivity of mammography.
There is an inverse relationship between breast density and age-younger people are more likely to have dense breast tissue (category C or D) compared to older people (see Figure 1). Although breast density generally decreases with age, there are outliers at both ends of the age spectrumsome younger individuals have fatty breasts, while some older individuals have extremely dense breasts. 14 For people with extremely dense breasts, the relative risk of developing breast cancer is about 2.1 times greater than average. 15 However, it should be noted that age remains a greater determinant of breast cancer risk than breast density alone. Breast density is a mammographic finding which cannot be reliably defined by a physical exam. Dense breast tissue limits the sensitivity of mammographic screening. 14 In one study, the sensitivity of screening mammography was 72% overall, but declined sharply from 80% to 59% to 30% for people with predominantly fatty breasts, heterogeneously dense breasts, and extremely dense breasts, respectively-with a commensurate increase in interval cancer rate. 17 Breast density may be assessed by the radiologist or by software designed to score breast density. The reporting of radiological breast density provides a general idea of the likelihood that cancer will be detected or missed.
Once diagnosed with breast cancer, people with high density breasts (category C or D) do not have a higher risk of death from breast cancer than people with lower density breasts after controlling for stage. 18
# HISTORY OF CERTAIN BENIGN BREAST CONDITIONS: BIOPSY-PROVEN ATYPICAL HYPERPLASIA OR LOBULAR CARCINOMA IN SITU
These are benign breast conditions but can elevate a person's risk to higher-than-average risk and require more intensive screening. In people with a history of breast biopsies showing atypical hyperplasia or lobular carcinoma in situ, the relative risk of breast cancer is increased by at least four-fold and the increased risk persists for at least 25 years. 19 Visit the American Cancer Society to see a list of other non-cancerous breast conditions that may or may not increase an individual's risk of breast cancer.
# HORMONAL INFLUENCES
Menarche and Menopause: Individuals with earlier age of menarche 20 and/or later age of menopause 21 have an increased risk of breast cancer, mediated in part by the increased number of menstrual cycles and longer lifetime exposure to estrogen and progesterone.
Reproductive History: Number of and age of delivery of successful pregnancies also affect a person's risk of breast cancer by way of affecting the number of lifetime menstrual cycles and cumulative estrogen/progesterone exposure. Every live birth reduces the risk of breast cancer by about 7%; additionally, the younger a person is at their first delivery, the lower their risk of breast cancer. 20 Breastfeeding: Reduced lifetime exposure to estrogen and progesterone may also explain the protective effect conferred by increasing duration of breastfeeding. The risk of breast cancer decreases by about 4% for every 12 months of breastfeeding. 22 Hormone Replacement Therapy (HRT): Among people who use combination estrogen-progesterone hormone replacement therapy, the risk of breast cancer increases with the length of use. 23 After five years of using combined HRT, the relative risk of breast cancer increases by about 15%, and the risk returns to baseline within about two years of stopping HRT. 24 Estrogen therapy alone increases breast cancer risk as well, but less so than for combined estrogen-progesterone therapy. 23,24
# CHEST WALL RADIATION
Individuals with a history of chest wall radiation as treatment for another cancer (such as Hodgkin lymphoma) have up to a ten-fold increased risk for breast cancer. The risk varies according to the patient's age at which they underwent radiation therapy-it is highest if the radiation was given before menarche. 25 Risk also varies with the dose of radiation administered. 26 Modifiable Risk Factors
# OBESITY
Obesity is associated with an increased risk of postmenopausal breast cancer, as is weight gain throughout adulthood. 27 Obesity also negatively affects the prognosis of early stage breast cancer. 28
# LIFESTYLE
In Alberta, approximately 26% of breast cancers are linked to modifiable risk factors. 29 This equates to 620 cases that could be prevented every year.
A. Physical Activity: The relative risk of breast cancer is reduced by about 25% when comparing physically active people to the least active people. 30 The evidence is strongest for recreational activity, for activity of at least moderate intensity, and for activity sustained over a lifetime. 30 B. Alcohol Consumption: Regular consumption of as little as one drink per day elevates the relative risk of breast cancer by about 4%. 31 Risk increases steadily with increasing consumption regardless of the type of alcohol consumed. There may also be a case for alcohol use being more strongly associated in risk of hormone-sensitive breast cancers. 31,32 C. Smoking: The Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk suggests that the association between active smoking and breast cancer is consistent with causality. 33 Also, the association between second hand smoke and breast cancer among younger, primarily premenopausal people who have never smoked is consistent with causality. 33 Further research is required to determine the magnitude of the effect.
D. Nutrition: Getting lots of fruits and vegetables into one's diet can also lower the risk of most cancers, including breast cancer. See Canada's Food Guide for more information on healthy eating.
Many of the modifiable risk factors for breast cancer are the same as for other types of cancer. A study by the Canadian Cancer Society identified the most beneficial behavioural changes to reduce one's chance of developing cancer (Figure 2). Modifiable risk factors for breast cancer specifically are presented in Figure 3. For information on modifiable risk factors for cancer, visit healthiertogether.ca.
# Updates to Screening Recommendations
# RISK ASSESSMENT
Screening for breast cancer should begin with an assessment of risk. Certain factors are known to increase breast cancer risk; these elevate a person's risk category from average-risk to higherthan-average risk and high risk. A discussion should occur about the benefits and risks of added screening modalities (screeningforlife.ca/for-health-providers-click on "Shared decision making" for healthcare provider resources, or "Patient education resources" for resources for patients). 34 A risk assessment tool (see the list of available risk assessment tools and what they measure at screeningforlife.ca) also provides additional insight about an individual's personal risk, but should not be solely relied on for clinical decision-making. In general, risk assessment tools have been found to have only moderate accuracy when applied to the general population. At this time, it is not possible to recommend one tool over another.
-- 11 - Clinical Practice Guideline 2022
# Average-Risk Screening
# Practice Point
The majority (80%+) of breast cancers occurs in people of average-risk.
# DIGITAL MAMMOGRAPHY
Mammography is the recommended method of breast cancer screening for the average-risk population. Screening regularly with mammography has been shown to reduce breast cancer mortality by 30% to 40%-no other screening modality affects breast cancer mortality risk. 38 As with all screening programs, there are limitations patients and physicians should be aware of, including: z Overdiagnosis/overtreatment: Cancer may be correctly diagnosed, but would not have become symptomatic in one's lifetime or affect one's life expectancy. 39 Treatment of these indolent (slow growing) cancers will continue to be an issue until available technology is good enough to differentiate these cases.
z False positives: Abnormal mammogram reported when cancer is not present, which leads to extra tests. In Alberta, approximately 94% of abnormal results do not result in a diagnosis of breast cancer.
z Anxiety: Concerns associated with false positive results.
z False negative results: Normal mammogram reported when cancer is actually present:
z Lobular cancer and lobular carcinoma in situ are difficult to diagnose on mammography alone. This is an uncommon form of breast cancer and requires additional imaging (usually MRI) to make a diagnosis. Clinicians and patients should be aware that a breast mass that is not seen on a mammogram may need additional work up for diagnosis.
z Breast density can also make breast cancer more difficult to detect.
z False sense of security that may delay diagnosis: Individuals do not report new breast concerns, since they believe they are safe from cancer after having a negative screen. This can be reduced through patient education.
A note about radiation risk from mammograms
Mammograms use very low doses of radiation. A screening digital mammogram is the equivalent to about 26 days of background radiation exposure from daily living, while DBT is equivalent to about 33 days. 40 Given the relative insensitivity of the mature breast to ionizing radiation, the risk of DM-induced cancer is generally considered to be very low. The standard for breast cancer screening remains 2D DM (with or without DBT). If using DBT, it should always be combined with either 2D synthetic (reconstructed two-dimensional images from DBT) or 2D DM for breast cancer screening. When using DBT in conjunction with DM the radiation dose is approximately double that of DM alone. However, it is still well within the limits set by the Canadian Association of Radiologists.
In summary, the amount of radiation exposure from DM alone or DM+DBT is so low that it should not be a deterrent to screening. 47 It is far more likely that a person's life will be saved by a screening mammogram (with or without DBT) than the risk of developing a radiation induced breast cancer.
# RECOMMENDATIONS BY AGE
Breast cancer incidence increases with age (Figure 4). Recommendations are therefore provided in age categories; however, there are no rigid delineations between categories. Clinical judgment should be used to adjust the frequency of screening, when considering individual differences. 39 Years and Under: For individuals 39 years and under, breast cancer screening is not recommended.
As the risk of breast cancer increases with age, the incidence of breast cancer is very low in this age group 7 and there is no evidence for mortality reduction from screening in this group. 39 Additionally, the harms of breast cancer screening remain.
-- 13 - Clinical Practice Guideline 2022
40-44 Years: Screening for ages 40-44 is not recommended.
The incidence of breast cancer is low in this age group. 9 While small mortality reductions have been demonstrated for this age group, the balance of benefits to harms is not strong enough to recommend routine screening. In comparison to older people, the absolute risk reduction from screening in this group is smaller because the overall risk of cancer is lower. 39 With a lower overall incidence of cancer, a higher proportion of positive results are false-positives and thus necessitate additional follow-up tests. 39 This can lead to unnecessary anxiety, procedures, increased radiation exposure, and potential discouragement of the patient from further breast cancer screening. Additionally, younger individuals can experience faster-growing and more aggressive cancer than older individuals. This makes it less likely that breast cancer screening will detect a cancer before it becomes symptomatic.
The ideal screening interval for this age group is also less clear than for other age groups. Due to the higher prevalence of high breast density (increased breast density has a masking effect on mammography abnormalities), screening mammography is also more likely to miss cancer in this age group. 14 It has also been suggested that more rapid growth of tumours and shorter sojourn time (time from onset of cancer to the presence of symptoms) in younger people support a shorter interval between screenings. If choosing to screen, expert opinion recommends screening every year in Alberta. Screening in this age category should only be done on people who choose to screen after having an informed discussion with their healthcare provider about the less favourable balance of benefits and harms of screening.
# UPDATED AGE GROUP
45-74 Years: Routine screening every 2 years is recommended for individuals 45 to 74.
The strongest evidence of mortality reduction associated with mammography screening is in the 50 to 69 year age subgroup. 39 The benefit is greater for the upper half of this age group, i.e., the number needed to screen (NNS) to prevent one death is 910 for those aged 50 to 59 years, while the NNS is 432 for those aged 60 to 69 years. Few breast cancer screening trials have included people aged 70 to 74; these studies demonstrated mortality reductions at least as large as for people aged 50 to 69. Given the high incidence of breast cancer in the 70 to 74 year age group, the benefit of screening mammography is expected to be similar to that for the 50 to 69 year age group. 39 The decision to lower the recommended screening age from 50 to 45 was based on multiple factors. Under the previous recommendations, participation rates for people in Alberta aged 45-49 were 24%. 52 By contrast, participation rates for the recommended screening age groups, 50-74, were 65%. 53 Despite the lower volume of screening in the 45-49 year-old age group when following previous guideline recommendations, 246 breast cancers were detected in Albertans aged 45-49 in 2018, compared with 287 breast cancers in Albertans aged 50-54. 54 New evidence reviews also demonstrated a mortality reduction by starting screening prior to age 50. 39,49,55,56 On the other hand, it should be noted that people in their 40s experience higher abnormal (recall) rates (12%) compared with people aged 50-74 (8%). 57,58 This can further lead to more invasive testing, such as biopsies.
Another consideration is the recommended screening interval. While one trial in the United Kingdom showed no difference in mortality between people randomized to annual screening versus triennial screening, the tumours detected in the annual group were significantly smaller. 59 Modelling studies
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suggest that compared to annual screening, biennial screening preserves at least 80% of the benefit of annual screening with almost 50% fewer false-positive results. 60
# DATA-MODELING
Population-based screening programs are carefully designed to bring the benefits of early cancer detection to a large number of seemingly healthy individuals. However, screening tests can cause harms to individuals, mostly in the form of additional tests and anxiety due to false positives. Since screening additional people means the possibility of increased harms and increased costs to the healthcare system, the potential benefits must be carefully weighed against anticipated harms and cost-effectiveness.
An analysis comparing the benefits and harms of various breast cancer screening options in people aged 40-49 years in Alberta was conducted using OncoSim-Breast. OncoSim-Breast is a mathematical model that simulates the breast cancer natural history of the Canadian population.
The analysis used Alberta data to forecast the outcomes of changing recommendations to include either annual or biennial screening for ages 45-49 or 40-49. The numbers were projected for a single year cohort followed over their lifetime. The four options were projected and numbers provided in Table 2 show the increase in screens, false positives and cancer deaths averted compared to the status quo (i.e. biennial screening recommended starting at age 50). Outcomes have been standardized to include the same number of Albertans (41,000) receiving screening in each option to allow for comparison of the benefits and harms. Although options such as the annual 40-49 strategy averted 9 more cancer deaths than the biennial 45-49 strategy, it was projected to result in triple the number of additional screens and false positives. Additionally, the projections calculated the healthcare costs and quality-adjusted - The analysis was conducted using a larger cohort of Albertans (aged 40-49y in Alberta in the next 20 years) and divided the outcomes by 20 because cancer death was a rare outcome. † Due to data limitations, the false positive rate for ages 40-49 were used for both 40-49y and 45-49y. If the false-positive rates are higher for younger people (40-44y), one would expect the 40-49y screening strategy to have more false-positives and be less cost-effective than the above results.
Clinical Practice Guideline 2022 life-years (QALY) of each strategy. A commonly cited threshold of $50,000 per QALY was used to assess if any of the alternatives were considered cost-effective. Of the four alternatives, only biennial screening starting at age 45 proved cost-effective. Therefore, recommending biennial screening starting at age 45 was considered the best balance of benefits to harms while also being the most cost-effective.
75 Years and Older: There are no studies that demonstrate benefit of screening in people 75 years and older; however, these people are at increased risk for developing breast cancer 61 OTHER SCREENING-RELATED TECHNOLOGY
# Practice Point
Digital mammography (2D) remains the standard for screening the average-risk population.
# Digital Breast Tomosynthesis (DBT/3D Mammography)
The Canadian Association of Radiologists/Canadian Society of Breast Imaging provides a useful position statement on the utilization of DBT in mammography screening:
Digital breast tomosynthesis (DBT) is a form of serial sectioning created by digital reconstruction of multiple low-dose mammographic projections into contiguous slices. It is often referred to as "tomo" or "three-dimensional" (3D) mammography, although it is not a truly multiplanar form of 3D. 62 Slice thickness may be adjusted depending on the vendor and/or software used for display. Images are obtained in the same plane as the original compression plane and are read as planar images. Tomosynthesis images can be acquired with ("combo-mode") or without standard two dimensional (2D) digital mammography (DM). Synthetic 2D mammograms are 2D projection images reconstructed from the information acquired during DBT data acquisition (post processing). The DBT slices or "stack" must be interpreted alongside the 2D imaging, either standard 2D DM or synthetic mammogram images. 63,64,65 Moderate-quality evidence indicates that combining DBT with DM improves invasive breast cancer detection by 2 per 1,000 screens. 66 Invasive cancer detection has been found to be significantly higher with DBT in people with heterogeneously dense breasts of all age groups. 61 Likewise, an analysis of two high volume clinics in Alberta found improvement in cancer detection rates, annual return to screen rates, and positive predictive values after switching from DM alone to DBT+DM. 67 However, abnormal call (recall) rates increased. There has also been inconsistency in findings from other studies on the impact DBT has on false positive results. 66 Evidence on interval cancer, advanced cancer rates and mortality data is still pending. A rapid review in 2019 by the Canadian Agency for Drugs and Technologies in Health (CADTH) found inconclusive evidence on the clinical benefits or harms of DBT. 68 More recent studies have found early evidence of improved interval cancer rates with DBT. 69,70 DBT also increases the radiation exposure compared with 2D DM alone, but remains within acceptable dose limits (see the section on Radiation Risk).
# DBT Recommendation
2D DM remains the standard for screening average-risk individuals. At the present time there is not enough evidence to provide a strong recommendation for or against the use of DBT in the average-risk population. If using DBT for screening, it should be used in conjunction with synthetic or standard 2D DM.
Ultrasound: Ultrasound should not be used as a stand-alone screening test. There is insufficient evidence to support the use of ultrasound for routine screening in the average-risk population.
Evidence to date shows that the addition of ultrasound to mammography can detect an additional 3.8 cancers (mostly invasive) per 1,000 people with dense breasts; 71 however, it also produces significantly more false positives. 72 The balance of benefits and harms of supplemental ultrasound is greater for people with category D (extremely dense) breasts, as denser breasts tend to mask abnormalities. 71,73 It is for this reason that we recommend considering annual breast ultrasound, in addition to mammography, for people with extremely dense breast (category D) for ages 45+.
# Magnetic Resonance Imaging (MRI):
To date, MRI screening studies have focused on the high risk population; there are limited studies evaluating the use of MRI for screening in the average-risk population. 40 Some preliminary studies suggest that abbreviated or fast MRI could improve cancer detection for average-risk people with dense breasts (category C or D), but further research is needed on its cost-effectiveness and impact on reducing breast cancer mortality. 74,75 Thermography: Breast thermography is not approved by Health Canada for use in breast cancer screening. There is no evidence that thermography reduces mortality related to breast cancer. 76,77 It may lead to a false sense of security and potential harm. People should be discouraged from using thermography for the detection of breast cancer.
# OTHER SCREENING RELATED APPROACHES
Clinical Breast Exam (CBE): The addition of CBE to screening mammography has not been proven to reduce mortality. Although some cancers may be identified by CBE, 78 there is no evidence that CBE results in fewer deaths. Additionally, CBE is not specific and generates a significant number of false positive results. 79 Expert opinion recommends that CBE be considered (particularly for individuals at higher-than-average risk or high-risk) as part of the physical examination and as a teaching opportunity to discuss breast awareness (see below).
Breast Awareness (BA): BA means being familiar with one's own breasts. Any unusual changes should be reported to their healthcare provider; in particular, nipple discharge/rash/inversion, skin dimpling, or new mass in the breast or axilla. 80 For a visual graphic that patients can use to help become breast aware, visit: screeningforlife.ca/breast/breast-cancer/#signs_and_symptoms Breast Self Exam (BSE): BSE is the practice of regularly checking one's own breasts for signs of cancer. It has not been shown to be beneficial for early detection of breast cancer; additionally, no major guidelines currently recommend it for screening. Instead, individuals should be encouraged
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to practice BA.
Remember, no test is perfect. Persistent or new changes should be followed up by the healthcare provider, even if recent investigations were normal.
Breast Cancer Screening for Individuals at Higher-than-Average Risk
Higher-than-average risk is a new category to these guidelines. It has been added to address several risk factors that do not qualify as high risk. Definitions of higher-than-average risk vary between guidelines and within the literature, but it is commonly described as people with a 15 to 20% lifetime risk of developing breast cancer. 34,81,82 Alternatively, several guidelines define higher-than-average risk according to specific criteria. 83,84 Expert opinion is that the use of pre-defined criteria to define this group can be more straightforward to follow, and is independent of the risk assessment model available; it is also more practical for implementing in a day-to-day healthcare setting since it doesn't require working through a risk assessment tool during a time-restricted visit.
# Breast Cancer Screening for Individuals at High Risk
The recommendations for the high risk population were developed in response to feedback from family physicians requesting guidance for people requiring more intensive screening or surveillance, and also for people requiring referral to medical genetics. 11. Personal history of breast cancer and family history of male breast cancer.
- Personal history of breast cancer at any age and a first degree relative meeting a criterion.
- Ashkenazi Jewish heritage and personal history of breast or ovarian cancer - at any age.
Ashkenazi Jewish heritage and a 1st or 2nd degree relative with breast/ovarian cancer - at any age.
- Ovarian cancer = invasive epithelial ovarian cancer, and includes primary peritoneal cancers and primary fallopian tube cancers. § = Mainstreaming criteria; patient meeting these criteria can have genetic testing ordered through approved surgeon/oncologist.
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gender diverse and non-binary people refers to those who are: 1) Assigned female at birth and have not undergone top surgery (mastectomy); or 2) Assigned male at birth and have been on feminizing hormone therapy for 5 or more years in total. † Cisgender refers to people who have a gender identity that matches the sex they were assigned at birth.To provide updated evidence-based guidance on screening for breast cancer. To help Albertans and their healthcare providers make informed choices about breast cancer screening.Asymptomatic women, transgender, gender diverse, and non-binary people * of all ages Exclusions z Persons with signs and symptoms suggesting breast cancer z Persons currently being treated for breast cancer z Cisgender † men These guidelines have not been updated since the last full update was completed in 2013. Since that time, new evidence has become available and other new guidelines have been published. The updated Alberta Breast Cancer Screening Clinical Practice Guidelines include new recommendations based on this new information.A provincial breast cancer screening clinical practice guideline committee was funded by the Alberta Medical Association's Accelerating Change Transformation Team (ACTT) for guideline review and update. The committee has representation from radiology, family medicine, nursing, medical oncology, public health & preventative medicine, surgery and the public. The topics of special interest (e.g. breast density, higher-than-average risk, tomosynthesis, recommended screening ages, etc.) were reviewed using systematic reviews, expert opinion, Alberta breast cancer screening data and micro-simulation modeling. Following evidence synthesis, committee members developed recommendations through careful consideration of the benefits and harms as well as the strength of the current evidence. A modified Delphi process was used to reach consensus and determine the best option. The guidelines herein represent the collective input of the experts on the committee. As new information becomes available, the balance of benefits and harms may change. As such, recommendations will continue to be updated accordingly.# Background
# RISK FACTORS
Breast cancer is the most common form of cancer in women in Alberta, apart from non-melanoma skin cancer. 6 Approximately 1 in 7 women are expected to be diagnosed with breast cancer during their lifetime, and 1 in 35 will die from the disease. 7 Age and family history are major non-modifiable risk factors. Other non-modifiable risk factors include breast density, certain benign breast conditions (atypical hyperplasia, lobular carcinoma in situ, etc.), several reproductive factors, and a history of chest wall radiation. Modifiable lifestyle factors such as body weight, physical activity, alcohol consumption, and smoking should be addressed in the context of overall wellness and breast cancer risk reduction.
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# ABSOLUTE VS RELATIVE RISK
When looking at the impact a risk factor has on breast cancer risk, it is important to remember the difference between absolute risk and relative risk.
Absolute Risk: Looks at the total risk of developing a disease.
For example, if your odds of developing breast cancer are 1 in 7, the risk is about 14%. If a certain risk factor changes the odds to 1 in 6, about 17%, the difference would be 17% -14% = 3%. This means the absolute risk has increased by about 3%.
Relative Risk: Looks at the change in risk as a proportion of the total risk. This can make the impact of a change appear much more significant. 8 Using the previous example, the change in relative risk would be 3% ÷ 14% = 21%. This means the relative risk has increased by about 21%.
Note: To avoid repetition, the type of risk used in this guideline is always relative risk, unless otherwise specified. This is due to the fact that relative risk is generally what is cited in the literature.
# Non-modifiable Risk Factors
# AGE
As people get older, their risk of breast cancer increases (see Table 1).
# AGE GROUP
PROBABILITY
# FAMILY HISTORY
Family History: It is important to assess history of cancer on both sides of the family. Having one or two first degree relatives affected by breast cancer is associated with a lifetime increased incidence of breast cancer of 5.5% and 13.3%, respectively. 10 The increase in relative risk is greater for younger individuals and is greater when the affected relative was diagnosed at a younger age. 10 Known Mutations: BRCA mutations are alterations to genes (mainly BRCA1 and BRCA2 genes) that normally help protect against breast cancer. Mutations to these genes can increase the risk of developing breast cancer. The cumulative lifetime risk of breast cancer is estimated to be 72% for BRCA1 and 69% for BRCA2 carriers, up to the age of 80. 11 The prevalence of BRCA1 and BRCA2 mutations in the general population has not been well established; however, modeling estimates are between 1 in 300 (0.3%) and 1 in 500 (0.2%) depending on ethnicity *. 12 However, approximately only 1 to 2% of breast cancer cases have a BRCA1 or BRCA2 mutation. 13 Both men and women can pass on these gene mutations to their children; transmission is autosomal dominant, so each child has a 50/50 chance of inheriting these gene mutations. It is important to assess history of cancer on both sides of the family.
Aside from BRCA mutations, other genetic syndromes may increase the risk of breast cancer and ovarian cancer. Clinics will consider assessment, counselling, and potential genetic testing for these syndromes, as appropriate. However, there may also be some mutations that increase risk of breast cancer, but whose exact identification is currently unknown and for which genetic testing is not available.
Medical Genetics referral should be made for a patient when they have a personal and/or family history as outlined in Appendix A.
# BREAST DENSITY
Below is a brief overview of breast density. For more information, including printable resources for both patients and healthcare providers, visit screeningforlife.ca/for-health-providers and select either Patient Education Resources (for patients) or Shared Decision Making (for healthcare providers).
Breast density refers to the amount of dense tissue compared to non-dense (fatty) tissue in the breasts. There are four categories of breast density (American College of Radiology categories A-D):
A The breasts are almost entirely fatty.
B There are scattered areas of fibroglandular density.
C The breasts are heterogeneously dense, which may obscure small masses.
D The breasts are extremely dense, which lowers the sensitivity of mammography.
There is an inverse relationship between breast density and age-younger people are more likely to have dense breast tissue (category C or D) compared to older people (see Figure 1). Although breast density generally decreases with age, there are outliers at both ends of the age spectrumsome younger individuals have fatty breasts, while some older individuals have extremely dense breasts. 14 For people with extremely dense breasts, the relative risk of developing breast cancer is about 2.1 times greater than average. 15 However, it should be noted that age remains a greater determinant of breast cancer risk than breast density alone. Breast density is a mammographic finding which cannot be reliably defined by a physical exam. Dense breast tissue limits the sensitivity of mammographic screening. 14 In one study, the sensitivity of screening mammography was 72% overall, but declined sharply from 80% to 59% to 30% for people with predominantly fatty breasts, heterogeneously dense breasts, and extremely dense breasts, respectively-with a commensurate increase in interval cancer rate. 17 Breast density may be assessed by the radiologist or by software designed to score breast density. The reporting of radiological breast density provides a general idea of the likelihood that cancer will be detected or missed.
Once diagnosed with breast cancer, people with high density breasts (category C or D) do not have a higher risk of death from breast cancer than people with lower density breasts after controlling for stage. 18
# HISTORY OF CERTAIN BENIGN BREAST CONDITIONS: BIOPSY-PROVEN ATYPICAL HYPERPLASIA OR LOBULAR CARCINOMA IN SITU
These are benign breast conditions but can elevate a person's risk to higher-than-average risk and require more intensive screening. In people with a history of breast biopsies showing atypical hyperplasia or lobular carcinoma in situ, the relative risk of breast cancer is increased by at least four-fold and the increased risk persists for at least 25 years. 19 Visit the American Cancer Society to see a list of other non-cancerous breast conditions that may or may not increase an individual's risk of breast cancer.
# HORMONAL INFLUENCES
Menarche and Menopause: Individuals with earlier age of menarche 20 and/or later age of menopause 21 have an increased risk of breast cancer, mediated in part by the increased number of menstrual cycles and longer lifetime exposure to estrogen and progesterone.
Reproductive History: Number of and age of delivery of successful pregnancies also affect a person's risk of breast cancer by way of affecting the number of lifetime menstrual cycles and cumulative estrogen/progesterone exposure. Every live birth reduces the risk of breast cancer by about 7%; additionally, the younger a person is at their first delivery, the lower their risk of breast cancer. 20 Breastfeeding: Reduced lifetime exposure to estrogen and progesterone may also explain the protective effect conferred by increasing duration of breastfeeding. The risk of breast cancer decreases by about 4% for every 12 months of breastfeeding. 22 Hormone Replacement Therapy (HRT): Among people who use combination estrogen-progesterone hormone replacement therapy, the risk of breast cancer increases with the length of use. 23 After five years of using combined HRT, the relative risk of breast cancer increases by about 15%, and the risk returns to baseline within about two years of stopping HRT. 24 Estrogen therapy alone increases breast cancer risk as well, but less so than for combined estrogen-progesterone therapy. 23,24
# CHEST WALL RADIATION
Individuals with a history of chest wall radiation as treatment for another cancer (such as Hodgkin lymphoma) have up to a ten-fold increased risk for breast cancer. The risk varies according to the patient's age at which they underwent radiation therapy-it is highest if the radiation was given before menarche. 25 Risk also varies with the dose of radiation administered. 26 Modifiable Risk Factors
# OBESITY
Obesity is associated with an increased risk of postmenopausal breast cancer, as is weight gain throughout adulthood. 27 Obesity also negatively affects the prognosis of early stage breast cancer. 28
# LIFESTYLE
In Alberta, approximately 26% of breast cancers are linked to modifiable risk factors. 29 This equates to 620 cases that could be prevented every year.
A. Physical Activity: The relative risk of breast cancer is reduced by about 25% when comparing physically active people to the least active people. 30 The evidence is strongest for recreational activity, for activity of at least moderate intensity, and for activity sustained over a lifetime. 30 B. Alcohol Consumption: Regular consumption of as little as one drink per day elevates the relative risk of breast cancer by about 4%. 31 Risk increases steadily with increasing consumption regardless of the type of alcohol consumed. There may also be a case for alcohol use being more strongly associated in risk of hormone-sensitive breast cancers. 31,32 C. Smoking: The Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk suggests that the association between active smoking and breast cancer is consistent with causality. 33 Also, the association between second hand smoke and breast cancer among younger, primarily premenopausal people who have never smoked is consistent with causality. 33 Further research is required to determine the magnitude of the effect.
D. Nutrition: Getting lots of fruits and vegetables into one's diet can also lower the risk of most cancers, including breast cancer. See Canada's Food Guide for more information on healthy eating.
Many of the modifiable risk factors for breast cancer are the same as for other types of cancer. A study by the Canadian Cancer Society identified the most beneficial behavioural changes to reduce one's chance of developing cancer (Figure 2). Modifiable risk factors for breast cancer specifically are presented in Figure 3. For information on modifiable risk factors for cancer, visit healthiertogether.ca.
# Updates to Screening Recommendations
# RISK ASSESSMENT
Screening for breast cancer should begin with an assessment of risk. Certain factors are known to increase breast cancer risk; these elevate a person's risk category from average-risk to higherthan-average risk and high risk. A discussion should occur about the benefits and risks of added screening modalities (screeningforlife.ca/for-health-providers-click on "Shared decision making" for healthcare provider resources, or "Patient education resources" for resources for patients). 34 A risk assessment tool (see the list of available risk assessment tools and what they measure at screeningforlife.ca) also provides additional insight about an individual's personal risk, but should not be solely relied on for clinical decision-making. In general, risk assessment tools have been found to have only moderate accuracy when applied to the general population. [35][36][37] At this time, it is not possible to recommend one tool over another.
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# Average-Risk Screening
# Practice Point
The majority (80%+) of breast cancers occurs in people of average-risk.
# DIGITAL MAMMOGRAPHY
Mammography is the recommended method of breast cancer screening for the average-risk population. Screening regularly with mammography has been shown to reduce breast cancer mortality by 30% to 40%-no other screening modality affects breast cancer mortality risk. 38 As with all screening programs, there are limitations patients and physicians should be aware of, including: z Overdiagnosis/overtreatment: Cancer may be correctly diagnosed, but would not have become symptomatic in one's lifetime or affect one's life expectancy. 39 Treatment of these indolent (slow growing) cancers will continue to be an issue until available technology is good enough to differentiate these cases.
z False positives: Abnormal mammogram reported when cancer is not present, which leads to extra tests. In Alberta, approximately 94% of abnormal results do not result in a diagnosis of breast cancer.
z Anxiety: Concerns associated with false positive results.
z False negative results: Normal mammogram reported when cancer is actually present:
z Lobular cancer and lobular carcinoma in situ are difficult to diagnose on mammography alone. This is an uncommon form of breast cancer and requires additional imaging (usually MRI) to make a diagnosis. Clinicians and patients should be aware that a breast mass that is not seen on a mammogram may need additional work up for diagnosis.
z Breast density can also make breast cancer more difficult to detect.
z False sense of security that may delay diagnosis: Individuals do not report new breast concerns, since they believe they are safe from cancer after having a negative screen. This can be reduced through patient education.
A note about radiation risk from mammograms
Mammograms use very low doses of radiation. A screening digital mammogram is the equivalent to about 26 days of background radiation exposure from daily living, while DBT is equivalent to about 33 days. 40 Given the relative insensitivity of the mature breast to ionizing radiation, the risk of DM-induced cancer is generally considered to be very low. [41][42][43] The standard for breast cancer screening remains 2D DM (with or without DBT). If using DBT, it should always be combined with either 2D synthetic (reconstructed two-dimensional images from DBT) or 2D DM for breast cancer screening. When using DBT in conjunction with DM the radiation dose is approximately double that of DM alone. [44][45][46] However, it is still well within the limits set by the Canadian Association of Radiologists.
In summary, the amount of radiation exposure from DM alone or DM+DBT is so low that it should not be a deterrent to screening. 47 It is far more likely that a person's life will be saved by a screening mammogram (with or without DBT) than the risk of developing a radiation induced breast cancer.
# RECOMMENDATIONS BY AGE
Breast cancer incidence increases with age (Figure 4). Recommendations are therefore provided in age categories; however, there are no rigid delineations between categories. Clinical judgment should be used to adjust the frequency of screening, when considering individual differences. 39 Years and Under: For individuals 39 years and under, breast cancer screening is not recommended.
As the risk of breast cancer increases with age, the incidence of breast cancer is very low in this age group 7 and there is no evidence for mortality reduction from screening in this group. 39 Additionally, the harms of breast cancer screening remain.
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40-44 Years: Screening for ages 40-44 is not recommended.
The incidence of breast cancer is low in this age group. 9 While small mortality reductions have been demonstrated for this age group, the balance of benefits to harms is not strong enough to recommend routine screening. In comparison to older people, the absolute risk reduction from screening in this group is smaller because the overall risk of cancer is lower. 39 With a lower overall incidence of cancer, a higher proportion of positive results are false-positives and thus necessitate additional follow-up tests. 39 This can lead to unnecessary anxiety, procedures, increased radiation exposure, and potential discouragement of the patient from further breast cancer screening. Additionally, younger individuals can experience faster-growing and more aggressive cancer than older individuals. [49][50][51][52] This makes it less likely that breast cancer screening will detect a cancer before it becomes symptomatic.
The ideal screening interval for this age group is also less clear than for other age groups. Due to the higher prevalence of high breast density (increased breast density has a masking effect on mammography abnormalities), screening mammography is also more likely to miss cancer in this age group. 14 It has also been suggested that more rapid growth of tumours and shorter sojourn time (time from onset of cancer to the presence of symptoms) in younger people support a shorter interval between screenings. [48][49][50][51] If choosing to screen, expert opinion recommends screening every year in Alberta. Screening in this age category should only be done on people who choose to screen after having an informed discussion with their healthcare provider about the less favourable balance of benefits and harms of screening.
# UPDATED AGE GROUP
45-74 Years: Routine screening every 2 years is recommended for individuals 45 to 74.
The strongest evidence of mortality reduction associated with mammography screening is in the 50 to 69 year age subgroup. 39 The benefit is greater for the upper half of this age group, i.e., the number needed to screen (NNS) to prevent one death is 910 for those aged 50 to 59 years, while the NNS is 432 for those aged 60 to 69 years. Few breast cancer screening trials have included people aged 70 to 74; these studies demonstrated mortality reductions at least as large as for people aged 50 to 69. Given the high incidence of breast cancer in the 70 to 74 year age group, the benefit of screening mammography is expected to be similar to that for the 50 to 69 year age group. 39 The decision to lower the recommended screening age from 50 to 45 was based on multiple factors. Under the previous recommendations, participation rates for people in Alberta aged 45-49 were 24%. 52 By contrast, participation rates for the recommended screening age groups, 50-74, were 65%. 53 Despite the lower volume of screening in the 45-49 year-old age group when following previous guideline recommendations, 246 breast cancers were detected in Albertans aged 45-49 in 2018, compared with 287 breast cancers in Albertans aged 50-54. 54 New evidence reviews also demonstrated a mortality reduction by starting screening prior to age 50. 39,49,55,56 On the other hand, it should be noted that people in their 40s experience higher abnormal (recall) rates (12%) compared with people aged 50-74 (8%). 57,58 This can further lead to more invasive testing, such as biopsies.
Another consideration is the recommended screening interval. While one trial in the United Kingdom showed no difference in mortality between people randomized to annual screening versus triennial screening, the tumours detected in the annual group were significantly smaller. 59 Modelling studies
••• 14 ••• AHS -Screening For Life
suggest that compared to annual screening, biennial screening preserves at least 80% of the benefit of annual screening with almost 50% fewer false-positive results. 60
# DATA-MODELING
Population-based screening programs are carefully designed to bring the benefits of early cancer detection to a large number of seemingly healthy individuals. However, screening tests can cause harms to individuals, mostly in the form of additional tests and anxiety due to false positives. Since screening additional people means the possibility of increased harms and increased costs to the healthcare system, the potential benefits must be carefully weighed against anticipated harms and cost-effectiveness.
An analysis comparing the benefits and harms of various breast cancer screening options in people aged 40-49 years in Alberta was conducted using OncoSim-Breast. OncoSim-Breast is a mathematical model that simulates the breast cancer natural history of the Canadian population.
The analysis used Alberta data to forecast the outcomes of changing recommendations to include either annual or biennial screening for ages 45-49 or 40-49. The numbers were projected for a single year cohort followed over their lifetime. The four options were projected and numbers provided in Table 2 show the increase in screens, false positives and cancer deaths averted compared to the status quo (i.e. biennial screening recommended starting at age 50). Outcomes have been standardized to include the same number of Albertans (41,000) receiving screening in each option to allow for comparison of the benefits and harms. Although options such as the annual 40-49 strategy averted 9 more cancer deaths than the biennial 45-49 strategy, it was projected to result in triple the number of additional screens and false positives. Additionally, the projections calculated the healthcare costs and quality-adjusted * The analysis was conducted using a larger cohort of Albertans (aged 40-49y in Alberta in the next 20 years) and divided the outcomes by 20 because cancer death was a rare outcome. † Due to data limitations, the false positive rate for ages 40-49 were used for both 40-49y and 45-49y. If the false-positive rates are higher for younger people (40-44y), one would expect the 40-49y screening strategy to have more false-positives and be less cost-effective than the above results.
# ••• 15 •••
Clinical Practice Guideline 2022 life-years (QALY) of each strategy. A commonly cited threshold of $50,000 per QALY was used to assess if any of the alternatives were considered cost-effective. Of the four alternatives, only biennial screening starting at age 45 proved cost-effective. Therefore, recommending biennial screening starting at age 45 was considered the best balance of benefits to harms while also being the most cost-effective.
75 Years and Older: There are no studies that demonstrate benefit of screening in people 75 years and older; however, these people are at increased risk for developing breast cancer 61 OTHER SCREENING-RELATED TECHNOLOGY
# Practice Point
Digital mammography (2D) remains the standard for screening the average-risk population.
# Digital Breast Tomosynthesis (DBT/3D Mammography)
The Canadian Association of Radiologists/Canadian Society of Breast Imaging provides a useful position statement on the utilization of DBT in mammography screening:
Digital breast tomosynthesis (DBT) is a form of serial sectioning created by digital reconstruction of multiple low-dose mammographic projections into contiguous slices. It is often referred to as "tomo" or "three-dimensional" (3D) mammography, although it is not a truly multiplanar form of 3D. 62 Slice thickness may be adjusted depending on the vendor and/or software used for display. Images are obtained in the same plane as the original compression plane and are read as planar images. Tomosynthesis images can be acquired with ("combo-mode") or without standard two dimensional (2D) digital mammography (DM). Synthetic 2D mammograms are 2D projection images reconstructed from the information acquired during DBT data acquisition (post processing). The DBT slices or "stack" must be interpreted alongside the 2D imaging, either standard 2D DM or synthetic mammogram images. 63,64,65 Moderate-quality evidence indicates that combining DBT with DM improves invasive breast cancer detection by 2 per 1,000 screens. 66 Invasive cancer detection has been found to be significantly higher with DBT in people with heterogeneously dense breasts of all age groups. 61 Likewise, an analysis of two high volume clinics in Alberta found improvement in cancer detection rates, annual return to screen rates, and positive predictive values after switching from DM alone to DBT+DM. 67 However, abnormal call (recall) rates increased. There has also been inconsistency in findings from other studies on the impact DBT has on false positive results. 66 Evidence on interval cancer, advanced cancer rates and mortality data is still pending. A rapid review in 2019 by the Canadian Agency for Drugs and Technologies in Health (CADTH) found inconclusive evidence on the clinical benefits or harms of DBT. 68 More recent studies have found early evidence of improved interval cancer rates with DBT. 69,70 DBT also increases the radiation exposure compared with 2D DM alone, but remains within acceptable dose limits (see the section on Radiation Risk).
# DBT Recommendation
2D DM remains the standard for screening average-risk individuals. At the present time there is not enough evidence to provide a strong recommendation for or against the use of DBT in the average-risk population. If using DBT for screening, it should be used in conjunction with synthetic or standard 2D DM.
Ultrasound: Ultrasound should not be used as a stand-alone screening test. There is insufficient evidence to support the use of ultrasound for routine screening in the average-risk population.
Evidence to date shows that the addition of ultrasound to mammography can detect an additional 3.8 cancers (mostly invasive) per 1,000 people with dense breasts; 71 however, it also produces significantly more false positives. 72 The balance of benefits and harms of supplemental ultrasound is greater for people with category D (extremely dense) breasts, as denser breasts tend to mask abnormalities. 71,73 It is for this reason that we recommend considering annual breast ultrasound, in addition to mammography, for people with extremely dense breast (category D) for ages 45+.
# Magnetic Resonance Imaging (MRI):
To date, MRI screening studies have focused on the high risk population; there are limited studies evaluating the use of MRI for screening in the average-risk population. 40 Some preliminary studies suggest that abbreviated or fast MRI could improve cancer detection for average-risk people with dense breasts (category C or D), but further research is needed on its cost-effectiveness and impact on reducing breast cancer mortality. 74,75 Thermography: Breast thermography is not approved by Health Canada for use in breast cancer screening. There is no evidence that thermography reduces mortality related to breast cancer. 76,77 It may lead to a false sense of security and potential harm. People should be discouraged from using thermography for the detection of breast cancer.
# OTHER SCREENING RELATED APPROACHES
Clinical Breast Exam (CBE): The addition of CBE to screening mammography has not been proven to reduce mortality. Although some cancers may be identified by CBE, 78 there is no evidence that CBE results in fewer deaths. Additionally, CBE is not specific and generates a significant number of false positive results. 79 Expert opinion recommends that CBE be considered (particularly for individuals at higher-than-average risk or high-risk) as part of the physical examination and as a teaching opportunity to discuss breast awareness (see below).
Breast Awareness (BA): BA means being familiar with one's own breasts. Any unusual changes should be reported to their healthcare provider; in particular, nipple discharge/rash/inversion, skin dimpling, or new mass in the breast or axilla. 80 For a visual graphic that patients can use to help become breast aware, visit: screeningforlife.ca/breast/breast-cancer/#signs_and_symptoms Breast Self Exam (BSE): BSE is the practice of regularly checking one's own breasts for signs of cancer. It has not been shown to be beneficial for early detection of breast cancer; additionally, no major guidelines currently recommend it for screening. Instead, individuals should be encouraged
••• 17 ••• Clinical Practice Guideline 2022
to practice BA.
Remember, no test is perfect. Persistent or new changes should be followed up by the healthcare provider, even if recent investigations were normal.
Breast Cancer Screening for Individuals at Higher-than-Average Risk
Higher-than-average risk is a new category to these guidelines. It has been added to address several risk factors that do not qualify as high risk. Definitions of higher-than-average risk vary between guidelines and within the literature, but it is commonly described as people with a 15 to 20% lifetime risk of developing breast cancer. 34,81,82 Alternatively, several guidelines define higher-than-average risk according to specific criteria. 83,84 Expert opinion is that the use of pre-defined criteria to define this group can be more straightforward to follow, and is independent of the risk assessment model available; it is also more practical for implementing in a day-to-day healthcare setting since it doesn't require working through a risk assessment tool during a time-restricted visit.
# Breast Cancer Screening for Individuals at High Risk
The recommendations for the high risk population were developed in response to feedback from family physicians requesting guidance for people requiring more intensive screening or surveillance, and also for people requiring referral to medical genetics. 11. Personal history of breast cancer and family history of male breast cancer.
12. Personal history of breast cancer at any age and a first degree relative meeting a [ § ] criterion.
13. Ashkenazi Jewish heritage and personal history of breast or ovarian cancer * at any age.
# 14.
Ashkenazi Jewish heritage and a 1st or 2nd degree relative with breast/ovarian cancer * at any age.
* Ovarian cancer = invasive epithelial ovarian cancer, and includes primary peritoneal cancers and primary fallopian tube cancers. § = Mainstreaming criteria; patient meeting these criteria can have genetic testing ordered through approved surgeon/oncologist.
# Acknowledgments
We would like to acknowledge the Accelerating Change Transformation Team for their contributions of funding for committee activities as well as their guidance on guideline development.
We would also like to acknowledge Dr. Karen Niederhoffer, Dr. Julia Sun, Sara Tod and Jean H.E. Yong for their contributions to the high risk referral criteria and data modeling used in the recommendations by age section.
#
Note: Family members should be blood relations to each other and the referred patient.
* Ovarian cancer refers to invasive non-mucinous epithelial ovarian cancer, includes cancer of the fallopian tubes or primary peritoneal cancer, excludes borderline or low malignant potential ovarian tumor.
# Appendix C EXPOSURE DEFINITIONS FOR MODIFIABLE ATTRIBUTABLE RISKS FOR BREAST CANCER
# RISK FACTOR EXPOSURE DEFINITION
# Smoking
Current smoker (smoked cigarettes daily or occasionally at the time of the interview) or former smoker (did not smoke at the time of the interview and had smoked more than 100 cigarettes in lifetime)
# Passive smoking
Regularly exposed to tobacco smoke in their home, a vehicle or a public place
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Managing patients with pain, especially chronic non-cancer pain (CNCP) is challenging given current practice realities. Practice patterns have changed with more patients receiving episodic care from walk-in-clinics, emergency departments, and group or team-based clinics with a variety of participating clinicians. Clinicians can be overwhelmed by guidelines, updates, algorithms, portals, and on-line journals. The British Columbia's Opioid Overdose Crisis has permeated our day-to-day practice and often create prescribing uncertainty. Many have fears (though often misplaced) about potential disciplinary and legal consequences from licensing and legislative bodies. Patients also have access to many sources of information, may come with a history of past trauma and unequal treatment by the health care system, and often struggle with reduced function and ability because of their pain.Team based care#
The intent of this guideline is to provide practical, accessible, and BC specific guidance. In essence, this is more of a Clinical Guidance Document and not a formal guideline. It's a distillation of many guidelines, expert recommendations, and standards of care. There are few overall pain guidelines for direct comparison. The guideline development working group were made aware of the Appraisal of Guidelines for Research and Evaluation (AGREE) process that helped inform their appraisal of these guidelines.
There is no clear or absolute clinical pathway to managing pain and many controversies persist, especially in the use of opioids and cannabis. The guideline development committee recommends reasonable clinical judgement, clear documentation, and frequent reassessment.
# Scope
This guideline comprises of two parts: 1. Pain Assessment and Management Approaches 2. Pain Management -Pharmacological and Procedural Within scope of this guideline: - Practical recommendations within the primary care setting for a graded, multimodal approach to supporting adult patients (≥ 19 years) with pain on a continuum from acute, subacute to chronic pain. A multimodal approach is one where patients with pain receive multiple interventions and supports, both concurrently and sequentially. - General approaches to treating patients with pain and links to supportive resources.
# Key Recommendations
- Patients with moderate to severe acute injury should receive adequate pain control and consideration of early referral to specialized services, where indicated and available. - Consider improving function and reducing disability, rather than elimination of pain, as the goal of pain management strategies, especially when pain progresses into the chronic pain continuum. - A supportive longitudinal therapeutic relationship is a foundation of pain management. Given the changing face of primary care with team-based care, walk-in care, and virtual care, use of databases like Electronic Medical Records (EMRs), PharmaNet, and CareConnect is increasingly important. - Throughout the pain continuum, especially in subacute and chronic phases, assess for biopsychosocial factors (yellow flags) and co-morbid conditions. Be alert to addressing risk factors for developing chronic pain. - Complex Regional Pain Syndrome (CRPS) is often considered a pain emergency and warrants urgent referral or consultation by a pain specialist and consideration of early intervention with steroids. - Consider all forms of interventions, including non-pharmacological and pharmacological, as a 'trial' to be reassessed for effectiveness on a regular basis. - For people with chronic pain not already on opioid therapy, optimize non-pharmacotherapy and non-opioid pharmacotherapy first before considering a trial of opioid therapy. - For all medication, aim for the optimal dose and be aware of the recommended maximal dose with fewest side effects and do regular, recurrent evaluation to assess for meaningful improvement in pain and function. See Managing Pain in Primary Care -Part 2: Pharmacological Management.
# Definition
The International Association for the Study of Pain (IASP) defines pain as "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. "
In addition, six key notes are added.
- Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.
- Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons.
- Through their life experiences, individuals learn the concept of pain.
- A person's report of an experience as pain should be respected.
- Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being. - Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.
While it is convenient to try and categorize pain in terms of mechanism, duration or origin, there can be significant differences in how individuals experience pain and how tissues may heal. The parameters for defining pain as acute or chronic may vary depending on the type of trauma and past history, which suggests that a more nuanced approach to applying a framework for resolution of the pain is often required.
Acute pain is pain generally expected to last less than 4 weeks and occurs within the context of tissue damage and repair, resolving with tissue healing.
Subacute pain (transition zone between acute and chronic) is defined as pain not resolving or diminishing as expected in 4-12 weeks after initial onset. The 'subacute' timeframe should trigger practitioners to pause and reflect on progress of pain management and take steps to reduce the likelihood of transition to chronic pain.
Chronic or persistent pain is pain persisting for greater than 3 months. It can arise from long-term medical conditions not expected to improve such as osteoarthritis, scoliosis, and multiple sclerosis, or it can also be pain that persists beyond expected time of healing.
Pain can be described in terms of mechanisms. Treatment modalities, including adjuvants, may differ significantly depending on the mechanism of pain.
- Nociceptive: arises from actual or threatened damage to underlying tissue (e.g., soft tissue, bone, viscera)
- Inflammatory: perception of noxious stimuli that occur during an inflammatory or immune response.
- Neuropathic: results from damaged or dysfunctional nerves (leads to misfiring pain signals).
- Nociplastic: altered pain perception without clear evidence of actual or threatened tissue damage such as in fibromyalgia.
When considering a patient's experience of pain, it can help to remember:
- Pain is always a personal, learned experience that is influenced to varying degrees by biological, psychological, social, and cultural factors and life experiences. - A person's report of their subjective experience of pain should be respected.
- Although pain usually serves an adaptive role, it may have adverse effects on function, and on social and psychological well-being. - Verbal description is only one of several ways to express pain; inability to communicate does not negate the possibility that a person experiences pain.
# Epidemiology of Chronic Pain
According to Statistics Canada, an estimated 7.6 million, or one in five people (across their lifespan) in Canada, live with chronic pain. 1 It is estimated that 1 in 5 adults in BC suffer with chronic pain. 2
# Approach to Care
Pain management is within the scope of practice of all primary care practitioners. Patients seeking management of their pain may at times face social stigma and negative assumptions about their motives, leading to less than adequate care. Successful pain management requires a highly individualized, respectful, evidence-informed treatment approach and benefits from a team-based, biopsychosocial approach. See Appendix A: Overarching Considerations of Pain Management. - Consider assessment for mood disorder and substance use disorder.
- Assess early for Red Flags. See Table 1: Pain Red Flags below.
# Constitutional
Unexplained fever (>38°C); unexplained weight loss; night sweats
# Complex Regional Pain Syndrome (CRPS)
Previously known as Reflex Sympathetic Dystrophy, an evolving CRPS is usually considered an emergency by pain specialists with a strong suggestion for at least a phone consultation and consideration of an urgent referral. While considered rare, it is occasionally progressive involving the arm, leg, hand, or foot. Symptoms may include excessive pain, swelling, and changes in skin colour, texture, and temperature. A subset of patients may benefit from early steroid therapy so again consider an urgent consultation and referral.
# Functional and Occupational Assessment
Support work rehabilitation, occupational review and return to work or education. Explore work accommodation options (e.g., part-time, modified duties), if appropriate, rather than complete disability.
- For WorkSafeBC and Insurance Corporation of British Columbia (ICBC) injuries, consider early intervention support and consultation. - Many occupational groups, employers and insurance companies have occupational health departments and clinician experts.
Engage early if complex pain or extended disability is anticipated. - If considering prescribing opioids, assess for active and past substance use disorder (SUD) (including nicotine, alcohol, opioids, marijuana) and psychiatric disorders. The presence of these disorders is not a reason to not prescribe but suggests a need to proceed with caution and to have a clear discussion with patient about risks. The presence of any SUD is not an absolute contraindication to prescribe opioids, though it does increase risk of overdose and addiction to opioids. Thus, more safeguards, including enhanced monitoring, need to be put in place and clear documentation of risks and benefits for that particular patient outlined. Certain pain medications may not be safe to prescribe. Patients with pain when on opioid agonist therapy (OAT) need to be referred to an addiction medicine specialist with knowledge of pain treatment. Specific management for individuals in this situation is outside the bounds of this guideline.
# Management
- If opioids are prescribed for acute pain, suggest limiting the duration of the first prescription of opioids to less than 7 days, and use short-acting agents only. 4 - When using the assessment tools, some pain specialists have noted that many patients will label every domain as 10/10. While it may not be an accurate reflection of the actual pain, it may reflect the patient's overall frustration and hopelessness and should not be dismissed as malingering or over-exaggeration. Consider that multiple pain mechanisms may now be involved in the patient's experience of pain. - Re-emphasize that total elimination of pain may not be the goal. Improving function and managing suffering are the priorities. Provide information on pain education and self-management. See Resources: Resources for Patients.
- If recovery is delayed, refer to specialists for expedited assessment or for specialized treatments/ procedures (e.g., epidural or nerve root injections, facet or SI joint injections, joint injections or vertebroplasty). For some conditions such as CRPS and worsening neuropathic pain, referral to specialty services should be as early as possible. This may be especially true in frail older adults as they experience greater functional impairment that can worsen frailty. - As complexity increases, consider combinations of treatments rather than a sequence of treatments. Consider other options, in addition to medications and non-pharmacological interventions. Consider involvement of allied health professionals and/ or teams, where available. See Appendix C: Allied Health Professionals to Support Pain Management. - Explore accommodations for work/school such as the WorkSafeBC Physician's Report.
- For patients involved in motor vehicle accidents who are not recovering as expected or have an unknown diagnosis or complicating factors, consider referral to an ICBC registered care advisor (RCA) within 90 days of the accident for an expedited medical consultation.
# Chronic Pain (3+ months) Assessment
It may be worthwhile considering a slightly different approach if the patient has long standing and well documented pain, versus the patient who has recently developed chronic pain after an acute event. Many strategies are the same, but a patient with long standing chronic pain may have adapted to achieve some stable level of function and ability, while a patient with new onset of chronic pain may still be uncertain about work options and activities of daily living (ADL) adaptations.
Evaluating and managing patients with chronic pain requires repeat history and physical exams as well as evaluation of disability and psychosocial domains. This can be beneficial even for long-term patients who appear stable. This process can be conducted over multiple office visits and may at various times include:
- Repeat / review history, physical exam - Consider asking yourself:
- What is going on? 2. Could it be something else? 3. Could two things be going on at once? 4. Is the diagnosis still supported by the available evidence? - Review medication history including over the counter (OTC) and "off label" products (including use of cannabis) - Repeat / review pain assessment tools, including functional and occupational assessments - Assess / reassess for mental health conditions (e.g., use screening tools for anxiety, depression, PTSD).
Both chronic pain and depression may frequently co-exist, especially in old age, and may be risk factors for each other. 10 Consider exploring other life changes as possible contributors to depression and/or pain symptoms.
# Management
- In B.C., many of these modalities are not publicly funded and availability of specialized care may not be equitably available. Access to many specialized pain management services outside of a few large urban centres is often extremely limited. Some of this can be mitigated through "telehealth" type options, which more specialists are using. - However, many patients who qualify for income or disability assistance may receive coverage or partial coverage for noninsured health benefits (NIHB) such as physical therapy, acupuncture, chiropractic care, massage therapy, mental health care, pharmacy coverage, medical supplies, and dental care. For more information see BC Family and social supports. - Federal employees, RCMP members, armed forces personnel, and military veterans may also have additional health benefits coverage. - Best practice treatment plans involve primary care providers working closely with allied health care providers, such as physiotherapists, occupational therapists, psychologists, chiropractors, massage therapists, and social workers, and should be centred around patient education and self-management. Despite many services not being publicly funded, explore coverage through ICBC, WorkSafe BC and patient's work disability services or private insurance, in addition to coverage through income assistance. Refer to Pain BC and PathwaysBC for listings of providers, self-management groups and clinics with experience and training in managing chronic pain. - Match non-pharmacological interventions that are best suited to patient's specific pain mechanism and history, such as physiotherapy or chiropractic therapy for mechanical low back pain (LBP); psychological intervention if there is a possible history of PTSD or Adverse Childhood Experiences (ACEs); Cognitive Behavioural Therapy (CBT) for depression and anxiety; and social work or occupational therapy if housing/financial/job insecurity are present. Using a layered and multimodal approach may be more effective than trying a single intervention at a time. For information on services available in the community, visit Pain BC and HealthLinkBC. - Discuss goals of care. Specifically, improved function, reduced suffering, and patient's other individual goals, and not necessarily removal of all pain. - Review patient expectations for treatment outcomes and address misconceptions or unrealistic expectations.
- Over multiple visits, develop an Individualized Care Plan or chronic pain flow sheet 3 to encourage a better systematic approach to chronic pain. Share and review the plan with the patient. - Provide guidance for practical steps that can be addressed in next visit.
- If a patient has been adherent to therapy for 3-4 months and is not responding, consider an alternative approach.
- Educate patients about chronic pain and the multidimensionality of pain. See Resources: Resources for Patients. It is often assumed that tissue damage will continue to heal, but there may be other interfering factors. - Educate patients that non-opioid treatment gives equal pain control and fewer side effects than opioid treatment for most types of chronic LBP and knee and hip arthritic pain. 11 - Educate patients that opioid use may increase pain sensitivity and add to pain at injury sites during withdrawal. 12,13 These procedures generally don't require imaging, can be performed in an office setting and are not restricted to an accredited facility. It is beyond the scope of this guideline to describe these procedures in detail and their indications, but they tend to be self-explanatory, and several online instruction resources exist.
# Procedural
For more complex procedures (e.g., epidural injections, facet joint injections, sympathetic nerve blocks) the BCMQI has described these procedures as Advanced Level I and II, which are required to be done in an approved facility or hospital. Delivery of these procedures in non-hospital settings (e.g., community based GP practices) require facility accreditation and practitioner credentialing. Refer to CPSBC and BCMQI websites for more information.
# Substance Use Reduction
A number of different psychoactive substances have been shown to temporarily supress pain perception in the euphoric phase (the reason the patient with pain may like the feel of the substance). Yet, these same substances can increase pain sensitivity and add to chronic pain in the long run. Alcohol, tobacco, and opioids are all examples. Patient education on this topic then a trial of tapering down or off of these substances may be needed to help pain perception. In those with CNCP, opioids can produce a dose-dependent pain sensitization that temporarily worsens during tapering. 12,17,18 For those with chronic pain or an opioid use disorder, previous injury sites can hurt again during abrupt withdrawal and add to the risk of opioid re-initiation. Thus, slow tapering along with the use of adjuvant medications like non steroidal anti-inflammatory drugs (NSAIDS) or gabapentinoids may be helpful in adults who do not meet an OUD diagnosis. Previously stable OAT or opioids used for the treatment of OUD should not be routinely tapered.
# Supported Self-Management
- Provide or refer patient to educational resources about science of pain. Pain education has been shown to decrease disability and increase self-efficacy. 19 Refer to Resources: Resources for Patients for helpful resources. - Provide patient with information about self-management (including focused breathing, nutrition, gentle movement, mindfulness meditation, sleep hygiene, etc.) connecting to additional support (e.g., community physical activity programs, dietitians, etc.). - Consider goal setting, including return to work and Brief Action Planning (BAP).
# Allied Health Professionals to Support Non-pharmacological Pain Management
Pain BC has developed an overview of Allied Health Approaches To Chronic Pain Management-A Tool For Primary Care Providers. Many non-pharmacological interventions may be partially or fully covered by third party insurers (e.g., ICBC or WorkSafeBC), or if patient is on disability or income assistance. See Appendix C: Allied Health Professionals to Support Pain Management for more details on allied practitioners.
# Considerations for Referral or Request for Expert Input
When patients DO NOT experience ongoing improvement in function and decrease in suffering then consider: - Consultation with an appropriate specialist.
- Structural cause such as a compression fracture.
- Psychological services if history of PTSD, ACEs, or catastrophizing. - Pain clinic if pain appears to have a nociplastic component.
Guiding principles for referral or request for expert input: - Not seeing appropriate progress and pain looks likely to persist longer than expected.
- Neuropathic features develop, persist, or worsen. - Post-op patients unable to reduce or discontinue opioid use.
- If patient is continuing to show biopsychosocial factors that increase risk of progression to chronic pain.
- Some pain specialists suggest that the emergence of CRPS symptoms warrants at least a phone consultation to assess the need for urgent referral. If WorkSafeBC or ICBC involved, phone the worker's medical advisor and ask for an expedited appointment. - If an interventional or surgical procedure is likely.
- If chronic non-cancer pain and OUD coexist a referral to an addiction specialist is warranted.
# Managing Pain in the Older Adult
Managing pain in the "Older Adult", especially the frail older adult, often requires modifications and adjustments in both approach and dosages. Many experts suggest that age greater than 70 may be an appropriate age to consider age related factors in assessing and managing pain. The definition of frailty is still being fully defined but its current definition is a medical syndrome with multiple causes and contributors, characterized by diminished strength and endurance and reduced physiological function, leading to increased vulnerability for adverse health outcomes such as functional decline and early mortality. While frailty is common with increasing age, it is not an inevitable part of aging. Additional information about Healthy Aging and Preventing Frailty can be found in the updated provincial healthy aging strategy.
# Guiding Principles:
- The frail older adult may require adjustments in medications and dosages, but the use of opioids is not contraindicated. See Part 2: Pharmacological Treatment for more specific guidance. - Persistent pain in frail older adults increases morbidity and poor health outcomes, making treatment a priority.
- Multiple morbidity, cognitive impairment and altered pharmacokinetics and dynamics mandate an individual approach. Some basic bloodwork, including renal function, may be appropriate in the initial assessment phase and intermittently if the use of medication persists. - As cognition worsens, pain is less likely to be reported and may manifest as other distress behaviours (e.g., agitation, resisting care, insomnia, poor appetite). - Older adults are more likely to be taking multiple medications (polypharmacy) and have co-morbidities. Therefore, assess individual patients for drug and disease interactions when prescribing NSAIDs and other medications. - Risk of falls is elevated. However, pain and decreased attention or poor sleep due to chronic pain can also increase the risk of falls. Monitoring the increased risk for managing pain in the elderly is necessary to reduce suffering and increased function. HealthLinkBC offers resources on Pain Control-Learn about pain control. At any time of the day or night, every day of the year, anyone can call 8-1-1 to be connected with a health service navigator. They provide health information, help navigate the health care system and find health services across the province, or connect with a registered nurse, registered dietitian, qualified exercise professional, or pharmacist. Registered nurses at HealthLink BC can help with nonemergency health concerns, to discuss symptoms and procedures, and to recommend whether a health care provider should be seen in person.
- Kelty's Key ("made in BC") also offers an excellent online resource for people with persistent pain.
- Wellness Together Canada basic wellness information, to one-on-one sessions with a counsellor, to participating in a community of support. - Collaboratively support patient with pain's choice in their self-management strategies, while at the same time prescribe safely to minimize adverse events.
# Team Based Care
- Pain management benefits from a multimodal approach (receiving multiple interventions at the same time e.g., yoga, physiotherapy, occupational therapy, counselling, medication). - Get to know pain practitioners in your local community who have training in the management of people with pain and build a network of resources, including low and no cost options and awareness of financial supports. Consider connecting with providers whom the patient has identified as part of their care team or recommend a local practitioner from your network. We acknowledge that access to care may be limited by geography and resources. - Team members may include pharmacists, physiotherapists, massage therapists, acupuncturists, chiropractors, osteopaths, occupational therapists, counsellors, social workers, lifestyle coaches, support for substance use and mental health, psychologists, cognitive behavioural therapists, Indigenous cultural and wellness supports, dietitians and qualified exercise professionals. Team members can also be your own office staff, who may assist with assessment using various tools such as the brief pain inventory and the pain disability index. This can make this complex and sometimes challenging care more manageable. - Refer to HealthLink BC (8-1-1), Pathways, or Pain BC for information on local practitioners and resources. Check the scope of the organization to ensure proper referral. At any time of the day or night, every day of the year, anyone can call 8-1-1 to be connected with a health service navigator. They provide health information, help navigate the health care system and find health services across the province, or connect with a registered nurse, registered dietitian, qualified exercise professional, or pharmacist. Registered nurses at HealthLink BC can help with non-emergency health concerns, to discuss symptoms and procedures, and to recommend whether a health care provider should be seen in person. Pain BC support line can help identify local pain providers including practitioners who can provide guidance and support for self-management. - Involve caregiver/family members as part of the team for frail older adults in pain, particularly if there is cognitive impairment present.
# Safety
- All modalities in a comprehensive plan for managing pain should be assessed from a safety perspective for the patient, practitioner, and the community at large. There may be some uncertainty about how clinicians navigate BCMQI and CPSBC standards, published guidelines, patient demands, family and caregiver concerns, as well as manage their own personal views and bias. As always, document your decisions and rationale well, especially if there is some deviation from College standards or established guidelines, or there are unique patient/family factors that contributed to your course of action. - Communication on the importance of safety is crucial when we have difficult discussions with patients.
- The most obvious safety issue is around medications, especially opioids. Initiating and changing doses, length of prescriptions, tapering doses, and dealing with (for example) unexpected urine drug tests, are all potential conflict points where an initial comment such as "I want this to be safe for you/me/our community", will reset the conversation to one involving safety.
# Patient Safety
Practitioner Safety Community Safety
The principles of the Guidelines and Protocols Advisory Committee are to:
- encourage appropriate responses to common medical situations - recommend actions that are sufficient and efficient, neither excessive nor deficient - permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: hlth.guidelines@gov.bc.ca Website: www.BCGuidelines.ca
|
Managing patients with pain, especially chronic non-cancer pain (CNCP) is challenging given current practice realities. Practice patterns have changed with more patients receiving episodic care from walk-in-clinics, emergency departments, and group or team-based clinics with a variety of participating clinicians. Clinicians can be overwhelmed by guidelines, updates, algorithms, portals, and on-line journals. The British Columbia's Opioid Overdose Crisis has permeated our day-to-day practice and often create prescribing uncertainty. Many have fears (though often misplaced) about potential disciplinary and legal consequences from licensing and legislative bodies. Patients also have access to many sources of information, may come with a history of past trauma and unequal treatment by the health care system, and often struggle with reduced function and ability because of their pain.Team based care#
The intent of this guideline is to provide practical, accessible, and BC specific guidance. In essence, this is more of a Clinical Guidance Document and not a formal guideline. It's a distillation of many guidelines, expert recommendations, and standards of care. There are few overall pain guidelines for direct comparison. The guideline development working group were made aware of the Appraisal of Guidelines for Research and Evaluation (AGREE) process that helped inform their appraisal of these guidelines.
There is no clear or absolute clinical pathway to managing pain and many controversies persist, especially in the use of opioids and cannabis. The guideline development committee recommends reasonable clinical judgement, clear documentation, and frequent reassessment.
# Scope
This guideline comprises of two parts: 1. Pain Assessment and Management Approaches 2. Pain Management -Pharmacological and Procedural Within scope of this guideline: • Practical recommendations within the primary care setting for a graded, multimodal approach to supporting adult patients (≥ 19 years) with pain on a continuum from acute, subacute to chronic pain. A multimodal approach is one where patients with pain receive multiple interventions and supports, both concurrently and sequentially. • General approaches to treating patients with pain and links to supportive resources.
# Key Recommendations
• Patients with moderate to severe acute injury should receive adequate pain control and consideration of early referral to specialized services, where indicated and available. • Consider improving function and reducing disability, rather than elimination of pain, as the goal of pain management strategies, especially when pain progresses into the chronic pain continuum. • A supportive longitudinal therapeutic relationship is a foundation of pain management. Given the changing face of primary care with team-based care, walk-in care, and virtual care, use of databases like Electronic Medical Records (EMRs), PharmaNet, and CareConnect is increasingly important. • Throughout the pain continuum, especially in subacute and chronic phases, assess for biopsychosocial factors (yellow flags) and co-morbid conditions. Be alert to addressing risk factors for developing chronic pain. • Complex Regional Pain Syndrome (CRPS) is often considered a pain emergency and warrants urgent referral or consultation by a pain specialist and consideration of early intervention with steroids. • Consider all forms of interventions, including non-pharmacological and pharmacological, as a 'trial' to be reassessed for effectiveness on a regular basis. • For people with chronic pain not already on opioid therapy, optimize non-pharmacotherapy and non-opioid pharmacotherapy first before considering a trial of opioid therapy. • For all medication, aim for the optimal dose and be aware of the recommended maximal dose with fewest side effects and do regular, recurrent evaluation to assess for meaningful improvement in pain and function. See Managing Pain in Primary Care -Part 2: Pharmacological Management.
# Definition
The International Association for the Study of Pain (IASP) defines pain as "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage. "
In addition, six key notes are added.
• Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.
• Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons.
• Through their life experiences, individuals learn the concept of pain.
• A person's report of an experience as pain should be respected.
• Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being. • Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.
While it is convenient to try and categorize pain in terms of mechanism, duration or origin, there can be significant differences in how individuals experience pain and how tissues may heal. The parameters for defining pain as acute or chronic may vary depending on the type of trauma and past history, which suggests that a more nuanced approach to applying a framework for resolution of the pain is often required.
Acute pain is pain generally expected to last less than 4 weeks and occurs within the context of tissue damage and repair, resolving with tissue healing.
Subacute pain (transition zone between acute and chronic) is defined as pain not resolving or diminishing as expected in 4-12 weeks after initial onset. The 'subacute' timeframe should trigger practitioners to pause and reflect on progress of pain management and take steps to reduce the likelihood of transition to chronic pain.
Chronic or persistent pain is pain persisting for greater than 3 months. It can arise from long-term medical conditions not expected to improve such as osteoarthritis, scoliosis, and multiple sclerosis, or it can also be pain that persists beyond expected time of healing.
Pain can be described in terms of mechanisms. Treatment modalities, including adjuvants, may differ significantly depending on the mechanism of pain.
• Nociceptive: arises from actual or threatened damage to underlying tissue (e.g., soft tissue, bone, viscera)
• Inflammatory: perception of noxious stimuli that occur during an inflammatory or immune response.
• Neuropathic: results from damaged or dysfunctional nerves (leads to misfiring pain signals).
• Nociplastic: altered pain perception without clear evidence of actual or threatened tissue damage such as in fibromyalgia.
When considering a patient's experience of pain, it can help to remember:
• Pain is always a personal, learned experience that is influenced to varying degrees by biological, psychological, social, and cultural factors and life experiences. • A person's report of their subjective experience of pain should be respected.
• Although pain usually serves an adaptive role, it may have adverse effects on function, and on social and psychological well-being. • Verbal description is only one of several ways to express pain; inability to communicate does not negate the possibility that a person experiences pain.
# Epidemiology of Chronic Pain
According to Statistics Canada, an estimated 7.6 million, or one in five people (across their lifespan) in Canada, live with chronic pain. 1 It is estimated that 1 in 5 adults in BC suffer with chronic pain. 2
# Approach to Care
Pain management is within the scope of practice of all primary care practitioners. Patients seeking management of their pain may at times face social stigma and negative assumptions about their motives, leading to less than adequate care. Successful pain management requires a highly individualized, respectful, evidence-informed treatment approach and benefits from a team-based, biopsychosocial approach. See Appendix A: Overarching Considerations of Pain Management. • Consider assessment for mood disorder and substance use disorder.
• Assess early for Red Flags. See Table 1: Pain Red Flags below.
# Constitutional
Unexplained fever (>38°C); unexplained weight loss; night sweats
# Complex Regional Pain Syndrome (CRPS)
Previously known as Reflex Sympathetic Dystrophy, an evolving CRPS is usually considered an emergency by pain specialists with a strong suggestion for at least a phone consultation and consideration of an urgent referral. While considered rare, it is occasionally progressive involving the arm, leg, hand, or foot. Symptoms may include excessive pain, swelling, and changes in skin colour, texture, and temperature. A subset of patients may benefit from early steroid therapy so again consider an urgent consultation and referral.
# Functional and Occupational Assessment
Support work rehabilitation, occupational review and return to work or education. Explore work accommodation options (e.g., part-time, modified duties), if appropriate, rather than complete disability.
• For WorkSafeBC and Insurance Corporation of British Columbia (ICBC) injuries, consider early intervention support and consultation. • Many occupational groups, employers and insurance companies have occupational health departments and clinician experts.
Engage early if complex pain or extended disability is anticipated. • If considering prescribing opioids, assess for active and past substance use disorder (SUD) (including nicotine, alcohol, opioids, marijuana) and psychiatric disorders. The presence of these disorders is not a reason to not prescribe but suggests a need to proceed with caution and to have a clear discussion with patient about risks. The presence of any SUD is not an absolute contraindication to prescribe opioids, though it does increase risk of overdose and addiction to opioids. Thus, more safeguards, including enhanced monitoring, need to be put in place and clear documentation of risks and benefits for that particular patient outlined. Certain pain medications may not be safe to prescribe. Patients with pain when on opioid agonist therapy (OAT) need to be referred to an addiction medicine specialist with knowledge of pain treatment. Specific management for individuals in this situation is outside the bounds of this guideline.
# Management
• If opioids are prescribed for acute pain, suggest limiting the duration of the first prescription of opioids to less than 7 days, and use short-acting agents only. 4 • When using the assessment tools, some pain specialists have noted that many patients will label every domain as 10/10. While it may not be an accurate reflection of the actual pain, it may reflect the patient's overall frustration and hopelessness and should not be dismissed as malingering or over-exaggeration. Consider that multiple pain mechanisms may now be involved in the patient's experience of pain. • Re-emphasize that total elimination of pain may not be the goal. Improving function and managing suffering are the priorities. Provide information on pain education and self-management. See Resources: Resources for Patients.
• If recovery is delayed, refer to specialists for expedited assessment or for specialized treatments/ procedures (e.g., epidural or nerve root injections, facet or SI joint injections, joint injections or vertebroplasty). For some conditions such as CRPS and worsening neuropathic pain, referral to specialty services should be as early as possible. This may be especially true in frail older adults as they experience greater functional impairment that can worsen frailty. • As complexity increases, consider combinations of treatments rather than a sequence of treatments. Consider other options, in addition to medications and non-pharmacological interventions. Consider involvement of allied health professionals and/ or teams, where available. See Appendix C: Allied Health Professionals to Support Pain Management. • Explore accommodations for work/school such as the WorkSafeBC Physician's Report.
• For patients involved in motor vehicle accidents who are not recovering as expected or have an unknown diagnosis or complicating factors, consider referral to an ICBC registered care advisor (RCA) within 90 days of the accident for an expedited medical consultation.
# Chronic Pain (3+ months) Assessment
It may be worthwhile considering a slightly different approach if the patient has long standing and well documented pain, versus the patient who has recently developed chronic pain after an acute event. Many strategies are the same, but a patient with long standing chronic pain may have adapted to achieve some stable level of function and ability, while a patient with new onset of chronic pain may still be uncertain about work options and activities of daily living (ADL) adaptations.
Evaluating and managing patients with chronic pain requires repeat history and physical exams as well as evaluation of disability and psychosocial domains. This can be beneficial even for long-term patients who appear stable. This process can be conducted over multiple office visits and may at various times include:
• Repeat / review history, physical exam • Consider asking yourself:
1. What is going on? 2. Could it be something else? 3. Could two things be going on at once? 4. Is the diagnosis still supported by the available evidence? • Review medication history including over the counter (OTC) and "off label" products (including use of cannabis) • Repeat / review pain assessment tools, including functional and occupational assessments • Assess / reassess for mental health conditions (e.g., use screening tools for anxiety, depression, PTSD).
Both chronic pain and depression may frequently co-exist, especially in old age, and may be risk factors for each other. 10 Consider exploring other life changes as possible contributors to depression and/or pain symptoms.
# Management
• In B.C., many of these modalities are not publicly funded and availability of specialized care may not be equitably available. Access to many specialized pain management services outside of a few large urban centres is often extremely limited. Some of this can be mitigated through "telehealth" type options, which more specialists are using. • However, many patients who qualify for income or disability assistance may receive coverage or partial coverage for noninsured health benefits (NIHB) such as physical therapy, acupuncture, chiropractic care, massage therapy, mental health care, pharmacy coverage, medical supplies, and dental care. For more information see BC Family and social supports. • Federal employees, RCMP members, armed forces personnel, and military veterans may also have additional health benefits coverage. • Best practice treatment plans involve primary care providers working closely with allied health care providers, such as physiotherapists, occupational therapists, psychologists, chiropractors, massage therapists, and social workers, and should be centred around patient education and self-management. Despite many services not being publicly funded, explore coverage through ICBC, WorkSafe BC and patient's work disability services or private insurance, in addition to coverage through income assistance. Refer to Pain BC and PathwaysBC for listings of providers, self-management groups and clinics with experience and training in managing chronic pain. • Match non-pharmacological interventions that are best suited to patient's specific pain mechanism and history, such as physiotherapy or chiropractic therapy for mechanical low back pain (LBP); psychological intervention if there is a possible history of PTSD or Adverse Childhood Experiences (ACEs); Cognitive Behavioural Therapy (CBT) for depression and anxiety; and social work or occupational therapy if housing/financial/job insecurity are present. Using a layered and multimodal approach may be more effective than trying a single intervention at a time. For information on services available in the community, visit Pain BC and HealthLinkBC. • Discuss goals of care. Specifically, improved function, reduced suffering, and patient's other individual goals, and not necessarily removal of all pain. • Review patient expectations for treatment outcomes and address misconceptions or unrealistic expectations.
• Over multiple visits, develop an Individualized Care Plan or chronic pain flow sheet 3 to encourage a better systematic approach to chronic pain. Share and review the plan with the patient. • Provide guidance for practical steps that can be addressed in next visit.
• If a patient has been adherent to therapy for 3-4 months and is not responding, consider an alternative approach.
• Educate patients about chronic pain and the multidimensionality of pain. See Resources: Resources for Patients. It is often assumed that tissue damage will continue to heal, but there may be other interfering factors. • Educate patients that non-opioid treatment gives equal pain control and fewer side effects than opioid treatment for most types of chronic LBP and knee and hip arthritic pain. 11 • Educate patients that opioid use may increase pain sensitivity and add to pain at injury sites during withdrawal. 12,13 These procedures generally don't require imaging, can be performed in an office setting and are not restricted to an accredited facility. It is beyond the scope of this guideline to describe these procedures in detail and their indications, but they tend to be self-explanatory, and several online instruction resources exist.
# Procedural
For more complex procedures (e.g., epidural injections, facet joint injections, sympathetic nerve blocks) the BCMQI has described these procedures as Advanced Level I and II, which are required to be done in an approved facility or hospital. Delivery of these procedures in non-hospital settings (e.g., community based GP practices) require facility accreditation and practitioner credentialing. Refer to CPSBC and BCMQI websites for more information.
# Substance Use Reduction
A number of different psychoactive substances have been shown to temporarily supress pain perception in the euphoric phase (the reason the patient with pain may like the feel of the substance). Yet, these same substances can increase pain sensitivity and add to chronic pain in the long run. Alcohol, tobacco, and opioids are all examples. [13][14][15][16] Patient education on this topic then a trial of tapering down or off of these substances may be needed to help pain perception. In those with CNCP, opioids can produce a dose-dependent pain sensitization that temporarily worsens during tapering. 12,17,18 For those with chronic pain or an opioid use disorder, previous injury sites can hurt again during abrupt withdrawal and add to the risk of opioid re-initiation. Thus, slow tapering along with the use of adjuvant medications like non steroidal anti-inflammatory drugs (NSAIDS) or gabapentinoids may be helpful in adults who do not meet an OUD diagnosis. Previously stable OAT or opioids used for the treatment of OUD should not be routinely tapered.
# Supported Self-Management
• Provide or refer patient to educational resources about science of pain. Pain education has been shown to decrease disability and increase self-efficacy. 19 Refer to Resources: Resources for Patients for helpful resources. • Provide patient with information about self-management (including focused breathing, nutrition, gentle movement, mindfulness meditation, sleep hygiene, etc.) connecting to additional support (e.g., community physical activity programs, dietitians, etc.). • Consider goal setting, including return to work and Brief Action Planning (BAP).
# Allied Health Professionals to Support Non-pharmacological Pain Management
Pain BC has developed an overview of Allied Health Approaches To Chronic Pain Management-A Tool For Primary Care Providers. Many non-pharmacological interventions may be partially or fully covered by third party insurers (e.g., ICBC or WorkSafeBC), or if patient is on disability or income assistance. See Appendix C: Allied Health Professionals to Support Pain Management for more details on allied practitioners.
# Considerations for Referral or Request for Expert Input
When patients DO NOT experience ongoing improvement in function and decrease in suffering then consider: • Consultation with an appropriate specialist.
• Structural cause such as a compression fracture.
• Psychological services if history of PTSD, ACEs, or catastrophizing. • Pain clinic if pain appears to have a nociplastic component.
Guiding principles for referral or request for expert input: • Not seeing appropriate progress and pain looks likely to persist longer than expected.
• Neuropathic features develop, persist, or worsen. • Post-op patients unable to reduce or discontinue opioid use.
• If patient is continuing to show biopsychosocial factors that increase risk of progression to chronic pain.
• Some pain specialists suggest that the emergence of CRPS symptoms warrants at least a phone consultation to assess the need for urgent referral. If WorkSafeBC or ICBC involved, phone the worker's medical advisor and ask for an expedited appointment. • If an interventional or surgical procedure is likely.
• If chronic non-cancer pain and OUD coexist a referral to an addiction specialist is warranted.
# Managing Pain in the Older Adult
Managing pain in the "Older Adult", especially the frail older adult, often requires modifications and adjustments in both approach and dosages. Many experts suggest that age greater than 70 may be an appropriate age to consider age related factors in assessing and managing pain. The definition of frailty is still being fully defined but its current definition is a medical syndrome with multiple causes and contributors, characterized by diminished strength and endurance and reduced physiological function, leading to increased vulnerability for adverse health outcomes such as functional decline and early mortality. While frailty is common with increasing age, it is not an inevitable part of aging. Additional information about Healthy Aging and Preventing Frailty can be found in the updated provincial healthy aging strategy.
# Guiding Principles:
• The frail older adult may require adjustments in medications and dosages, but the use of opioids is not contraindicated. See Part 2: Pharmacological Treatment for more specific guidance. • Persistent pain in frail older adults increases morbidity and poor health outcomes, making treatment a priority.
• Multiple morbidity, cognitive impairment and altered pharmacokinetics and dynamics mandate an individual approach. Some basic bloodwork, including renal function, may be appropriate in the initial assessment phase and intermittently if the use of medication persists. • As cognition worsens, pain is less likely to be reported and may manifest as other distress behaviours (e.g., agitation, resisting care, insomnia, poor appetite). • Older adults are more likely to be taking multiple medications (polypharmacy) and have co-morbidities. Therefore, assess individual patients for drug and disease interactions when prescribing NSAIDs and other medications. • Risk of falls is elevated. However, pain and decreased attention or poor sleep due to chronic pain can also increase the risk of falls. Monitoring the increased risk for managing pain in the elderly is necessary to reduce suffering and increased function. HealthLinkBC offers resources on Pain Control-Learn about pain control. At any time of the day or night, every day of the year, anyone can call 8-1-1 to be connected with a health service navigator. They provide health information, help navigate the health care system and find health services across the province, or connect with a registered nurse, registered dietitian, qualified exercise professional, or pharmacist. Registered nurses at HealthLink BC can help with nonemergency health concerns, to discuss symptoms and procedures, and to recommend whether a health care provider should be seen in person.
• Kelty's Key ("made in BC") also offers an excellent online resource for people with persistent pain.
• Wellness Together Canada basic wellness information, to one-on-one sessions with a counsellor, to participating in a community of support. • Collaboratively support patient with pain's choice in their self-management strategies, while at the same time prescribe safely to minimize adverse events.
# Team Based Care
• Pain management benefits from a multimodal approach (receiving multiple interventions at the same time e.g., yoga, physiotherapy, occupational therapy, counselling, medication). • Get to know pain practitioners in your local community who have training in the management of people with pain and build a network of resources, including low and no cost options and awareness of financial supports. Consider connecting with providers whom the patient has identified as part of their care team or recommend a local practitioner from your network. We acknowledge that access to care may be limited by geography and resources. • Team members may include pharmacists, physiotherapists, massage therapists, acupuncturists, chiropractors, osteopaths, occupational therapists, counsellors, social workers, lifestyle coaches, support for substance use and mental health, psychologists, cognitive behavioural therapists, Indigenous cultural and wellness supports, dietitians and qualified exercise professionals. Team members can also be your own office staff, who may assist with assessment using various tools such as the brief pain inventory and the pain disability index. This can make this complex and sometimes challenging care more manageable. • Refer to HealthLink BC (8-1-1), Pathways, or Pain BC for information on local practitioners and resources. Check the scope of the organization to ensure proper referral. At any time of the day or night, every day of the year, anyone can call 8-1-1 to be connected with a health service navigator. They provide health information, help navigate the health care system and find health services across the province, or connect with a registered nurse, registered dietitian, qualified exercise professional, or pharmacist. Registered nurses at HealthLink BC can help with non-emergency health concerns, to discuss symptoms and procedures, and to recommend whether a health care provider should be seen in person. Pain BC support line can help identify local pain providers including practitioners who can provide guidance and support for self-management. • Involve caregiver/family members as part of the team for frail older adults in pain, particularly if there is cognitive impairment present.
# Safety
• All modalities in a comprehensive plan for managing pain should be assessed from a safety perspective for the patient, practitioner, and the community at large. There may be some uncertainty about how clinicians navigate BCMQI and CPSBC standards, published guidelines, patient demands, family and caregiver concerns, as well as manage their own personal views and bias. As always, document your decisions and rationale well, especially if there is some deviation from College standards or established guidelines, or there are unique patient/family factors that contributed to your course of action. • Communication on the importance of safety is crucial when we have difficult discussions with patients.
• The most obvious safety issue is around medications, especially opioids. Initiating and changing doses, length of prescriptions, tapering doses, and dealing with (for example) unexpected urine drug tests, are all potential conflict points where an initial comment such as "I want this to be safe for you/me/our community", will reset the conversation to one involving safety.
# Patient Safety
Practitioner Safety Community Safety
#
The principles of the Guidelines and Protocols Advisory Committee are to:
• encourage appropriate responses to common medical situations • recommend actions that are sufficient and efficient, neither excessive nor deficient • permit exceptions when justified by clinical circumstances
# Contact Information:
Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 Email: hlth.guidelines@gov.bc.ca Website: www.BCGuidelines.ca
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This guideline is based on scientific evidence current as of effective date.
The guideline was developed by the Guidelines and Protocols Advisory Committee and adopted by the Medical Services Commission.
For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook.
# Appendix A: Overarching Considerations of Pain Management
# Communication and Relationship Building
Self-reflection and Learning • Reflect on potential bias or stigma related to treating complex pain patients. Treating patients with complex pain is challenging and can be frustrating. Recognize your own triggers and be aware of one's own bias towards people in pain in general and specific patients in pain. Consider strategies for responding in a way that can create more successful relationships. • Reflect on your current pain management practices and consider both new approaches and the reassessment of previous strategies that may have been less effective. A trauma-informed approach for all patients can be beneficial, regardless of their trauma history • In this case, trauma is defined as the psychological effects of a life event (or events) that is/are out of an individual's control and overwhelms an individual's capacity to cope. 21,22 As such, trauma refers to the psychological impact of events rather than to the acute physical trauma (e.g., car accident). • The aim of trauma-informed practice recognizes the impact on health and uses a strengths-based approach to build a safe, trusting, and collaborative relationship between patient and provider. • Consider reframing your perspective. Practitioners who apply a trauma-informed approach may find it helpful to think 'What happened to you?' when reflecting on complex, challenging patients instead of 'What's wrong with you?' . • Refer to BC Trauma-Informed Practice Guide for more information about trauma-informed practice. The learning module addresses strategies primary care providers can use to identify patients who have been impacted by trauma, to provide additional support, and to help patients build resilience. • Recognize the patient as an expert in their pain. Consider a person-centred approach to empower patients.
• Focus on actively listening to and validating the patient's experience of pain.
• Use evidence-informed tools to assess the level of suffering and disability that the patient with pain is experiencing.
• Engage the patient in shared decision making and work together to integrate the values, goals, and concerns of the patient with the best available evidence about the benefits, risks of the treatment and/or care. The objective advice and expertise of the practitioner and the preferences of the patients should work in a complimentary manner to achieve an optimal decision to decrease suffering, improve function, and general wellbeing.
# Appendix B: Non-pharmacological Treatment Modalities for Pain
Lifestyle Interventions and Strategies 23 A good overall management tool for non-pharmacological management can be found at the CEP Management of Chronic Non-Cancer Pain: Non-Pharmacological Therapies.
# Nutritional Support
• Nutrition plays a key role in fighting infection, healing, managing chronic conditions that involve pain, and optimizing overall health and well-being. 24,25 The evidence base for therapeutic diets varies depending on the condition. • Emerging research suggests an association between some chronic pain conditions such as fibromyalgia and a disordered gut "microbiome" (the totality of microorganisms including bacteria, viruses, protozoa and fungi). Understanding of the role of gut microbiota in pain is still in the early stages with varying levels of support, though emerging evidence suggests that dysregulation of gut microbiota participates in visceral pain, inflammatory pain, neuropathic pain, migraine and opioid tolerance. 26 • Consider the impact of acute and chronic pain on the patient's ability to plan, shop for, and prepare healthy meals. Pain can also impact appetite, dietary intake, and nutritional status. • Registered Dietitians at HealthLink BC (8-1-1) offer nutrition assessments, advice and guidance, counselling, care plans and therapeutic diets care coordination.
# Sleep
There is increasing evidence that pain and sleep have a bidirectional relationship. Poor sleep commonly occurs in those with chronic pain and may in turn lead to additional fatigue and exacerbate pain. 27 both non-pharmacological and pharmacological interventions can help those with pain obtain a better sleep. 8,27 When appropriate, assess for obstructive sleep apnea. The Centre for Effective Practice (CEP) has a well-resourced and pragmatic tool for primary care clinicians to assist patients with chronic insomnia. cep.health/clinical-products/insomnia-management-of-chronic-insomnia-tool/ "Say Good Night to Insomnia" by Dr. Gregg Jacobs is an excellent patient resource for a drug free approach to chronic insomnia.
# Breath
Pain, especially acute pain, can cause breath holding and hyperventilation which may accentuate the pain. More consideration is now being given to the importance of "breath work" as an integral component of self-management of pain. 28,29 While the exact mechanism is not well understood, the effect of "paced slow deep breathing" on vagal nerve stimulation may contribute to modulating pain as well as improving the V/Q match and improving oxygenation. See Resources: Resources for Patients for breathing techniques and integration with meditation and yoga practices. The Victoria Hospice Society has an excellent pdf summary of breathing and relaxation techniques. (victoriahospice.org/wp-content/uploads/2019/07/26188-vichospice_relax_bro_sept14)
# Mindfulness-Based Interventions
• Mindfulness meditation is demonstrated to work by paying attention, on purpose, in the present moment and nonjudgementally, and increasing awareness of one's external surroundings and inner sensations, allowing the individual to step back and reframe experiences. 30 Clinical use of mindfulness has included applications in substance use disorders, tobacco cessation, stress reduction, and treatment of chronic pain. 30 The goal of this approach is to reduce pain, increase functioning and improve the quality of life, by empowering the patient with skills to live a productive life despite the presence of discomfort or disability. • Multiple reviews of mindfulness interventions suggest there are varying levels of evidence evaluating different outcomes. 30,31 • Refer to Pain Education material on Pain BC's Live Plan Be or the Toronto Academic Pain Medicine Institute for information on mind-body therapies and techniques. • Specific therapeutic approaches such as Cognitive Behavioral Therapy (CBT) and Acceptance and Commitment Therapy (ACT) are good options to consider for some patients.
# Physical Activity and Therapeutic Movement
• Recent systematic reviews suggest physical activity alone can decrease severity of pain and improve physical function in adults with chronic non-cancer pain. 32 Physical activity can improve symptoms of stiffness 33 , fatigue 34 , health-related fitness 33 , and/or quality of life 34,35 in those with fibromyalgia and depression as well as self-efficacy and social function for patients with chronic hip and knee pain from osteoarthritis. 36 • The main goal is restoration of movement and activity. There is no optimal type of physical activity for chronic pain 37
# Appendix C: Allied Health Professionals to Support Pain Management
The following is a summary of allied health professionals and evidenced-based approaches. Evidence summaries, tools, resources for practitioners and patients are available in CADTH: Non-Drug Ways to Manage Chronic Pain and Agency for Healthcare Research and Quality: Non-invasive Nonpharmacological Treatment for Chronic Pain.
• Acupuncture or TENS: Evidence for reducing pain, mitigate withdrawal side effects. [38][39][40] Acupuncture may be beneficial in certain conditions 41 as well as other Traditional Chinese Medicine techniques, including cupping and massage.
• Chiropractic Services: Pain related to musculoskeletal and axial pathology (both acute and chronic) may respond to chiropractic treatment.
• Occupational Therapy: Referral highly recommended when a patient's function in daily activities is disrupted by pain (e.g., the ability to take care of themselves, family/home responsibilities, work, school, etc).
• Physiotherapy: For active acute musculoskeletal type injuries; some physiotherapists may have skills at managing chronic pain. Evidence for an activity/exercise plan. Passive modalities i.e., hot compresses and use of TENS machines can complement and not replace the mobility programs. Active Release Therapy (ART), and targeted manipulation are two of common techniques that manual therapists may utilize for reducing pain and increasing joint mobility.
• Registered Massage Therapy: Help in desensitizing affected areas and helping to restore and/or maintain optimum movement and function.
• Osteopathic Therapy: Osteopathy follows the principle that there is a strong relationship between structure and function of the body. As the body possesses its own self-healing mechanisms; manual osteopathy aids these mechanisms by using techniques to restore the body to harmony with the aim of relieving pain and improving mobility.
• Psychological Services: Patients with chronic pain very often have depression and anxiety. Useful for improved selfmanagement, goal setting, sleep hygiene; specific approaches including CBT and ACT, PTSD counselling, mindfulness and biofeedback. Consider when chronic pain has other variables such as relationship instability, financial and work insecurity, past traumas, or other medical co-morbidities. Eye Movement Desensitization and Reprocessing (EMDR) therapy has shown promise especially in patients with PTSD or past trauma.
• Social Work: Provide a safe supportive environment to deal with issues such as work impacts, personal and social relationships, accessing benefits, drug and alcohol misuse and cultural perspectives.
• Traditional Healers: For many Indigenous people and others from different cultural backgrounds, the continuity of their community culture and the inclusion of traditional healing will add a layer of support to the management of pain. This is rarely an either/or decision, rather an exploration of ways to complement the on-going plan. This may already be going on "in the background" if the patient is unsure of the reaction of other caregivers, so ask about what resources are available through their own Indigenous/cultural community.
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Background and Aims: Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. Methods: We performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator and outcome questions were developed through an iterative process and were voted on by a group of specialists. Results: The certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75 selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea and Crohn's disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn's disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review and reinvestigation for patients whose symptoms persist despite BAST. Conclusions: Based on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with cholestyramine, is suggested.#
Diarrhea is a common symptom in the general population of developed countries. Among community-dwelling persons the 1-month rate of diarrhea was 7.6% in Canada and the United States, 6.4% in Australia and 3.4% in Ireland; approximately 20% of subjects sought medical care for this symptom (1). The prevalence of chronic diarrhea has been estimated to affect approximately 5% of this population overall (2), and may be higher among older individuals (3).
The most common causes of chronic diarrhea in clinical practice are functional disorders (e.g., irritable bowel syndrome ), and inflammatory diseases (e.g., Crohn's disease, celiac disease) (3). However, a common but frequently underdiagnosed cause of chronic diarrhea is dysregulated bile acid recycling within the enterohepatic circulation: either excessive biosynthesis/secretion of bile acids, or malabsorption of bile acids by the ileum. Unabsorbed bile acids in the colon appear to cause diarrhea by stimulating fluid, mucus, or sodium secretion; increasing gastrointestinal motility; damaging the mucosa or stimulating defecation (3,4).
Three subtypes of bile acid diarrhea (BAD) have been described: type 1, patients with terminal ileal disease (e.g., Crohn's disease, resection) or radiation injury resulting in impaired reabsorption of bile acids; type 2, idiopathic or primary; and type 3, other conditions (e.g., celiac disease, cholecystectomy) that alter intestinal motility or bile acid absorption (3,5). BAD has been reported in approximately 25% to 35% of patients with chronic diarrhea or diarrhea-predominant IBS (IBS-D) (6). Rates are even higher in patients with underlying terminal ileal disease, or other conditions such as cholecystectomy.
The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests (discussed later). Although a treatment trial with bile acid sequestrant therapy (BAST) often is used, this approach has not been studied adequately, and likely os imprecise, and may lead to both under-treatment and overtreatment. Specific diagnostic tests are under investigation, particularly radiodiagnostic measurement of bile acid pool loss with 75 selenium homocholic acid taurine (SeHCAT; GE Healthcare Canada, Inc, Ontario, Canada), or measurement of serum levels of biomarkers of bile acid synthesis including 7α-hydroxy-4-cholesten-3-one (C4) or the ileal regulatory hormone, fibroblast growth factor 19 (FGF19). SeHCAT testing is unavailable in some countries (including the United States).
BAD generally is not cured, and as is the case with many chronic gastrointestinal diseases or disorders, many patients will require lifelong treatment (7,8). Treatment is generally with BAST, but also is dependent on the underlying causes of BAD, severity of symptoms or the presence of other comorbid illnesses (e.g., Crohn's disease, celiac disease).
BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment. There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association (9), and the British Society of Gastroenterology (10), but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults (11), published after the consensus meeting, addressed some issues related to BAD.
The purpose of this guideline is to critically review the literature relating to diagnostic testing, and the induction and maintenance treatment of BAD, with the aim of developing specific consensus recommendations for patients with BAD.
# Methods
# Scope and Purpose
These consensus statements focused on specific issues pertaining to the medical management of BAD, which the participants and GRADE experts (F.T., G.I.L.) identified a priori.
# Sources, Literature Searches and Systematic Reviews
The Editorial Office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University performed a systematic search of Medline, Embase, and the Cochrane Central Register of Controlled Trials for literature published between 1990 and September 2017. Key search terms were as follows: bile acid, cholecystectomy, cholestyramine, colestipol, colesevelam, diarrhea, loperamide, malabsorption, resection, SeHCAT and sequestrants. An additional search of the databases for SeHCAT trials published before 1990 (database inception as start date) also was performed. Only human studies published in English were considered. Further details of the search strategies are provided in Supplementary Appendix 1.
# Assessment of the Certainty (Quality) of Evidence
Before the face-to-face meeting, the statements were converted to specific patient population, intervention, comparator and outcome (PICO) questions by the two nonvoting methodologists (F.T., G.I.L.). The overall certainty of evidence (CoE) was determined using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach (12) to assess risk of bias (of individual studies and overall across studies), indirectness, inconsistency, imprecision, as well as other considerations (including publication bias). As described in GRADE (12,13) and used in previous consensus guidelines from the Canadian Association of Gastroenterology (CAG) (14)(15)(16)(17)(18), CoE was graded as very low, low, moderate or high. GRADE evaluations for each statement were provided before the consensus meeting and discussed during the consensus meeting.
The consensus group agreed that four statements (Statements 11, 13, 14 and 17) met GRADE criteria for good practice statements that these recommendations were clinically obvious, and that collection and GRADE assessment of evidence Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1 e11 for these statements was not a good use of resources (19).
Although formal GRADE evaluations were not performed, details of these statements are provided in the text. Approved product labeling from government regulatory agencies varies from country to country, and although not ignored, recommendations are based on evidence from the literature and consensus discussion and may not fully reflect the product labeling for a given country.
# Consensus Process
A face-to-face consensus meeting was held in Toronto, Canada, in February 2018. The international consensus group comprised five voting gastroenterologists (including the chair: D.C.S.), from Canada, the United States and the United Kingdom. Other participants included a nonvoting moderator ( J.K.M.), the two GRADE experts (F.T., G.I.L.) and a nonvoting observer.
The consensus process was facilitated by the CAG via a webbased consensus platform (ECD Solutions, Atlanta, GA). The platform allowed consensus participants to review results of the initial literature searches and select and link the references to specific statements. Copies of the selected references were available to all members of the consensus group. The full consensus group voted anonymously on their level of agreement with the individual statements using a modified Delphi process (20,21). Participants suggested revisions and commented on the statements, after which, the specific statements were revised through two iterations.
At the 1-day consensus meeting, evidence for each of the PICO questions was presented, after which an Evidence-to-Decision framework was completed (22). Each PICO question was discussed and revised, and voting members anonymously indicated their level of agreement on a scale of 1 to 5. In favour of a specific strategy was defined as 75% or more of votes being 5 (strongly yes) or 4 (yes). A vote against the strategy was defined as 75% or more of votes being 1 (strongly no) or 2 (no). A vote of 3 indicated neutrality. Once reaching agreement on the PICO question, the strength of the recommendation (strong versus conditional) was determined based on the following four components: (i) CoE, (ii) benefit/harm balance, (iii) patients' values/preferences and (iv) resource requirements (23). When the CoE was low or very low, unless at least one of the other three factors was overwhelmingly strong, the strength of the recommendation typically would default (without a vote) to conditional, using the phrasing 'we suggest' . If the statement warranted a vote, and 75% or more of participants voted as strong, then the recommendation would be designated as strong and the phrasing contained 'we recommend' .
During the meeting, consensus was not reached on four of the PICO questions; therefore, no statement was developed and no recommendations were made. Evidence and subsequent discussion pertaining to these four questions is summarized briefly in the text.
The manuscript was drafted initially by the meeting chair (D.C.S.), and then reviewed and revised by the remaining members of the consensus group. The manuscript then was made available to all CAG members for comment over a 2-week period before submission for publication.
In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months before the consensus meeting were provided by all participants, reviewed by the CAG ethics committee and made available to all group members.
# Recommendation Statements
The individual recommendation statements are provided and include the strength of recommendation and certainty of supporting evidence (according to the GRADE approach), and the voting result. This is followed by a discussion of the evidence considered for the specific statement. A summary of the recommendation statements is provided in Table 1. See Supplementary Appendix 1 for detailed CoE assessments (including a description of the study limitations, inconsistency, indirectness, imprecision and publication bias) and the Evidence-to-Decision frameworks.
# Diagnosis of BAD
# Key Evidence
No published randomized controlled trials (RCTs) were available comparing the clinical impact of using versus not using risk factors or symptom presentation for the diagnosis of BAD, therefore evidence from observational, diagnostic test accuracy (DTA) studies was evaluated. Overall, studies have shown that history of terminal ileal resection, cholecystectomy or radiotherapy are the risk factors associated most commonly with having a positive SeHCAT test suggestive of a BAD diagnosis (Table 2) (24-30).
# Statement 1. In patients with chronic nonbloody diarrhea, we recommend using risk factors (history of terminal ileal resection, cholecystectomy, or abdominal radiotherapy) as the initial assessment to identify patients with possible BAD.
GRADE: Strong recommendation, very-lowcertainty evidence. Vote: on PICO question: strongly yes, 60%; yes, 40%.
# Statement 2. In patients with chronic nonbloody diarrhea, we suggest against using symptom presentation as the initial assessment to identify patients with possible BAD.
GRADE: conditional recommendation, verylow-certainty evidence. Vote: on PICO question: no, 100%.
# e12
Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1 No symptoms have consistently been predictive of a greater likelihood of having SeHCAT-diagnosed BAD among patients with chronic diarrhea. Rates of abdominal pain or discomfort, distension, bloating, flatulence and urgency, were similar or less frequent among patients with BAD and those with diarrhea resulting from other causes (24,(31)(32)(33). Some studies have reported an association between stool weight, consistency or frequency, and a higher risk of BAD among patients with chronic diarrhea, but no diagnostic accuracy data, or definitions, are available (7,(31)(32)(33)(34)(35).
All studies had either a high or unclear risk of bias, inconsistency (with respect to the specific symptoms and clinical characteristics as risk factors for BAD) and imprecision.
# Discussion
In patients presenting with nonbloody chronic diarrhea or IBS-D, rates of SeHCAT retention suggestive of BAD are much higher in those with risk factors compared with those in whom other possible causes have been excluded. Rates of Maintenance therapy for BAD (BAST) Statement 16. In patients with BAD and recurrent or worsening symptoms despite stable BAST, diagnostic re-evaluation should be conducted. Designated a good practice statement Statement 17. In patients being considered for BAST, a review of concurrent medications should be conducted to minimize the potential for drug interactions. Designated a good practice statement
# Statements with no recommendations
No recommendation A. In patients with chronic diarrhea including IBS-D and functional diarrhea, the consensus group could not make a recommendation for or against the use of FGF19 assay to identify possible BAD. GRADE. NO recommendation, very-low-certainty evidence. Vote on PICO question: strongly yes, 20%; neutral, 80%. No recommendation B. In patients receiving long-term maintenance therapy with BAST, the consensus group could not make a recommendation for or against measuring fat-soluble vitamin levels at baseline and annually thereafter. GRADE. NO recommendation; very-low-certainty evidence. Vote on PICO question: yes, 20%; neutral, 80%.
The strength of each recommendation was assigned by the consensus group, per the GRADE system, as strong ("we recommend... ") or conditional ("we suggest... "). A recommendation could be classified as strong despite low-certainty evidence to support it, or conditional despite the existence of high-certainty evidence due to the 4 components considered in each recommendation (risk:benefit balance, patients' values and preferences, cost and resource allocation and certainty of evidence).
BAD, bile acid diarrhea; BAST, bile acid sequestrant therapy; C4, 7α-hydroxy-4-cholesten-3-one; FGF19, fibroblast growth factor 19; GRADE, Grading of Recommendation Assessment, Development and Evaluation; IBS-D, diarrhea-predominant irritable bowel syndrome; PICO, patient population, intervention, comparator, and outcome; SeHCAT, 75 selenium homocholic acid taurine; SIBO, small intestinal bacterial overgrowth. (24,26,29), rates of at least moderate BAD (SeHCAT retention, <10%) were 19% to 39% (6,25,34,36) compared with 38% to 58% (24,26,29), and rates of at least mild BAD (SeHCAT retention, <15%) were 24% to 27% (6,24,36) compared with 46% to 68% (24,26,29). The risk factors most commonly identified are shown in Table 2. In patients with ileal resection, BAD appeared to be independent of resection length; resections of less than 10 cm were sufficient to cause BAD (26).
The potential harms of using clinical risk factors as a triage test for BAD could include overdiagnoses leading to unnecessary diagnostic tests and/or treatments, or underdiagnoses leading to ongoing patient suffering. In patients with ileal resection, there is an extremely high risk of BAD, and diagnostic testing may not be necessary before treatment, whereas patients with chronic diarrhea after a cholecystectomy or after radiotherapy may warrant diagnostic tests. No consistent correlation has been found between the length of resection and SeHCAT retention, therefore, all patients should be considered at high risk after resection (25,26,37).
Other conditions such as diabetes, pancreatitis, small intestinal bacterial overgrowth (SIBO), microscopic colitis, vagotomy and celiac disease have been associated occasionally, but not consistently, with an increased risk of BAD (26,38).
No symptoms have been identified that reliably will predict a diagnosis of BAD. In fact, data suggest that reliance on symptoms can lead to underdiagnosis in clinical practice; one survey found that 44% of patients reported they had experienced symptoms for more than 5 years before diagnosis (39). Although symptom presentation is inaccurate for BAD, it continues to play a role in the differential diagnosis to rule out other conditions.
Based on the available data, the consensus group recommends that in patients with chronic nonbloody diarrhea, a history of terminal ileal resection, cholecystectomy or radiotherapy, but not symptom presentation, be used during the initial assessment to help identify patients with BAD.
# Key Evidence
Data on the diagnostic accuracy of the SeHCAT retention test (as an initial test for diagnosis) were derived from two prospective DTA studies, both conducted by Sciarretta et al. (37,40) in Italy. These were designed as case-control studies to assess the ability of SeHCAT retention to discriminate between cases and controls. However, using other secondary results, a 2013 Health Technology Assessment calculated the diagnostic accuracy of SeHCAT retention for predicting the response to BAST (41). In the first study, the sensitivity and specificity of SeHCAT retention (cut-off value, <5%) were 85.7% (95% confidence interval , 42.1 to 99.6) and 100% (95% CI, 54.1 to 100), respectively, in a subgroup of patients (n = 13) with diarrhea without evidence of intestinal or extraintestinal pathology (37,41). The second study, which included 46 patients with IBS-D or cholecystectomy, found the sensitivity and specificity of SeHCAT retention (cut-off value, <8%) were 95.0% (95% CI, 75.1 to 99.9) and 96.2% (95% CI, 80.4 to 99.9), respectively (40,41). In both studies, a response to BAST was defined as the disappearance of diarrhea. No studies were found that measured the diagnostic accuracy of SeHCAT in patients with chronic diarrhea, which avoided a case-control design and used a proven reference standard (because there is currently no such reference standard, apart from the surrogate response to BAST).
Both DTA studies were found to be at serious risk of bias with respect to the index tests and reference standards used, serious indirectness of the study populations and index tests, and very serious imprecision as a result of the very small sample sizes, and the lower limit of the CI crossing the threshold for a clinically useful diagnostic test. This suggests that the data are insufficient to support or refute the clinical utility of SeHCAT in patients with IBS-D. Therefore, other factors and indirect supportive evidence were considered.
# Discussion
Overall, the CoE for the diagnostic accuracy of SeHCAT was determined to be very low. As discussed in Statement 1, the prevalence data suggest that up to 40% of patients with functional diarrhea or IBS-D may have at least moderate BAD as assessed by a SeHCAT cut-off value less than 10% (6,25,34,36).
In addition, a systematic review (SR) including 15 observational studies showed a correlation between the severity of SeHCAT loss and response to treatment with BAST: response to cholestyramine was 96% in patients with less than 5% retention, 80% at less than 10% retention and 70% at less than 15% retention (6). This was not confirmed by a newer SR of 21 studies that found response rates with BAST of 67% at less than 5% retention, 73% at less than 8% to 11.7% retention and 59% at less than 15% retention (42). However, one study (26) published after the earlier SR, which included a large number of patients
# Statement 3. In patients with chronic diarrhea including IBS-D and functional diarrhea, we suggest SeHCAT testing to identify patients with BAD. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: strongly yes, 20%; yes, 80%.
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with secondary BAD, made a disproportionately large contribution to the group with less than 5% retention in this second analysis. Response rates were much lower in patients with negative SeHCAT tests; only 15% of patients had a good or partial response compared with 65.6% of patients with a SeHCAT retention less than 15% (29). A study has been proposed to evaluate the diagnostic accuracy of SeHCAT retention in which the test result will be concealed from clinicians and patients, and all patients will receive BAST (43).
Cost effectiveness and feasibility also were considered. The Health Technology Assessment assessed the cost effectiveness of SeHCAT testing compared with response to BAST based on data from three small trials and rather limited assumptions (41). They concluded that for the short term (first 6 months), the optimal choice between SeHCAT testing and no SeHCAT testing depended on willingness to pay, but that a trial of BAST would be more cost effective. From the long-term perspective, the optimal choice was a trial of BAST, no SeHCAT testing, or SeHCAT testing with a cut-off retention value of less than 15% depending on the scenario. Feasibility can be an issue in some areas because nuclear medicine facilities or the isotope may not be available.
BAST has poor tolerance and a high dropout rate; a positive SeHCAT test may have the additional benefit of providing the clinician with a stronger argument to encourage patients to stay on therapy when a definite diagnosis of BAD has been made (44). Other factors to consider are the potential harms of SeHCAT use, such as radiation risk, patient inconvenience and anxiety and loss of opportunity to use BAST in cases of falsenegative results. Cut-off values to initiate treatment are sometimes inconsistent (45), and the role of borderline SeHCAT retention in therapeutic decisions is ill defined.
Taking all of these issues together, the consensus group concluded that SeHCAT retention is a relatively safe test, BAST is a relatively safe treatment (although poorly tolerated), and the anticipated benefit of SeHCAT retention testing likely outweighs the uncertainty of the evidence. Although other tests show promise for the future, SeHCAT retention has been the most widely tested, with consistent results.
# Key Evidence
An observational cohort study included a subgroup of 44 patients with unoperated Crohn's disease in clinical remission (other than diarrhea) who had normal hematology and C-reactive protein levels (28). SeHCAT retention was abnormal (<10%) in 54% of patients. Of the 24 patients with abnormal SeHCAT retention, 20 received initial conventional treatment (prednisolone ± mesalamine), followed by BAST when conventional treatment failed. Response rates were 55% with conventional treatment, and 40% with BAST, with 5% failing both treatments. The treatment duration and outcome assessments, as well as the use of BAST in patients with normal SeHCAT retention, were not clearly described. The diagnostic accuracy and the effects of using test results to inform management choices could not be calculated because of the lack of a control group.
The CoE was downgraded to very low because of a very serious risk of bias (with regard to the reference standard, patient flow and timing) and very serious imprecision (very small sample size).
# Discussion
Although there is very-low-certainty evidence supporting the use of SeHCAT testing to guide management decisions in patients with Crohn's disease, testing may play a role in patients with ileal Crohn's disease in complete remission who have ongoing chronic diarrhea.
Observational studies have suggested that almost half of the patients with ileal Crohn's disease who have not undergone resection will have a positive SeHCAT, suggestive of a diagnosis of at least moderate BAD (Table 3) (25,26,28,29). These patients may have a two to four times greater likelihood of having a positive SeHCAT compared with having a negative test (25,29).
Given the association between positive SeHCAT testing and response to BAST in patients with Crohn's disease who continue to have persistent diarrhea despite conventional treatments, the consensus group made a conditional recommendation in favour of SeHCAT testing in patients with Crohn's disease who have no objective evidence of active inflammation.
# Key Evidence
The majority of published DTAs compared C4(46-48) and FGF19 (32,49,50) assays with SeHCAT testing. These showed good inverse correlation between C4 and SeHCAT testing, and between FGF19 and SeHCAT testing, however, the overall CoE for the diagnostic accuracy of SeHCAT was assessed for Statement 3 and determined to be very low. Therefore, the true diagnostic accuracy of these tests cannot be estimated from these studies.
One study assessing C4 and FGF19 assays used direct measurement of 48-hour fecal bile acid as a reference standard (51). This prospective DTA study included 30 patients with IBS-D who had replicate C4 and FGF19 samples 5 years apart that could be compared with fecal bile acid levels. When patients with a prior cholecystectomy were excluded, the sensitivity and specificity of serum C4 were 40% and 85%, respectively, with a 40% positive predictive value and an 85% negative predictive value for the diagnosis of BAD. For FGF19, the sensitivity and specificity were 20% and 75%, respectively, with a 17% positive predictive value and a 79% negative predictive value for the diagnosis of BAD.
The CoE was downgraded to very low because of the moderately serious risk of bias and very serious imprecision (CI lower limits crossed the threshold for clinically useful diagnostic tests, small sample sizes) in the DTA that used fecal bile acid levels as the reference standard (51). Similarly, there was very serious risk of bias and serious indirectness in the studies that used SeHCAT retention as the reference standard.
# Discussion
Although there appears to be a good correlation (inverse) between C4 and SeHCAT results, and between FGF19 and SeHCAT results, SeHCAT retention has not been validated adequately as a reference standard. Theoretically, C4 and FGF19 should be good markers of bile acid loss. C4 is a metabolic intermediate in the rate-limiting step for the synthesis of bile acids from hepatic cholesterol. FGF19 is a hormone released by ileal enterocytes after stimulation of nuclear farnesoid X receptors, typically by absorbed bile acids. Both markers have been correlated with fecal loss of bile acids (Figure 1) (51-53). In addition, FGF19 levels have been shown to correlate with C4 levels (54).
Currently, there are no well-defined cut-off values for the diagnosis of BAD. In one prospective study, a C4 level of 52.5 ng/ mL or greater and a FGF19 level of 61.7 pg/mL or less were diagnostic for BAD (51). Other observational studies have used cut-off values of 30 to 48 ng/mL for C4 (46,55). One study found a wide range of normal values for C4 (corrected for cholesterol) from 0.76 to 8.0 mg/mol and for FGF19 from 48 to 343 pg/mL (33).
# Statement 5. In patients with chronic diarrhea including IBS-D and functional diarrhea, we suggest using a C4 assay to identify possible BAD. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: strongly yes, 20%; yes, 60%; neutral, 20%.
# No recommendation A: In patients with chronic diarrhea including IBS-D and functional diarrhea, the consensus group could not make a recommendation for or against the use of the FGF19 assay to identify possible BAD. GRADE: No recommendation, very-lowcertainty evidence.
Vote: on PICO question: strongly yes, 20%; neutral, 80%.
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Insufficient evidence is available with C4, and even less with FGF19. In addition, the FGF19 assay was not available as a commercial clinical test at the time of the meeting, which impacts the feasibility of implementing that test. Therefore, the consensus group made a conditional recommendation in favour of C4, but was unable to make a recommendation for or against the use of the FGF19 assay to identify BAD.
# Key Evidence
No direct comparative or DTA studies were found to inform this statement. As described in Statement 3, the two studies on the diagnostic accuracy of SeHCAT testing for predicting response to BAST yielded very low-certainty evidence in favour of using SeHCAT testing (37,40). The cost-effectiveness analysis included in the Health Technology Assessment conducted by Riemsma et al. (41) found that in the short term, a trial of BAST may be the optimal choice. However, over the long term, the optimal choice (trial of BAST, no SeHCAT testing, or SeHCAT at a cut-off retention value 15%) varied depending on the scenario. The analysis provided very low CoE regarding the optimal strategy.
# Discussion
There is very little evidence to determine the relative role of testing with SeHCAT testing versus using an empiric trial of BAST to make a diagnosis of BAD. Other factors were considered when making a conditional recommendation against empiric treatment.
A poor response to a therapeutic trial of BAST could be related to noncompliance and early discontinuation, which could result in a falsely negative diagnosis with patients being denied other effective alternative BAST that may be better tolerated (38,56). As discussed in Statement 3, a definitive diagnosis of BAD may help educate and motivate patients to adhere to treatment (38,44).
Conversely, in patients in whom there is a very high index of suspicion (in whom a positive SeHCAT test is found in >90%), such as terminal ileum resection or right hemicolectomy, early initiation of therapy may be preferred. In addition, although a test-and-treat strategy was preferred for most patients, it was recognized that SeHCAT testing or other diagnostic tests are not available in some areas. In these cases, a trial of BAST may be the only option.
# Induction Therapy for BAD
# Key Evidence
No RCTs or directly applicable cohort studies were identified in which treatment for remediable causes was compared with BAST in patients with type 1 or type 3 BAD. A cohort study (described in Statement 4), included subgroups of patients with IBS-D (n = 65, n = 40 treated) and unoperated Crohn's disease in clinical remission (other than diarrhea, n = 24, n = 20 treated) who were diagnosed with BAD (SeHCAT retention, <10%) (28). The rates of response to initial conventional treatment (prednisone ± mesalamine for Crohn's disease patients, or antidiarrheal agents for non-Crohn's disease patients) were 55% among treated Crohn's disease patients, and 15% among treated IBS-D patients. Conventional therapy followed by BAST was successful in 40% of treated Crohn's disease patients and 70% of treated IBS-D patients.
This study lacked a control group and blinding, and had a subjective outcome measure. No evidence was found for other conditions (e.g., microscopic colitis, SIBO). The CoE was downgraded to very low because of serious risk of bias, indirectness and imprecision.
# Discussion
Little data were available to define the role of other non-BAST treatments in patients with BAST and comorbid conditions. Specific treatments for comorbid conditions that may cause diarrhea (e.g., Crohn's disease, microscopic colitis, SIBO) may achieve control of diarrhea and other symptoms, but, conversely, this may delay BAST for BAD. In addition, depending on the condition, the treatment (e.g., corticosteroids, immunosuppressive agents, biologics or antibiotics) may be associated with more risks or side effects than BAST treatment, and the investigations may be more invasive and costly (e.g., colonoscopy).
# Statement 6. In patients with suspected BAD, we suggest against initiating empiric BAST over performing SeHCAT to establish a diagnosis of BAD. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question (in patients with suspected BAD, should we initiate empiric BAST over performing SeHCAT to establish a diagnosis of BAD?): yes, 20%; no, 40%; strongly no, 40%.
# Statement 7. In patients with type 1 or type 3 BAD, we suggest the use of treatments for remediable causes (e.g., Crohn's disease, microscopic colitis, SIBO) in addition to treatment for BAD for induction of clinical response. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: strongly yes, 80%; yes, 20%.
# e18
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As mentioned in Statement 4, patients with Crohn's disease with continuing diarrhea have a high rate of BAD. These patients were still more likely to benefit from conventional treatment, although some did benefit from BAST (28).
Some studies have suggested that BAD and collagenous colitis are associated, but likely are independent diseases (57)(58)(59). In case series of collagenous colitis, BAST improved symptoms, but had no effect on histopathology (57). In another case series, 86% of patients with microscopic colitis who had BAD benefited from BAST, whereas no patients with collagenous colitis without BAD improved (59). The etiology of microscopic colitis is not well defined, and may include infectious agents, medications, or other causes in some patients, which may require other specific treatments. Other treatments that may be beneficial include corticosteroids, antibiotics, antidiarrheal agents or immunosuppressive therapies (59,60).
In a large case series, 36% of patients with SIBO who were tested had SeHCAT retention less than 10% (26). These patients may benefit from BAST, but antibiotic therapy is the current standard for SIBO (61). The etiology of SIBO is very complex and may involve disorders of protective antibacterial mechanisms, anatomic abnormalities, or motility disorders. Patients with SIBO require treatment of the underlying disease, as well as nutritional support (62).
Although there is little evidence to guide therapeutic decisions, in patients with comorbid conditions, BAD may not be the sole cause of symptoms. Although some patients will respond to BAST for BAD, others might not, or may have other symptoms in addition to diarrhea that will not benefit from BAST. Therefore, the consensus group agreed that it was prudent to individualize therapy and address other remedial causes of gastrointestinal symptoms, with the order of therapy guided by severity of each condition.
# Key Evidence
One RCT compared cholestyramine with hydroxypropyl cellulose (HPC) (63). Although HPC was chosen as a placebo, it may be pharmacologically active, and a small case series suggested it may be effective in BAD (63,64). The RCT was an 8-week study in 26 patients with chronic functional watery diarrhea or IBS-D, of which 77% of the cholestyramine-treated and 54% of HPCtreated patients had a SeHCAT retention rate of 10% or less (63). There was no significant difference in clinical remission rates (defined as <3 bowel movements/d over 1 week, with <1 watery stool/d) between treatments (53.8% versus 38.4%; P = 0.43). However, there was a significant improvement in the decrease in watery stools per day (−92.4% ± 3.5% versus −75.8% ± 7.1%; P = 0.048). Because HPC binds bile acids and may have a bulking effect, it may have some efficacy for BAD (63)(64)(65)(66); this makes it difficult to interpret the lack of significant differences in clinical remission rates with HPC compared with cholestyramine.
A SR of 23 cohort studies including 801 patients with BAD found that first-line cholestyramine was successful in 69.8% of patients overall, 67% of those with SeHCAT retention less than 5%, 73% of those with SeHCAT retention less than 8% to 11.7%, and 59% of those with SeHCAT retention less than 15% (42). Study designs, patient populations, inclusion and exclusion criteria, diagnostic tests and cut-off values for BAD, cholestyramine dosing and timing of administration, and definitions of clinical response varied widely among the studies. An additional cohort study published after the SR reported a response rate of 56% with first-line cholestyramine in 87 patients with BAD (defined as SeHCAT <15%) (67).
Although the RCT found that the rate of drug-related adverse events did not differ between cholestyramine and hydroxypropyl cellulose (63), the SR of cohort studies reported that 11% of patients found cholestyramine intolerable because of unpalatability or side effects (range, 0% to 46%) (42). The most common side effects included abdominal bloating and pain, dyspepsia, nausea/vomiting, flatulence, borborygmi, abdominal distension, constipation and increased severity of diarrhea. In the additional cohort study, almost half (45%) of treatment failures were related to medication intolerance (67). However, both studies had no control group for comparisons, and relationships to the study drug were not assessed.
RCTs assessing the efficacy of cholestyramine compared with other BAST in patients with BAD were not found. Evidence for using cholestyramine over other BASTs as initial therapy considered other factors such as adverse events, clinical experience and cost. There is no direct evidence that cholestyramine is associated with more side effects than other BAST. However, an RCT of BAST for cardiovascular disease prevention reported higher rates of gastrointestinal side effects (55% versus 16%), and lower rates of compliance (53% versus 77%) with adjunctive cholestyramine compared with monotherapy with a statin (68). In contrast, a SR of 6 RCTs in patients with diabetes found
# Statement 8. In patients with BAD, we suggest using cholestyramine over no treatment for induction of clinical response. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: strongly yes, 60%; yes, 40%.
# Statement 9. In patients with BAD, we suggest using cholestyramine over other BASTs as initial therapy for induction of clinical response. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: yes, 80%; neutral, 20%.
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that adverse rates with adjunctive colesevelam were similar to placebo (relative risk, 1.06; 95% CI, 0.97 to 1.15), with the most common events with colesevelam being gastrointestinalrelated (e.g., constipation, dyspepsia and nausea) and minor in nature (69). The majority of clinical experiences with BASTs in BAD has been with cholestyramine, with few data on the other agents; in addition, colesevelam and colestipol tend to be more costly compared with cholestyramine. The overall CoE was very low. Very serious indirectness and serious imprecision were found in the RCT (63), with a serious risk of bias, indirectness and imprecision in the cohort studies (42,67).
# Discussion
Clear RCT evidence showing the benefits of BAST was not available, however, case series and SRs of observational studies support a dramatic and rapid response for many patients. Although no patient preference data were found, the high dropout rates in all of these studies suggest that some patients may place a greater value on being free of the side effects or unpalatability of cholestyramine compared with reduction in their diarrhea frequency or severity. However, because BAST targets the problem, the potential higher response rates in patients with more severe BAD (as measured by SeHCAT retention) ( 6) and the lack of response in patients who test negative for BAD (29) (see Statement 3), the consensus group suggested that patients with BAD receive treatment with BAST over no treatment. This was a conditional recommendation because of the very low CoE and poor tolerability profile, making it important to discuss the benefits and side effects with patients.
Although the consensus group suggested that cholestyramine be used initially over the other BAST agents (colesevelam or colestipol), there are few comparative data. Compared with cholestyramine, colesevelam has a four to six times stronger binding affinity to bile acids. It may be better tolerated and have fewer clinical interactions (67). The majority of clinical experiences to date are with cholestyramine, with a limited number of cases using other BAST agents (29,33,38,70). Response rates with first-line use of other BASTs have been reported at 67% with colesevelam (70) and 55% with colestipol (33). Although cholestyramine appears to be less costly than colesevelam or colestipol, the lack of comparative data casts doubt on whether cholestyramine should be preferred; therefore, this was a conditional recommendation.
# Key Evidence
No RCT data were available comparing alternate BASTs with either placebo or other treatments as second-line therapy in patients with BAD who are unable to tolerate cholestyramine. One RCT compared first-line colesevelam and placebo for BAD-associated diarrhea in 26 patients with Crohn's disease in remission (70). There was a statistically nonsignificant improvement in the primary end point (proportion of patients with >30% reduction of liquid stools/day) with colesevelam (66.7%) versus placebo (27.3%) based on intention-totreat analysis (risk difference, 0.394; 95% CI, −0.012 to 0.706; P = 0.0566). Colesevelam significantly improved the secondary end points of the reduction in the number of liquid stools per day and improvement in stool consistency compared with placebo. This trial did not assess colesevelam as second-line therapy, and had a very small sample size; therefore, the CoE was downgraded to low for serious indirectness and imprecision.
Additional evidence comes from a SR of four observational cohort studies (n = 63) that assessed the efficacy of secondline colesevelam after failure of cholestyramine and reported a success rate of 57% (range, 42% to 100%) (42). One other cohort study published after the SR included 15 patients who had not responded to cholestyramine and received secondline treatment with colesevelam (67). Of these patients, 47% had a successful response. The CoE from the observational trials was downgraded to very low for serious risks of bias and imprecision.
There is no direct evidence that colesevelam is associated with a higher or lower frequency of adverse effects than cholestyramine or other BASTs. In the RCT, colesevelam generally was well tolerated; adverse events were mild (constipation, bloating and nausea) and occurred in similar proportions to colesevelam and placebo groups (40.0% versus 36.4%) (70). For safety, the SR included one RCT and four observational cohort studies, and found that 9% were unable to tolerate colesevelam because of unpalatability or side effects (42). In the additional observational study, no patients reported treatment intolerance with colesevelam (67). As discussed in Statement 8, tolerability data for BASTs in nongastrointestinal conditions suggested high rates of gastrointestinal side effects with cholestyramine, while colesevelam had side effects rates similar to placebo (68,69).
There have been limited reports describing the use of colestipol as second-line therapy after failure of cholestyramine (42,71).
# Discussion
Case series data have suggested that patients who fail or are unable to tolerate cholestyramine may benefit from secondline BAST (29). In a large series of patients given one or Statement 10. In patients with BAD who are unable to tolerate cholestyramine, we suggest using an alternate BAST for induction of clinical response. GRADE: Conditional recommendation, lowcertainty evidence. Vote: on PICO question: strongly yes, 40%; yes, 60%.
# e20
Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1 more BAST, there were no significant differences in good/ partial response rates between the cholestyramine (74%) and colesevelam (73%). However, whether alternate BAST was used as first-or second-line therapy was not described (29). Although, not regulatory approved for BAD, use of second-line colesevelam in clinical practice appears to be quite common. In a survey of patients followed up for up to 13 years, 38% of respondents continued with cholestyramine, while 32% had switched to colesevelam (56). The consensus group agreed that compared with cholestyramine, colesevelam has a favourable benefit:risk profile and greater ease of administration (tablet versus granules/powder). However, because of the limited clinical experience and higher cost, it is suggested that it be reserved for second-line use.
# Key Evidence
Good practice statement, CoE not assessed.
# Discussion
In general, most cohort studies reported gradual dose titration for cholestyramine to clinical response (42,67). However, there was no mention of dose titration of colesevelam or colestipol.
In BAD studies, cholestyramine generally was started at a low dose of 2 to 4 g/day and titrated based on response (maximum, 4 to 24 g/day) (42,67). In an open-label study, the colestipol dose was initiated at 1 g twice daily, with an increase of 1 g/d every other day (33). In BAD studies, colesevelam has been prescribed in a dose of two tablets (625 mg) three times per day (70,72).
Product labeling for BAST agents recommends that cholestyramine be started at one 4-g dose daily and titrated to effect with a maximum of 24 g/day for all patients (73). Initiation of colestipol granules (tablets) is recommended at 5 g (2 g) either once or twice daily, increasing by 5 g/day (2 g once or twice per day), but no more frequently than 1 per month, with a maximum of 30 g/day (16 g/day). No dose titration is recommended for colesevelam. Colesevelam is dosed at 3.75 g/day as three 625-mg tablets twice daily, 6 tablets once daily, or one 3.75-g powder packet once daily. These colestipol and colesevelam doses are regulatory approved for cholesterollowering indications.
Generally, it is intuitive to gradually titrate medication to maximize symptom relief and minimize side effects. This is particularly relevant with BAST because of the high frequency of side effects and intolerance (42). Gradual dose titration of BAST may reduce the risks of side effects, increase compliance and potentially reduce costs.
# Key Evidence
There are no long-term studies assessing the safety of cholestyramine in patients with extensive ileal resection. It has been suggested that use of BAST in these patients can lead to an increased rate of steatorrhea (74,75). A small series of nine patients, in whom three had ileal resection greater than 100 cm and steatorrhea greater than 20 g/day, found that the use of cholestyramine led to a small decrease in diarrhea, but an increase in steatorrhea with substantial caloric loss (74,75).
# Discussion
It is unclear how extensive a resection is required to produce negative consequences with BAST. In the case reports, the risk of steatorrhea was increased in patients with resections of greater than 100 cm (74,75).
Other data have shown no correlation between the length of resection, SeHCAT retention and response to BAST. In case series of patients with ileal resection of up to 200 cm, the majority had severe BAD and responded to BAST (26,76,77). In one case series, the mean length of resection was not significantly different in patients who did or did not respond to BAST (35 versus 46 cm) (78).
SeHCAT testing in patients with large ileal resection almost universally will indicate severe bile acid wasting and is unlikely to be of discriminatory clinical value. Although there are very few reports of adverse consequences of BAST use in patients with extensive resection, the consensus group concluded that the risk of steatorrhea makes it prudent to err on the side of caution and avoid BAST in this patient group. Furthermore, there is concern that these patients may have extensive inflammatory disease that should be identified and treated with anti-inflammatory approaches rather than BAST. However, in some cases, the benefits may outweigh the risks, and patients should be evaluated on a case-by-case basis.
# Statement 12.
In patients with Crohn's disease with extensive ileal involvement or resection, we suggest against using BAST. GRADE: Conditional recommendation, verylow-certainty evidence. Vote: on PICO question (In patients with Crohn's disease with extensive ileal involvement or resection, should we use BAST vs no BAST?): yes, 20%; no, 80%.
# Statement 11. In patients with BAD receiving empiric BAST, gradual daily dose titration should be used to minimize side effects. Designated a good practice statement
Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1 e21
Maintenance Therapy for BAD
# Key Evidence
No studies were found that directly compared different dosing strategies in patients with BAD who had responded to BAST. Two small cohort studies suggested that for some patients, BAD symptoms could remain controlled with on-demand therapy or no therapy at all (7,8). In a prospective cohort study of patients with postcholecystectomy BAD, cholestyramine (2 to 12 g/day for 1-6 months) was effective in 23 of 26 patients, and 9 of 23 (39%) patients experienced recurrent diarrhea when treatment was withdrawn. Bowel habit remained regular in 14 patients (61%) who took the drug occasionally (on demand) in the event of sporadic episodes of slight diarrhea (8). In the other cohort study in patients with BAD and IBS-D, recurrent diarrhea occurred in 33 of 35 (94%) of patients when cholestyramine (2-8 mg/ day for 1 month) was withdrawn, and the drug was prescribed again at the dose that controlled the patient's symptoms (7). Only 6% of patients were able to discontinue therapy without suffering recurrent diarrhea.
# Discussion
Evidence suggests that some patients with BAD will require regular daily dosing, whereas others may be able to discontinue completely or use on-demand therapy for symptom control. The dose or frequency of BAST required to control symptoms may be dependent on the severity of symptoms, underlying causes of BAD, or the presence of other comorbid illnesses (e.g., gastroenteritis, Clostridium difficile infection).
The need for BAST also may be affected by use of medications that cause constipation, which may reduce the need for BAST, or by medications that cause diarrhea, which may increase the need for BAST. Long-term use of BAST should balance the potentially high rate of relapse of diarrhea against the high rate of adverse events, poor palatability and uncertainty around long-term harms (e.g., malabsorption of fat and vitamins). Therefore, the consensus group suggested that during ongoing longterm therapy, intermittent, on-demand therapy should be attempted to minimize exposure to BAST, encourage compliance and minimize costs.
# Key Evidence
No studies were found that systematically assessed the effectiveness of other antidiarrheal agents in patients with BAD who are unable to tolerate BAST. As described in Statement 8, 1 RCT that compared cholestyramine with HPC found no difference in clinical remission (53.8% versus 38.4%) or adverse events (63).
Three cohort studies assessed first-line loperamide in patients with BAD; however, the effectiveness was difficult to estimate because of differences in patient populations, study designs and outcome measurements (mainly subjective improvement of symptoms) (28,79,80). A randomized, double-blind, cross-over RCT in 18 patients with chronic diarrhea resulting from chronic radiation enteritis compared loperamide (3 mg twice daily) and placebo for 14 days (79). The study did not include dichotomized response rates, but did report significant improvements in stool frequency, stool weight and SeHCAT retention with loperamide as compared with placebo. In a prospective cohort study of 19 patients with chronic diarrhea resulting from ileal irradiation and/or resection, 13 patients with resections of 20 to 50 cm (n = 7) or no resection (n = 6) showed normalized or improved SeHCAT retention, with symptomatic improvement while on loperamide (80). In six patients with resection greater than 80 cm, SeHCAT retention remained abnormal, and only three patients had slight improvement of diarrhea with loperamide. In another cohort study, 27 of 96 (28%) patients reported improvement with conventional antidiarrheal agents; however, this included codeine, loperamide or prednisolone (not considered an antidiarrheal agent), and did not specify response to individual medications (28).
# Discussion
Given the poor tolerability and high discontinuation rates with BAST, alternative treatments often are needed. HPC may improve diarrhea in patients with BAD through its bulking effects and its ability to bind bile acids (63)(64)(65)(66). In addition, some patients may benefit from loperamide; given its low cost and relatively good safety profile (although no cost-effectiveness data are available), a treatment trial may be warranted.
# Key Evidence
Good practice statement, CoE not assessed.
# Discussion
The importance of minimizing exposure to BAST was discussed in Statement 11 (dose titration during induction) and Statement 13 (use of intermittent or discontinuing dosing during maintenance therapy).
Cohort studies have reported the use of cholestyramine for 6 to 44 months, which was titrated to response (42). In one study, patients were allowed to titrate their own dose of cholestyramine (between 2 and 16 g/day) and sustained responses for over 1 year (81). Colesevelam has been used for up to 44 months with some patients titrating the dose down (72).
# Key Evidence
Good practice statement, CoE not assessed.
# Discussion
Other diagnoses are common in patients with BAD, and a diagnosis of BAD is seen frequently in patients with other conditions (see Statement 1). As discussed in Statement 7, some patients may need specific treatments for other causes of chronic diarrhea.
BAD can have a variable course, and fat intake can cause fluctuations in SeHCAT retention and severity of BAD. Low-fat dietary interventions can improve gastrointestinal symptoms for some patients (82). However, sudden worsening of symptoms not related to dietary changes should prompt re-evaluation. The differential diagnosis should consider conditions such as microscopic colitis, Crohn's disease, celiac disease, SIBO and functional bowel disease. Strategies in patients with worsening symptoms might include repeating SeHCAT testing with an escalation of therapy if needed, as well as other tests, such as stool tests for infectious etiologies, blood tests, colonoscopy, hydrogen breath tests as determined by the underlying cause of BAD, and the patient's history, risk factors and symptoms.
# Key Evidence
Good practice statement, CoE not assessed.
# Discussion
BAST agents may bind other drugs given concurrently, which necessitates separating administration to minimize the risk of reduced absorption of the concomitant medication. Health Canada recommends that when a drug interaction cannot be excluded, patients should take other drugs at least 1 hour before or 4 to 6 hours after the BAST (73,83,84). Gastric emptying studies have suggested that a window of 3 hours between administration of BAST and other medications is adequate to avoid potential interactions such as binding (85).
Examples of some medications that may interact when coadministered with cholestyramine or colestipol include thyroid preparations, warfarin, hydrochlorothiazide, furosemide, phenylbutazone, phenobarbital, tetracycline, penicillin G, digoxin, mycophenolic acid and estrogen-containing drugs (3,73,84). Colesevelam has a different structure that maximizes interactions with bile salt and reduces the potential for interactions with other drugs (86,87). Colesevelam does not appear to interact with some medications (e.g., digoxin, fenofibrate, lovastatin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil), but has been found to reduce the absorption of others (e.g., glyburide, levothyroxine and oral contraceptives), and may interact with warfarin and phenytoin (83).
# Key Evidence
The literature search failed to identify any relevant article assessing fat-soluble vitamin levels before and after initiation of long-term maintenance therapy with BAST. Because of the action of BAST agents in sequestering bile acids, these agents theoretically may interfere with normal fat absorption, thus reducing absorption of folic acid and fat-soluble vitamins A,
# Statement 17. In patients being considered for BAST, a review of concurrent medications should be conducted to minimize the potential for drug interactions. Designated a good practice statement
# No recommendation B. In patients receiving long-term maintenance therapy with BAST, the consensus group could not make a recommendation for or against measuring fat-soluble vitamin levels at baseline and an
# Discussion
Cholestyramine has been associated with reduced vitamin and folate levels during long-term use (73). However, colestipol use for 1 to 2 years had no effect on vitamin A or folic acid levels, and only a small effect on vitamin D levels (84). Colesevelam was not associated with significant reductions in the absorption of vitamins A, D, E or K during clinical studies of up to 1 year (83). In general, the approved product labels recommend supplementation of vitamins A, D and K only if a deficiency occurs (73,83,84).
The rare cases of vitamin K deficiency resulting in increased risk of coagulopathy have occurred within a few weeks to months or years after the start of therapy (89), and generally can be corrected with oral vitamin K. Although during long-term use periodic monitoring of vitamin levels and prothrombin time sometimes are advised (3,93), the group did not reach consensus on the value of annual routine monitoring. Most of the consensus participants were neutral on this issue, although it was suggested that performing an international normalized ratio at intervals during long-term treatment may be prudent.
# Conclusions
The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodological evaluations.
In DTA studies, the diagnostic accuracy of an index test (a test under evaluation) is determined by comparing its results with that of a reference standard (best available method to determine the presence or absence of a target condition), by applying both in individuals who are suspected of having the target condition of interest. However, if the reference standard does not correspond perfectly to a true target condition, estimates of the accuracy of the index test can be biased. The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST). In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design (41). In studies in which all patients are tested with the index tests and all patients are treated with BAST, response to treatment can provide an imperfect, but the best available, reference standard. This is because patients responding to BAST may be true-positive patients with a true response, but also may be false-positive patients with a placebo response. To date, only two small DTA studies have reported information on the probability of response to treatment with BAST for people with a negative SeHCAT test, and no DTA studies have incorporated a blinded placebo arm (37,40). Consequently, the lack of evidence of the accuracy of the SeHACT test based on a reference standard and the variation in cut-off values of test results led to important uncertainties in the cost-effectiveness analyses in determining the optimal strategy in investigating BAD (41). Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.
Given the paucity of high-certainty evidence on diagnostic tests, there is also a need for well-designed DTA studies comparing SeHCAT, C4 assay, FGF19, and total and primary bile acid measurement in stool, with a reference standard for BAD (e.g., response to BAST) by applying both the index tests and reference standard to all patients (94,95), as well as RCTs comparing SeHCAT testing versus an empiric trial of BAST in patients with suspected BAD including an assessment of objective clinical efficacy and safety outcome measures. A placebo-controlled RCT of BAST (colesevelam) in patients with evidence of BAD, based on fecal bile acid measurements, is ongoing (NCT03270085) and the results will help to inform the role of fecal bile acids as a diagnostic test for BAD (96).
It is important to note that the diagnostic accuracy of total and primary bile acid excretion has not been assessed formally by GRADE for this guideline because it was not a topic initially proposed for inclusion a priori. Nevertheless, there have been recent publications on assessing 48-hour total and primary bile acid fecal excretion (a test available in North America) as a diagnostic test for BAD (95). Recent advances also have assessed whether this test could be optimized by including assays of primary bile acids (95). Most (if not all) have been observational studies that have found significant correlation or association between increased fecal bile acids and certain conditions that can cause diarrhea (i.e., IBS-D, chronic functional diarrhea) (95,(97)(98)(99). Although observational studies can provide evidence of significant association or correlation between predictor and outcome variables, they cannot prove causality because there are always residual confounding variables (unmeasured or imprecisely measured) that may have affected the results. Spurious associations also can arise with reverse causality. Future prospective studies are required to validate the diagnostic accuracy for BAD of primary bile acids at various cut-off concentrations in a single stool sample against a reference standard (i.e., the ability of this test to accurately predict response to BAST).
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Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1
RCTs are needed to compare cholestyramine with other BASTs for the treatment of BAD. In addition, evidence is needed to guide dosing schedules. This includes assessment of whether there is any advantage to morning versus evening dosing and once-daily versus divided doses of BAST to maximize benefits and minimize interactions with other medications. Theoretically, there may be some efficacy benefits to targeting dosing to times of maximum gallbladder emptying, such as postprandially or in the morning, but more research is needed. In hypercholesterolemia there were no significant variations in the hypocholesterolemic effects when cholestyramine was timed with meals to optimize exposure to bile in the duodenum that followed gallbladder emptying (100). However, the relevant mechanisms in BAD may be different, particularly because the therapeutic aim is to reduce the effects of free secretory bile acid in the colon.
In conclusion, current evidence suggests that the accuracy of diagnostic tests (e.g., SeHCAT, C4) in predicting BAD or response to treatment are highly uncertain. Economic evaluation suggests that strategies of either an empiric trial of BAST or performing SeHCAT testing may be cost effective depending on the scenarios and society's willingness to pay. Therefore, either strategy may be used to identify patients with possible BAD depending on cost, available resources, local expertise and patient preferences.
# Canadian Association of Gastroenterology Statement
This clinical practice guideline on the management of BAD was developed under the direction of Dr Daniel Sadowski, in accordance with the policies and procedures of the Canadian Association of Gastroenterology and under the direction of the Canadian Association of Gastroenterology Clinical Affairs. It has been reviewed by the Canadian Association of Gastroenterology Practice Affairs and Clinical Affairs Committees and the Canadian Association of Gastroenterology Board of Directors. The clinical practice guideline was developed after a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian, U.S. and UK panel comprising experts on this topic. The clinical practice guideline aims to provide a reasonable and practical approach to care for specialists, and allied health professionals are charged with the duty of providing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The clinical practice guideline is not intended to be a substitute for physicians using their individual judgment in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.
Novartis Pharma, and Prometheus Diagnostics, and has served on the speaker's bureau of GE Healthcare; and Eldon A. Shaffer has served on the speaker's bureau of Pendopharm. The remaining authors disclose no conflicts.
# SUPPLEMENTARY DATA
Supplementary data are available at Journal of the Canadian Association of Gastroenterology online.
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Background and Aims: Chronic diarrhea affects about 5% of the population overall. Altered bile acid metabolism is a common but frequently undiagnosed cause. Methods: We performed a systematic search of publication databases for studies of assessment and management of bile acid diarrhea (BAD). The certainty (quality) of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach. Patient population, intervention, comparator and outcome questions were developed through an iterative process and were voted on by a group of specialists. Results: The certainty of evidence was generally rated as very low. Therefore, 16 of 17 recommendations are conditional. In patients with chronic diarrhea, consideration of risk factors (terminal ileal resection, cholecystectomy or abdominal radiotherapy), but not additional symptoms, was recommended for identification of patients with possible BAD. The group suggested testing using 75 selenium homocholic acid taurine (where available) or 7α-hydroxy-4-cholesten-3-one, including patients with irritable bowel syndrome with diarrhea, functional diarrhea and Crohn's disease without inflammation. Testing was suggested over empiric bile acid sequestrant therapy (BAST). Once remediable causes are managed, the group suggested cholestyramine as initial therapy, with alternate BAST when tolerability is an issue. The group suggested against BAST for patients with extensive ileal Crohn's disease or resection and suggested alternative antidiarrheal agents if BAST is not tolerated. Maintenance BAST should be given at the lowest effective dose, with a trial of intermittent, on-demand administration, concurrent medication review and reinvestigation for patients whose symptoms persist despite BAST. Conclusions: Based on a systematic review, BAD should be considered for patients with chronic diarrhea. For patients with positive results from tests for BAD, a trial of BAST, initially with cholestyramine, is suggested.#
Diarrhea is a common symptom in the general population of developed countries. Among community-dwelling persons the 1-month rate of diarrhea was 7.6% in Canada and the United States, 6.4% in Australia and 3.4% in Ireland; approximately 20% of subjects sought medical care for this symptom (1). The prevalence of chronic diarrhea has been estimated to affect approximately 5% of this population overall (2), and may be higher among older individuals (3).
The most common causes of chronic diarrhea in clinical practice are functional disorders (e.g., irritable bowel syndrome [IBS]), and inflammatory diseases (e.g., Crohn's disease, celiac disease) (3). However, a common but frequently underdiagnosed cause of chronic diarrhea is dysregulated bile acid recycling within the enterohepatic circulation: either excessive biosynthesis/secretion of bile acids, or malabsorption of bile acids by the ileum. Unabsorbed bile acids in the colon appear to cause diarrhea by stimulating fluid, mucus, or sodium secretion; increasing gastrointestinal motility; damaging the mucosa or stimulating defecation (3,4).
Three subtypes of bile acid diarrhea (BAD) have been described: type 1, patients with terminal ileal disease (e.g., Crohn's disease, resection) or radiation injury resulting in impaired reabsorption of bile acids; type 2, idiopathic or primary; and type 3, other conditions (e.g., celiac disease, cholecystectomy) that alter intestinal motility or bile acid absorption (3,5). BAD has been reported in approximately 25% to 35% of patients with chronic diarrhea or diarrhea-predominant IBS (IBS-D) (6). Rates are even higher in patients with underlying terminal ileal disease, or other conditions such as cholecystectomy.
The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests (discussed later). Although a treatment trial with bile acid sequestrant therapy (BAST) often is used, this approach has not been studied adequately, and likely os imprecise, and may lead to both under-treatment and overtreatment. Specific diagnostic tests are under investigation, particularly radiodiagnostic measurement of bile acid pool loss with 75 selenium homocholic acid taurine (SeHCAT; GE Healthcare Canada, Inc, Ontario, Canada), or measurement of serum levels of biomarkers of bile acid synthesis including 7α-hydroxy-4-cholesten-3-one (C4) or the ileal regulatory hormone, fibroblast growth factor 19 (FGF19). SeHCAT testing is unavailable in some countries (including the United States).
BAD generally is not cured, and as is the case with many chronic gastrointestinal diseases or disorders, many patients will require lifelong treatment (7,8). Treatment is generally with BAST, but also is dependent on the underlying causes of BAD, severity of symptoms or the presence of other comorbid illnesses (e.g., Crohn's disease, celiac disease).
BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment. There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association (9), and the British Society of Gastroenterology (10), but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults (11), published after the consensus meeting, addressed some issues related to BAD.
The purpose of this guideline is to critically review the literature relating to diagnostic testing, and the induction and maintenance treatment of BAD, with the aim of developing specific consensus recommendations for patients with BAD.
# Methods
# Scope and Purpose
These consensus statements focused on specific issues pertaining to the medical management of BAD, which the participants and GRADE experts (F.T., G.I.L.) identified a priori.
# Sources, Literature Searches and Systematic Reviews
The Editorial Office of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University performed a systematic search of Medline, Embase, and the Cochrane Central Register of Controlled Trials for literature published between 1990 and September 2017. Key search terms were as follows: bile acid, cholecystectomy, cholestyramine, colestipol, colesevelam, diarrhea, loperamide, malabsorption, resection, SeHCAT and sequestrants. An additional search of the databases for SeHCAT trials published before 1990 (database inception as start date) also was performed. Only human studies published in English were considered. Further details of the search strategies are provided in Supplementary Appendix 1.
# Assessment of the Certainty (Quality) of Evidence
Before the face-to-face meeting, the statements were converted to specific patient population, intervention, comparator and outcome (PICO) questions by the two nonvoting methodologists (F.T., G.I.L.). The overall certainty of evidence (CoE) was determined using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach (12) to assess risk of bias (of individual studies and overall across studies), indirectness, inconsistency, imprecision, as well as other considerations (including publication bias). As described in GRADE (12,13) and used in previous consensus guidelines from the Canadian Association of Gastroenterology (CAG) (14)(15)(16)(17)(18), CoE was graded as very low, low, moderate or high. GRADE evaluations for each statement were provided before the consensus meeting and discussed during the consensus meeting.
The consensus group agreed that four statements (Statements 11, 13, 14 and 17) met GRADE criteria for good practice statements that these recommendations were clinically obvious, and that collection and GRADE assessment of evidence Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1 e11 for these statements was not a good use of resources (19).
Although formal GRADE evaluations were not performed, details of these statements are provided in the text. Approved product labeling from government regulatory agencies varies from country to country, and although not ignored, recommendations are based on evidence from the literature and consensus discussion and may not fully reflect the product labeling for a given country.
# Consensus Process
A face-to-face consensus meeting was held in Toronto, Canada, in February 2018. The international consensus group comprised five voting gastroenterologists (including the chair: D.C.S.), from Canada, the United States and the United Kingdom. Other participants included a nonvoting moderator ( J.K.M.), the two GRADE experts (F.T., G.I.L.) and a nonvoting observer.
The consensus process was facilitated by the CAG via a webbased consensus platform (ECD Solutions, Atlanta, GA). The platform allowed consensus participants to review results of the initial literature searches and select and link the references to specific statements. Copies of the selected references were available to all members of the consensus group. The full consensus group voted anonymously on their level of agreement with the individual statements using a modified Delphi process (20,21). Participants suggested revisions and commented on the statements, after which, the specific statements were revised through two iterations.
At the 1-day consensus meeting, evidence for each of the PICO questions was presented, after which an Evidence-to-Decision framework was completed (22). Each PICO question was discussed and revised, and voting members anonymously indicated their level of agreement on a scale of 1 to 5. In favour of a specific strategy was defined as 75% or more of votes being 5 (strongly yes) or 4 (yes). A vote against the strategy was defined as 75% or more of votes being 1 (strongly no) or 2 (no). A vote of 3 indicated neutrality. Once reaching agreement on the PICO question, the strength of the recommendation (strong versus conditional) was determined based on the following four components: (i) CoE, (ii) benefit/harm balance, (iii) patients' values/preferences and (iv) resource requirements (23). When the CoE was low or very low, unless at least one of the other three factors was overwhelmingly strong, the strength of the recommendation typically would default (without a vote) to conditional, using the phrasing 'we suggest' . If the statement warranted a vote, and 75% or more of participants voted as strong, then the recommendation would be designated as strong and the phrasing contained 'we recommend' .
During the meeting, consensus was not reached on four of the PICO questions; therefore, no statement was developed and no recommendations were made. Evidence and subsequent discussion pertaining to these four questions is summarized briefly in the text.
The manuscript was drafted initially by the meeting chair (D.C.S.), and then reviewed and revised by the remaining members of the consensus group. The manuscript then was made available to all CAG members for comment over a 2-week period before submission for publication.
In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months before the consensus meeting were provided by all participants, reviewed by the CAG ethics committee and made available to all group members.
# Recommendation Statements
The individual recommendation statements are provided and include the strength of recommendation and certainty of supporting evidence (according to the GRADE approach), and the voting result. This is followed by a discussion of the evidence considered for the specific statement. A summary of the recommendation statements is provided in Table 1. See Supplementary Appendix 1 for detailed CoE assessments (including a description of the study limitations, inconsistency, indirectness, imprecision and publication bias) and the Evidence-to-Decision frameworks.
# Diagnosis of BAD
# Key Evidence
No published randomized controlled trials (RCTs) were available comparing the clinical impact of using versus not using risk factors or symptom presentation for the diagnosis of BAD, therefore evidence from observational, diagnostic test accuracy (DTA) studies was evaluated. Overall, studies have shown that history of terminal ileal resection, cholecystectomy or radiotherapy are the risk factors associated most commonly with having a positive SeHCAT test suggestive of a BAD diagnosis (Table 2) (24-30).
# Statement 1. In patients with chronic nonbloody diarrhea, we recommend using risk factors (history of terminal ileal resection, cholecystectomy, or abdominal radiotherapy) as the initial assessment to identify patients with possible BAD.
GRADE: Strong recommendation, very-lowcertainty evidence. Vote: on PICO question: strongly yes, 60%; yes, 40%.
# Statement 2. In patients with chronic nonbloody diarrhea, we suggest against using symptom presentation as the initial assessment to identify patients with possible BAD.
GRADE: conditional recommendation, verylow-certainty evidence. Vote: on PICO question: no, 100%.
# e12
Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1 No symptoms have consistently been predictive of a greater likelihood of having SeHCAT-diagnosed BAD among patients with chronic diarrhea. Rates of abdominal pain or discomfort, distension, bloating, flatulence and urgency, were similar or less frequent among patients with BAD and those with diarrhea resulting from other causes (24,(31)(32)(33). Some studies have reported an association between stool weight, consistency or frequency, and a higher risk of BAD among patients with chronic diarrhea, but no diagnostic accuracy data, or definitions, are available (7,(31)(32)(33)(34)(35).
All studies had either a high or unclear risk of bias, inconsistency (with respect to the specific symptoms and clinical characteristics as risk factors for BAD) and imprecision.
# Discussion
In patients presenting with nonbloody chronic diarrhea or IBS-D, rates of SeHCAT retention suggestive of BAD are much higher in those with risk factors compared with those in whom other possible causes have been excluded. Rates of Maintenance therapy for BAD (BAST) Statement 16. In patients with BAD and recurrent or worsening symptoms despite stable BAST, diagnostic re-evaluation should be conducted. Designated a good practice statement Statement 17. In patients being considered for BAST, a review of concurrent medications should be conducted to minimize the potential for drug interactions. Designated a good practice statement
# Statements with no recommendations
No recommendation A. In patients with chronic diarrhea including IBS-D and functional diarrhea, the consensus group could not make a recommendation for or against the use of FGF19 assay to identify possible BAD. GRADE. NO recommendation, very-low-certainty evidence. Vote on PICO question: strongly yes, 20%; neutral, 80%. No recommendation B. In patients receiving long-term maintenance therapy with BAST, the consensus group could not make a recommendation for or against measuring fat-soluble vitamin levels at baseline and annually thereafter. GRADE. NO recommendation; very-low-certainty evidence. Vote on PICO question: yes, 20%; neutral, 80%.
The strength of each recommendation was assigned by the consensus group, per the GRADE system, as strong ("we recommend... ") or conditional ("we suggest... "). A recommendation could be classified as strong despite low-certainty evidence to support it, or conditional despite the existence of high-certainty evidence due to the 4 components considered in each recommendation (risk:benefit balance, patients' values and preferences, cost and resource allocation and certainty of evidence).
BAD, bile acid diarrhea; BAST, bile acid sequestrant therapy; C4, 7α-hydroxy-4-cholesten-3-one; FGF19, fibroblast growth factor 19; GRADE, Grading of Recommendation Assessment, Development and Evaluation; IBS-D, diarrhea-predominant irritable bowel syndrome; PICO, patient population, intervention, comparator, and outcome; SeHCAT, 75 selenium homocholic acid taurine; SIBO, small intestinal bacterial overgrowth. (24,26,29), rates of at least moderate BAD (SeHCAT retention, <10%) were 19% to 39% (6,25,34,36) compared with 38% to 58% (24,26,29), and rates of at least mild BAD (SeHCAT retention, <15%) were 24% to 27% (6,24,36) compared with 46% to 68% (24,26,29). The risk factors most commonly identified are shown in Table 2. In patients with ileal resection, BAD appeared to be independent of resection length; resections of less than 10 cm were sufficient to cause BAD (26).
The potential harms of using clinical risk factors as a triage test for BAD could include overdiagnoses leading to unnecessary diagnostic tests and/or treatments, or underdiagnoses leading to ongoing patient suffering. In patients with ileal resection, there is an extremely high risk of BAD, and diagnostic testing may not be necessary before treatment, whereas patients with chronic diarrhea after a cholecystectomy or after radiotherapy may warrant diagnostic tests. No consistent correlation has been found between the length of resection and SeHCAT retention, therefore, all patients should be considered at high risk after resection (25,26,37).
Other conditions such as diabetes, pancreatitis, small intestinal bacterial overgrowth (SIBO), microscopic colitis, vagotomy and celiac disease have been associated occasionally, but not consistently, with an increased risk of BAD (26,38).
No symptoms have been identified that reliably will predict a diagnosis of BAD. In fact, data suggest that reliance on symptoms can lead to underdiagnosis in clinical practice; one survey found that 44% of patients reported they had experienced symptoms for more than 5 years before diagnosis (39). Although symptom presentation is inaccurate for BAD, it continues to play a role in the differential diagnosis to rule out other conditions.
Based on the available data, the consensus group recommends that in patients with chronic nonbloody diarrhea, a history of terminal ileal resection, cholecystectomy or radiotherapy, but not symptom presentation, be used during the initial assessment to help identify patients with BAD.
# Key Evidence
Data on the diagnostic accuracy of the SeHCAT retention test (as an initial test for diagnosis) were derived from two prospective DTA studies, both conducted by Sciarretta et al. (37,40) in Italy. These were designed as case-control studies to assess the ability of SeHCAT retention to discriminate between cases and controls. However, using other secondary results, a 2013 Health Technology Assessment calculated the diagnostic accuracy of SeHCAT retention for predicting the response to BAST (41). In the first study, the sensitivity and specificity of SeHCAT retention (cut-off value, <5%) were 85.7% (95% confidence interval [CI], 42.1 to 99.6) and 100% (95% CI, 54.1 to 100), respectively, in a subgroup of patients (n = 13) with diarrhea without evidence of intestinal or extraintestinal pathology (37,41). The second study, which included 46 patients with IBS-D or cholecystectomy, found the sensitivity and specificity of SeHCAT retention (cut-off value, <8%) were 95.0% (95% CI, 75.1 to 99.9) and 96.2% (95% CI, 80.4 to 99.9), respectively (40,41). In both studies, a response to BAST was defined as the disappearance of diarrhea. No studies were found that measured the diagnostic accuracy of SeHCAT in patients with chronic diarrhea, which avoided a case-control design and used a proven reference standard (because there is currently no such reference standard, apart from the surrogate response to BAST).
Both DTA studies were found to be at serious risk of bias with respect to the index tests and reference standards used, serious indirectness of the study populations and index tests, and very serious imprecision as a result of the very small sample sizes, and the lower limit of the CI crossing the threshold for a clinically useful diagnostic test. This suggests that the data are insufficient to support or refute the clinical utility of SeHCAT in patients with IBS-D. Therefore, other factors and indirect supportive evidence were considered.
# Discussion
Overall, the CoE for the diagnostic accuracy of SeHCAT was determined to be very low. As discussed in Statement 1, the prevalence data suggest that up to 40% of patients with functional diarrhea or IBS-D may have at least moderate BAD as assessed by a SeHCAT cut-off value less than 10% (6,25,34,36).
In addition, a systematic review (SR) including 15 observational studies showed a correlation between the severity of SeHCAT loss and response to treatment with BAST: response to cholestyramine was 96% in patients with less than 5% retention, 80% at less than 10% retention and 70% at less than 15% retention (6). This was not confirmed by a newer SR of 21 studies that found response rates with BAST of 67% at less than 5% retention, 73% at less than 8% to 11.7% retention and 59% at less than 15% retention (42). However, one study (26) published after the earlier SR, which included a large number of patients
# Statement 3. In patients with chronic diarrhea including IBS-D and functional diarrhea, we suggest SeHCAT testing to identify patients with BAD. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: strongly yes, 20%; yes, 80%.
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with secondary BAD, made a disproportionately large contribution to the group with less than 5% retention in this second analysis. Response rates were much lower in patients with negative SeHCAT tests; only 15% of patients had a good or partial response compared with 65.6% of patients with a SeHCAT retention less than 15% (29). A study has been proposed to evaluate the diagnostic accuracy of SeHCAT retention in which the test result will be concealed from clinicians and patients, and all patients will receive BAST (43).
Cost effectiveness and feasibility also were considered. The Health Technology Assessment assessed the cost effectiveness of SeHCAT testing compared with response to BAST based on data from three small trials and rather limited assumptions (41). They concluded that for the short term (first 6 months), the optimal choice between SeHCAT testing and no SeHCAT testing depended on willingness to pay, but that a trial of BAST would be more cost effective. From the long-term perspective, the optimal choice was a trial of BAST, no SeHCAT testing, or SeHCAT testing with a cut-off retention value of less than 15% depending on the scenario. Feasibility can be an issue in some areas because nuclear medicine facilities or the isotope may not be available.
BAST has poor tolerance and a high dropout rate; a positive SeHCAT test may have the additional benefit of providing the clinician with a stronger argument to encourage patients to stay on therapy when a definite diagnosis of BAD has been made (44). Other factors to consider are the potential harms of SeHCAT use, such as radiation risk, patient inconvenience and anxiety and loss of opportunity to use BAST in cases of falsenegative results. Cut-off values to initiate treatment are sometimes inconsistent (45), and the role of borderline SeHCAT retention in therapeutic decisions is ill defined.
Taking all of these issues together, the consensus group concluded that SeHCAT retention is a relatively safe test, BAST is a relatively safe treatment (although poorly tolerated), and the anticipated benefit of SeHCAT retention testing likely outweighs the uncertainty of the evidence. Although other tests show promise for the future, SeHCAT retention has been the most widely tested, with consistent results.
# Key Evidence
An observational cohort study included a subgroup of 44 patients with unoperated Crohn's disease in clinical remission (other than diarrhea) who had normal hematology and C-reactive protein levels (28). SeHCAT retention was abnormal (<10%) in 54% of patients. Of the 24 patients with abnormal SeHCAT retention, 20 received initial conventional treatment (prednisolone ± mesalamine), followed by BAST when conventional treatment failed. Response rates were 55% with conventional treatment, and 40% with BAST, with 5% failing both treatments. The treatment duration and outcome assessments, as well as the use of BAST in patients with normal SeHCAT retention, were not clearly described. The diagnostic accuracy and the effects of using test results to inform management choices could not be calculated because of the lack of a control group.
The CoE was downgraded to very low because of a very serious risk of bias (with regard to the reference standard, patient flow and timing) and very serious imprecision (very small sample size).
# Discussion
Although there is very-low-certainty evidence supporting the use of SeHCAT testing to guide management decisions in patients with Crohn's disease, testing may play a role in patients with ileal Crohn's disease in complete remission who have ongoing chronic diarrhea.
Observational studies have suggested that almost half of the patients with ileal Crohn's disease who have not undergone resection will have a positive SeHCAT, suggestive of a diagnosis of at least moderate BAD (Table 3) (25,26,28,29). These patients may have a two to four times greater likelihood of having a positive SeHCAT compared with having a negative test (25,29).
Given the association between positive SeHCAT testing and response to BAST in patients with Crohn's disease who continue to have persistent diarrhea despite conventional treatments, the consensus group made a conditional recommendation in favour of SeHCAT testing in patients with Crohn's disease who have no objective evidence of active inflammation.
# Key Evidence
The majority of published DTAs compared C4(46-48) and FGF19 (32,49,50) assays with SeHCAT testing. These showed good inverse correlation between C4 and SeHCAT testing, and between FGF19 and SeHCAT testing, however, the overall CoE for the diagnostic accuracy of SeHCAT was assessed for Statement 3 and determined to be very low. Therefore, the true diagnostic accuracy of these tests cannot be estimated from these studies.
One study assessing C4 and FGF19 assays used direct measurement of 48-hour fecal bile acid as a reference standard (51). This prospective DTA study included 30 patients with IBS-D who had replicate C4 and FGF19 samples 5 years apart that could be compared with fecal bile acid levels. When patients with a prior cholecystectomy were excluded, the sensitivity and specificity of serum C4 were 40% and 85%, respectively, with a 40% positive predictive value and an 85% negative predictive value for the diagnosis of BAD. For FGF19, the sensitivity and specificity were 20% and 75%, respectively, with a 17% positive predictive value and a 79% negative predictive value for the diagnosis of BAD.
The CoE was downgraded to very low because of the moderately serious risk of bias and very serious imprecision (CI lower limits crossed the threshold for clinically useful diagnostic tests, small sample sizes) in the DTA that used fecal bile acid levels as the reference standard (51). Similarly, there was very serious risk of bias and serious indirectness in the studies that used SeHCAT retention as the reference standard.
# Discussion
Although there appears to be a good correlation (inverse) between C4 and SeHCAT results, and between FGF19 and SeHCAT results, SeHCAT retention has not been validated adequately as a reference standard. Theoretically, C4 and FGF19 should be good markers of bile acid loss. C4 is a metabolic intermediate in the rate-limiting step for the synthesis of bile acids from hepatic cholesterol. FGF19 is a hormone released by ileal enterocytes after stimulation of nuclear farnesoid X receptors, typically by absorbed bile acids. Both markers have been correlated with fecal loss of bile acids (Figure 1) (51-53). In addition, FGF19 levels have been shown to correlate with C4 levels (54).
Currently, there are no well-defined cut-off values for the diagnosis of BAD. In one prospective study, a C4 level of 52.5 ng/ mL or greater and a FGF19 level of 61.7 pg/mL or less were diagnostic for BAD (51). Other observational studies have used cut-off values of 30 to 48 ng/mL for C4 (46,55). One study found a wide range of normal values for C4 (corrected for cholesterol) from 0.76 to 8.0 mg/mol and for FGF19 from 48 to 343 pg/mL (33).
# Statement 5. In patients with chronic diarrhea including IBS-D and functional diarrhea, we suggest using a C4 assay to identify possible BAD. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: strongly yes, 20%; yes, 60%; neutral, 20%.
# No recommendation A: In patients with chronic diarrhea including IBS-D and functional diarrhea, the consensus group could not make a recommendation for or against the use of the FGF19 assay to identify possible BAD. GRADE: No recommendation, very-lowcertainty evidence.
Vote: on PICO question: strongly yes, 20%; neutral, 80%.
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Insufficient evidence is available with C4, and even less with FGF19. In addition, the FGF19 assay was not available as a commercial clinical test at the time of the meeting, which impacts the feasibility of implementing that test. Therefore, the consensus group made a conditional recommendation in favour of C4, but was unable to make a recommendation for or against the use of the FGF19 assay to identify BAD.
# Key Evidence
No direct comparative or DTA studies were found to inform this statement. As described in Statement 3, the two studies on the diagnostic accuracy of SeHCAT testing for predicting response to BAST yielded very low-certainty evidence in favour of using SeHCAT testing (37,40). The cost-effectiveness analysis included in the Health Technology Assessment conducted by Riemsma et al. (41) found that in the short term, a trial of BAST may be the optimal choice. However, over the long term, the optimal choice (trial of BAST, no SeHCAT testing, or SeHCAT at a cut-off retention value 15%) varied depending on the scenario. The analysis provided very low CoE regarding the optimal strategy.
# Discussion
There is very little evidence to determine the relative role of testing with SeHCAT testing versus using an empiric trial of BAST to make a diagnosis of BAD. Other factors were considered when making a conditional recommendation against empiric treatment.
A poor response to a therapeutic trial of BAST could be related to noncompliance and early discontinuation, which could result in a falsely negative diagnosis with patients being denied other effective alternative BAST that may be better tolerated (38,56). As discussed in Statement 3, a definitive diagnosis of BAD may help educate and motivate patients to adhere to treatment (38,44).
Conversely, in patients in whom there is a very high index of suspicion (in whom a positive SeHCAT test is found in >90%), such as terminal ileum resection or right hemicolectomy, early initiation of therapy may be preferred. In addition, although a test-and-treat strategy was preferred for most patients, it was recognized that SeHCAT testing or other diagnostic tests are not available in some areas. In these cases, a trial of BAST may be the only option.
# Induction Therapy for BAD
# Key Evidence
No RCTs or directly applicable cohort studies were identified in which treatment for remediable causes was compared with BAST in patients with type 1 or type 3 BAD. A cohort study (described in Statement 4), included subgroups of patients with IBS-D (n = 65, n = 40 treated) and unoperated Crohn's disease in clinical remission (other than diarrhea, n = 24, n = 20 treated) who were diagnosed with BAD (SeHCAT retention, <10%) (28). The rates of response to initial conventional treatment (prednisone ± mesalamine for Crohn's disease patients, or antidiarrheal agents for non-Crohn's disease patients) were 55% among treated Crohn's disease patients, and 15% among treated IBS-D patients. Conventional therapy followed by BAST was successful in 40% of treated Crohn's disease patients and 70% of treated IBS-D patients.
This study lacked a control group and blinding, and had a subjective outcome measure. No evidence was found for other conditions (e.g., microscopic colitis, SIBO). The CoE was downgraded to very low because of serious risk of bias, indirectness and imprecision.
# Discussion
Little data were available to define the role of other non-BAST treatments in patients with BAST and comorbid conditions. Specific treatments for comorbid conditions that may cause diarrhea (e.g., Crohn's disease, microscopic colitis, SIBO) may achieve control of diarrhea and other symptoms, but, conversely, this may delay BAST for BAD. In addition, depending on the condition, the treatment (e.g., corticosteroids, immunosuppressive agents, biologics or antibiotics) may be associated with more risks or side effects than BAST treatment, and the investigations may be more invasive and costly (e.g., colonoscopy).
# Statement 6. In patients with suspected BAD, we suggest against initiating empiric BAST over performing SeHCAT to establish a diagnosis of BAD. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question (in patients with suspected BAD, should we initiate empiric BAST over performing SeHCAT to establish a diagnosis of BAD?): yes, 20%; no, 40%; strongly no, 40%.
# Statement 7. In patients with type 1 or type 3 BAD, we suggest the use of treatments for remediable causes (e.g., Crohn's disease, microscopic colitis, SIBO) in addition to treatment for BAD for induction of clinical response. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: strongly yes, 80%; yes, 20%.
# e18
Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1
As mentioned in Statement 4, patients with Crohn's disease with continuing diarrhea have a high rate of BAD. These patients were still more likely to benefit from conventional treatment, although some did benefit from BAST (28).
Some studies have suggested that BAD and collagenous colitis are associated, but likely are independent diseases (57)(58)(59). In case series of collagenous colitis, BAST improved symptoms, but had no effect on histopathology (57). In another case series, 86% of patients with microscopic colitis who had BAD benefited from BAST, whereas no patients with collagenous colitis without BAD improved (59). The etiology of microscopic colitis is not well defined, and may include infectious agents, medications, or other causes in some patients, which may require other specific treatments. Other treatments that may be beneficial include corticosteroids, antibiotics, antidiarrheal agents or immunosuppressive therapies (59,60).
In a large case series, 36% of patients with SIBO who were tested had SeHCAT retention less than 10% (26). These patients may benefit from BAST, but antibiotic therapy is the current standard for SIBO (61). The etiology of SIBO is very complex and may involve disorders of protective antibacterial mechanisms, anatomic abnormalities, or motility disorders. Patients with SIBO require treatment of the underlying disease, as well as nutritional support (62).
Although there is little evidence to guide therapeutic decisions, in patients with comorbid conditions, BAD may not be the sole cause of symptoms. Although some patients will respond to BAST for BAD, others might not, or may have other symptoms in addition to diarrhea that will not benefit from BAST. Therefore, the consensus group agreed that it was prudent to individualize therapy and address other remedial causes of gastrointestinal symptoms, with the order of therapy guided by severity of each condition.
# Key Evidence
One RCT compared cholestyramine with hydroxypropyl cellulose (HPC) (63). Although HPC was chosen as a placebo, it may be pharmacologically active, and a small case series suggested it may be effective in BAD (63,64). The RCT was an 8-week study in 26 patients with chronic functional watery diarrhea or IBS-D, of which 77% of the cholestyramine-treated and 54% of HPCtreated patients had a SeHCAT retention rate of 10% or less (63). There was no significant difference in clinical remission rates (defined as <3 bowel movements/d over 1 week, with <1 watery stool/d) between treatments (53.8% versus 38.4%; P = 0.43). However, there was a significant improvement in the decrease in watery stools per day (−92.4% ± 3.5% versus −75.8% ± 7.1%; P = 0.048). Because HPC binds bile acids and may have a bulking effect, it may have some efficacy for BAD (63)(64)(65)(66); this makes it difficult to interpret the lack of significant differences in clinical remission rates with HPC compared with cholestyramine.
A SR of 23 cohort studies including 801 patients with BAD found that first-line cholestyramine was successful in 69.8% of patients overall, 67% of those with SeHCAT retention less than 5%, 73% of those with SeHCAT retention less than 8% to 11.7%, and 59% of those with SeHCAT retention less than 15% (42). Study designs, patient populations, inclusion and exclusion criteria, diagnostic tests and cut-off values for BAD, cholestyramine dosing and timing of administration, and definitions of clinical response varied widely among the studies. An additional cohort study published after the SR reported a response rate of 56% with first-line cholestyramine in 87 patients with BAD (defined as SeHCAT <15%) (67).
Although the RCT found that the rate of drug-related adverse events did not differ between cholestyramine and hydroxypropyl cellulose (63), the SR of cohort studies reported that 11% of patients found cholestyramine intolerable because of unpalatability or side effects (range, 0% to 46%) (42). The most common side effects included abdominal bloating and pain, dyspepsia, nausea/vomiting, flatulence, borborygmi, abdominal distension, constipation and increased severity of diarrhea. In the additional cohort study, almost half (45%) of treatment failures were related to medication intolerance (67). However, both studies had no control group for comparisons, and relationships to the study drug were not assessed.
RCTs assessing the efficacy of cholestyramine compared with other BAST in patients with BAD were not found. Evidence for using cholestyramine over other BASTs as initial therapy considered other factors such as adverse events, clinical experience and cost. There is no direct evidence that cholestyramine is associated with more side effects than other BAST. However, an RCT of BAST for cardiovascular disease prevention reported higher rates of gastrointestinal side effects (55% versus 16%), and lower rates of compliance (53% versus 77%) with adjunctive cholestyramine compared with monotherapy with a statin (68). In contrast, a SR of 6 RCTs in patients with diabetes found
# Statement 8. In patients with BAD, we suggest using cholestyramine over no treatment for induction of clinical response. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: strongly yes, 60%; yes, 40%.
# Statement 9. In patients with BAD, we suggest using cholestyramine over other BASTs as initial therapy for induction of clinical response. GRADE: Conditional recommendation, verylow-certainty evidence.
Vote: on PICO question: yes, 80%; neutral, 20%.
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that adverse rates with adjunctive colesevelam were similar to placebo (relative risk, 1.06; 95% CI, 0.97 to 1.15), with the most common events with colesevelam being gastrointestinalrelated (e.g., constipation, dyspepsia and nausea) and minor in nature (69). The majority of clinical experiences with BASTs in BAD has been with cholestyramine, with few data on the other agents; in addition, colesevelam and colestipol tend to be more costly compared with cholestyramine. The overall CoE was very low. Very serious indirectness and serious imprecision were found in the RCT (63), with a serious risk of bias, indirectness and imprecision in the cohort studies (42,67).
# Discussion
Clear RCT evidence showing the benefits of BAST was not available, however, case series and SRs of observational studies support a dramatic and rapid response for many patients. Although no patient preference data were found, the high dropout rates in all of these studies suggest that some patients may place a greater value on being free of the side effects or unpalatability of cholestyramine compared with reduction in their diarrhea frequency or severity. However, because BAST targets the problem, the potential higher response rates in patients with more severe BAD (as measured by SeHCAT retention) ( 6) and the lack of response in patients who test negative for BAD (29) (see Statement 3), the consensus group suggested that patients with BAD receive treatment with BAST over no treatment. This was a conditional recommendation because of the very low CoE and poor tolerability profile, making it important to discuss the benefits and side effects with patients.
Although the consensus group suggested that cholestyramine be used initially over the other BAST agents (colesevelam or colestipol), there are few comparative data. Compared with cholestyramine, colesevelam has a four to six times stronger binding affinity to bile acids. It may be better tolerated and have fewer clinical interactions (67). The majority of clinical experiences to date are with cholestyramine, with a limited number of cases using other BAST agents (29,33,38,70). Response rates with first-line use of other BASTs have been reported at 67% with colesevelam (70) and 55% with colestipol (33). Although cholestyramine appears to be less costly than colesevelam or colestipol, the lack of comparative data casts doubt on whether cholestyramine should be preferred; therefore, this was a conditional recommendation.
# Key Evidence
No RCT data were available comparing alternate BASTs with either placebo or other treatments as second-line therapy in patients with BAD who are unable to tolerate cholestyramine. One RCT compared first-line colesevelam and placebo for BAD-associated diarrhea in 26 patients with Crohn's disease in remission (70). There was a statistically nonsignificant improvement in the primary end point (proportion of patients with >30% reduction of liquid stools/day) with colesevelam (66.7%) versus placebo (27.3%) based on intention-totreat analysis (risk difference, 0.394; 95% CI, −0.012 to 0.706; P = 0.0566). Colesevelam significantly improved the secondary end points of the reduction in the number of liquid stools per day and improvement in stool consistency compared with placebo. This trial did not assess colesevelam as second-line therapy, and had a very small sample size; therefore, the CoE was downgraded to low for serious indirectness and imprecision.
Additional evidence comes from a SR of four observational cohort studies (n = 63) that assessed the efficacy of secondline colesevelam after failure of cholestyramine and reported a success rate of 57% (range, 42% to 100%) (42). One other cohort study published after the SR included 15 patients who had not responded to cholestyramine and received secondline treatment with colesevelam (67). Of these patients, 47% had a successful response. The CoE from the observational trials was downgraded to very low for serious risks of bias and imprecision.
There is no direct evidence that colesevelam is associated with a higher or lower frequency of adverse effects than cholestyramine or other BASTs. In the RCT, colesevelam generally was well tolerated; adverse events were mild (constipation, bloating and nausea) and occurred in similar proportions to colesevelam and placebo groups (40.0% versus 36.4%) (70). For safety, the SR included one RCT and four observational cohort studies, and found that 9% were unable to tolerate colesevelam because of unpalatability or side effects (42). In the additional observational study, no patients reported treatment intolerance with colesevelam (67). As discussed in Statement 8, tolerability data for BASTs in nongastrointestinal conditions suggested high rates of gastrointestinal side effects with cholestyramine, while colesevelam had side effects rates similar to placebo (68,69).
There have been limited reports describing the use of colestipol as second-line therapy after failure of cholestyramine (42,71).
# Discussion
Case series data have suggested that patients who fail or are unable to tolerate cholestyramine may benefit from secondline BAST (29). In a large series of patients given one or Statement 10. In patients with BAD who are unable to tolerate cholestyramine, we suggest using an alternate BAST for induction of clinical response. GRADE: Conditional recommendation, lowcertainty evidence. Vote: on PICO question: strongly yes, 40%; yes, 60%.
# e20
Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1 more BAST, there were no significant differences in good/ partial response rates between the cholestyramine (74%) and colesevelam (73%). However, whether alternate BAST was used as first-or second-line therapy was not described (29). Although, not regulatory approved for BAD, use of second-line colesevelam in clinical practice appears to be quite common. In a survey of patients followed up for up to 13 years, 38% of respondents continued with cholestyramine, while 32% had switched to colesevelam (56). The consensus group agreed that compared with cholestyramine, colesevelam has a favourable benefit:risk profile and greater ease of administration (tablet versus granules/powder). However, because of the limited clinical experience and higher cost, it is suggested that it be reserved for second-line use.
# Key Evidence
Good practice statement, CoE not assessed.
# Discussion
In general, most cohort studies reported gradual dose titration for cholestyramine to clinical response (42,67). However, there was no mention of dose titration of colesevelam or colestipol.
In BAD studies, cholestyramine generally was started at a low dose of 2 to 4 g/day and titrated based on response (maximum, 4 to 24 g/day) (42,67). In an open-label study, the colestipol dose was initiated at 1 g twice daily, with an increase of 1 g/d every other day (33). In BAD studies, colesevelam has been prescribed in a dose of two tablets (625 mg) three times per day (70,72).
Product labeling for BAST agents recommends that cholestyramine be started at one 4-g dose daily and titrated to effect with a maximum of 24 g/day for all patients (73). Initiation of colestipol granules (tablets) is recommended at 5 g (2 g) either once or twice daily, increasing by 5 g/day (2 g once or twice per day), but no more frequently than 1 per month, with a maximum of 30 g/day (16 g/day). No dose titration is recommended for colesevelam. Colesevelam is dosed at 3.75 g/day as three 625-mg tablets twice daily, 6 tablets once daily, or one 3.75-g powder packet once daily. These colestipol and colesevelam doses are regulatory approved for cholesterollowering indications.
Generally, it is intuitive to gradually titrate medication to maximize symptom relief and minimize side effects. This is particularly relevant with BAST because of the high frequency of side effects and intolerance (42). Gradual dose titration of BAST may reduce the risks of side effects, increase compliance and potentially reduce costs.
# Key Evidence
There are no long-term studies assessing the safety of cholestyramine in patients with extensive ileal resection. It has been suggested that use of BAST in these patients can lead to an increased rate of steatorrhea (74,75). A small series of nine patients, in whom three had ileal resection greater than 100 cm and steatorrhea greater than 20 g/day, found that the use of cholestyramine led to a small decrease in diarrhea, but an increase in steatorrhea with substantial caloric loss (74,75).
# Discussion
It is unclear how extensive a resection is required to produce negative consequences with BAST. In the case reports, the risk of steatorrhea was increased in patients with resections of greater than 100 cm (74,75).
Other data have shown no correlation between the length of resection, SeHCAT retention and response to BAST. In case series of patients with ileal resection of up to 200 cm, the majority had severe BAD and responded to BAST (26,76,77). In one case series, the mean length of resection was not significantly different in patients who did or did not respond to BAST (35 versus 46 cm) (78).
SeHCAT testing in patients with large ileal resection almost universally will indicate severe bile acid wasting and is unlikely to be of discriminatory clinical value. Although there are very few reports of adverse consequences of BAST use in patients with extensive resection, the consensus group concluded that the risk of steatorrhea makes it prudent to err on the side of caution and avoid BAST in this patient group. Furthermore, there is concern that these patients may have extensive inflammatory disease that should be identified and treated with anti-inflammatory approaches rather than BAST. However, in some cases, the benefits may outweigh the risks, and patients should be evaluated on a case-by-case basis.
# Statement 12.
In patients with Crohn's disease with extensive ileal involvement or resection, we suggest against using BAST. GRADE: Conditional recommendation, verylow-certainty evidence. Vote: on PICO question (In patients with Crohn's disease with extensive ileal involvement or resection, should we use BAST vs no BAST?): yes, 20%; no, 80%.
# Statement 11. In patients with BAD receiving empiric BAST, gradual daily dose titration should be used to minimize side effects. Designated a good practice statement
Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1 e21
Maintenance Therapy for BAD
# Key Evidence
No studies were found that directly compared different dosing strategies in patients with BAD who had responded to BAST. Two small cohort studies suggested that for some patients, BAD symptoms could remain controlled with on-demand therapy or no therapy at all (7,8). In a prospective cohort study of patients with postcholecystectomy BAD, cholestyramine (2 to 12 g/day for 1-6 months) was effective in 23 of 26 patients, and 9 of 23 (39%) patients experienced recurrent diarrhea when treatment was withdrawn. Bowel habit remained regular in 14 patients (61%) who took the drug occasionally (on demand) in the event of sporadic episodes of slight diarrhea (8). In the other cohort study in patients with BAD and IBS-D, recurrent diarrhea occurred in 33 of 35 (94%) of patients when cholestyramine (2-8 mg/ day for 1 month) was withdrawn, and the drug was prescribed again at the dose that controlled the patient's symptoms (7). Only 6% of patients were able to discontinue therapy without suffering recurrent diarrhea.
# Discussion
Evidence suggests that some patients with BAD will require regular daily dosing, whereas others may be able to discontinue completely or use on-demand therapy for symptom control. The dose or frequency of BAST required to control symptoms may be dependent on the severity of symptoms, underlying causes of BAD, or the presence of other comorbid illnesses (e.g., gastroenteritis, Clostridium difficile infection).
The need for BAST also may be affected by use of medications that cause constipation, which may reduce the need for BAST, or by medications that cause diarrhea, which may increase the need for BAST. Long-term use of BAST should balance the potentially high rate of relapse of diarrhea against the high rate of adverse events, poor palatability and uncertainty around long-term harms (e.g., malabsorption of fat and vitamins). Therefore, the consensus group suggested that during ongoing longterm therapy, intermittent, on-demand therapy should be attempted to minimize exposure to BAST, encourage compliance and minimize costs.
# Key Evidence
No studies were found that systematically assessed the effectiveness of other antidiarrheal agents in patients with BAD who are unable to tolerate BAST. As described in Statement 8, 1 RCT that compared cholestyramine with HPC found no difference in clinical remission (53.8% versus 38.4%) or adverse events (63).
Three cohort studies assessed first-line loperamide in patients with BAD; however, the effectiveness was difficult to estimate because of differences in patient populations, study designs and outcome measurements (mainly subjective improvement of symptoms) (28,79,80). A randomized, double-blind, cross-over RCT in 18 patients with chronic diarrhea resulting from chronic radiation enteritis compared loperamide (3 mg twice daily) and placebo for 14 days (79). The study did not include dichotomized response rates, but did report significant improvements in stool frequency, stool weight and SeHCAT retention with loperamide as compared with placebo. In a prospective cohort study of 19 patients with chronic diarrhea resulting from ileal irradiation and/or resection, 13 patients with resections of 20 to 50 cm (n = 7) or no resection (n = 6) showed normalized or improved SeHCAT retention, with symptomatic improvement while on loperamide (80). In six patients with resection greater than 80 cm, SeHCAT retention remained abnormal, and only three patients had slight improvement of diarrhea with loperamide. In another cohort study, 27 of 96 (28%) patients reported improvement with conventional antidiarrheal agents; however, this included codeine, loperamide or prednisolone (not considered an antidiarrheal agent), and did not specify response to individual medications (28).
# Discussion
Given the poor tolerability and high discontinuation rates with BAST, alternative treatments often are needed. HPC may improve diarrhea in patients with BAD through its bulking effects and its ability to bind bile acids (63)(64)(65)(66). In addition, some patients may benefit from loperamide; given its low cost and relatively good safety profile (although no cost-effectiveness data are available), a treatment trial may be warranted.
# Key Evidence
Good practice statement, CoE not assessed.
# Discussion
The importance of minimizing exposure to BAST was discussed in Statement 11 (dose titration during induction) and Statement 13 (use of intermittent or discontinuing dosing during maintenance therapy).
Cohort studies have reported the use of cholestyramine for 6 to 44 months, which was titrated to response (42). In one study, patients were allowed to titrate their own dose of cholestyramine (between 2 and 16 g/day) and sustained responses for over 1 year (81). Colesevelam has been used for up to 44 months with some patients titrating the dose down (72).
# Key Evidence
Good practice statement, CoE not assessed.
# Discussion
Other diagnoses are common in patients with BAD, and a diagnosis of BAD is seen frequently in patients with other conditions (see Statement 1). As discussed in Statement 7, some patients may need specific treatments for other causes of chronic diarrhea.
BAD can have a variable course, and fat intake can cause fluctuations in SeHCAT retention and severity of BAD. Low-fat dietary interventions can improve gastrointestinal symptoms for some patients (82). However, sudden worsening of symptoms not related to dietary changes should prompt re-evaluation. The differential diagnosis should consider conditions such as microscopic colitis, Crohn's disease, celiac disease, SIBO and functional bowel disease. Strategies in patients with worsening symptoms might include repeating SeHCAT testing with an escalation of therapy if needed, as well as other tests, such as stool tests for infectious etiologies, blood tests, colonoscopy, hydrogen breath tests as determined by the underlying cause of BAD, and the patient's history, risk factors and symptoms.
# Key Evidence
Good practice statement, CoE not assessed.
# Discussion
BAST agents may bind other drugs given concurrently, which necessitates separating administration to minimize the risk of reduced absorption of the concomitant medication. Health Canada recommends that when a drug interaction cannot be excluded, patients should take other drugs at least 1 hour before or 4 to 6 hours after the BAST (73,83,84). Gastric emptying studies have suggested that a window of 3 hours between administration of BAST and other medications is adequate to avoid potential interactions such as binding (85).
Examples of some medications that may interact when coadministered with cholestyramine or colestipol include thyroid preparations, warfarin, hydrochlorothiazide, furosemide, phenylbutazone, phenobarbital, tetracycline, penicillin G, digoxin, mycophenolic acid and estrogen-containing drugs (3,73,84). Colesevelam has a different structure that maximizes interactions with bile salt and reduces the potential for interactions with other drugs (86,87). Colesevelam does not appear to interact with some medications (e.g., digoxin, fenofibrate, lovastatin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil), but has been found to reduce the absorption of others (e.g., glyburide, levothyroxine and oral contraceptives), and may interact with warfarin and phenytoin (83).
# Key Evidence
The literature search failed to identify any relevant article assessing fat-soluble vitamin levels before and after initiation of long-term maintenance therapy with BAST. Because of the action of BAST agents in sequestering bile acids, these agents theoretically may interfere with normal fat absorption, thus reducing absorption of folic acid and fat-soluble vitamins A,
# Statement 17. In patients being considered for BAST, a review of concurrent medications should be conducted to minimize the potential for drug interactions. Designated a good practice statement
# No recommendation B. In patients receiving long-term maintenance therapy with BAST, the consensus group could not make a recommendation for or against measuring fat-soluble vitamin levels at baseline and an
# Discussion
Cholestyramine has been associated with reduced vitamin and folate levels during long-term use (73). However, colestipol use for 1 to 2 years had no effect on vitamin A or folic acid levels, and only a small effect on vitamin D levels (84). Colesevelam was not associated with significant reductions in the absorption of vitamins A, D, E or K during clinical studies of up to 1 year (83). In general, the approved product labels recommend supplementation of vitamins A, D and K only if a deficiency occurs (73,83,84).
The rare cases of vitamin K deficiency resulting in increased risk of coagulopathy have occurred within a few weeks to months or years after the start of therapy (89), and generally can be corrected with oral vitamin K. Although during long-term use periodic monitoring of vitamin levels and prothrombin time sometimes are advised (3,93), the group did not reach consensus on the value of annual routine monitoring. Most of the consensus participants were neutral on this issue, although it was suggested that performing an international normalized ratio at intervals during long-term treatment may be prudent.
# Conclusions
The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodological evaluations.
In DTA studies, the diagnostic accuracy of an index test (a test under evaluation) is determined by comparing its results with that of a reference standard (best available method to determine the presence or absence of a target condition), by applying both in individuals who are suspected of having the target condition of interest. However, if the reference standard does not correspond perfectly to a true target condition, estimates of the accuracy of the index test can be biased. The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST). In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design (41). In studies in which all patients are tested with the index tests and all patients are treated with BAST, response to treatment can provide an imperfect, but the best available, reference standard. This is because patients responding to BAST may be true-positive patients with a true response, but also may be false-positive patients with a placebo response. To date, only two small DTA studies have reported information on the probability of response to treatment with BAST for people with a negative SeHCAT test, and no DTA studies have incorporated a blinded placebo arm (37,40). Consequently, the lack of evidence of the accuracy of the SeHACT test based on a reference standard and the variation in cut-off values of test results led to important uncertainties in the cost-effectiveness analyses in determining the optimal strategy in investigating BAD (41). Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.
Given the paucity of high-certainty evidence on diagnostic tests, there is also a need for well-designed DTA studies comparing SeHCAT, C4 assay, FGF19, and total and primary bile acid measurement in stool, with a reference standard for BAD (e.g., response to BAST) by applying both the index tests and reference standard to all patients (94,95), as well as RCTs comparing SeHCAT testing versus an empiric trial of BAST in patients with suspected BAD including an assessment of objective clinical efficacy and safety outcome measures. A placebo-controlled RCT of BAST (colesevelam) in patients with evidence of BAD, based on fecal bile acid measurements, is ongoing (NCT03270085) and the results will help to inform the role of fecal bile acids as a diagnostic test for BAD (96).
It is important to note that the diagnostic accuracy of total and primary bile acid excretion has not been assessed formally by GRADE for this guideline because it was not a topic initially proposed for inclusion a priori. Nevertheless, there have been recent publications on assessing 48-hour total and primary bile acid fecal excretion (a test available in North America) as a diagnostic test for BAD (95). Recent advances also have assessed whether this test could be optimized by including assays of primary bile acids (95). Most (if not all) have been observational studies that have found significant correlation or association between increased fecal bile acids and certain conditions that can cause diarrhea (i.e., IBS-D, chronic functional diarrhea) (95,(97)(98)(99). Although observational studies can provide evidence of significant association or correlation between predictor and outcome variables, they cannot prove causality because there are always residual confounding variables (unmeasured or imprecisely measured) that may have affected the results. Spurious associations also can arise with reverse causality. Future prospective studies are required to validate the diagnostic accuracy for BAD of primary bile acids at various cut-off concentrations in a single stool sample against a reference standard (i.e., the ability of this test to accurately predict response to BAST).
# e24
Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1
RCTs are needed to compare cholestyramine with other BASTs for the treatment of BAD. In addition, evidence is needed to guide dosing schedules. This includes assessment of whether there is any advantage to morning versus evening dosing and once-daily versus divided doses of BAST to maximize benefits and minimize interactions with other medications. Theoretically, there may be some efficacy benefits to targeting dosing to times of maximum gallbladder emptying, such as postprandially or in the morning, but more research is needed. In hypercholesterolemia there were no significant variations in the hypocholesterolemic effects when cholestyramine was timed with meals to optimize exposure to bile in the duodenum that followed gallbladder emptying (100). However, the relevant mechanisms in BAD may be different, particularly because the therapeutic aim is to reduce the effects of free secretory bile acid in the colon.
In conclusion, current evidence suggests that the accuracy of diagnostic tests (e.g., SeHCAT, C4) in predicting BAD or response to treatment are highly uncertain. Economic evaluation suggests that strategies of either an empiric trial of BAST or performing SeHCAT testing may be cost effective depending on the scenarios and society's willingness to pay. Therefore, either strategy may be used to identify patients with possible BAD depending on cost, available resources, local expertise and patient preferences.
# Canadian Association of Gastroenterology Statement
This clinical practice guideline on the management of BAD was developed under the direction of Dr Daniel Sadowski, in accordance with the policies and procedures of the Canadian Association of Gastroenterology and under the direction of the Canadian Association of Gastroenterology Clinical Affairs. It has been reviewed by the Canadian Association of Gastroenterology Practice Affairs and Clinical Affairs Committees and the Canadian Association of Gastroenterology Board of Directors. The clinical practice guideline was developed after a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian, U.S. and UK panel comprising experts on this topic. The clinical practice guideline aims to provide a reasonable and practical approach to care for specialists, and allied health professionals are charged with the duty of providing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The clinical practice guideline is not intended to be a substitute for physicians using their individual judgment in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.
Novartis Pharma, and Prometheus Diagnostics, and has served on the speaker's bureau of GE Healthcare; and Eldon A. Shaffer has served on the speaker's bureau of Pendopharm. The remaining authors disclose no conflicts.
# SUPPLEMENTARY DATA
Supplementary data are available at Journal of the Canadian Association of Gastroenterology online.
# Acknowledgments
The consensus group would like to thank Pauline Lavigne and Steven Portelance (unaffiliated) who provided medical writing services and editorial assistance on their behalf, supported by funds from the Canadian Association of Gastroenterology; and Paul Sinclair, Cindy Roll and Adria Cehovin (Canadian Association of Gastroenterology representatives: administrative and technical support, and logistical assistance).
As per Canadian Association of Gastroenterology policy for all clinical practice guidelines, the manuscript was made available to all Canadian Association of Gastroenterology members for commenting before submission for publication. Members were notified that the manuscript was available on the members-only section of the Canadian Association of Gastroenterology website and open for comment for a 2-week period.
# Funding
This guideline was supported through unrestricted grants to the Canadian Association of Gastroenterology by Pendopharm and GE Healthcare Canada, neither of which had any involvement in the development of this guideline. The Canadian Association of Gastroenterology administered all aspects of the meeting, and the funding sources had no involvement in the process at any point, and were not made aware of any part of the process from the development of search strings and the statements, to drafting and approval of these guidelines.
# Conflicts of interest
These authors disclose the following: John K. Marshall has served on the advisory boards of AbbVie, Allergan, AstraZeneca, Boehringer-Ingelheim, Celgene, Celltrion, Ferring, Hospira, Janssen, Merck, Pfizer, Pharmascience, Shire, and Takeda, has consulted for Lupin, Merck, and Pharmascience, and has served on the speaker's bureau for AbbVie, Allergan, Ferring, Janssen, Shire, and Takeda; Michael Camilleri has served on the advisory boards of Allergan and BioKier, has consulted for AstraZeneca, Dignify Therapeutics, Elobix AB, Enterin, Ironwood, Shire, Takeda, and Theravance, and has received educational and/or research grants from Allergan, AstraZeneca, Elira, NGM Biopharma, Novartis Pharma, Novo Nordisk, and Rhythm; William D. Chey has served on the advisory boards of the American College of Gastroenterology, the American Neurogastroenterology and Motility Society, and the Rome Foundation, and has consulted for Allergan, Biomerican, IM Health, Ironwood, Nestle, Prometheus Diagnostics, QOL Medical, Ritter, Salix, and Shire; Julian R. F. Walters has consulted for ENYO Pharma, GE Healthcare, Intercept Pharma, Metacrine, Inc, Novartis Pharma, Pharmascience, Prometheus Diagnostics, and Zealand Pharma, has received educational and/or research grants from ENYO Pharma, GE Healthcare, Intercept Pharma, Journal of the Canadian Association of Gastroenterology, 2020, Vol. 3, No. 1 e25
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} Family physicians are faced with a range of options when selecting the most appropriate treatment approach for people with diabetes. The challenge is compounded by the vast amount of new evidence that is disseminated to both clinicians and to people with diabetes. Guidelines are meant to summarize this evidence, but it is not feasible for FPs to implement every single guideline recommendation relevant to primary care. } In this review the authors aimed to summarize the Diabetes Canada 2018 guidelines and identify key messages and recommendations for FPs. From the 313 recommendations in the guidelines, they highlight the 22 they deemed the highest priority for primary care. } Providing care that is concordant with the latest guidelines requires repeated discussions featuring shared decision making with people with diabetes about opportunities to reduce the risk of diabetes complications, keep patients safe, and support self-management.# Main message
Three key messages were identified from the 2018 guidelines as priorities for FPs: discussing opportunities to reduce the risk of diabetes complications, discussing opportunities to ensure safety and prevent hypoglycemia, and discussing progress on self-management goals and addressing barriers. A theme cutting across these key messages was the need to tailor discussions to the needs and preferences of each person. These important guideline recommendations are highlighted, along with information about relevant tools for implementing the recommendations in real-world practice.
Conclusion High-quality diabetes care involves a series of periodic conversations about self-management and about pharmacologic and nonpharmacologic treatments that fit with each patient's goals (ie, shared decision making). Incorporating these conversations into regular practice provides FPs with opportunities to maximize likely benefits of treatments and decrease the risk of harms, to support patients in initiating and sustaining desired lifestyle changes, and to help patients cope with the burdens of diabetes and comorbid conditions. F amily doctors and other primary care clinicians provide most of the care for Canadians living with diabetes and its complications. 1 The increasing number and complexity of cases of this chronic disease 2 provides an opportunity to ensure better supports are in place for persons with diabetes and their care providers. Given recent pharmacologic advances, as well as new evidence about the potential for specific benefits and harms, clinicians today are faced with a range of options when selecting the most appropriate treatment approach for people with diabetes. The challenge for FPs is compounded by the vast amount of new evidence available on a range of clinical topics relevant to the people with diabetes whom they see in their practices. Guidelines help to summarize evidence, but it is not feasible 3 or appropriate 4 for FPs to incorporate every single guideline recommendation relevant to primary care into practice. Which highpriority items deserve attention and action? Which recommendations should FPs make a special effort to understand and discuss with their patients?
Guidelines do not implement themselves. 5 To integrate guideline recommendations into routine clinical care, FPs must not only be aware of and agree with them, but also must be able to adopt and adhere to them whenever applicable. 6 To this end, a clinical practice guideline dissemination and implementation (D&I) committee, composed of interprofessional diabetes providers from across the country (some of whom contributed to writing the guideline but many of whom did not), was organized by Diabetes Canada to develop strategies for both people with diabetes and providers, hoping to support translating evidence-based recommendations into practice. Evaluation of the effects of these efforts is ongoing. 7 The "Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada" were published in April 2018. 8 As part of the dissemination effort, a series of readable articles summarizing high-priority recommendations for primary care providers and outlining easy-to-apply practices were planned. This article summarizes the new guidelines, focusing on high-priority recommendations for FPs managing people who live with type 2 diabetes. Herein, we present these guideline recommendations and link these recommendations to approaches and tools that will help FPs put them into practice.
# Quality of evidence
Diabetes Canada is a health charity and advocacy organization that produces comprehensive national guidelines for the prevention and management of diabetes in adults and children, with a focus on special populations (those with renal failure, Indigenous peoples, women of childbearing age, etc). Following a rigorous methodology, 9,10 a guideline writing committee, composed of interprofessional diabetes experts, posed then answered clinically relevant questions, resulting in a series of recommendations. 10 The evidence supporting the recommendations ranges from levels I to IV and grades A to D. 8 The Diabetes Canada guideline committee includes primary care practitioners, endocrinologists, diabetes educators, other specialists, and people living with diabetes from across Canada. The resulting diabetes guideline is reviewed and launched in a 5-year cycle, with interim revisions in the event of important practice-changing evidence and treatment options. For the 2018 guidelines, 9 of the 10 authors responsible for developing recommendations for pharmacologic management of type 2 diabetes had no conflicts of interest with industry. In the case of disagreement about conflicts or outright conflicts of interest, committee members removed themselves from discussions. This article does not attempt to revise or critique the Diabetes Canada guideline recommendations but presents a family medicine-oriented approach to applying relevant recommendations in practice.
The guideline D&I committee co-chairs developed a process of prioritizing and distilling key messages relevant to primary care from 313 recommendations in 38 guideline chapters (Figure 1). 8 The prioritization was completed anonymously by members of the guideline writing committee, people with diabetes, and members of the D&I committee. Given the large number of recommendations, the first step of the prioritization exercise was to select guideline chapters; each member was asked to select 10 chapters, then, from these chapters, to select and rank 10 recommendations. Based on the number of votes for each recommendation, a list of 22 recommendations was compiled. This was followed by thematic analysis and member checking to summarize key messages. Specifically, the co-chairs (endocrinologist C.H.Y. and FP N.M.I.) collaboratively sorted the recommendations into conceptually similar groups (themes) and drafted key messages that represented these themes. Next, they sought input from the committee members to refine the key messages, similar to the process of member checking in qualitative research. 11 For this manuscript, we sought further input from FPs on the D&I committee to ensure that no important recommendations or concepts had been missed in summarizing the high-priority aspects of the guideline for the management of people with type 2 diabetes by FPs. This involved providing these FPs with the full list of recommendations via e-mail and asking them to identify any missing high-priority recommendations. During the process of converting themes into key messages, and during the process of writing this manuscript, input was sought from members of the D&I committee who live with diabetes to ensure that the content was informed by their needs and perspectives. As a final step, the entire committee identified tools that might support implementation of the key messages. To the extent possible, tools are informed by evidence regarding implementation of evidence in practice. Some of these tools are identified in this manuscript; these and many others can be accessed at guidelines.diabetes.ca.
# Main message
The prioritization exercise resulted in 22 recommendations nominated for emphasis in dissemination and implementation efforts. These were then categorized into 3 key messages (Table 1) 8,16 and a cross-cutting theme, as described below.
Providing care that is concordant with the latest guidelines requires repeated discussions featuring shared decision making with people with diabetes about opportunities to reduce the risk of diabetes complications, keep patients safe, and support self-management. For this reason, long-term and short-term risks must be balanced in a way that incorporates consideration of each person's needs, preferences, and capabilities, along with the research evidence and clinician judgment. For example, glycemic targets will vary based on patient circumstances (Figure 2). 8 The recommendations highlighted here presume that diabetes care is being provided in an ongoing, relationship-based primary care context, in which repeated consultations occur to routinely and iteratively set care goals and develop plans to achieve them. A revised acronym was developed as an aid to facilitate rapid assessment and action that incorporates the key messages presented here during these routine diabetes visits: ABCDES3 (Figure 3). 8 As part of the guideline dissemination and implementation, Diabetes Canada produced updated diabetes care flow sheets, available online (guidelines.diabetes. ca/docs/cpg/Appendix-3.pdf); a quick version focusing on ABCDES3 has also been produced (guidelines. diabetes.ca/docs/CPG-quick-reference-guideweb-EN.pdf#page=10), and providers might consider adapting this for use as a "stamp" (or form or template) in electronic medical records.
Key message 1: discuss opportunities to reduce the risk of diabetes complications. The guideline states that treatments should be added (as tolerated) to achieve hemoglobin A 1c (HbA 1c ), blood pressure, and cholesterol targets in accordance with patient preferences and goals. Since the last guideline update in 2013, the main change in this aspect of the guideline reflects new evidence that canagliflozin, empagliflozin, and liraglutide reduce the risk of cardiovascular events in patients who have a history of vascular disease. 8 (Similar evidence for additional medications was not available at the time of guideline development.) The guideline states that evidence-based medications for vascular protection should be prescribed whenever appropriate: - statins in those aged 40 or older or with complications; - angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in those aged 55 or older or with complications; and - acetylsalicylic acid plus a sodium glucose transporter 2 inhibitor or glucagonlike peptide 1 receptor agonist with proven cardiovascular benefit (canagliflozin, empagliflozin, liraglutide) for those with vascular disease. Diabetes Canada has created several interactive clinical decision support tools to help reduce some of the barriers to implementing these recommendations, including an interactive tool to consider pharmacotherapy options for glycemic control that compares the relative advantages or limitations of different agents (guidelines.diabetes.ca/bloodglucoselowering/ pharmacologyt2), an interactive tool for selecting agents for vascular protection (guidelines.diabetes.ca/ vascularprotection/riskassessment), and a prescription for cardiovascular protection (guidelines.diabetes. ca/docs/resources/prescription-for-cardiovascularprotection-with-diabetes.pdf). People with diabetes also require routine monitoring (and relevant action) for neuropathy, nephropathy, and retinopathy, which can be facilitated with a flow sheet (guidelines.diabetes.ca/ docs/cpg/Appendix-3.pdf). 8 Table 1. Selected high-priority type 2 diabetes recommendations and relevant tools for FPs: Highlighted recommendations were prioritized for dissemination by those involved in preparing this review. They are not presented in any particular order and are not necessarily the most important recommendations for a given practice or patient; the full guideline is available at guidelines.diabetes.ca.
# KEY MESSAGE GUIDELINE RECOMMENDATION RELEVANT TOOLS
# Discuss opportunities to reduce the risk of diabetes complications
If glycemic targets are not achieved with existing antihyperglycemic medications, other classes of agents should be added to improve glycemic control. The choice should be individualized taking into account the information below and in Figure 2 8 (grade B, level II)
Interactive tool for selecting agents for glycemic control:
guidelines.diabetes.ca/ bloodglucoselowering/ pharmacologyt2 In people without clinical CVD in whom glycemic targets are not achieved with existing antihyperglycemic medication, incretin agents (DPP4Is or GLP1RAs) or SGLT2Is should be considered as add-on medication over insulin secretagogues, insulin, and TZDs to improve glycemic control, if lower risk of hypoglycemia or weight gain are priorities (grade A, level IA). Acarbose and orlistat can also be considered as add-on medication to improve glycemic control with a low risk of hypoglycemia and weight gain (grade D, consensus)
In people with clinical CVD in whom glycemic targets are not achieved with existing antihyperglycemic medication, an antihyperglycemic agent with demonstrated CV outcome benefit should be added to reduce the risk of major CV events (grade A, level IA for empagliflozin; grade A, level IA for liraglutide; grade C, level II for canagliflozin) Insulin can be used at any time in the course of type 2 diabetes (grade D, consensus) (see link in Relevant Tools column for examples of insulin initiation and titration in people with type 2 diabetes). In people not achieving glycemic targets with existing non-insulin antihyperglycemic medication, the addition of a once-daily basal insulin regimen should be considered over premixed insulin or bolus-only regimens to reduce weight gain and hypoglycemia (grade B, level II)
Long-acting insulin analogues should be considered over NPH insulin to reduce the risk of nocturnal and symptomatic hypoglycemia (grade A, level IA)
In people receiving insulin, doses should be adjusted or additional antihyperglycemic medication (non-insulin or bolus insulin) should be added if glycemic targets are not achieved (grade D, consensus)
- A GLP1RA should be considered as add-on therapy to improve glycemic control with weight loss (grade A, level IA) before initiating bolus insulin or intensifying insulin to improve glycemic control with weight loss and a lower hypoglycemia risk compared with single or multiple bolus-insulin injections (grade A, level IA) - An SGLT2I should be considered as add-on therapy to improve glycemic control with weight loss and lower hypoglycemic risk compared with additional insulin (grade A, level IA) - A DPP4I could be considered as add-on therapy to improve glycemic control without weight gain or increased hypoglycemia risk compared with additional insulin (grade B, level II) -warrants therapy based on the presence of other risk factors according to the "2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult" 16 (grade D, consensus) For individuals not at their LDL-C goal despite statin therapy, a combination of statin therapy with second-line agents can be used to achieve the goal, and the agent used should be selected based upon the size of the existing gap to LDL-C goal (grade D, consensus). Generally, ezetimibe should be considered (grade D, consensus). In people with diabetes who also have concomitant clinical CVD, a PCSK9 inhibitor can be used (grade A, level I) ACEIs or ARBs, at doses that have demonstrated vascular protection, should be used to reduce CV risk in adults with type 1 or type 2 diabetes with any of the following:
- Interval training (short periods of vigorous exercise alternating with short recovery periods at low to moderate intensity or rest from 30 s to 3 min each) can be recommended to people willing and able to perform such training to increase gains in cardiorespiratory fitness in type 2 diabetes (grade B, level II) People with diabetes (including elderly people) should perform resistance exercise at least twice a wk and preferably 3 times/wk (grade B, level II) in addition to aerobic exercise (grade B, level II). Initial instruction and periodic supervision by an exercise specialist can be recommended (grade C, level III) Setting specific exercise goals, problem solving potential barriers to physical activity, providing information on where and when to exercise, and selfmonitoring should be performed collaboratively between the person with diabetes and the health care provider to increase physical activity and improve HbA 1c levels (grade B, level II)
In addition to achieving physical activity goals, people with diabetes should minimize the amount of time spent in sedentary activities and periodically break up long periods of sitting (grade C, level III) People with diabetes should be offered timely self-management education that is tailored to enhancing self-care practices and behaviour (grade A, level IA) Technologies, such as Internet-based computer programs and glucose monitoring systems, brief text messages, and mobile applications can be used to support self-management in order to improve glycemic control (grade A, level IA) Interactive tool to provide specific exercise advice:
# guidelines.diabetes.ca/ selfmanagementeducation/ patool
Sample exercise prescriptions for patients with diabetes: guidelines.diabetes.ca/ docs/resources/diabetesand-physical-activity-yourexercise-prescription.pdf ACEI-angiotensin-converting enzyme inhibitor, ARB-angiotensin receptor blocker, ASA-acetylsalicylic acid, BG-blood glucose, BP-blood pressure, CGM-continuous glucose monitoring, CKD-chronic kidney disease, CV-cardiovascular, CVD-cardiovascular disease, DPP4I-dipeptidyl peptidase 4 inhibitor, GLP1RA-glucagonlike peptide 1 receptor agonist, HbA 1c -hemoglobin A 1c , LDL-C-low-density lipoprotein cholesterol, MR-modified release, NPH-neutral protamine Hagedorn, PCSK9-proprotein convertase subtilisin-kexin type 9, SGLT2I-sodium glucose transporter 2 inhibitor, SMBG-self-monitoring of blood glucose, TZD-thiazolidinedione. Grades and levels of evidence are defined in the methods chapter of the guidelines (guidelines.diabetes.ca/browse/chapter2). Briefly, grade A and level I evidence is the strongest and most relevant. Level IV evidence is the weakest, and grade D recommendations are supported by level IV evidence or consensus. 8 Data from the Diabetes Canada Clinical Practice Guidelines Expert Committee. 8 Table 1 continued from page 19 Key message 2: discuss opportunities to ensure safety and prevent hypoglycemia. The guideline states that targets for HbA 1c levels and treatments should be individualized based on goals, preferences, and functional status, as described in Figure 2. 8 Lower targets are appropriate when priority is placed on reducing the risk of microvascular outcomes and when the treatments used do not place the patient at risk of hypoglycemia. Higher targets are appropriate when reducing the risk of long-term complications is a lower priority. Diabetes Canada has an interactive tool to help tailor glycemic targets to optimize relevant outcomes while avoiding hypoglycemia (guide lines.diabetes.ca/bloodglucoselowering/a1ctarget).
Two new high-priority recommendations in the 2018 guidelines involve preventing hypoglycemia. First, all people with diabetes who take agents that can cause hypoglycemia (ie, insulin or insulin secretagogues) should be counseled on safe driving (ie, having sugar on-hand to prevent lows). A new chapter in the 2018 guidelines (guidelines.diabetes.ca/cpg/chapter21) describes how to assess and manage private and commercial drivers, especially those who take insulin or insulin secretagogues. 8 Diabetes Canada has handouts to support conversations regarding safe driving, and the guidelines feature a sample diabetes and driving educational resource to fill out with people who have diabetes (guidelines.diabetes.ca/docs/patient-resources/ drive-safe-with-diabetes.pdf). Second, the guidelines recommend that medications that pose less risk of hypoglycemia should be used preferentially, especially in the elderly (ie, metformin or dipeptidyl peptidase 4 inhibitors in preference to insulin or insulin secretagogues). Likewise, risks of hypotension should be considered when managing blood pressure. As noted in the previous guideline, recommendations emphasize the safe use of medications when people with diabetes are unwell and when they are at risk of hypovolemia. Euglycemic ketoacidosis is a particular risk with sodium glucose transporter 2 inhibitors, and these should be held on sick days (ie, when patients are at risk of dehydration). 17 The Diabetes Canada guidelines have an appendix to support sick-day planning (guidelines.diabetes.ca/ docs/cpg/Appendix-8.pdf) and an appendix for therapeutic considerations for renal impairment (guidelines. diabetes.ca/docs/cpg/Appendix-7.pdf). 8 The website also features patient resources for primary care physicians to use with their patients for sick-day management (guidelines.diabetes.ca/docs/patient-resources/ stay-safe-when-you-have-diabetes-and-sick-or-atrisk-of-dehydration.pdf), as well as for hypoglycemia identification, treatment, and prevention (guidelines. diabetes.ca/docs/patient-resources/hypoglycemialow-blood-sugar-in-adults.pdf). There is evidence that FPs can influence exercise levels. 18 The guidelines recommend routinely setting specific exercise goals with each patient, problem solving to address potential barriers to physical activity, providing information on where and when to exercise, and encouraging self-monitoring (eg, pedometer or other tracking system) are recommended. Diabetes Canada has an interactive tool that can help FPs to provide specific exercise advice (guidelines.diabetes.ca/ selfmanagementeducation/patool), as well as various instructional videos demonstrating resistance and core exercises (guidelines.diabetes.ca/patient-videos).
Supporting self-management also involves helping people address barriers to a healthy lifestyle including diabetes-related distress and comorbid conditions, such as depression or pain. Family physicians are particularly well positioned to identify the stressors experienced by patients and to support them in addressing their highest-priority needs. More frequent visits for people struggling to achieve their goals, ideally involving a structured team-based approach, can enable more effective implementation of self-management support. 19 For those not practising in contexts with easy access to a multidisciplinary team, resources from Diabetes Canada have been developed to help implement these recommendations in practice (guidelines.diabetes.ca/reducecomplications/the-5rs), including handouts for people about self-management in general, featuring ABCDES3 for patients (guidelines.diabetes.ca/docs/patientresources/my-diabetes-care-not-just-about-bloodsugar.pdf), plus handouts and practice tools that assist in identifying and managing sources of diabetes-related distress (guidelines.diabetes.ca/selfmanagement education/psychosocial).
Cross-cutting theme: tailor discussions based on the needs and preferences of each person. Family physicians play a key role in managing care and supporting people with diabetes throughout the lifespan. The Diabetes Canada guideline features numerous recommendations that are specific to stages in the lifespan and the cultural contexts of people with diabetes. Specific chapters detail issues relevant to children, women of childbearing age, functionally dependent or frail elderly, as well as Indigenous peoples; we encourage providers to review the key messages and recommendations from these chapters. Diabetes Canada has handouts in French (guide lines.diabetes.ca/ressourcesfrancaises) and Chinese (guidelines.diabetes.ca/chinese), covering, for example, dietary options for people with a range of backgrounds, and additional cultural adaptations are forthcoming. Diabetes Canada also offers a toll-free number (1 800 BANTING), as well as a resource manual (guidelines.diabetes.ca/ financial-support-and-services), to support patients with diabetes who have low income or other need to identify local resources and services that might be helpful.
Discussion. Guidelines are meant to support clinical judgment not replace it. They should support shared decision making in practice. In that spirit, we present thematic groupings of guideline recommendations for adults with type 2 diabetes that we believe FPs will find important and useful. Specifically, the guidelines encourage 3 crucial conversations that FPs can have regularly with their patients to identify key considerations for comprehensive primary care across the lifespan. Family physicians might like to ask themselves and their patients with diabetes whether there are opportunities at each visit for the following: - add treatments that might reduce the risk of diabetes complications, - adjust treatment strategies to keep patients safe, and - support patients in self-management by addressing their sources of stress and helping them set goals and plan accordingly. Diabetes management typically requires adaptation over time by both the patient and the health professional with iterative goal setting. As biopsychosocial circumstances change, the treatment recommendations will also need to change. In the context of shared decision making, where the needs and preferences of the patient are considered, FPs can periodically identify opportunities to optimize treatment so that the risk of long-term complications is minimized and to prevent immediate symptoms or side effects. The recommendations highlighted here offer guidance on how to achieve this. However, the evidence suggests that the best possible outcomes are achieved when FPs organize their diabetes care in a way that incorporates the patient-centred and evidence-based approaches of the chronic care model.
# Limitations
This summary tries to organize information from the full guideline relevant for FPs, but we understand that each practice and each patient is unique. The recommendations prioritized for emphasis in this document might not match the needs of each practice, and the needs of each patient must be assessed through shared decision making. Many patients with type 2 diabetes might not have coverage for medications, and the newer agents might be prohibitively expensive for such patients. It is also plausible that emergent evidence based on real-world data will identify issues with the newer agents that lead to changes in the guideline recommendations. We further recognize that access to supports to implement best practices is not equitably distributed. 20,21 For example, some patients have more ready access to allied health professionals than others. These factors (and others) undoubtedly affect diabetes care and outcomes. While many clinical activities are appropriate and advisable in the primary care of a patient with diabetes, the starting point for this summary was the text of the Diabetes Canada clinical practice guidelines. Many other guidelines related to the care of patients who have diabetes exist. The Diabetes Canada guidelines are aligned with the Canadian Cardiovascular Society guidelines for lipids 16 and the Hypertension Canada guidelines for blood pressure targets. 22 However, not all guidelines have the same recommendations, likely owing to variable weighting of the importance of different outcomes in the evidence base. For instance, recent guidelines from the American College of Physicians encourage higher HbA 1c targets owing to the lack of evidence that lower targets are associated with reduced risk of cardiovascular outcomes. 23 Additionally, simplified lipid guidelines for FPs de-emphasize targets for low-density lipoprotein to focus on use of evidence-based medications (eg, statins). 24 Finally, it is important to note that this manuscript seeks only to summarize Diabetes Canada guideline recommendations deemed most relevant for the primary care management of adults with type 2 diabetes by a selected, albeit multidisciplinary, group; further information about prevention and management of all types of diabetes can be accessed at guidelines.diabetes.ca.
# Conclusion
High-quality diabetes care involves a series of periodic conversations about self-management and about both pharmacologic and nonpharmacologic treatments that fit with each patient's goals (ie, shared decision making).
Incorporating these conversations into regular practice provides FPs with opportunities to maximize likely benefits of treatments and decrease the risk of harms, to support patients in initiating and sustaining desired lifestyle changes, and to help patients cope with the burdens of both diabetes and comorbid conditions. Family physicians can access the guideline at guidelines.diabetes.ca and might consider downloading the free smartphone app for quick access to guideline chapters and interactive tools at guidelines.diabetes.ca/app.
# Contributors
All authors participated in the process of prioritizing the recommendations and contributed to preparing the manuscript for submission.
# Competing interests None declared
Correspondence Dr Noah M. Ivers; e-mail noah.ivers@utoronto.ca
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} Family physicians are faced with a range of options when selecting the most appropriate treatment approach for people with diabetes. The challenge is compounded by the vast amount of new evidence that is disseminated to both clinicians and to people with diabetes. Guidelines are meant to summarize this evidence, but it is not feasible for FPs to implement every single guideline recommendation relevant to primary care. } In this review the authors aimed to summarize the Diabetes Canada 2018 guidelines and identify key messages and recommendations for FPs. From the 313 recommendations in the guidelines, they highlight the 22 they deemed the highest priority for primary care. } Providing care that is concordant with the latest guidelines requires repeated discussions featuring shared decision making with people with diabetes about opportunities to reduce the risk of diabetes complications, keep patients safe, and support self-management.# Main message
Three key messages were identified from the 2018 guidelines as priorities for FPs: discussing opportunities to reduce the risk of diabetes complications, discussing opportunities to ensure safety and prevent hypoglycemia, and discussing progress on self-management goals and addressing barriers. A theme cutting across these key messages was the need to tailor discussions to the needs and preferences of each person. These important guideline recommendations are highlighted, along with information about relevant tools for implementing the recommendations in real-world practice.
Conclusion High-quality diabetes care involves a series of periodic conversations about self-management and about pharmacologic and nonpharmacologic treatments that fit with each patient's goals (ie, shared decision making). Incorporating these conversations into regular practice provides FPs with opportunities to maximize likely benefits of treatments and decrease the risk of harms, to support patients in initiating and sustaining desired lifestyle changes, and to help patients cope with the burdens of diabetes and comorbid conditions. F amily doctors and other primary care clinicians provide most of the care for Canadians living with diabetes and its complications. 1 The increasing number and complexity of cases of this chronic disease 2 provides an opportunity to ensure better supports are in place for persons with diabetes and their care providers. Given recent pharmacologic advances, as well as new evidence about the potential for specific benefits and harms, clinicians today are faced with a range of options when selecting the most appropriate treatment approach for people with diabetes. The challenge for FPs is compounded by the vast amount of new evidence available on a range of clinical topics relevant to the people with diabetes whom they see in their practices. Guidelines help to summarize evidence, but it is not feasible 3 or appropriate 4 for FPs to incorporate every single guideline recommendation relevant to primary care into practice. Which highpriority items deserve attention and action? Which recommendations should FPs make a special effort to understand and discuss with their patients?
Guidelines do not implement themselves. 5 To integrate guideline recommendations into routine clinical care, FPs must not only be aware of and agree with them, but also must be able to adopt and adhere to them whenever applicable. 6 To this end, a clinical practice guideline dissemination and implementation (D&I) committee, composed of interprofessional diabetes providers from across the country (some of whom contributed to writing the guideline but many of whom did not), was organized by Diabetes Canada to develop strategies for both people with diabetes and providers, hoping to support translating evidence-based recommendations into practice. Evaluation of the effects of these efforts is ongoing. 7 The "Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada" were published in April 2018. 8 As part of the dissemination effort, a series of readable articles summarizing high-priority recommendations for primary care providers and outlining easy-to-apply practices were planned. This article summarizes the new guidelines, focusing on high-priority recommendations for FPs managing people who live with type 2 diabetes. Herein, we present these guideline recommendations and link these recommendations to approaches and tools that will help FPs put them into practice.
# Quality of evidence
Diabetes Canada is a health charity and advocacy organization that produces comprehensive national guidelines for the prevention and management of diabetes in adults and children, with a focus on special populations (those with renal failure, Indigenous peoples, women of childbearing age, etc). Following a rigorous methodology, 9,10 a guideline writing committee, composed of interprofessional diabetes experts, posed then answered clinically relevant questions, resulting in a series of recommendations. 10 The evidence supporting the recommendations ranges from levels I to IV and grades A to D. 8 The Diabetes Canada guideline committee includes primary care practitioners, endocrinologists, diabetes educators, other specialists, and people living with diabetes from across Canada. The resulting diabetes guideline is reviewed and launched in a 5-year cycle, with interim revisions in the event of important practice-changing evidence and treatment options. For the 2018 guidelines, 9 of the 10 authors responsible for developing recommendations for pharmacologic management of type 2 diabetes had no conflicts of interest with industry. In the case of disagreement about conflicts or outright conflicts of interest, committee members removed themselves from discussions. This article does not attempt to revise or critique the Diabetes Canada guideline recommendations but presents a family medicine-oriented approach to applying relevant recommendations in practice.
The guideline D&I committee co-chairs developed a process of prioritizing and distilling key messages relevant to primary care from 313 recommendations in 38 guideline chapters (Figure 1). 8 The prioritization was completed anonymously by members of the guideline writing committee, people with diabetes, and members of the D&I committee. Given the large number of recommendations, the first step of the prioritization exercise was to select guideline chapters; each member was asked to select 10 chapters, then, from these chapters, to select and rank 10 recommendations. Based on the number of votes for each recommendation, a list of 22 recommendations was compiled. This was followed by thematic analysis and member checking to summarize key messages. Specifically, the co-chairs (endocrinologist C.H.Y. and FP N.M.I.) collaboratively sorted the recommendations into conceptually similar groups (themes) and drafted key messages that represented these themes. Next, they sought input from the committee members to refine the key messages, similar to the process of member checking in qualitative research. 11 For this manuscript, we sought further input from FPs on the D&I committee to ensure that no important recommendations or concepts had been missed in summarizing the high-priority aspects of the guideline for the management of people with type 2 diabetes by FPs. This involved providing these FPs with the full list of recommendations via e-mail and asking them to identify any missing high-priority recommendations. During the process of converting themes into key messages, and during the process of writing this manuscript, input was sought from members of the D&I committee who live with diabetes to ensure that the content was informed by their needs and perspectives. As a final step, the entire committee identified tools that might support implementation of the key messages. To the extent possible, tools are informed by evidence regarding implementation of evidence in practice. [12][13][14][15] Some of these tools are identified in this manuscript; these and many others can be accessed at guidelines.diabetes.ca.
# Main message
The prioritization exercise resulted in 22 recommendations nominated for emphasis in dissemination and implementation efforts. These were then categorized into 3 key messages (Table 1) 8,16 and a cross-cutting theme, as described below.
Providing care that is concordant with the latest guidelines requires repeated discussions featuring shared decision making with people with diabetes about opportunities to reduce the risk of diabetes complications, keep patients safe, and support self-management. For this reason, long-term and short-term risks must be balanced in a way that incorporates consideration of each person's needs, preferences, and capabilities, along with the research evidence and clinician judgment. For example, glycemic targets will vary based on patient circumstances (Figure 2). 8 The recommendations highlighted here presume that diabetes care is being provided in an ongoing, relationship-based primary care context, in which repeated consultations occur to routinely and iteratively set care goals and develop plans to achieve them. A revised acronym was developed as an aid to facilitate rapid assessment and action that incorporates the key messages presented here during these routine diabetes visits: ABCDES3 (Figure 3). 8 As part of the guideline dissemination and implementation, Diabetes Canada produced updated diabetes care flow sheets, available online (guidelines.diabetes. ca/docs/cpg/Appendix-3.pdf); a quick version focusing on ABCDES3 has also been produced (guidelines. diabetes.ca/docs/CPG-quick-reference-guideweb-EN.pdf#page=10), and providers might consider adapting this for use as a "stamp" (or form or template) in electronic medical records.
Key message 1: discuss opportunities to reduce the risk of diabetes complications. The guideline states that treatments should be added (as tolerated) to achieve hemoglobin A 1c (HbA 1c ), blood pressure, and cholesterol targets in accordance with patient preferences and goals. Since the last guideline update in 2013, the main change in this aspect of the guideline reflects new evidence that canagliflozin, empagliflozin, and liraglutide reduce the risk of cardiovascular events in patients who have a history of vascular disease. 8 (Similar evidence for additional medications was not available at the time of guideline development.) The guideline states that evidence-based medications for vascular protection should be prescribed whenever appropriate: • statins in those aged 40 or older or with complications; • angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in those aged 55 or older or with complications; and • acetylsalicylic acid plus a sodium glucose transporter 2 inhibitor or glucagonlike peptide 1 receptor agonist with proven cardiovascular benefit (canagliflozin, empagliflozin, liraglutide) for those with vascular disease. Diabetes Canada has created several interactive clinical decision support tools to help reduce some of the barriers to implementing these recommendations, including an interactive tool to consider pharmacotherapy options for glycemic control that compares the relative advantages or limitations of different agents (guidelines.diabetes.ca/bloodglucoselowering/ pharmacologyt2), an interactive tool for selecting agents for vascular protection (guidelines.diabetes.ca/ vascularprotection/riskassessment), and a prescription for cardiovascular protection (guidelines.diabetes. ca/docs/resources/prescription-for-cardiovascularprotection-with-diabetes.pdf). People with diabetes also require routine monitoring (and relevant action) for neuropathy, nephropathy, and retinopathy, which can be facilitated with a flow sheet (guidelines.diabetes.ca/ docs/cpg/Appendix-3.pdf). 8 Table 1. Selected high-priority type 2 diabetes recommendations and relevant tools for FPs: Highlighted recommendations were prioritized for dissemination by those involved in preparing this review. They are not presented in any particular order and are not necessarily the most important recommendations for a given practice or patient; the full guideline is available at guidelines.diabetes.ca.
# KEY MESSAGE GUIDELINE RECOMMENDATION RELEVANT TOOLS
# Discuss opportunities to reduce the risk of diabetes complications
If glycemic targets are not achieved with existing antihyperglycemic medications, other classes of agents should be added to improve glycemic control. The choice should be individualized taking into account the information below and in Figure 2 8 (grade B, level II)
Interactive tool for selecting agents for glycemic control:
guidelines.diabetes.ca/ bloodglucoselowering/ pharmacologyt2 In people without clinical CVD in whom glycemic targets are not achieved with existing antihyperglycemic medication, incretin agents (DPP4Is or GLP1RAs) or SGLT2Is should be considered as add-on medication over insulin secretagogues, insulin, and TZDs to improve glycemic control, if lower risk of hypoglycemia or weight gain are priorities (grade A, level IA). Acarbose and orlistat can also be considered as add-on medication to improve glycemic control with a low risk of hypoglycemia and weight gain (grade D, consensus)
In people with clinical CVD in whom glycemic targets are not achieved with existing antihyperglycemic medication, an antihyperglycemic agent with demonstrated CV outcome benefit should be added to reduce the risk of major CV events (grade A, level IA for empagliflozin; grade A, level IA for liraglutide; grade C, level II for canagliflozin) Insulin can be used at any time in the course of type 2 diabetes (grade D, consensus) (see link in Relevant Tools column for examples of insulin initiation and titration in people with type 2 diabetes). In people not achieving glycemic targets with existing non-insulin antihyperglycemic medication, the addition of a once-daily basal insulin regimen should be considered over premixed insulin or bolus-only regimens to reduce weight gain and hypoglycemia (grade B, level II)
Long-acting insulin analogues should be considered over NPH insulin to reduce the risk of nocturnal and symptomatic hypoglycemia (grade A, level IA)
In people receiving insulin, doses should be adjusted or additional antihyperglycemic medication (non-insulin or bolus insulin) should be added if glycemic targets are not achieved (grade D, consensus)
• A GLP1RA should be considered as add-on therapy to improve glycemic control with weight loss (grade A, level IA) before initiating bolus insulin or intensifying insulin to improve glycemic control with weight loss and a lower hypoglycemia risk compared with single or multiple bolus-insulin injections (grade A, level IA) • An SGLT2I should be considered as add-on therapy to improve glycemic control with weight loss and lower hypoglycemic risk compared with additional insulin (grade A, level IA) • A DPP4I could be considered as add-on therapy to improve glycemic control without weight gain or increased hypoglycemia risk compared with additional insulin (grade B, level II) -warrants therapy based on the presence of other risk factors according to the "2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult" 16 (grade D, consensus) For individuals not at their LDL-C goal despite statin therapy, a combination of statin therapy with second-line agents can be used to achieve the goal, and the agent used should be selected based upon the size of the existing gap to LDL-C goal (grade D, consensus). Generally, ezetimibe should be considered (grade D, consensus). In people with diabetes who also have concomitant clinical CVD, a PCSK9 inhibitor can be used (grade A, level I) ACEIs or ARBs, at doses that have demonstrated vascular protection, should be used to reduce CV risk in adults with type 1 or type 2 diabetes with any of the following:
• Interval training (short periods of vigorous exercise alternating with short recovery periods at low to moderate intensity or rest from 30 s to 3 min each) can be recommended to people willing and able to perform such training to increase gains in cardiorespiratory fitness in type 2 diabetes (grade B, level II) People with diabetes (including elderly people) should perform resistance exercise at least twice a wk and preferably 3 times/wk (grade B, level II) in addition to aerobic exercise (grade B, level II). Initial instruction and periodic supervision by an exercise specialist can be recommended (grade C, level III) Setting specific exercise goals, problem solving potential barriers to physical activity, providing information on where and when to exercise, and selfmonitoring should be performed collaboratively between the person with diabetes and the health care provider to increase physical activity and improve HbA 1c levels (grade B, level II)
In addition to achieving physical activity goals, people with diabetes should minimize the amount of time spent in sedentary activities and periodically break up long periods of sitting (grade C, level III) People with diabetes should be offered timely self-management education that is tailored to enhancing self-care practices and behaviour (grade A, level IA) Technologies, such as Internet-based computer programs and glucose monitoring systems, brief text messages, and mobile applications can be used to support self-management in order to improve glycemic control (grade A, level IA) Interactive tool to provide specific exercise advice:
# guidelines.diabetes.ca/ selfmanagementeducation/ patool
Sample exercise prescriptions for patients with diabetes: guidelines.diabetes.ca/ docs/resources/diabetesand-physical-activity-yourexercise-prescription.pdf ACEI-angiotensin-converting enzyme inhibitor, ARB-angiotensin receptor blocker, ASA-acetylsalicylic acid, BG-blood glucose, BP-blood pressure, CGM-continuous glucose monitoring, CKD-chronic kidney disease, CV-cardiovascular, CVD-cardiovascular disease, DPP4I-dipeptidyl peptidase 4 inhibitor, GLP1RA-glucagonlike peptide 1 receptor agonist, HbA 1c -hemoglobin A 1c , LDL-C-low-density lipoprotein cholesterol, MR-modified release, NPH-neutral protamine Hagedorn, PCSK9-proprotein convertase subtilisin-kexin type 9, SGLT2I-sodium glucose transporter 2 inhibitor, SMBG-self-monitoring of blood glucose, TZD-thiazolidinedione. Grades and levels of evidence are defined in the methods chapter of the guidelines (guidelines.diabetes.ca/browse/chapter2). Briefly, grade A and level I evidence is the strongest and most relevant. Level IV evidence is the weakest, and grade D recommendations are supported by level IV evidence or consensus. 8 Data from the Diabetes Canada Clinical Practice Guidelines Expert Committee. 8 Table 1 continued from page 19 Key message 2: discuss opportunities to ensure safety and prevent hypoglycemia. The guideline states that targets for HbA 1c levels and treatments should be individualized based on goals, preferences, and functional status, as described in Figure 2. 8 Lower targets are appropriate when priority is placed on reducing the risk of microvascular outcomes and when the treatments used do not place the patient at risk of hypoglycemia. Higher targets are appropriate when reducing the risk of long-term complications is a lower priority. Diabetes Canada has an interactive tool to help tailor glycemic targets to optimize relevant outcomes while avoiding hypoglycemia (guide lines.diabetes.ca/bloodglucoselowering/a1ctarget).
Two new high-priority recommendations in the 2018 guidelines involve preventing hypoglycemia. First, all people with diabetes who take agents that can cause hypoglycemia (ie, insulin or insulin secretagogues) should be counseled on safe driving (ie, having sugar on-hand to prevent lows). A new chapter in the 2018 guidelines (guidelines.diabetes.ca/cpg/chapter21) describes how to assess and manage private and commercial drivers, especially those who take insulin or insulin secretagogues. 8 Diabetes Canada has handouts to support conversations regarding safe driving, and the guidelines feature a sample diabetes and driving educational resource to fill out with people who have diabetes (guidelines.diabetes.ca/docs/patient-resources/ drive-safe-with-diabetes.pdf). Second, the guidelines recommend that medications that pose less risk of hypoglycemia should be used preferentially, especially in the elderly (ie, metformin or dipeptidyl peptidase 4 inhibitors in preference to insulin or insulin secretagogues). Likewise, risks of hypotension should be considered when managing blood pressure. As noted in the previous guideline, recommendations emphasize the safe use of medications when people with diabetes are unwell and when they are at risk of hypovolemia. Euglycemic ketoacidosis is a particular risk with sodium glucose transporter 2 inhibitors, and these should be held on sick days (ie, when patients are at risk of dehydration). 17 The Diabetes Canada guidelines have an appendix to support sick-day planning (guidelines.diabetes.ca/ docs/cpg/Appendix-8.pdf) and an appendix for therapeutic considerations for renal impairment (guidelines. diabetes.ca/docs/cpg/Appendix-7.pdf). 8 The website also features patient resources for primary care physicians to use with their patients for sick-day management (guidelines.diabetes.ca/docs/patient-resources/ stay-safe-when-you-have-diabetes-and-sick-or-atrisk-of-dehydration.pdf), as well as for hypoglycemia identification, treatment, and prevention (guidelines. diabetes.ca/docs/patient-resources/hypoglycemialow-blood-sugar-in-adults.pdf). There is evidence that FPs can influence exercise levels. 18 The guidelines recommend routinely setting specific exercise goals with each patient, problem solving to address potential barriers to physical activity, providing information on where and when to exercise, and encouraging self-monitoring (eg, pedometer or other tracking system) are recommended. Diabetes Canada has an interactive tool that can help FPs to provide specific exercise advice (guidelines.diabetes.ca/ selfmanagementeducation/patool), as well as various instructional videos demonstrating resistance and core exercises (guidelines.diabetes.ca/patient-videos).
Supporting self-management also involves helping people address barriers to a healthy lifestyle including diabetes-related distress and comorbid conditions, such as depression or pain. Family physicians are particularly well positioned to identify the stressors experienced by patients and to support them in addressing their highest-priority needs. More frequent visits for people struggling to achieve their goals, ideally involving a structured team-based approach, can enable more effective implementation of self-management support. 19 For those not practising in contexts with easy access to a multidisciplinary team, resources from Diabetes Canada have been developed to help implement these recommendations in practice (guidelines.diabetes.ca/reducecomplications/the-5rs), including handouts for people about self-management in general, featuring ABCDES3 for patients (guidelines.diabetes.ca/docs/patientresources/my-diabetes-care-not-just-about-bloodsugar.pdf), plus handouts and practice tools that assist in identifying and managing sources of diabetes-related distress (guidelines.diabetes.ca/selfmanagement education/psychosocial).
Cross-cutting theme: tailor discussions based on the needs and preferences of each person. Family physicians play a key role in managing care and supporting people with diabetes throughout the lifespan. The Diabetes Canada guideline features numerous recommendations that are specific to stages in the lifespan and the cultural contexts of people with diabetes. Specific chapters detail issues relevant to children, women of childbearing age, functionally dependent or frail elderly, as well as Indigenous peoples; we encourage providers to review the key messages and recommendations from these chapters. Diabetes Canada has handouts in French (guide lines.diabetes.ca/ressourcesfrancaises) and Chinese (guidelines.diabetes.ca/chinese), covering, for example, dietary options for people with a range of backgrounds, and additional cultural adaptations are forthcoming. Diabetes Canada also offers a toll-free number (1 800 BANTING), as well as a resource manual (guidelines.diabetes.ca/ financial-support-and-services), to support patients with diabetes who have low income or other need to identify local resources and services that might be helpful.
Discussion. Guidelines are meant to support clinical judgment not replace it. They should support shared decision making in practice. In that spirit, we present thematic groupings of guideline recommendations for adults with type 2 diabetes that we believe FPs will find important and useful. Specifically, the guidelines encourage 3 crucial conversations that FPs can have regularly with their patients to identify key considerations for comprehensive primary care across the lifespan. Family physicians might like to ask themselves and their patients with diabetes whether there are opportunities at each visit for the following: • add treatments that might reduce the risk of diabetes complications, • adjust treatment strategies to keep patients safe, and • support patients in self-management by addressing their sources of stress and helping them set goals and plan accordingly. Diabetes management typically requires adaptation over time by both the patient and the health professional with iterative goal setting. As biopsychosocial circumstances change, the treatment recommendations will also need to change. In the context of shared decision making, where the needs and preferences of the patient are considered, FPs can periodically identify opportunities to optimize treatment so that the risk of long-term complications is minimized and to prevent immediate symptoms or side effects. The recommendations highlighted here offer guidance on how to achieve this. However, the evidence suggests that the best possible outcomes are achieved when FPs organize their diabetes care in a way that incorporates the patient-centred and evidence-based approaches of the chronic care model.
# Limitations
This summary tries to organize information from the full guideline relevant for FPs, but we understand that each practice and each patient is unique. The recommendations prioritized for emphasis in this document might not match the needs of each practice, and the needs of each patient must be assessed through shared decision making. Many patients with type 2 diabetes might not have coverage for medications, and the newer agents might be prohibitively expensive for such patients. It is also plausible that emergent evidence based on real-world data will identify issues with the newer agents that lead to changes in the guideline recommendations. We further recognize that access to supports to implement best practices is not equitably distributed. 20,21 For example, some patients have more ready access to allied health professionals than others. These factors (and others) undoubtedly affect diabetes care and outcomes. While many clinical activities are appropriate and advisable in the primary care of a patient with diabetes, the starting point for this summary was the text of the Diabetes Canada clinical practice guidelines. Many other guidelines related to the care of patients who have diabetes exist. The Diabetes Canada guidelines are aligned with the Canadian Cardiovascular Society guidelines for lipids 16 and the Hypertension Canada guidelines for blood pressure targets. 22 However, not all guidelines have the same recommendations, likely owing to variable weighting of the importance of different outcomes in the evidence base. For instance, recent guidelines from the American College of Physicians encourage higher HbA 1c targets owing to the lack of evidence that lower targets are associated with reduced risk of cardiovascular outcomes. 23 Additionally, simplified lipid guidelines for FPs de-emphasize targets for low-density lipoprotein to focus on use of evidence-based medications (eg, statins). 24 Finally, it is important to note that this manuscript seeks only to summarize Diabetes Canada guideline recommendations deemed most relevant for the primary care management of adults with type 2 diabetes by a selected, albeit multidisciplinary, group; further information about prevention and management of all types of diabetes can be accessed at guidelines.diabetes.ca.
# Conclusion
High-quality diabetes care involves a series of periodic conversations about self-management and about both pharmacologic and nonpharmacologic treatments that fit with each patient's goals (ie, shared decision making).
Incorporating these conversations into regular practice provides FPs with opportunities to maximize likely benefits of treatments and decrease the risk of harms, to support patients in initiating and sustaining desired lifestyle changes, and to help patients cope with the burdens of both diabetes and comorbid conditions. Family physicians can access the guideline at guidelines.diabetes.ca and might consider downloading the free smartphone app for quick access to guideline chapters and interactive tools at guidelines.diabetes.ca/app.
# Contributors
All authors participated in the process of prioritizing the recommendations and contributed to preparing the manuscript for submission.
# Competing interests None declared
Correspondence Dr Noah M. Ivers; e-mail noah.ivers@utoronto.ca
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Également disponible en français sous le titre : Déclaration provisoire sur l'utilisation du vaccin rVSVΔG-ZEBOV-GP pour la prévention de la maladie à virus Ebola This publication can be made available in alternative formats upon request.# PREAMBLE
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidencebased recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this interim statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. As the advice is provided for an investigational product that has not yet received regulatory authorization for sale in Canada, people administering the premarket vaccine should also be aware of the contents of the pharmacy manual and investigator's brochure provided by the manufacturer. Recommendations for use and other information set out herein may differ from that set out in the pharmacy manual and investigator's brochure of the pre-market vaccine. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# TABLE OF CONTENTS
SUMMARY
# How
NACI makes the following interim recommendations for post-exposure prophylaxis against ZEBOV for the pre-market rVSVΔG-ZEBOV-GP vaccine stockpiled in the NESS:
- The vaccine should be offered to non-pregnant immunocompetent adults who have had an exposure to ZEBOV in Canada; and The vaccine may be considered for pregnant women, infants, children, adolescents, and immunocompromised individuals who have had an exposure to ZEBOV in Canada.
NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine stockpiled in the NESS may be considered as pre-exposure prophylaxis against ZEBOV for non-pregnant immunocompetent adults in exceptional situations when a dedicated team of healthcare workers is anticipated to provide direct care for a confirmed case with symptomatic ZEBOV infection, if vaccine is available.
# Why
EVD is a rare, severe, acute viral illness with a case fatality rate in humans ranging from 25-90%. Although uncertainties around safety, immunogenicity, efficacy, and effectiveness remain, vaccination with the rVSVΔG-ZEBOV-GP vaccine currently offers the best available protection against EVD caused by ZEBOV infection given the potential for severe harm from EVD and few options for reducing case fatality. The rVSVΔG-ZEBOV-GP vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination.
# I. INTRODUCTION
Ebola virus disease (EVD) is a rare, severe, acute viral illness in humans and non-human primates caused by ribonucleic acid viruses from the genus Ebolavirus, a member of the Filoviridae family (1) . Of the five well-described Ebolavirus species, four are known to cause illness in humans. The Zaire ebolavirus (ZEBOV) is considered the most virulent of these species, having the highest case fatality rate and being responsible for the majority of outbreaks to date.
EVD has an incubation period of 2-21 days, with most cases experiencing onset of symptoms around 4-10 days after exposure. Within 10 days of symptom onset, fatal cases will experience severe symptoms and succumb to the disease. Symptoms usually begin with a sudden onset of flu-like symptoms, such as fever, myalgia, severe headache, and malaise, typically followed by worsening gastrointestinal symptoms and fluid loss. Haemorrhage is a late manifestation and, in recent outbreaks, occurs in fewer than half of cases, usually from the gastrointestinal tract or other mucosa. Case fatality in humans ranges from 25-90%.
Non-fatal cases typically begin recovery 6-11 days after onset of symptoms. Full recovery occurs over a long period of time and is often associated with long-term sequelae. During recovery, Ebolavirus can persist in some body fluids such as semen, urine, and breast milk. Follow-up of a cohort of EVD survivors in Liberia has demonstrated persistence of ZEBOV in semen for up to 40 months with a range of 233 to 1178 days and a median of 551 days (2) . Viral relapse can also occur (3) .
Infectiousness starts from the time of symptom onset and the risk of transmission is highest when viral load is greatest. Person-to-person transmission can occur through direct physical contact with body fluids from an infected symptomatic person or dead body, or indirectly through physical contact with surfaces and fomites that are contaminated with these fluids. With the exception of the potential for sexual transmission during the convalescent period, Ebolavirus has not been demonstrated to spread to others by an asymptomatic person. Ebolavirus is not transmitted between humans through casual interactions or airborne transmission, but can be transmitted by aerosol-generating medical procedures.
EVD has generally been geographically limited to outbreak-prone areas of sub-Saharan Africa.
Between 1976 and 2012, sporadic cases and outbreaks of EVD were reported in several African countries. During the 2014-2016 West Africa EVD outbreak, the largest recorded outbreak of EVD to date, imported cases were identified in other countries in Africa, Europe, and North America. Limited secondary transmission in the United States and Spain from cases that have travelled from Africa has been reported (4,5) . There has been an ongoing outbreak of EVD since August 2018 in the Democratic Republic of the Congo (DRC), which is the second largest outbreak at the time of writing. No cases of EVD have been identified in Canada to date.
With the ongoing outbreak of EVD in the DRC, it is possible that Canada will receive an imported case of EVD prior to the authorization of a vaccine for EVD by Health Canada. As part of contingency planning for an imported EVD case, the Public Health Agency of Canada (PHAC) has procured Merck's investigational vaccine for EVD, the rVSVΔG-ZEBOV-GP vaccine (also referred to as the V920 Ebola Zaire Vaccine and Ervebo), for the National Emergency Strategic Stockpile (NESS) through Health Canada's Special Access Programme. On recommendation of the European Medicines Agency (EMA), the European Commission granted a conditional marketing authorization for this vaccine on November 11, 2019 and the World Health Organization (WHO) prequalified the vaccine (i.e., the vaccine met WHO's standards for quality, safety, and efficacy) on November 12, 2019. The rVSVΔG-ZEBOV-GP vaccine was approved by the United States Food and Drug Administration on December 19, 2019. NACI generally issues guidance only for immunizing agents that have been authorized by Health Canada. However, in this exceptional circumstance, PHAC has requested pre-market guidance from NACI on this investigational product because a limited quantity has been stockpiled in Canada for emergency use.
Merck's rVSVΔG-ZEBOV-GP vaccine is a live-attenuated, recombinant vesicular stomatitis virus (rVSV)-based vector vaccine, in which the vaccine vector's envelope glycoprotein (GP) is deleted and replaced with the ZEBOV envelope GP. The vaccine does not contain live ZEBOV. Many clinical trials have been completed using Merck's investigational vaccine, including doseranging trials to assess its safety and immunogenicity and a large cluster-randomized trial to evaluate its efficacy during the 2014-2016 West Africa outbreak.
There are several other investigational vaccines for EVD undergoing human trials (6) , but the rVSVΔG-ZEBOV-GP vaccine is the only one that is currently in widespread use despite its investigational status. The rVSVΔG-ZEBOV-GP vaccine has been available on compassionate grounds for both the 2014-2016 West Africa outbreak and the ongoing outbreak in the DRC. As of November 16, 2019, 253,545 people at risk in the DRC have received the vaccine (7) .
For the DRC outbreak, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization recommended a "ring vaccination" strategy to protect those at highest risk of EVD in the outbreak (8) . Ring vaccination involves contact tracing and vaccination of the contacts of an EVD case and the contacts of those contacts. As the situation in the DRC deteriorated in early 2019, additional vaccination strategies have been recommended for outbreak control (9) . These recommendations were devised for the epidemiological and public health situation in Africa and therefore are not directly applicable for the Canadian context.
Further details on EVD, including outbreak updates, can be found on the Government of Canada website.
# Guidance objective
The objective of this advisory committee interim statement is to review the safety, immunogenicity, efficacy, and effectiveness evidence available for the rVSVΔG-ZEBOV-GP vaccine and to provide interim guidance on the emergency use of this pre-market vaccine stockpiled in the NESS for the prevention of severe disease in individuals exposed to ZEBOV.
Advice on the following are outside the scope of NACI's mandate and therefore are not addressed in this interim statement: a) vaccination of travellers to areas outside of Canada that are prone to EVD outbreaks - ; b) the use of passive immunizing agents such as ZMapp for treating EVD; c) symptom management and clinical treatment of EVD; d) stockpile recommendations; and e) infection prevention and control (IPC) measures for EVD.
# II. METHODS
In brief, the broad stages in the preparation of a NACI advisory committee statement are:
- Knowledge synthesis; 2. Synthesis of the body of evidence of benefits and harms, considering the quality of the evidence and magnitude of effects observed; and 3. Translation of evidence into a recommendation. Details regarding NACI's evidence-based process for developing a statement are outlined in Evidence-based Recommendations for Immunization − Methods of the National Advisory Committee on Immunization.
Rapid reviews were conducted on the safety, immunogenicity, efficacy, and effectiveness of the rVSVΔG-ZEBOV-GP vaccine in humans and non-human primates and the effectiveness of the ring vaccination strategy in preventing EVD transmission. The search strategy was developed in consultation with a librarian from the Health Library of Health Canada and PHAC and included two separate searches (search strategies can be found in Appendix A). One search included terms specific to the rVSVΔG-ZEBOV-GP vaccine and the other included terms for ring vaccination. The literature searches were performed in 12 bibliographic databases and one clinical trial database. The searches were restricted to studies published in English or French. No publication date restrictions were applied. The final database search was executed on March 29, 2019 for the rVSVΔG-ZEBOV-GP vaccine and March 14, 2019 for ring vaccination. Hand searches of the reference lists of included articles and relevant reviews were performed. As the rVSVΔG-ZEBOV-GP vaccine has not yet been licensed for use in any jurisdiction at the time of literature review, adverse event reporting for this pre-market vaccine are not expected through passive vaccine safety surveillance systems such as the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) and therefore these surveillance systems were not searched for case reports.
Articles retrieved from the searches were screened by title and abstract. The full text of articles deemed relevant based on inclusion and exclusion criteria, or that had insufficient information to exclude, were retrieved and assessed for eligibility through full-text screening. Study selection was completed independently by two reviewers. Disagreements between the two reviewers were resolved by discussion and reaching a consensus. Data from included studies were extracted into evidence tables. The quality of evidence for individual studies and for the body of evidence was assessed using the criteria outlined by Harris et al. (10) . Data extraction and quality assessment were both completed by one reviewer and verified by a second reviewer. Results from included studies were synthesized narratively in the evidence tables. Geometric mean titre (GMT) values for varying dose levels of the rVSVΔG-ZEBOV-GP vaccine were extracted separately.
Knowledge synthesis was performed by LZ and AK. Proposed recommendations for vaccine use were developed by NACI's EVD Vaccine Working Group and reviewed for input by NACI's Vaccine Safety Working Group, the Canadian Immunization Committee, the Council of Chief Medical Officers of Health, and the EVD-Clinical Treatment Centre Task Group. The manufacturer was invited to present preclinical and clinical data for their vaccine to the EVD Vaccine Working Group on May 7, 2019 and was further consulted to identify additional safety data for the following special populations: pregnant and breastfeeding women, infants, children, adolescents, and immunocompromised individuals. A PHAC technical advisor (LZ) presented the findings of the knowledge synthesis to NACI on June 6, 2019. The evidence and proposed recommendations were discussed by the NACI EVD Vaccine Working Group in June and July 2019 and the proposed recommendations were deliberated by NACI on July 31, 2019. Given that this is a pre-market vaccine, NACI's Vaccine Safety Working Group was also consulted in June 2019 on the proposed recommendations. Following thorough review of the evidence and assessing the risk-benefit of vaccination with the pre-market vaccine, NACI reached consensus on specific recommendations. As part of the standard pre-release process for NACI statements, the manufacturer was consulted to identify any factual errors contained in the interim statement prior to publication. The descriptions of relevant considerations, rationale, and knowledge gaps on the use of the pre-market rVSVΔG-ZEBOV-GP vaccine are described in the following sections.
# III. VACCINE
A flow diagram of the study selection process can be found in Appendix B. After database searching, hand searching, and eligibility screening, 37 studies-26 studies in humans (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(41)(42)(43)(44) and 11 studies in non-human primates, including an unpublished study not reported here (31)(32)(33)(34)(35)(36)(37)(38)(39)(40) were included for review. Of the 26 studies in humans, 19 studies reported on unique subjects (12-16, 19-21, 24-29, 41-44) while the remainder offered supplemental data or provided additional analyses. Of these 19 studies, there were seven phase 1 dose-ranging clinical trials (12)(13)(14)(15)(16)19) (five were randomized placebo-controlled (12)(13)(14)(15)(16)19) ), one phase 2 randomized controlled trial (20) (the phase 3 component of this study was cancelled due to declining EVD cases), three phase 3 randomized controlled trials (21,24,25) (two were cluster-randomized comparing immediate to delayed vaccination (21,24) ), three ring vaccination field studies (26,27,44) , two prospective cohort studies (29,41) , one cross-sectional survey on safety (42) , and two case reports of post-exposure prophylaxis (PEP) following needlestick or sharps injuries (28,43) . The total vaccinated sample sizes by dose and outcome for the studies conducted in humans are tabulated in Table 1. The majority of subjects received the 2×10 7 plaque-forming unit (PFU) dose, which is the nominal dose of the vaccine deployed for use in the 2014-2016 West Africa outbreak and in the ongoing outbreak in the DRC. Safety information that was presented to the Global Advisory Committee on Vaccine Safety on June 5-6, 2019 (45) are included to supplement the review findings.
Six modelling studies were also identified that modeled the effects of ring vaccination on control of EVD outbreaks in the African context (46)(47)(48)(49)(50)(51) . These modeling studies were reviewed by NACI, but are not further discussed in this interim statement as the findings do not directly relate to the Canadian context. 3×10 3 n/a 2 (n=84) 3 (n=104) 3×10 4 n/a 2 (n=84) 2 (n=84) 1×10 5 n/a 1 (n=10) 1 (n=10) 3×10 5 n/a 3 (n=135) 4 (n=145) 5×10 5 n/a 1 (n=10) 1 (n=10) 3×10 6 n/a 6 (n=169) 5 (n=159) 9×10 6 n/a 1 (n=50) 1 (n=50) 1×10 7 n/a 1 (n=35) 1 (n=35) 2×10 7 4 (n=99,049) 8 (n=1652) 13 (n=150,204) * 5×10 7 n/a 1 (n=16) 2 (n=17) 1×10 8 n/a 3 (n=319) 4 (n=341)
Abbreviations: n/a: not available; PFU: plaque-forming unit. - Total vaccinated sample sizes by dose level and outcome are approximated based on the number of study subjects planned to be given the vaccine. These numbers are based on published articles included for review and therefore may differ from other tabulated sources. Dose values are based on the vaccine potencies reported in the included studies. These dose values may not correspond directly to the potency of the pre-market vaccine product available for use in Canada. * The vaccinated sample size for this dose level includes an estimated 130,000 individuals who were vaccinated in the DRC (45) .
Most included studies with evaluable study designs according to the Harris et al. criteria (10) received a "good" rating, with the exception of two studies receiving a "fair" rating due to interruptions in study protocol (15,21) . For all other study designs that were not evaluable with the Harris et al. criteria, no critical flaws were noted besides the intrinsic limitations of those designs.
Extracted study data are presented in the evidence table in Appendix C for human studies and Appendix D for non-human primate studies (data from an unpublished study in non-human primates are not summarized in the evidence table ). GMT point estimates and corresponding 95% confidence intervals (95% CI) from the human studies for the varying dose levels of the rVSVΔG-ZEBOV-GP vaccine are summarized in Appendix E. The overall patterns in the data are described for the outcomes of interest in the following sections.
# III.1 EFFICACY AND EFFECTIVENESS
Four studies assessed vaccine efficacy or effectiveness in humans in the context of ring vaccination (21,26,27,44) . Two case reports described PEP of healthcare or laboratory workers following high-risk needlestick or sharps injuries (28,43) . Six studies looking at survival following lethal ZEBOV challenge after pre-exposure prophylaxis (PrEP) (32)(33)(34)(35)(36)40) and two studies looking at survival following PEP after lethal ZEBOV challenge (31,38) were conducted in non-human primates.
# Ring vaccination
Ring vaccination, originally used for smallpox control and eradication, has been used broadly as an outbreak control measure in response to EVD activity. Ring vaccination involves tracking the epidemic and recruiting individuals at increased risk of infection based on their connection to a confirmed case of disease (52) . Ring vaccination typically includes a mix of PEP and PrEP based on confirmed and anticipated (e.g., for healthcare and frontline workers) exposure, respectively, for contacts of cases and contacts of those contacts.
In a phase 3 cluster randomized ring vaccination trial conducted in Guinea during the 2014-2016 West Africa outbreak, vaccine efficacy against EVD occurring 10 or more days after randomization was 100% (95% CI: 77.0-100.0%) comparing all vaccinated contacts and contacts of contacts randomized to receive the vaccine immediately (n=3775) with all contacts and contacts of contacts randomized to receive the vaccine 21 days after randomization and never-vaccinated (n=7995) (21) . The overall vaccine effectiveness in protecting all contacts and contacts of contacts in the randomized clusters (including unvaccinated cluster members; n=4513 immediate and 4529 delayed vaccination) against onset of EVD 10 days or more from randomization was 64.6% (95% CI: -44.2-91.3%). EVD cases occurred at similar attack rates within the first 10 days after randomization regardless of vaccination status; 11 cases among immediately vaccinated adults (0.5%) and 21 cases among all eligible adults assigned to delayed vaccination (0.7%) had onset of symptoms within 10 days of randomization. No cases of EVD occurred 10 days or more after randomization in the immediately vaccinated clusters compared with 16 cases among eligible individuals in delayed clusters. Vaccine effectiveness at 10 days or more post-vaccination against death due to EVD was 100%.
The preliminary estimate of vaccine effectiveness from the ongoing compassionate use ring vaccination program in the DRC (n=93,965 vaccinated) against onset of illness 10 days or more post-vaccination was 97.5% (95% CI: 95.8-98.5%) (44) . There were 71 cases of EVD among vaccinated individuals; 56 developed symptoms within 10 days of vaccination and only nine of these individuals died while 15 individuals developed symptoms 10 days or later following vaccination and none of these individuals died. Vaccine effectiveness at 10 days or more postvaccination against death due to EVD was also 100% in this study.
Results from these ring vaccination studies suggest that the vaccine was efficacious in preventing EVD, if symptoms of EVD did not appear within 10 days of vaccination. Based on these study findings, 10 days is the time after which vaccinees are assumed to be protected whereas less than 10 days post-vaccination is the period where vaccinees are not protected or partially protected (44) . Correlation between immune response and protection was not investigated in these studies. Ring vaccination was also found to be effective in contributing to outbreak control. However, the relative impact of vaccination on outbreak control compared to other factors (e.g., declining incidence of EVD, other public health measures) was not determined. Furthermore, as these studies were performed during ongoing community-based outbreaks and included contacts who may not have had a high-risk interaction with an index case, the study findings provide evidence of protection but do not differentiate whether it is preor post-exposure protection. Two other ring vaccination studies conducted during communitybased outbreaks of ZEBOV in Guinea (n=1510 vaccinated) (27) and Liberia (n=210 vaccinated) (26) did not identify secondary cases of EVD occurring among vaccine recipients. These two studies were not designed to assess the impact of vaccination on outbreak control.
The characteristics of the rings, or clusters, that comprise these ring vaccination studies were expectedly heterogeneous: 73-96% of contacts were contacts of contacts (i.e., secondary contacts), 4-27% of contacts were high-risk contacts (i.e., had close physical contact with an EVD case's body, body fluids, linens, or clothing), 7-20% of contacts were healthcare or frontline workers, median number of days from confirmation of EVD in the index case to vaccination of contacts ranged from 7-15 days, and cluster sizes ranged from several dozen to several hundred people (21,26,27,44) . Pregnant or breastfeeding women and children under six years of age were excluded from receiving the vaccine in these studies. Vaccine efficacy or effectiveness for children and adolescents 6-17 years of age and immunocompromised individuals were not separately reported.
# Prophylaxis after needlestick or sharps injury
There are several case reports of PEP following needlestick or sharps injuries. A laboratory worker was vaccinated with a 5×10 7 PFU dose 48 hours after needlestick injury with a syringe containing live ZEBOV (28) . Five healthcare workers were vaccinated with a 1×10 8 PFU dose 1-3 days after potential ZEBOV exposure resulting from sharps injuries sustained in West Africa (43) . These exposures did not result in evidence of infection, but it is not possible to determine whether this was due to vaccine effect or lack of transmission following the needlestick injury.
# Efficacy in non-human primates
For PrEP, complete protection was achieved with the vaccine (mostly at the 1×10 7 PFU dose) given 7-28 days before intramuscularly-administered lethal ZEBOV challenge (1000 PFU) (32,(34)(35)(36)40) and partial protection was achieved with the vaccine (5×10 7 PFU dose) given three days before lethal challenge in healthy animals (36) . Partial protection was also achieved with the vaccine (1×10 7 PFU dose) given 31 days before lethal challenge in immunodeficient SHIVinfected animals (33) .
For PEP, one study found that 50% of animals survived without showing signs of severe disease after vaccination (2×10 7 PFU dose) within 20-30 minutes of lethal challenge while both controls died (31) . Another study found no difference in survival among vaccinated (2×10 7 PFU dose) or control groups when vaccinated at 1 hour and/or 24 hours after lethal challenge (38) .
# III.2 IMMUNOGENICITY
Ten studies evaluated immunogenicity following vaccination with the rVSVΔG-ZEBOV-GP vaccine of varying dose levels in humans (12-16, 19, 20, 26, 29) and eight studies assessed immunogenicity following vaccination in non-human primates (31)(32)(33)(34)(35)(36)(37)40) . It is important to note that no immunological correlate of protection has been established for EVD, so it is difficult to interpret immunogenicity findings in the context of disease prevention.
# Immunoglobulin G antibody response
The most robustly assessed immunogenicity outcome was the ZEBOV envelope GP-specific immunoglobulin G (IgG) antibody response (12-16, 19, 20, 26, 29) . Most subjects seroconverted (i.e., had a four-fold or greater increase from baseline titre) by day 14 post-vaccination and all subjects seroconverted by day 28 regardless of dose. There was a high degree of interindividual variability in IgG antibody response regardless of dose. A dose-response relationship was observed with the speed and amplitude of response. However, there appeared to be diminishing marginal antibody response with increasing dose; GMTs were similar at higher doses due to the wide and overlapping 95% CI, suggesting a plateau of the dose-response curve at higher doses. One trial found a potential age-response relationship, where children and adolescents 6-17 years of age were observed to respond slower than adults (19) . GMTs generally peaked by day 28 and persisted to 1-2 years post-vaccination without significant decline and without significant difference across dose levels. Persistence of IgG antibody response beyond two years after vaccination is unknown. There are ongoing studies looking at antibody persistence up to three (53) or five (54,55) years following primary vaccination. A protective threshold of IgG antibody response has not been established.
A phase 1 dose-ranging trial looking at a two-dose regimen given on days 0 and 28 found that the second dose was associated with a short-term advantage with respect to the amplitude of response, but there was no significant difference in long-term titres between one-and two-dose regimens (12) . Anamnestic response following a booster dose more than 28 days after the priming dose has not been characterized. There are currently ongoing studies investigating a booster given at 56 days (55) or 18 months (53) .
Seroconversion rates at one-month post-vaccination was found to be significantly lower in a small sample of HIV-infected adults (n=13) compared to non-HIV-infected adults (n=383) in Liberia (20) . There is currently a phase 2 randomized controlled trial in progress evaluating the safety and immunogenicity of the vaccine in HIV-infected adults and adolescents at two Canadian sites and two African sites (Burkina Faso and Senegal) (56) . Immunogenicity data for pregnant and breastfeeding women, infants, children under six years of age, and persons with other immunocompromising conditions are not available.
# Neutralizing antibody response
Several phase 1 clinical trials also looked at neutralizing antibody responses (12)(13)(14)(15)(16)19) . The neutralizing antibody response appeared to be well-correlated with the IgG response; there was a dose-dependent response, with titres peaking at day 28 post-vaccination, and some evidence of persistence over 6 months-2 years. A neutralizing antibody protective threshold has not been established.
# Other immune response outcomes
A few studies were identified that investigated cell-mediated responses and changes to cytokine profiles and circulating host microRNA following vaccination. A dose-dependent CD169 expression was observed, suggesting a dose effect in monocyte activation (15) . Both CD4+ and CD8+ T cells showed increased activity post-vaccination (17) . Circulating follicular T helper cells were correlated with IgG titres (11) . One study found that vaccination led to a skewing in the cytokine profiles that promote humoral immune responses (11) . Another study found a significant induction of cytokines involved in the promotion of cell-mediated response, activation of antigenpresenting cells, and growth and survival of antigen-specific cytotoxic T lymphocytes (17) . Higher doses were found to elicit stronger interlocked cytokine networks compared with lower doses (17) . Vaccination was also found to be accompanied by dose-dependent changes in circulating host microRNA (18) . The importance and impact of these responses have not been elucidated.
# Immunogenicity in non-human primates
For PrEP, modest IgG titres were detected in most animals by day 28 post-vaccination (day of lethal ZEBOV challenge) (31-36, 38, 40) , including in immunodeficient SHIV-infected animals (33) , whereas neutralizing antibody was not detectable in most animals (31,35,36,40) . A depletion study revealed a minimal role for CD8+ T cell immunity in vaccine-mediated protection (37) .
For PEP, IgG titres were detectable between 1-2 weeks after vaccination at 20-30 minutes, 1 hour, or 24 hours after lethal ZEBOV challenge (31,38) .
# III.3 SAFETY
Sixteen studies evaluated safety following vaccination with the rVSVΔG-ZEBOV-GP vaccine of varying dose levels in humans (12-16, 19-21, 24-28, 41-43) . Five studies in non-human primates reported clinical symptoms following vaccination (32)(33)(34)(35)(36) and one study in non-human primates specifically looked at neurological symptoms following intrathalamic injection of the vaccine or wild-type rVSV (39) .
# Solicited adverse events
The majority of study subjects vaccinated with the rVSVΔG-ZEBOV-GP vaccine were immunocompetent adults who were not pregnant or breastfeeding. The vaccine is highly reactogenic; over 80% of study subjects were reported by multiple studies as having experienced at least one adverse event (15,16,24,25,42) . The most frequently reported symptoms were injection site pain, fever, headache, malaise, and myalgia. Although the degree of reactogenicity was high across dose levels, these adverse events were generally transient and mild-to-moderate in intensity. The onset of systemic symptoms typically occurred within three days after vaccination. A phase 1 dose-ranging trial looking at a two-dose regimen given on days 0 and 28 found a lower rate of adverse events after the second dose than after the first dose (12) .
# Unexpected adverse events
Unexpected adverse events reported in an early clinical trial include arthralgia, arthritis, dermatitis, and vasculitis (15) . Follow up studies, including the large phase 3 ring vaccination trial in Guinea, found arthralgia and arthritis to be less frequent, transient, and of mild-to-moderate intensity (13,14,16,20,21,42,43) , but occurring at higher rates compared to placebo (25) or no vaccination (24,41) . One study found the female sex and a medical history of arthritis as significant risk factors for the development of arthritis post-vaccination, but not treatment dose or age (30) . The median time to onset of arthritis was about 10 days and the mean duration was 6 days in blinded trials, though a few events persisted for months to years (45) . Dermatitis and vasculitis were also infrequently reported, generally mild-to-moderate in intensity, and of short duration (12,16,42,43) , and occurred at higher rates compared to placebo (25) or no vaccination (24) . Some dose-ranging studies found that there is likely a trend towards lower reactogenicity with lower doses (13)(14)(15) , but the unexpected adverse events did not appear to be related to the dose.
# Serious adverse events
Serious adverse events were infrequently reported following more than 150,000 vaccinations across all dose levels. In the studies included for review, only two serious adverse events were judged to be vaccine-related (both for the 2×10 7 PFU dose): one febrile reaction and one anaphylaxis (21) . Analysis of double-blinded trials found serious adverse events occurred in 3.4% of vaccine recipients, with the most common event being malaria, compared with 7.8% of placebo recipients (45) . In over 130,000 vaccinated individuals in the DRC, 228 serious adverse events were identified between August 7, 2018 and June 5, 2019; of these events, only a few, including one case of anaphylaxis, were attributed to the vaccine (45) .
# Special populations
There are limited safety data in pregnant women, children and adolescents 6-17 years of age, and immunocompromised individuals. In three studies that excluded pregnant and breastfeeding women from vaccination, a small number of enrolled subjects became pregnant within two months after vaccination and very few were pregnant when vaccinated (19,24,41,45) . One randomized trial (n=261) found a higher frequency of pregnancy loss in those who received the vaccine immediately compared with those who received delayed vaccination. The reasons for this observation are unknown. Three studies that included children and adolescents 6-17 years of age (n=537) found an adverse events profile that is similar to adults (19,21,27) , but with fewer arthralgia events than adults (21,27) . Two serious adverse events attributed to gastroenteritis and respiratory failure occurred in one of 22 HIV-infected vaccinees (20) . Safety data are currently not available for breastfeeding women, infants, children under 6 years of age, and persons with other immunocompromising conditions.
A phase 2 randomized controlled trial including children with age greater than or equal to 1 year (54) and a phase 2 randomized controlled trial in HIV-infected adults and adolescents with oneand two-dose regimens are in progress (56) . As of June 29, 2019, 34,522 children and adolescents 1-17 years of age have been vaccinated under the WHO compassionate use protocol in the ongoing outbreak in the DRC (7) . In February 2019, the ethics committee of the DRC authorized the expansion of the compassionate use protocol to include vaccination of pregnant and breastfeeding women and children under 1 year of age (8) . In May 2019, authorities in the DRC simplified safety follow-up requirements to passive reporting of serious adverse events by phone and active follow-up of only pregnant women and children under 1 year of age (9) . Specific safety results have not yet been published for these vaccinated individuals; however, no serious safety concerns have been identified so far by WHO or the manufacturer.
# Vaccine vector viremia and shedding
Low-level, transient, and dose-dependent rVSV viremia was seen for some subjects on days 1-3 after vaccination, becoming undetectable by days 7-14 (12-16, 20, 28, 43) . Viremia was seen more frequently in children and adolescents compared to adults in one study (19) .
Transmissibility of vaccine virus to people outside of the target vaccine population is not known, as no data are available on secondary transmission (45) , but is unlikely. Very few vaccinees had measurable shedding of the vaccine virus in urine and saliva (13,14,16) . Viral shedding in saliva was seen more frequently in children and adolescents compared to adults (19) . Absent or minimal vaccine virus shedding was observed in oral, nasal, and/or rectal swab samples from animal studies and the wild-type rVSV has naturally low transmissibility (57,58) .
# Leukocyte counts
Transient, asymptomatic, dose-related decreases in leukocytes were observed in some subjects and mostly within 2 days post-vaccination (12,14,15,19) .
# Safety in non-human primates
The rVSVΔG-ZEBOV-GP vaccine appeared to be well-tolerated in non-human primates, showing no evidence of clinical illness in the period following pre-exposure vaccination (32)(33)(34)(35)(36) . Intrathalamic injection of the vaccine showed a lack of neurovirulence compared to the wild-type rVSV (39) .
# IV. PRECAUTIONS
# Potential interference with ZMapp
No individuals have received both the rVSVΔG-ZEBOV-GP vaccine and the ZMapp monoclonal antibody cocktail for EVD treatment to date. Therefore, timing of administration and potential interference between these two products are currently unknown. Administration of these products close together may result in decreased effectiveness of the rVSVΔG-ZEBOV-GP vaccine and/or ZMapp because the monoclonal antibody has high affinity for the ZEBOV envelope GP expressed by the vaccine vector and the vaccine virus must replicate over time in order to elicit immune responses.
In the post-exposure setting, expert clinical opinion should be sought when deciding whether ZMapp, the rVSVΔG-ZEBOV-GP vaccine, or a combination of the two is the most appropriate response, taking into account the specifics of the exposure event.
# Vaccine virus shedding
Transmission of the vaccine virus has not been reported to date. In clinical trials, very few vaccine recipients had measurable shedding of the vaccine virus in urine and saliva (13,14,16) and low-level rVSV viremia observed in some vaccine recipients became undetectable by days 7-14 (12-16, 20, 28, 43) . It is not known if the vaccine virus is secreted in human breast milk. There is no data available regarding the effects of vaccinating breastfeeding women on their infants. Absent or minimal vaccine virus shedding was observed in oral, nasal, and/or rectal swab samples from animal studies and the wild-type rVSV has naturally low transmissibility (57,58) . Although the risk of transmitting the rVSVΔG-ZEBOV-GP vaccine virus to people outside of the target vaccine population appears to be extremely low, vaccine recipients should be informed that the rVSVΔG-ZEBOV-GP vaccine does not contain live Ebolavirus, but is comprised of a liveattenuated recombinant virus, rVSV, that has the theoretical potential to be transmitted to contacts of the vaccinated individual.
Based on expert opinion and taking into consideration the precautions for use made by the EMA (59) , individuals vaccinated with the rVSVΔG-ZEBOV-GP vaccine should avoid close contact (including exposure to blood and body fluids) with immunocompromised individuals, pregnant or breastfeeding women, and infants for at least six weeks following vaccination, unless those individuals also have an indication for the rVSVΔG-ZEBOV-GP vaccine.
Similarly, as a precaution, women should avoid breastfeeding and their infants should not have contact with maternal blood and body fluids, where feasible, for at least six weeks following vaccination, unless vaccination with the rVSVΔG-ZEBOV-GP vaccine is also indicated for the infant.
# V. INTERIM RECOMMENDATIONS
After careful review of available evidence (see Section III) and considering current knowledge gaps (see Section VI), NACI makes the following interim recommendations on the emergency use of the pre-market rVSVΔG-ZEBOV-GP vaccine stockpiled in the NESS for PEP and PrEP in a Canadian context, recognizing:
- The lack of regulatory approval of the rVSVΔG-ZEBOV-GP vaccine in Canada at the time of writing; The limited quantity of this pre-market vaccine available in Canada; and The fact that the EVD outbreak in the DRC is a Public Health Emergency of International Concern at the time of writing, and the global rVSVΔG-ZEBOV-GP vaccine supply is being prioritized for those most at risk in Africa where there can be the greatest impact.
As the regulatory, supply, and evidence context for the rVSVΔG-ZEBOV-GP vaccine evolves, NACI will revisit these interim recommendations as needed.
A dose-sparing strategy for the use of the rVSVΔG-ZEBOV-GP vaccine, and associated evidence, may be reviewed and considered by NACI if the need arises.
# Exposure definition
For the interim recommendations, exposures - to ZEBOV that are considered to pose risk are: Unprotected direct physical contact (i.e., through non-intact skin or mucous membranes) with (60,61) : o non-intact skin, mucous membranes, blood, or other body fluids (e.g., stool, emesis, urine, saliva, semen, sweat, breast milk) of a ZEBOV-infected individual; o linens or clothing contaminated with ZEBOV-infected blood or body fluids; o the dead body of a ZEBOV-infected individual; and/or o any other known source of ZEBOV, including contaminated medical instruments, fomites or other contaminated environmental surfaces, laboratory specimens, or animals; Unprotected exposure following assistance with the performance of an aerosolgenerating medical procedure (62) ; Unprotected sexual contact with an acute or convalescent EVD case (ZEBOV has been demonstrated to persist in semen for up to 40 months (2) ) with laboratory-confirmed ZEBOV infection (60) ; and/or Unprotected handling and/or consumption of ZEBOV-contaminated bush meat products from Africa (63) .
# Strength of NACI recommendations
Please note: A strong NACI recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present. A discretionary NACI recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
Please see Table 2 for a more detailed explanation of strength of NACI recommendations and grade of the body of evidence. Please see Tables 3 and 4 for details on the ratings of the quality of individual studies.
V.
# Summary of evidence and rationale
- The vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of post-exposure protection. The lack of regulatory review and authorization may decrease the acceptability of this pre-market vaccine; however, the potential for severe harm from EVD in those who have had an exposure to ZEBOV and the safety and immunogenicity profile of the vaccine established in non-pregnant immunocompetent adults may improve its acceptability among these individuals.
# Interim recommendation 1b
1b. NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine may be considered as PEP against ZEBOV for pregnant women, infants, children, adolescents, and immunocompromised individuals who have had an exposure to ZEBOV (Discretionary NACI Recommendation) NACI concludes that there is currently insufficient evidence to recommend vaccination of pregnant women, infants, children, adolescents, and immunocompromised individuals who have had an exposure to ZEBOV with the rVSVΔG-ZEBOV-GP vaccine (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
- There are limited safety data for pregnant women, children and adolescents 6-17 years of age, and immunocompromised individuals. One randomized trial found a higher frequency of pregnancy loss in those who received immediate vaccination vs. delayed vaccination. Three studies that included children and adolescents 6-17 years of age found an adverse events profile that is similar to adults, but with fewer arthralgia events than adults. Two serious adverse events attributed to gastroenteritis and respiratory failure occurred in one of 22 HIV-infected vaccinees. Safety data are not currently available for infants and children under 6 years of age. There is limited evidence of slower immune response in children 6-17 years of age after vaccination than adults. There is also limited evidence of less optimal immune response in HIV-infected individuals compared with non-HIV-infected individuals. No immunogenicity data are available for pregnant women, infants, and children under 6 years of age. Vaccine has been given to these special populations as part of outbreak control measures in the DRC. As of June 29, 2019, 34,522 children and adolescents 1-17 years of age have been vaccinated. In February 2019, the authorities in the DRC authorized the expansion of the compassionate use protocol to include pregnant and breastfeeding women and children under 1 year of age. In May 2019, the authorities simplified safety follow-up requirements to passive reporting of serious adverse events by phone and active follow-up was limited to pregnant women and children under 1 year of age. Specific safety results have not yet been published for these vaccinated individuals; however, no serious safety concerns have been identified so far by WHO or the manufacturer. A risk-benefit assessment of this pre-market vaccine, taking into consideration uncertainties in the safety and efficacy of the vaccine, the potential for severe harm from EVD, and the nature and intensity of exposure, should be conducted when deciding whether to vaccinate individuals in these special populations.
Interim recommendation 2 2. When used as PEP against ZEBOV, NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine should be given as expeditiously as possible, targeting within 72 hours of exposure for susceptible, asymptomatic exposed individuals, but may be considered up to 10 days post-exposure, as the incubation period for EVD can range from 2-21 days and vaccination within 10 days of exposure may confer protection (Strong NACI Recommendation) NACI concludes that there is currently insufficient evidence to define a vaccination window for effective PEP in preventing severe disease after exposure to ZEBOV (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
- The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination.
The median time from confirmation of EVD in an index case to vaccination of contacts in these studies ranged from 7-15 days. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of timing for post-exposure protection. In studies with non-human primates, partial post-exposure protection against EVD was achieved if vaccinated within 20-30 minutes of intramuscular challenge with a lethal concentration of ZEBOV. No protection against EVD was observed if vaccinated at 1 and/or 24 hours after lethal intramuscular ZEBOV challenge. Data derived from animal studies should be interpreted with caution when used to inform clinical decision making since time-to-death is shorter and mortality rate is higher following intramuscular infection, likely shortening the window of efficacy of post-exposure vaccination compared to mucosal infection. Several instances of PEP given within 3 days of a needlestick or sharps injury have been reported. A laboratory worker was vaccinated with a 5×10 7 PFU dose 48 hours after a needlestick injury with a syringe containing ZEBOV. Five healthcare workers were vaccinated with a 1×10 8 PFU dose 1-3 days after sharps injuries in West Africa. There was no evidence that these exposures resulted in infection but it is not possible to determine whether this was due to vaccine effect or lack of transmission following the needlestick injury. Expert clinical opinion should be emergently sought in the management of individuals who are potentially exposed to ZEBOV from a needlestick injury, as the window for effective PEP after intramuscular exposure to ZEBOV is unknown, but likely to be small, and the vaccine may not be immediately available for administration. The risk of severe disease from intramuscular exposure to ZEBOV (e.g., needlestick injury from a ZEBOVcontaminated needle and syringe) is greater than mucosal exposure (e.g., unprotected direct physical contact through non-intact skin or mucous membranes with non-intact skin, mucous membranes, blood, or other body fluids of a ZEBOV-infected individual). Common systemic reactions following vaccination include fever, headache, malaise, and myalgia, resembling the early symptoms of EVD. However, typical onset of vaccine reactions is expected within 3 days after vaccination compared with onset of clinical symptoms 4-10 days after exposure to ZEBOV. Therefore, clinical management of reported illness among individuals who have had an exposure to ZEBOV should take into consideration vaccination status, timing of symptom onset relative to vaccination, and presence of any symptoms typically associated with EVD but not with vaccination (e.g., sore throat, nausea and vomiting, diarrhea, haemorrhaging) to mitigate unnecessary referrals to EVD treatment units. Antipyretics have been used for the management or prevention of post-vaccination fever without identified safety concerns (21) , but the use of antipyretics may mask early EVD symptoms.
# Interim recommendation 3
- NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine may be considered as PEP against ZEBOV for individuals who have received a previous dose of the premarket rVSVΔG-ZEBOV-GP vaccine more than 18 months prior to a current exposure to ZEBOV (Discretionary NACI Recommendation) NACI concludes that while there is currently fair evidence of immunogenicity up to two years post-vaccination (Grade B Evidence), there is insufficient evidence to define a serological threshold of protection against ZEBOV or to suggest a need for revaccination (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
Summary of evidence and rationale GMTs of IgG antibody to the ZEBOV envelope GP reported in clinical trials generally peaked by day 28 and persisted to two years post-vaccination without significant decline. Immune correlates of protection and the relative importance of IgG antibody response
have not yet been established. Long-term vaccine efficacy has not been demonstrated.
There is limited evidence that the rate of adverse events following a second dose given at 28 days post-vaccination is lower than after the first dose. Due to the potential for severe harm from EVD and the uncertainty around the durability and thresholds of vaccine protection, re-vaccination with the rVSVΔG-ZEBOV-GP vaccine may be considered as a precaution after an exposure to ZEBOV occurring more than 18 months after a previous dose of the rVSVΔG-ZEBOV-GP vaccine. Expert clinical opinion should be sought when deciding whether to re-vaccinate an individual who has previously received another vaccine for EVD with the rVSVΔG-ZEBOV-GP vaccine.
# Interim recommendation 4 4. When used as PEP against ZEBOV, NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine should not be given simultaneously with other live or inactivated vaccines due to the potential for immune interference and the need to be able to monitor for potential symptoms of EVD and rVSVΔG-ZEBOV-GP vaccine adverse events without potential confounding from other vaccine adverse events (Strong NACI Recommendation)
- NACI concludes that there is currently insufficient evidence to recommend concurrent administration of the pre-market rVSVΔG-ZEBOV-GP vaccine with other vaccines (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
- Although live-attenuated or inactivated vaccines given by the parenteral route may generally be administered concurrently with other vaccines without concern, there is no data available on the concurrent administration of the rVSVΔG-ZEBOV-GP vaccine with other vaccines. Given the potential for immune interference and the need to be able to monitor for potential symptoms of EVD and rVSVΔG-ZEBOV-GP vaccine adverse events without potential confounding from other vaccine adverse events, the pre-market rVSVΔG-ZEBOV-GP vaccine should not be given as PEP against ZEBOV simultaneously with other live or inactivated vaccines in this exceptional situation. Other live-attenuated or inactivated vaccines should be administered at a minimal interval of four weeks after vaccination with the rVSVΔG-ZEBOV-GP vaccine. However, given the potential for severe harm from EVD, vaccination with the rVSVΔG-ZEBOV-GP vaccine should not be delayed even if it is within four weeks of a previous vaccine. Considering the ethical principles of beneficence and non-maleficence, delaying any other vaccines to prioritize the pre-market rVSVΔG-ZEBOV-GP vaccine for individuals who have had an exposure to ZEBOV is acceptable and ethically justifiable.
V.
# Summary of evidence and rationale
- The vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of post-exposure protection. Expert clinical opinion should be emergently sought in the management of individuals who are potentially exposed to ZEBOV from a needlestick injury. Appropriately implemented IPC measures, such as using personal protective equipment and following correct donning and doffing procedures, offer feasible and effective methods of protection against EVD infection. However, due to the nature of the work, there exists a small risk of needlestick injury among healthcare workers providing direct care to EVD cases and laboratory workers handling ZEBOV. The risk of severe disease from intramuscular exposure to ZEBOV (e.g., needlestick injury from a ZEBOV-contaminated needle and syringe) is greater than mucosal exposure (e.g., unprotected direct physical contact through non-intact skin or mucous membranes with non-intact skin, mucous membranes, blood, or other body fluids of a ZEBOV-infected individual). The lack of regulatory review and authorization may decrease the acceptability of this pre-market vaccine. However, given the potential for severe harm from EVD in those who have had an exposure to ZEBOV and the safety and immunogenicity profile of the vaccine for non-pregnant immunocompetent adults, offering the pre-market rVSVΔG-ZEBOV-GP vaccine to these individuals is acceptable and ethically justifiable.
# Interim recommendation 5b
5b. NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine may be considered as PEP against ZEBOV for pregnant or immunocompromised individuals who have had an occupational exposure to ZEBOV in Canadian healthcare or laboratory settings (Discretionary NACI Recommendation) NACI concludes that there is currently insufficient evidence to recommend vaccination of pregnant and immunocompromised individuals who have had an occupational exposure to ZEBOV in Canadian healthcare or laboratory settings with the rVSVΔG-ZEBOV-GP vaccine (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
- Safety data are limited for pregnant and immunocompromised individuals. One randomized trial found a higher frequency of pregnancy loss in those who received immediate vaccination vs. delayed vaccination. Two serious adverse events attributed to gastroenteritis and respiratory failure occurred in one of 22 HIV-infected vaccinees. There is limited evidence of less optimal immune response in HIV-infected individuals compared with non-HIV-infected individuals. No immunogenicity data are available for pregnant women. Vaccine has been given to these special populations, as well as infants, children, and adolescents, as part of outbreak control measures in the DRC. In February 2019, the authorities in the DRC authorized the expansion of the compassionate use protocol to include pregnant and breastfeeding women and children under 1 year of age. In May 2019, the authorities simplified safety follow-up requirements to passive reporting of serious adverse events by phone and active follow-up was limited to pregnant women and children under 1 year of age. Specific safety results have not yet been published for these vaccinated individuals; however, no serious safety concerns have been identified so far by WHO or the manufacturer. Expert clinical opinion should be emergently sought in the management of individuals who are potentially exposed to ZEBOV from a needlestick injury. Appropriately implemented IPC measures, such as using personal protective equipment and following correct donning and doffing procedures, offer feasible and effective methods of protection against EVD infection. However, due to the nature of the work, there exists a small risk of needlestick injury among healthcare workers providing direct care to EVD cases and laboratory workers handling ZEBOV. The risk of severe disease from intramuscular exposure to ZEBOV (e.g., needlestick injury from a ZEBOV-contaminated needle and syringe) is greater than mucosal exposure (e.g., unprotected direct physical contact through non-intact skin or mucous membranes with non-intact skin, mucous membranes, blood, or other body fluids of a ZEBOV-infected individual). A risk-benefit assessment of this pre-market vaccine, taking into consideration uncertainties in the safety and efficacy of the vaccine, the potential for severe harm from EVD, and the nature and intensity of exposure, should be conducted when deciding whether to vaccinate individuals in these special populations.
Interim recommendations 2 through 4 also apply to individuals who have had an occupational exposure to ZEBOV in Canadian healthcare or laboratory settings.
# V.3 PRE-EXPOSURE PROPHYLAXIS
Advice on PrEP for travellers is not provided in this interim statement on the emergency use of the pre-market rVSVΔG-ZEBOV-GP vaccine stockpiled in the NESS.
# Interim recommendation 6
- NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine may be considered as PrEP against ZEBOV for non-pregnant immunocompetent adults in exceptional situations when a dedicated team of healthcare workers is anticipated to provide direct care for a confirmed case with symptomatic ZEBOV infection, if vaccine is available (Discretionary NACI Recommendation) NACI concludes that there is currently fair evidence of safety, immunogenicity, efficacy, and effectiveness to recommend vaccination of non-pregnant immunocompetent adults at risk of exposure to ZEBOV (Grade B Evidence) and insufficient evidence of long-term protection beyond two years post-vaccination (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
- The vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of pre-exposure protection. GMTs of IgG antibody to the ZEBOV envelope GP reported in clinical trials generally peaked by day 28 and persisted to two years post-vaccination without significant decline. Long-term vaccine efficacy is unknown. Although the acceptability of this narrow interim recommendation for PrEP may be low among healthcare workers who perceive themselves to be at risk of exposure to ZEBOV, wider PrEP against ZEBOV is currently not feasible or recommended at this time in Canada based on the limited availability of the pre-market vaccine in Canada and globally and the potentially large number of Canadian healthcare workers who may have some perceived risk of exposure to ZEBOV (there have been no cases of EVD in Canada to date). Appropriately implemented IPC measures, such as using personal protective equipment and following correct donning and doffing procedures, offer feasible and effective methods of protection against EVD infection and should be followed as the situation dictates, regardless of vaccination status. Vaccine-derived adverse events may mimic early EVD symptoms; therefore, clinical management of reported illness among vaccinated individuals who have had an exposure to ZEBOV should take into consideration vaccination status, timing of symptom onset relative to vaccination, and presence of any symptoms typically associated with EVD but not with vaccination.
# VI. KNOWLEDGE GAPS
After careful review of available evidence, NACI has identified the need for further research to address current knowledge gaps where data are absent or limited. NACI recognizes that there are studies already in progress that may address many of these gaps but the findings of these studies were not yet available at the time of review. Identified knowledge gaps include:
- Immune correlates of protection have not been established. The window of vaccination for effective PEP is unknown. The degree of post-exposure protection (e.g., decreasing infectiousness and clinical illness in individuals that had already acquired infection) is unknown. Cross-protective efficacy against other Ebolavirus species or Marburg virus in humans is unknown, though the vaccine is unlikely to protect against these other viruses of the Filoviridae family due to significant differences in viral antigens. Safety and immunogenicity data for children and adolescents 6-17 years of age and immunocompromised individuals are limited. Safety data are limited and immunogenicity data are not available for pregnant women. Safety and immunogenicity data are not available for breastfeeding women, infants, and children under 6 years of age. Transmissibility of the vaccine virus is unknown, including whether the vaccine virus is secreted in human breast milk. Persistence of immune response beyond two years after vaccination is unknown. Long-term vaccine efficacy is unknown. Anamnestic response following a booster dose more than 28 days after the priming dose has not been characterized. Interference with ZMapp or other passive immunizing agents against EVD is unknown. Safety of concurrent administration with other vaccines is unknown.
# TABLES
# Quality rating Description
Good A study (including meta-analyses or systematic reviews) that meets all design-specific criteria - well.
# Fair
A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion - but has no known "fatal flaw".
# Poor
A study (including meta-analyses or systematic reviews) that has at least one design-specific - "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
# LIST OF ABBREVIATIONS
# Search strategy for rVSVΔG-ZEBOV-GP vaccine in Scopus ( ( ( TITLE-ABS-KEY ( rvsv-zebov OR vsvdg-zebov OR vsv-ebov OR v920 ) ) OR ( TITLE-ABS-KEY ( recombinant AND vesicular AND stomatitis AND virus AND zaire AND ebola AND virus OR recombinant AND vesicular AND stomatitis AND virus AND zaire AND ebolavirus ) ) ) OR ( ( TITLE-ABS-KEY ( merck OR "National Microbiology Laboratory" OR "Public Health Agency of
Canada" OR phac OR newlink ) ) AND ( TITLE-ABS-KEY ( ebola- ) ) ) ) AND ( LIMIT-TO ( LANGUAGE , "English" ) OR LIMIT-TO ( LANGUAGE , "French" ) ) PFU dose groups) and persisting with minimal change to day 360. Dose response was observed with the highest titres at day 28 postvaccination in the 1×10 8 and 2×10 7 PFU dose groups (no statistically significant difference between these dose groups) and the lowest titres in the 3×10 3 and 3×10 4 PFU dose groups. Time to onset of the immune response was dose-related, with seroconversion rates lower in the low-dose groups than in the highdose groups. IgG and neutralizing antibodies were both dose-related, strongly correlated at day 28, and persisted for 1 year. concentrations than adults without baseline GP-specific antibodies at day 56 post-vaccination at some doses. 70-100% vaccinated with doses ≥3×10 4 PFU reached ≥4-fold increase of GP-specific GMT by day 28, with titres peaking at day 56 and persisting higher than baseline up to 180 days post-vaccination. Highest titres were observed with the 2×10 7 PFU dose regardless of baseline antibody status.
# Search strategy for rVSVΔG-ZEBOV-GP vaccine in
# Safety
Children and adolescents 0% and 7% of children and adolescents, respectively, were seropositive for GP-specific IgG antibodies at baseline. As in adults, those with pre-existing immunity had higher responses to the vaccine at days 28 and 56 post-vaccination. 95% of children and 100% of adolescents who received a 2×10 7 PFU dose reached ≥4-fold increase of GP-specific GMT by day 28, with titres peaking at 180 days postvaccination. HIV-infected individuals Of 22 HIV-infected individuals who received the vaccine, two serious adverse events that were attributed to gastroenteritis and respiratory failure occurred in one subject.
# All vaccinees
# Citation
Henao-Restrepo et al. 2017 (21) Henao-Restrepo et al. 2015 (22) (interim findings) Control animals started to show clinical signs of disease and high ZEBOV plasma titres on day 6 after challenge and succumbed to ZEBOV infection on days 6, 7, and 8. None of the 3 rVSVΔG-ZEBOV-GP-vaccinated animals became sick from the ZEBOV challenge and all 3 animals survived. A transient low level rVSV viremia was detected on day 2 after vaccination in plasma from 4 of 6 rVSVΔG-ZEBOV-GP-vaccinated animals. rVSV was not detected in swab samples of any animal. By day of ZEBOV challenge (28 days postvaccination), all rVSVΔG-ZEBOV-GP-vaccinated animals had developed modest IgG antibody titres against ZEBOV GP and these titres increased after ZEBOV challenge. No evidence of IFN-γ or TNF-α production in CD4+ or CD8+ T cells was found before or after ZEBOV challenges in any of the animals. No animals showed any signs of clinical symptoms after vaccination. Tissue viremia from aerosol challenge mimicked patterns found in IM challenge.
# Citation
Geisbert et al.
2008 (33) Vaccine rVSVΔG-ZEBOV-GP: 1×10 7 PFU Saline placebo
# Time of administration
Pre-exposure: 31 days before lethal ZEBOV challenge Of 9 adult rhesus macaques with clinical evidence of SHIV infection (reduced CD4+ T cell counts and SHIV viremia in 4 of 9), 6 received the rVSVΔG-ZEBOV-GP vaccine and 3 receive placebo. All vaccine recipients and 2 controls were challenged with an IM 4 of the 6 rVSVΔG-ZEBOV-GP-vaccinated SHIVinfected animals and both placebo control animals started to show clinical signs of disease on day 6 after challenge. Disease progressed in 2 of the rVSVΔG-ZEBOV-GP-vaccinated SHIV-infected animals and both of the placebo control animals; these 2 rVSVΔG-ZEBOV-GP-vaccinated animals died on days 9 and 13 and the placebo control animals died on days 9 and 10. Animals that did not survive had the lowest CD4+ counts, suggesting that CD4+ T cells may play a role in mediating protection
# Study Intervention - Population Summary of key findings
The Sudan ebolavirus macaque challenge model was not uniformly lethal.
# Study
# Study design Intervention - Population Summary of key findings
Level & quality of evidence hospital of the treatment unit.
# Sample size
Total: 210 of 650 (32%) of enumerated contacts and contacts of contacts were vaccinated.
# Baseline characteristics
Median age of 33 years. 14% female.
# Citation
Gsell et al. 2017 (27) Design Ring vaccination study from March 17 to April 21, 2016 Location Guinea
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Également disponible en français sous le titre : Déclaration provisoire sur l'utilisation du vaccin rVSVΔG-ZEBOV-GP pour la prévention de la maladie à virus Ebola This publication can be made available in alternative formats upon request.# PREAMBLE
The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidencebased recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select statements will include varying degrees of programmatic analyses for public health programs.
PHAC acknowledges that the advice and recommendations set out in this interim statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. As the advice is provided for an investigational product that has not yet received regulatory authorization for sale in Canada, people administering the premarket vaccine should also be aware of the contents of the pharmacy manual and investigator's brochure provided by the manufacturer. Recommendations for use and other information set out herein may differ from that set out in the pharmacy manual and investigator's brochure of the pre-market vaccine. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# TABLE OF CONTENTS
SUMMARY
# How
NACI makes the following interim recommendations for post-exposure prophylaxis against ZEBOV for the pre-market rVSVΔG-ZEBOV-GP vaccine stockpiled in the NESS:
The vaccine should be offered to non-pregnant immunocompetent adults who have had an exposure to ZEBOV in Canada; and The vaccine may be considered for pregnant women, infants, children, adolescents, and immunocompromised individuals who have had an exposure to ZEBOV in Canada.
NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine stockpiled in the NESS may be considered as pre-exposure prophylaxis against ZEBOV for non-pregnant immunocompetent adults in exceptional situations when a dedicated team of healthcare workers is anticipated to provide direct care for a confirmed case with symptomatic ZEBOV infection, if vaccine is available.
# Why
EVD is a rare, severe, acute viral illness with a case fatality rate in humans ranging from 25-90%. Although uncertainties around safety, immunogenicity, efficacy, and effectiveness remain, vaccination with the rVSVΔG-ZEBOV-GP vaccine currently offers the best available protection against EVD caused by ZEBOV infection given the potential for severe harm from EVD and few options for reducing case fatality. The rVSVΔG-ZEBOV-GP vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination.
# I. INTRODUCTION
Ebola virus disease (EVD) is a rare, severe, acute viral illness in humans and non-human primates caused by ribonucleic acid viruses from the genus Ebolavirus, a member of the Filoviridae family (1) . Of the five well-described Ebolavirus species, four are known to cause illness in humans. The Zaire ebolavirus (ZEBOV) is considered the most virulent of these species, having the highest case fatality rate and being responsible for the majority of outbreaks to date.
EVD has an incubation period of 2-21 days, with most cases experiencing onset of symptoms around 4-10 days after exposure. Within 10 days of symptom onset, fatal cases will experience severe symptoms and succumb to the disease. Symptoms usually begin with a sudden onset of flu-like symptoms, such as fever, myalgia, severe headache, and malaise, typically followed by worsening gastrointestinal symptoms and fluid loss. Haemorrhage is a late manifestation and, in recent outbreaks, occurs in fewer than half of cases, usually from the gastrointestinal tract or other mucosa. Case fatality in humans ranges from 25-90%.
Non-fatal cases typically begin recovery 6-11 days after onset of symptoms. Full recovery occurs over a long period of time and is often associated with long-term sequelae. During recovery, Ebolavirus can persist in some body fluids such as semen, urine, and breast milk. Follow-up of a cohort of EVD survivors in Liberia has demonstrated persistence of ZEBOV in semen for up to 40 months with a range of 233 to 1178 days and a median of 551 days (2) . Viral relapse can also occur (3) .
Infectiousness starts from the time of symptom onset and the risk of transmission is highest when viral load is greatest. Person-to-person transmission can occur through direct physical contact with body fluids from an infected symptomatic person or dead body, or indirectly through physical contact with surfaces and fomites that are contaminated with these fluids. With the exception of the potential for sexual transmission during the convalescent period, Ebolavirus has not been demonstrated to spread to others by an asymptomatic person. Ebolavirus is not transmitted between humans through casual interactions or airborne transmission, but can be transmitted by aerosol-generating medical procedures.
EVD has generally been geographically limited to outbreak-prone areas of sub-Saharan Africa.
Between 1976 and 2012, sporadic cases and outbreaks of EVD were reported in several African countries. During the 2014-2016 West Africa EVD outbreak, the largest recorded outbreak of EVD to date, imported cases were identified in other countries in Africa, Europe, and North America. Limited secondary transmission in the United States and Spain from cases that have travelled from Africa has been reported (4,5) . There has been an ongoing outbreak of EVD since August 2018 in the Democratic Republic of the Congo (DRC), which is the second largest outbreak at the time of writing. No cases of EVD have been identified in Canada to date.
With the ongoing outbreak of EVD in the DRC, it is possible that Canada will receive an imported case of EVD prior to the authorization of a vaccine for EVD by Health Canada. As part of contingency planning for an imported EVD case, the Public Health Agency of Canada (PHAC) has procured Merck's investigational vaccine for EVD, the rVSVΔG-ZEBOV-GP vaccine (also referred to as the V920 Ebola Zaire Vaccine and Ervebo), for the National Emergency Strategic Stockpile (NESS) through Health Canada's Special Access Programme. On recommendation of the European Medicines Agency (EMA), the European Commission granted a conditional marketing authorization for this vaccine on November 11, 2019 and the World Health Organization (WHO) prequalified the vaccine (i.e., the vaccine met WHO's standards for quality, safety, and efficacy) on November 12, 2019. The rVSVΔG-ZEBOV-GP vaccine was approved by the United States Food and Drug Administration on December 19, 2019. NACI generally issues guidance only for immunizing agents that have been authorized by Health Canada. However, in this exceptional circumstance, PHAC has requested pre-market guidance from NACI on this investigational product because a limited quantity has been stockpiled in Canada for emergency use.
Merck's rVSVΔG-ZEBOV-GP vaccine is a live-attenuated, recombinant vesicular stomatitis virus (rVSV)-based vector vaccine, in which the vaccine vector's envelope glycoprotein (GP) is deleted and replaced with the ZEBOV envelope GP. The vaccine does not contain live ZEBOV. Many clinical trials have been completed using Merck's investigational vaccine, including doseranging trials to assess its safety and immunogenicity and a large cluster-randomized trial to evaluate its efficacy during the 2014-2016 West Africa outbreak.
There are several other investigational vaccines for EVD undergoing human trials (6) , but the rVSVΔG-ZEBOV-GP vaccine is the only one that is currently in widespread use despite its investigational status. The rVSVΔG-ZEBOV-GP vaccine has been available on compassionate grounds for both the 2014-2016 West Africa outbreak and the ongoing outbreak in the DRC. As of November 16, 2019, 253,545 people at risk in the DRC have received the vaccine (7) .
For the DRC outbreak, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization recommended a "ring vaccination" strategy to protect those at highest risk of EVD in the outbreak (8) . Ring vaccination involves contact tracing and vaccination of the contacts of an EVD case and the contacts of those contacts. As the situation in the DRC deteriorated in early 2019, additional vaccination strategies have been recommended for outbreak control (9) . These recommendations were devised for the epidemiological and public health situation in Africa and therefore are not directly applicable for the Canadian context.
Further details on EVD, including outbreak updates, can be found on the Government of Canada website.
# Guidance objective
The objective of this advisory committee interim statement is to review the safety, immunogenicity, efficacy, and effectiveness evidence available for the rVSVΔG-ZEBOV-GP vaccine and to provide interim guidance on the emergency use of this pre-market vaccine stockpiled in the NESS for the prevention of severe disease in individuals exposed to ZEBOV.
Advice on the following are outside the scope of NACI's mandate and therefore are not addressed in this interim statement: a) vaccination of travellers to areas outside of Canada that are prone to EVD outbreaks * ; b) the use of passive immunizing agents such as ZMapp for treating EVD; c) symptom management and clinical treatment of EVD; d) stockpile recommendations; and e) infection prevention and control (IPC) measures for EVD.
# II. METHODS
In brief, the broad stages in the preparation of a NACI advisory committee statement are:
1. Knowledge synthesis; 2. Synthesis of the body of evidence of benefits and harms, considering the quality of the evidence and magnitude of effects observed; and 3. Translation of evidence into a recommendation. Details regarding NACI's evidence-based process for developing a statement are outlined in Evidence-based Recommendations for Immunization − Methods of the National Advisory Committee on Immunization.
Rapid reviews were conducted on the safety, immunogenicity, efficacy, and effectiveness of the rVSVΔG-ZEBOV-GP vaccine in humans and non-human primates and the effectiveness of the ring vaccination strategy in preventing EVD transmission. The search strategy was developed in consultation with a librarian from the Health Library of Health Canada and PHAC and included two separate searches (search strategies can be found in Appendix A). One search included terms specific to the rVSVΔG-ZEBOV-GP vaccine and the other included terms for ring vaccination. The literature searches were performed in 12 bibliographic databases and one clinical trial database. The searches were restricted to studies published in English or French. No publication date restrictions were applied. The final database search was executed on March 29, 2019 for the rVSVΔG-ZEBOV-GP vaccine and March 14, 2019 for ring vaccination. Hand searches of the reference lists of included articles and relevant reviews were performed. As the rVSVΔG-ZEBOV-GP vaccine has not yet been licensed for use in any jurisdiction at the time of literature review, adverse event reporting for this pre-market vaccine are not expected through passive vaccine safety surveillance systems such as the Canadian Adverse Events Following Immunization Surveillance System (CAEFISS) and therefore these surveillance systems were not searched for case reports.
Articles retrieved from the searches were screened by title and abstract. The full text of articles deemed relevant based on inclusion and exclusion criteria, or that had insufficient information to exclude, were retrieved and assessed for eligibility through full-text screening. Study selection was completed independently by two reviewers. Disagreements between the two reviewers were resolved by discussion and reaching a consensus. Data from included studies were extracted into evidence tables. The quality of evidence for individual studies and for the body of evidence was assessed using the criteria outlined by Harris et al. (10) . Data extraction and quality assessment were both completed by one reviewer and verified by a second reviewer. Results from included studies were synthesized narratively in the evidence tables. Geometric mean titre (GMT) values for varying dose levels of the rVSVΔG-ZEBOV-GP vaccine were extracted separately.
Knowledge synthesis was performed by LZ and AK. Proposed recommendations for vaccine use were developed by NACI's EVD Vaccine Working Group and reviewed for input by NACI's Vaccine Safety Working Group, the Canadian Immunization Committee, the Council of Chief Medical Officers of Health, and the EVD-Clinical Treatment Centre Task Group. The manufacturer was invited to present preclinical and clinical data for their vaccine to the EVD Vaccine Working Group on May 7, 2019 and was further consulted to identify additional safety data for the following special populations: pregnant and breastfeeding women, infants, children, adolescents, and immunocompromised individuals. A PHAC technical advisor (LZ) presented the findings of the knowledge synthesis to NACI on June 6, 2019. The evidence and proposed recommendations were discussed by the NACI EVD Vaccine Working Group in June and July 2019 and the proposed recommendations were deliberated by NACI on July 31, 2019. Given that this is a pre-market vaccine, NACI's Vaccine Safety Working Group was also consulted in June 2019 on the proposed recommendations. Following thorough review of the evidence and assessing the risk-benefit of vaccination with the pre-market vaccine, NACI reached consensus on specific recommendations. As part of the standard pre-release process for NACI statements, the manufacturer was consulted to identify any factual errors contained in the interim statement prior to publication. The descriptions of relevant considerations, rationale, and knowledge gaps on the use of the pre-market rVSVΔG-ZEBOV-GP vaccine are described in the following sections.
# III. VACCINE
A flow diagram of the study selection process can be found in Appendix B. After database searching, hand searching, and eligibility screening, 37 studies-26 studies in humans (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(41)(42)(43)(44) and 11 studies in non-human primates, including an unpublished study not reported here (31)(32)(33)(34)(35)(36)(37)(38)(39)(40) were included for review. Of the 26 studies in humans, 19 studies reported on unique subjects (12-16, 19-21, 24-29, 41-44) while the remainder offered supplemental data or provided additional analyses. Of these 19 studies, there were seven phase 1 dose-ranging clinical trials (12)(13)(14)(15)(16)19) (five were randomized placebo-controlled (12)(13)(14)(15)(16)19) ), one phase 2 randomized controlled trial (20) (the phase 3 component of this study was cancelled due to declining EVD cases), three phase 3 randomized controlled trials (21,24,25) (two were cluster-randomized comparing immediate to delayed vaccination (21,24) ), three ring vaccination field studies (26,27,44) , two prospective cohort studies (29,41) , one cross-sectional survey on safety (42) , and two case reports of post-exposure prophylaxis (PEP) following needlestick or sharps injuries (28,43) . The total vaccinated sample sizes by dose and outcome for the studies conducted in humans are tabulated in Table 1. The majority of subjects received the 2×10 7 plaque-forming unit (PFU) dose, which is the nominal dose of the vaccine deployed for use in the 2014-2016 West Africa outbreak and in the ongoing outbreak in the DRC. Safety information that was presented to the Global Advisory Committee on Vaccine Safety on June 5-6, 2019 (45) are included to supplement the review findings.
Six modelling studies were also identified that modeled the effects of ring vaccination on control of EVD outbreaks in the African context (46)(47)(48)(49)(50)(51) . These modeling studies were reviewed by NACI, but are not further discussed in this interim statement as the findings do not directly relate to the Canadian context. 3×10 3 n/a 2 (n=84) 3 (n=104) 3×10 4 n/a 2 (n=84) 2 (n=84) 1×10 5 n/a 1 (n=10) 1 (n=10) 3×10 5 n/a 3 (n=135) 4 (n=145) 5×10 5 n/a 1 (n=10) 1 (n=10) 3×10 6 n/a 6 (n=169) 5 (n=159) 9×10 6 n/a 1 (n=50) 1 (n=50) 1×10 7 n/a 1 (n=35) 1 (n=35) 2×10 7 4 (n=99,049) 8 (n=1652) 13 (n=150,204) *** 5×10 7 n/a 1 (n=16) 2 (n=17) 1×10 8 n/a 3 (n=319) 4 (n=341)
Abbreviations: n/a: not available; PFU: plaque-forming unit. * Total vaccinated sample sizes by dose level and outcome are approximated based on the number of study subjects planned to be given the vaccine. These numbers are based on published articles included for review and therefore may differ from other tabulated sources. ** Dose values are based on the vaccine potencies reported in the included studies. These dose values may not correspond directly to the potency of the pre-market vaccine product available for use in Canada. *** The vaccinated sample size for this dose level includes an estimated 130,000 individuals who were vaccinated in the DRC (45) .
Most included studies with evaluable study designs according to the Harris et al. criteria (10) received a "good" rating, with the exception of two studies receiving a "fair" rating due to interruptions in study protocol (15,21) . For all other study designs that were not evaluable with the Harris et al. criteria, no critical flaws were noted besides the intrinsic limitations of those designs.
Extracted study data are presented in the evidence table in Appendix C for human studies and Appendix D for non-human primate studies (data from an unpublished study in non-human primates are not summarized in the evidence table ). GMT point estimates and corresponding 95% confidence intervals (95% CI) from the human studies for the varying dose levels of the rVSVΔG-ZEBOV-GP vaccine are summarized in Appendix E. The overall patterns in the data are described for the outcomes of interest in the following sections.
# III.1 EFFICACY AND EFFECTIVENESS
Four studies assessed vaccine efficacy or effectiveness in humans in the context of ring vaccination (21,26,27,44) . Two case reports described PEP of healthcare or laboratory workers following high-risk needlestick or sharps injuries (28,43) . Six studies looking at survival following lethal ZEBOV challenge after pre-exposure prophylaxis (PrEP) (32)(33)(34)(35)(36)40) and two studies looking at survival following PEP after lethal ZEBOV challenge (31,38) were conducted in non-human primates.
# Ring vaccination
Ring vaccination, originally used for smallpox control and eradication, has been used broadly as an outbreak control measure in response to EVD activity. Ring vaccination involves tracking the epidemic and recruiting individuals at increased risk of infection based on their connection to a confirmed case of disease (52) . Ring vaccination typically includes a mix of PEP and PrEP based on confirmed and anticipated (e.g., for healthcare and frontline workers) exposure, respectively, for contacts of cases and contacts of those contacts.
In a phase 3 cluster randomized ring vaccination trial conducted in Guinea during the 2014-2016 West Africa outbreak, vaccine efficacy against EVD occurring 10 or more days after randomization was 100% (95% CI: 77.0-100.0%) comparing all vaccinated contacts and contacts of contacts randomized to receive the vaccine immediately (n=3775) with all contacts and contacts of contacts randomized to receive the vaccine 21 days after randomization and never-vaccinated (n=7995) (21) . The overall vaccine effectiveness in protecting all contacts and contacts of contacts in the randomized clusters (including unvaccinated cluster members; n=4513 immediate and 4529 delayed vaccination) against onset of EVD 10 days or more from randomization was 64.6% (95% CI: -44.2-91.3%). EVD cases occurred at similar attack rates within the first 10 days after randomization regardless of vaccination status; 11 cases among immediately vaccinated adults (0.5%) and 21 cases among all eligible adults assigned to delayed vaccination (0.7%) had onset of symptoms within 10 days of randomization. No cases of EVD occurred 10 days or more after randomization in the immediately vaccinated clusters compared with 16 cases among eligible individuals in delayed clusters. Vaccine effectiveness at 10 days or more post-vaccination against death due to EVD was 100%.
The preliminary estimate of vaccine effectiveness from the ongoing compassionate use ring vaccination program in the DRC (n=93,965 vaccinated) against onset of illness 10 days or more post-vaccination was 97.5% (95% CI: 95.8-98.5%) (44) . There were 71 cases of EVD among vaccinated individuals; 56 developed symptoms within 10 days of vaccination and only nine of these individuals died while 15 individuals developed symptoms 10 days or later following vaccination and none of these individuals died. Vaccine effectiveness at 10 days or more postvaccination against death due to EVD was also 100% in this study.
Results from these ring vaccination studies suggest that the vaccine was efficacious in preventing EVD, if symptoms of EVD did not appear within 10 days of vaccination. Based on these study findings, 10 days is the time after which vaccinees are assumed to be protected whereas less than 10 days post-vaccination is the period where vaccinees are not protected or partially protected (44) . Correlation between immune response and protection was not investigated in these studies. Ring vaccination was also found to be effective in contributing to outbreak control. However, the relative impact of vaccination on outbreak control compared to other factors (e.g., declining incidence of EVD, other public health measures) was not determined. Furthermore, as these studies were performed during ongoing community-based outbreaks and included contacts who may not have had a high-risk interaction with an index case, the study findings provide evidence of protection but do not differentiate whether it is preor post-exposure protection. Two other ring vaccination studies conducted during communitybased outbreaks of ZEBOV in Guinea (n=1510 vaccinated) (27) and Liberia (n=210 vaccinated) (26) did not identify secondary cases of EVD occurring among vaccine recipients. These two studies were not designed to assess the impact of vaccination on outbreak control.
The characteristics of the rings, or clusters, that comprise these ring vaccination studies were expectedly heterogeneous: 73-96% of contacts were contacts of contacts (i.e., secondary contacts), 4-27% of contacts were high-risk contacts (i.e., had close physical contact with an EVD case's body, body fluids, linens, or clothing), 7-20% of contacts were healthcare or frontline workers, median number of days from confirmation of EVD in the index case to vaccination of contacts ranged from 7-15 days, and cluster sizes ranged from several dozen to several hundred people (21,26,27,44) . Pregnant or breastfeeding women and children under six years of age were excluded from receiving the vaccine in these studies. Vaccine efficacy or effectiveness for children and adolescents 6-17 years of age and immunocompromised individuals were not separately reported.
# Prophylaxis after needlestick or sharps injury
There are several case reports of PEP following needlestick or sharps injuries. A laboratory worker was vaccinated with a 5×10 7 PFU dose 48 hours after needlestick injury with a syringe containing live ZEBOV (28) . Five healthcare workers were vaccinated with a 1×10 8 PFU dose 1-3 days after potential ZEBOV exposure resulting from sharps injuries sustained in West Africa (43) . These exposures did not result in evidence of infection, but it is not possible to determine whether this was due to vaccine effect or lack of transmission following the needlestick injury.
# Efficacy in non-human primates
For PrEP, complete protection was achieved with the vaccine (mostly at the 1×10 7 PFU dose) given 7-28 days before intramuscularly-administered lethal ZEBOV challenge (1000 PFU) (32,(34)(35)(36)40) and partial protection was achieved with the vaccine (5×10 7 PFU dose) given three days before lethal challenge in healthy animals (36) . Partial protection was also achieved with the vaccine (1×10 7 PFU dose) given 31 days before lethal challenge in immunodeficient SHIVinfected animals (33) .
For PEP, one study found that 50% of animals survived without showing signs of severe disease after vaccination (2×10 7 PFU dose) within 20-30 minutes of lethal challenge while both controls died (31) . Another study found no difference in survival among vaccinated (2×10 7 PFU dose) or control groups when vaccinated at 1 hour and/or 24 hours after lethal challenge (38) .
# III.2 IMMUNOGENICITY
Ten studies evaluated immunogenicity following vaccination with the rVSVΔG-ZEBOV-GP vaccine of varying dose levels in humans (12-16, 19, 20, 26, 29) and eight studies assessed immunogenicity following vaccination in non-human primates (31)(32)(33)(34)(35)(36)(37)40) . It is important to note that no immunological correlate of protection has been established for EVD, so it is difficult to interpret immunogenicity findings in the context of disease prevention.
# Immunoglobulin G antibody response
The most robustly assessed immunogenicity outcome was the ZEBOV envelope GP-specific immunoglobulin G (IgG) antibody response (12-16, 19, 20, 26, 29) . Most subjects seroconverted (i.e., had a four-fold or greater increase from baseline titre) by day 14 post-vaccination and all subjects seroconverted by day 28 regardless of dose. There was a high degree of interindividual variability in IgG antibody response regardless of dose. A dose-response relationship was observed with the speed and amplitude of response. However, there appeared to be diminishing marginal antibody response with increasing dose; GMTs were similar at higher doses due to the wide and overlapping 95% CI, suggesting a plateau of the dose-response curve at higher doses. One trial found a potential age-response relationship, where children and adolescents 6-17 years of age were observed to respond slower than adults (19) . GMTs generally peaked by day 28 and persisted to 1-2 years post-vaccination without significant decline and without significant difference across dose levels. Persistence of IgG antibody response beyond two years after vaccination is unknown. There are ongoing studies looking at antibody persistence up to three (53) or five (54,55) years following primary vaccination. A protective threshold of IgG antibody response has not been established.
A phase 1 dose-ranging trial looking at a two-dose regimen given on days 0 and 28 found that the second dose was associated with a short-term advantage with respect to the amplitude of response, but there was no significant difference in long-term titres between one-and two-dose regimens (12) . Anamnestic response following a booster dose more than 28 days after the priming dose has not been characterized. There are currently ongoing studies investigating a booster given at 56 days (55) or 18 months (53) .
Seroconversion rates at one-month post-vaccination was found to be significantly lower in a small sample of HIV-infected adults (n=13) compared to non-HIV-infected adults (n=383) in Liberia (20) . There is currently a phase 2 randomized controlled trial in progress evaluating the safety and immunogenicity of the vaccine in HIV-infected adults and adolescents at two Canadian sites and two African sites (Burkina Faso and Senegal) (56) . Immunogenicity data for pregnant and breastfeeding women, infants, children under six years of age, and persons with other immunocompromising conditions are not available.
# Neutralizing antibody response
Several phase 1 clinical trials also looked at neutralizing antibody responses (12)(13)(14)(15)(16)19) . The neutralizing antibody response appeared to be well-correlated with the IgG response; there was a dose-dependent response, with titres peaking at day 28 post-vaccination, and some evidence of persistence over 6 months-2 years. A neutralizing antibody protective threshold has not been established.
# Other immune response outcomes
A few studies were identified that investigated cell-mediated responses and changes to cytokine profiles and circulating host microRNA following vaccination. A dose-dependent CD169 expression was observed, suggesting a dose effect in monocyte activation (15) . Both CD4+ and CD8+ T cells showed increased activity post-vaccination (17) . Circulating follicular T helper cells were correlated with IgG titres (11) . One study found that vaccination led to a skewing in the cytokine profiles that promote humoral immune responses (11) . Another study found a significant induction of cytokines involved in the promotion of cell-mediated response, activation of antigenpresenting cells, and growth and survival of antigen-specific cytotoxic T lymphocytes (17) . Higher doses were found to elicit stronger interlocked cytokine networks compared with lower doses (17) . Vaccination was also found to be accompanied by dose-dependent changes in circulating host microRNA (18) . The importance and impact of these responses have not been elucidated.
# Immunogenicity in non-human primates
For PrEP, modest IgG titres were detected in most animals by day 28 post-vaccination (day of lethal ZEBOV challenge) (31-36, 38, 40) , including in immunodeficient SHIV-infected animals (33) , whereas neutralizing antibody was not detectable in most animals (31,35,36,40) . A depletion study revealed a minimal role for CD8+ T cell immunity in vaccine-mediated protection (37) .
For PEP, IgG titres were detectable between 1-2 weeks after vaccination at 20-30 minutes, 1 hour, or 24 hours after lethal ZEBOV challenge (31,38) .
# III.3 SAFETY
Sixteen studies evaluated safety following vaccination with the rVSVΔG-ZEBOV-GP vaccine of varying dose levels in humans (12-16, 19-21, 24-28, 41-43) . Five studies in non-human primates reported clinical symptoms following vaccination (32)(33)(34)(35)(36) and one study in non-human primates specifically looked at neurological symptoms following intrathalamic injection of the vaccine or wild-type rVSV (39) .
# Solicited adverse events
The majority of study subjects vaccinated with the rVSVΔG-ZEBOV-GP vaccine were immunocompetent adults who were not pregnant or breastfeeding. The vaccine is highly reactogenic; over 80% of study subjects were reported by multiple studies as having experienced at least one adverse event (15,16,24,25,42) . The most frequently reported symptoms were injection site pain, fever, headache, malaise, and myalgia. Although the degree of reactogenicity was high across dose levels, these adverse events were generally transient and mild-to-moderate in intensity. The onset of systemic symptoms typically occurred within three days after vaccination. A phase 1 dose-ranging trial looking at a two-dose regimen given on days 0 and 28 found a lower rate of adverse events after the second dose than after the first dose (12) .
# Unexpected adverse events
Unexpected adverse events reported in an early clinical trial include arthralgia, arthritis, dermatitis, and vasculitis (15) . Follow up studies, including the large phase 3 ring vaccination trial in Guinea, found arthralgia and arthritis to be less frequent, transient, and of mild-to-moderate intensity (13,14,16,20,21,42,43) , but occurring at higher rates compared to placebo (25) or no vaccination (24,41) . One study found the female sex and a medical history of arthritis as significant risk factors for the development of arthritis post-vaccination, but not treatment dose or age (30) . The median time to onset of arthritis was about 10 days and the mean duration was 6 days in blinded trials, though a few events persisted for months to years (45) . Dermatitis and vasculitis were also infrequently reported, generally mild-to-moderate in intensity, and of short duration (12,16,42,43) , and occurred at higher rates compared to placebo (25) or no vaccination (24) . Some dose-ranging studies found that there is likely a trend towards lower reactogenicity with lower doses (13)(14)(15) , but the unexpected adverse events did not appear to be related to the dose.
# Serious adverse events
Serious adverse events were infrequently reported following more than 150,000 vaccinations across all dose levels. In the studies included for review, only two serious adverse events were judged to be vaccine-related (both for the 2×10 7 PFU dose): one febrile reaction and one anaphylaxis (21) . Analysis of double-blinded trials found serious adverse events occurred in 3.4% of vaccine recipients, with the most common event being malaria, compared with 7.8% of placebo recipients (45) . In over 130,000 vaccinated individuals in the DRC, 228 serious adverse events were identified between August 7, 2018 and June 5, 2019; of these events, only a few, including one case of anaphylaxis, were attributed to the vaccine (45) .
# Special populations
There are limited safety data in pregnant women, children and adolescents 6-17 years of age, and immunocompromised individuals. In three studies that excluded pregnant and breastfeeding women from vaccination, a small number of enrolled subjects became pregnant within two months after vaccination and very few were pregnant when vaccinated (19,24,41,45) . One randomized trial (n=261) found a higher frequency of pregnancy loss in those who received the vaccine immediately compared with those who received delayed vaccination. The reasons for this observation are unknown. Three studies that included children and adolescents 6-17 years of age (n=537) found an adverse events profile that is similar to adults (19,21,27) , but with fewer arthralgia events than adults (21,27) . Two serious adverse events attributed to gastroenteritis and respiratory failure occurred in one of 22 HIV-infected vaccinees (20) . Safety data are currently not available for breastfeeding women, infants, children under 6 years of age, and persons with other immunocompromising conditions.
A phase 2 randomized controlled trial including children with age greater than or equal to 1 year (54) and a phase 2 randomized controlled trial in HIV-infected adults and adolescents with oneand two-dose regimens are in progress (56) . As of June 29, 2019, 34,522 children and adolescents 1-17 years of age have been vaccinated under the WHO compassionate use protocol in the ongoing outbreak in the DRC (7) . In February 2019, the ethics committee of the DRC authorized the expansion of the compassionate use protocol to include vaccination of pregnant and breastfeeding women and children under 1 year of age (8) . In May 2019, authorities in the DRC simplified safety follow-up requirements to passive reporting of serious adverse events by phone and active follow-up of only pregnant women and children under 1 year of age (9) . Specific safety results have not yet been published for these vaccinated individuals; however, no serious safety concerns have been identified so far by WHO or the manufacturer.
# Vaccine vector viremia and shedding
Low-level, transient, and dose-dependent rVSV viremia was seen for some subjects on days 1-3 after vaccination, becoming undetectable by days 7-14 (12-16, 20, 28, 43) . Viremia was seen more frequently in children and adolescents compared to adults in one study (19) .
Transmissibility of vaccine virus to people outside of the target vaccine population is not known, as no data are available on secondary transmission (45) , but is unlikely. Very few vaccinees had measurable shedding of the vaccine virus in urine and saliva (13,14,16) . Viral shedding in saliva was seen more frequently in children and adolescents compared to adults (19) . Absent or minimal vaccine virus shedding was observed in oral, nasal, and/or rectal swab samples from animal studies and the wild-type rVSV has naturally low transmissibility (57,58) .
# Leukocyte counts
Transient, asymptomatic, dose-related decreases in leukocytes were observed in some subjects and mostly within 2 days post-vaccination (12,14,15,19) .
# Safety in non-human primates
The rVSVΔG-ZEBOV-GP vaccine appeared to be well-tolerated in non-human primates, showing no evidence of clinical illness in the period following pre-exposure vaccination (32)(33)(34)(35)(36) . Intrathalamic injection of the vaccine showed a lack of neurovirulence compared to the wild-type rVSV (39) .
# IV. PRECAUTIONS
# Potential interference with ZMapp
No individuals have received both the rVSVΔG-ZEBOV-GP vaccine and the ZMapp monoclonal antibody cocktail for EVD treatment to date. Therefore, timing of administration and potential interference between these two products are currently unknown. Administration of these products close together may result in decreased effectiveness of the rVSVΔG-ZEBOV-GP vaccine and/or ZMapp because the monoclonal antibody has high affinity for the ZEBOV envelope GP expressed by the vaccine vector and the vaccine virus must replicate over time in order to elicit immune responses.
In the post-exposure setting, expert clinical opinion should be sought when deciding whether ZMapp, the rVSVΔG-ZEBOV-GP vaccine, or a combination of the two is the most appropriate response, taking into account the specifics of the exposure event.
# Vaccine virus shedding
Transmission of the vaccine virus has not been reported to date. In clinical trials, very few vaccine recipients had measurable shedding of the vaccine virus in urine and saliva (13,14,16) and low-level rVSV viremia observed in some vaccine recipients became undetectable by days 7-14 (12-16, 20, 28, 43) . It is not known if the vaccine virus is secreted in human breast milk. There is no data available regarding the effects of vaccinating breastfeeding women on their infants. Absent or minimal vaccine virus shedding was observed in oral, nasal, and/or rectal swab samples from animal studies and the wild-type rVSV has naturally low transmissibility (57,58) . Although the risk of transmitting the rVSVΔG-ZEBOV-GP vaccine virus to people outside of the target vaccine population appears to be extremely low, vaccine recipients should be informed that the rVSVΔG-ZEBOV-GP vaccine does not contain live Ebolavirus, but is comprised of a liveattenuated recombinant virus, rVSV, that has the theoretical potential to be transmitted to contacts of the vaccinated individual.
Based on expert opinion and taking into consideration the precautions for use made by the EMA (59) , individuals vaccinated with the rVSVΔG-ZEBOV-GP vaccine should avoid close contact (including exposure to blood and body fluids) with immunocompromised individuals, pregnant or breastfeeding women, and infants for at least six weeks following vaccination, unless those individuals also have an indication for the rVSVΔG-ZEBOV-GP vaccine.
Similarly, as a precaution, women should avoid breastfeeding and their infants should not have contact with maternal blood and body fluids, where feasible, for at least six weeks following vaccination, unless vaccination with the rVSVΔG-ZEBOV-GP vaccine is also indicated for the infant.
# V. INTERIM RECOMMENDATIONS
After careful review of available evidence (see Section III) and considering current knowledge gaps (see Section VI), NACI makes the following interim recommendations on the emergency use of the pre-market rVSVΔG-ZEBOV-GP vaccine stockpiled in the NESS for PEP and PrEP in a Canadian context, recognizing:
The lack of regulatory approval of the rVSVΔG-ZEBOV-GP vaccine in Canada at the time of writing; The limited quantity of this pre-market vaccine available in Canada; and The fact that the EVD outbreak in the DRC is a Public Health Emergency of International Concern at the time of writing, and the global rVSVΔG-ZEBOV-GP vaccine supply is being prioritized for those most at risk in Africa where there can be the greatest impact.
As the regulatory, supply, and evidence context for the rVSVΔG-ZEBOV-GP vaccine evolves, NACI will revisit these interim recommendations as needed.
A dose-sparing strategy for the use of the rVSVΔG-ZEBOV-GP vaccine, and associated evidence, may be reviewed and considered by NACI if the need arises.
# Exposure definition
For the interim recommendations, exposures * to ZEBOV that are considered to pose risk are: Unprotected direct physical contact (i.e., through non-intact skin or mucous membranes) with (60,61) : o non-intact skin, mucous membranes, blood, or other body fluids (e.g., stool, emesis, urine, saliva, semen, sweat, breast milk) of a ZEBOV-infected individual; o linens or clothing contaminated with ZEBOV-infected blood or body fluids; o the dead body of a ZEBOV-infected individual; and/or o any other known source of ZEBOV, including contaminated medical instruments, fomites or other contaminated environmental surfaces, laboratory specimens, or animals; Unprotected exposure following assistance with the performance of an aerosolgenerating medical procedure (62) ; Unprotected sexual contact with an acute or convalescent EVD case (ZEBOV has been demonstrated to persist in semen for up to 40 months (2) ) with laboratory-confirmed ZEBOV infection (60) ; and/or Unprotected handling and/or consumption of ZEBOV-contaminated bush meat products from Africa (63) .
# Strength of NACI recommendations
Please note: A strong NACI recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present. A discretionary NACI recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
Please see Table 2 for a more detailed explanation of strength of NACI recommendations and grade of the body of evidence. Please see Tables 3 and 4 for details on the ratings of the quality of individual studies.
V.
# Summary of evidence and rationale
The vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of post-exposure protection. The lack of regulatory review and authorization may decrease the acceptability of this pre-market vaccine; however, the potential for severe harm from EVD in those who have had an exposure to ZEBOV and the safety and immunogenicity profile of the vaccine established in non-pregnant immunocompetent adults may improve its acceptability among these individuals.
# Interim recommendation 1b
1b. NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine may be considered as PEP against ZEBOV for pregnant women, infants, children, adolescents, and immunocompromised individuals who have had an exposure to ZEBOV (Discretionary NACI Recommendation) NACI concludes that there is currently insufficient evidence to recommend vaccination of pregnant women, infants, children, adolescents, and immunocompromised individuals who have had an exposure to ZEBOV with the rVSVΔG-ZEBOV-GP vaccine (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
There are limited safety data for pregnant women, children and adolescents 6-17 years of age, and immunocompromised individuals. One randomized trial found a higher frequency of pregnancy loss in those who received immediate vaccination vs. delayed vaccination. Three studies that included children and adolescents 6-17 years of age found an adverse events profile that is similar to adults, but with fewer arthralgia events than adults. Two serious adverse events attributed to gastroenteritis and respiratory failure occurred in one of 22 HIV-infected vaccinees. Safety data are not currently available for infants and children under 6 years of age. There is limited evidence of slower immune response in children 6-17 years of age after vaccination than adults. There is also limited evidence of less optimal immune response in HIV-infected individuals compared with non-HIV-infected individuals. No immunogenicity data are available for pregnant women, infants, and children under 6 years of age. Vaccine has been given to these special populations as part of outbreak control measures in the DRC. As of June 29, 2019, 34,522 children and adolescents 1-17 years of age have been vaccinated. In February 2019, the authorities in the DRC authorized the expansion of the compassionate use protocol to include pregnant and breastfeeding women and children under 1 year of age. In May 2019, the authorities simplified safety follow-up requirements to passive reporting of serious adverse events by phone and active follow-up was limited to pregnant women and children under 1 year of age. Specific safety results have not yet been published for these vaccinated individuals; however, no serious safety concerns have been identified so far by WHO or the manufacturer. A risk-benefit assessment of this pre-market vaccine, taking into consideration uncertainties in the safety and efficacy of the vaccine, the potential for severe harm from EVD, and the nature and intensity of exposure, should be conducted when deciding whether to vaccinate individuals in these special populations.
Interim recommendation 2 2. When used as PEP against ZEBOV, NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine should be given as expeditiously as possible, targeting within 72 hours of exposure for susceptible, asymptomatic exposed individuals, but may be considered up to 10 days post-exposure, as the incubation period for EVD can range from 2-21 days and vaccination within 10 days of exposure may confer protection (Strong NACI Recommendation) NACI concludes that there is currently insufficient evidence to define a vaccination window for effective PEP in preventing severe disease after exposure to ZEBOV (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination.
The median time from confirmation of EVD in an index case to vaccination of contacts in these studies ranged from 7-15 days. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of timing for post-exposure protection. In studies with non-human primates, partial post-exposure protection against EVD was achieved if vaccinated within 20-30 minutes of intramuscular challenge with a lethal concentration of ZEBOV. No protection against EVD was observed if vaccinated at 1 and/or 24 hours after lethal intramuscular ZEBOV challenge. Data derived from animal studies should be interpreted with caution when used to inform clinical decision making since time-to-death is shorter and mortality rate is higher following intramuscular infection, likely shortening the window of efficacy of post-exposure vaccination compared to mucosal infection. Several instances of PEP given within 3 days of a needlestick or sharps injury have been reported. A laboratory worker was vaccinated with a 5×10 7 PFU dose 48 hours after a needlestick injury with a syringe containing ZEBOV. Five healthcare workers were vaccinated with a 1×10 8 PFU dose 1-3 days after sharps injuries in West Africa. There was no evidence that these exposures resulted in infection but it is not possible to determine whether this was due to vaccine effect or lack of transmission following the needlestick injury. Expert clinical opinion should be emergently sought in the management of individuals who are potentially exposed to ZEBOV from a needlestick injury, as the window for effective PEP after intramuscular exposure to ZEBOV is unknown, but likely to be small, and the vaccine may not be immediately available for administration. The risk of severe disease from intramuscular exposure to ZEBOV (e.g., needlestick injury from a ZEBOVcontaminated needle and syringe) is greater than mucosal exposure (e.g., unprotected direct physical contact through non-intact skin or mucous membranes with non-intact skin, mucous membranes, blood, or other body fluids of a ZEBOV-infected individual). Common systemic reactions following vaccination include fever, headache, malaise, and myalgia, resembling the early symptoms of EVD. However, typical onset of vaccine reactions is expected within 3 days after vaccination compared with onset of clinical symptoms 4-10 days after exposure to ZEBOV. Therefore, clinical management of reported illness among individuals who have had an exposure to ZEBOV should take into consideration vaccination status, timing of symptom onset relative to vaccination, and presence of any symptoms typically associated with EVD but not with vaccination (e.g., sore throat, nausea and vomiting, diarrhea, haemorrhaging) to mitigate unnecessary referrals to EVD treatment units. Antipyretics have been used for the management or prevention of post-vaccination fever without identified safety concerns (21) , but the use of antipyretics may mask early EVD symptoms.
# Interim recommendation 3
3. NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine may be considered as PEP against ZEBOV for individuals who have received a previous dose of the premarket rVSVΔG-ZEBOV-GP vaccine more than 18 months prior to a current exposure to ZEBOV (Discretionary NACI Recommendation) NACI concludes that while there is currently fair evidence of immunogenicity up to two years post-vaccination (Grade B Evidence), there is insufficient evidence to define a serological threshold of protection against ZEBOV or to suggest a need for revaccination (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
Summary of evidence and rationale GMTs of IgG antibody to the ZEBOV envelope GP reported in clinical trials generally peaked by day 28 and persisted to two years post-vaccination without significant decline. Immune correlates of protection and the relative importance of IgG antibody response
have not yet been established. Long-term vaccine efficacy has not been demonstrated.
There is limited evidence that the rate of adverse events following a second dose given at 28 days post-vaccination is lower than after the first dose. Due to the potential for severe harm from EVD and the uncertainty around the durability and thresholds of vaccine protection, re-vaccination with the rVSVΔG-ZEBOV-GP vaccine may be considered as a precaution after an exposure to ZEBOV occurring more than 18 months after a previous dose of the rVSVΔG-ZEBOV-GP vaccine. Expert clinical opinion should be sought when deciding whether to re-vaccinate an individual who has previously received another vaccine for EVD with the rVSVΔG-ZEBOV-GP vaccine.
# Interim recommendation 4 4. When used as PEP against ZEBOV, NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine should not be given simultaneously with other live or inactivated vaccines due to the potential for immune interference and the need to be able to monitor for potential symptoms of EVD and rVSVΔG-ZEBOV-GP vaccine adverse events without potential confounding from other vaccine adverse events (Strong NACI Recommendation)
NACI concludes that there is currently insufficient evidence to recommend concurrent administration of the pre-market rVSVΔG-ZEBOV-GP vaccine with other vaccines (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
Although live-attenuated or inactivated vaccines given by the parenteral route may generally be administered concurrently with other vaccines without concern, there is no data available on the concurrent administration of the rVSVΔG-ZEBOV-GP vaccine with other vaccines. Given the potential for immune interference and the need to be able to monitor for potential symptoms of EVD and rVSVΔG-ZEBOV-GP vaccine adverse events without potential confounding from other vaccine adverse events, the pre-market rVSVΔG-ZEBOV-GP vaccine should not be given as PEP against ZEBOV simultaneously with other live or inactivated vaccines in this exceptional situation. Other live-attenuated or inactivated vaccines should be administered at a minimal interval of four weeks after vaccination with the rVSVΔG-ZEBOV-GP vaccine. However, given the potential for severe harm from EVD, vaccination with the rVSVΔG-ZEBOV-GP vaccine should not be delayed even if it is within four weeks of a previous vaccine. Considering the ethical principles of beneficence and non-maleficence, delaying any other vaccines to prioritize the pre-market rVSVΔG-ZEBOV-GP vaccine for individuals who have had an exposure to ZEBOV is acceptable and ethically justifiable.
V.
# Summary of evidence and rationale
The vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of post-exposure protection. Expert clinical opinion should be emergently sought in the management of individuals who are potentially exposed to ZEBOV from a needlestick injury. Appropriately implemented IPC measures, such as using personal protective equipment and following correct donning and doffing procedures, offer feasible and effective methods of protection against EVD infection. However, due to the nature of the work, there exists a small risk of needlestick injury among healthcare workers providing direct care to EVD cases and laboratory workers handling ZEBOV. The risk of severe disease from intramuscular exposure to ZEBOV (e.g., needlestick injury from a ZEBOV-contaminated needle and syringe) is greater than mucosal exposure (e.g., unprotected direct physical contact through non-intact skin or mucous membranes with non-intact skin, mucous membranes, blood, or other body fluids of a ZEBOV-infected individual). The lack of regulatory review and authorization may decrease the acceptability of this pre-market vaccine. However, given the potential for severe harm from EVD in those who have had an exposure to ZEBOV and the safety and immunogenicity profile of the vaccine for non-pregnant immunocompetent adults, offering the pre-market rVSVΔG-ZEBOV-GP vaccine to these individuals is acceptable and ethically justifiable.
# Interim recommendation 5b
5b. NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine may be considered as PEP against ZEBOV for pregnant or immunocompromised individuals who have had an occupational exposure to ZEBOV in Canadian healthcare or laboratory settings (Discretionary NACI Recommendation) NACI concludes that there is currently insufficient evidence to recommend vaccination of pregnant and immunocompromised individuals who have had an occupational exposure to ZEBOV in Canadian healthcare or laboratory settings with the rVSVΔG-ZEBOV-GP vaccine (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
Safety data are limited for pregnant and immunocompromised individuals. One randomized trial found a higher frequency of pregnancy loss in those who received immediate vaccination vs. delayed vaccination. Two serious adverse events attributed to gastroenteritis and respiratory failure occurred in one of 22 HIV-infected vaccinees. There is limited evidence of less optimal immune response in HIV-infected individuals compared with non-HIV-infected individuals. No immunogenicity data are available for pregnant women. Vaccine has been given to these special populations, as well as infants, children, and adolescents, as part of outbreak control measures in the DRC. In February 2019, the authorities in the DRC authorized the expansion of the compassionate use protocol to include pregnant and breastfeeding women and children under 1 year of age. In May 2019, the authorities simplified safety follow-up requirements to passive reporting of serious adverse events by phone and active follow-up was limited to pregnant women and children under 1 year of age. Specific safety results have not yet been published for these vaccinated individuals; however, no serious safety concerns have been identified so far by WHO or the manufacturer. Expert clinical opinion should be emergently sought in the management of individuals who are potentially exposed to ZEBOV from a needlestick injury. Appropriately implemented IPC measures, such as using personal protective equipment and following correct donning and doffing procedures, offer feasible and effective methods of protection against EVD infection. However, due to the nature of the work, there exists a small risk of needlestick injury among healthcare workers providing direct care to EVD cases and laboratory workers handling ZEBOV. The risk of severe disease from intramuscular exposure to ZEBOV (e.g., needlestick injury from a ZEBOV-contaminated needle and syringe) is greater than mucosal exposure (e.g., unprotected direct physical contact through non-intact skin or mucous membranes with non-intact skin, mucous membranes, blood, or other body fluids of a ZEBOV-infected individual). A risk-benefit assessment of this pre-market vaccine, taking into consideration uncertainties in the safety and efficacy of the vaccine, the potential for severe harm from EVD, and the nature and intensity of exposure, should be conducted when deciding whether to vaccinate individuals in these special populations.
Interim recommendations 2 through 4 also apply to individuals who have had an occupational exposure to ZEBOV in Canadian healthcare or laboratory settings.
# V.3 PRE-EXPOSURE PROPHYLAXIS
Advice on PrEP for travellers is not provided in this interim statement on the emergency use of the pre-market rVSVΔG-ZEBOV-GP vaccine stockpiled in the NESS.
# Interim recommendation 6
6. NACI recommends that the pre-market rVSVΔG-ZEBOV-GP vaccine may be considered as PrEP against ZEBOV for non-pregnant immunocompetent adults in exceptional situations when a dedicated team of healthcare workers is anticipated to provide direct care for a confirmed case with symptomatic ZEBOV infection, if vaccine is available (Discretionary NACI Recommendation) NACI concludes that there is currently fair evidence of safety, immunogenicity, efficacy, and effectiveness to recommend vaccination of non-pregnant immunocompetent adults at risk of exposure to ZEBOV (Grade B Evidence) and insufficient evidence of long-term protection beyond two years post-vaccination (Grade I Evidence). Therefore, this interim recommendation is based on expert opinion.
# Summary of evidence and rationale
The vaccine has shown few serious adverse events, despite a high degree of reactogenicity, and is immunogenic in non-pregnant immunocompetent adults. The vaccine has been shown to be efficacious in preventing EVD in the context of community outbreaks, if symptoms of EVD did not appear within 10 days of vaccination. However, because these efficacy studies were performed during community-based outbreaks of ZEBOV in Africa, they do not provide direct evidence of pre-exposure protection. GMTs of IgG antibody to the ZEBOV envelope GP reported in clinical trials generally peaked by day 28 and persisted to two years post-vaccination without significant decline. Long-term vaccine efficacy is unknown. Although the acceptability of this narrow interim recommendation for PrEP may be low among healthcare workers who perceive themselves to be at risk of exposure to ZEBOV, wider PrEP against ZEBOV is currently not feasible or recommended at this time in Canada based on the limited availability of the pre-market vaccine in Canada and globally and the potentially large number of Canadian healthcare workers who may have some perceived risk of exposure to ZEBOV (there have been no cases of EVD in Canada to date). Appropriately implemented IPC measures, such as using personal protective equipment and following correct donning and doffing procedures, offer feasible and effective methods of protection against EVD infection and should be followed as the situation dictates, regardless of vaccination status. Vaccine-derived adverse events may mimic early EVD symptoms; therefore, clinical management of reported illness among vaccinated individuals who have had an exposure to ZEBOV should take into consideration vaccination status, timing of symptom onset relative to vaccination, and presence of any symptoms typically associated with EVD but not with vaccination.
# VI. KNOWLEDGE GAPS
After careful review of available evidence, NACI has identified the need for further research to address current knowledge gaps where data are absent or limited. NACI recognizes that there are studies already in progress that may address many of these gaps but the findings of these studies were not yet available at the time of review. Identified knowledge gaps include:
Immune correlates of protection have not been established. The window of vaccination for effective PEP is unknown. The degree of post-exposure protection (e.g., decreasing infectiousness and clinical illness in individuals that had already acquired infection) is unknown. Cross-protective efficacy against other Ebolavirus species or Marburg virus in humans is unknown, though the vaccine is unlikely to protect against these other viruses of the Filoviridae family due to significant differences in viral antigens. Safety and immunogenicity data for children and adolescents 6-17 years of age and immunocompromised individuals are limited. Safety data are limited and immunogenicity data are not available for pregnant women. Safety and immunogenicity data are not available for breastfeeding women, infants, and children under 6 years of age. Transmissibility of the vaccine virus is unknown, including whether the vaccine virus is secreted in human breast milk. Persistence of immune response beyond two years after vaccination is unknown. Long-term vaccine efficacy is unknown. Anamnestic response following a booster dose more than 28 days after the priming dose has not been characterized. Interference with ZMapp or other passive immunizing agents against EVD is unknown. Safety of concurrent administration with other vaccines is unknown.
# TABLES
# Quality rating Description
Good A study (including meta-analyses or systematic reviews) that meets all design-specific criteria * well.
# Fair
A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterion * but has no known "fatal flaw".
# Poor
A study (including meta-analyses or systematic reviews) that has at least one design-specific * "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
# LIST OF ABBREVIATIONS
# Search strategy for rVSVΔG-ZEBOV-GP vaccine in Scopus ( ( ( TITLE-ABS-KEY ( rvsv-zebov OR vsvdg-zebov OR vsv-ebov OR v920 ) ) OR ( TITLE-ABS-KEY ( recombinant AND vesicular AND stomatitis AND virus AND zaire AND ebola AND virus OR recombinant AND vesicular AND stomatitis AND virus AND zaire AND ebolavirus ) ) ) OR ( ( TITLE-ABS-KEY ( merck OR "National Microbiology Laboratory" OR "Public Health Agency of
Canada" OR phac OR newlink ) ) AND ( TITLE-ABS-KEY ( ebola* ) ) ) ) AND ( LIMIT-TO ( LANGUAGE , "English" ) OR LIMIT-TO ( LANGUAGE , "French" ) ) PFU dose groups) and persisting with minimal change to day 360. Dose response was observed with the highest titres at day 28 postvaccination in the 1×10 8 and 2×10 7 PFU dose groups (no statistically significant difference between these dose groups) and the lowest titres in the 3×10 3 and 3×10 4 PFU dose groups. Time to onset of the immune response was dose-related, with seroconversion rates lower in the low-dose groups than in the highdose groups. IgG and neutralizing antibodies were both dose-related, strongly correlated at day 28, and persisted for 1 year. concentrations than adults without baseline GP-specific antibodies at day 56 post-vaccination at some doses. 70-100% vaccinated with doses ≥3×10 4 PFU reached ≥4-fold increase of GP-specific GMT by day 28, with titres peaking at day 56 and persisting higher than baseline up to 180 days post-vaccination. Highest titres were observed with the 2×10 7 PFU dose regardless of baseline antibody status.
# Search strategy for rVSVΔG-ZEBOV-GP vaccine in
# Safety
Children and adolescents 0% and 7% of children and adolescents, respectively, were seropositive for GP-specific IgG antibodies at baseline. As in adults, those with pre-existing immunity had higher responses to the vaccine at days 28 and 56 post-vaccination. 95% of children and 100% of adolescents who received a 2×10 7 PFU dose reached ≥4-fold increase of GP-specific GMT by day 28, with titres peaking at 180 days postvaccination. HIV-infected individuals Of 22 HIV-infected individuals who received the vaccine, two serious adverse events that were attributed to gastroenteritis and respiratory failure occurred in one subject.
# All vaccinees
# Citation
Henao-Restrepo et al. 2017 (21) Henao-Restrepo et al. 2015 (22) (interim findings) Control animals started to show clinical signs of disease and high ZEBOV plasma titres on day 6 after challenge and succumbed to ZEBOV infection on days 6, 7, and 8. None of the 3 rVSVΔG-ZEBOV-GP-vaccinated animals became sick from the ZEBOV challenge and all 3 animals survived. A transient low level rVSV viremia was detected on day 2 after vaccination in plasma from 4 of 6 rVSVΔG-ZEBOV-GP-vaccinated animals. rVSV was not detected in swab samples of any animal. By day of ZEBOV challenge (28 days postvaccination), all rVSVΔG-ZEBOV-GP-vaccinated animals had developed modest IgG antibody titres against ZEBOV GP and these titres increased after ZEBOV challenge. No evidence of IFN-γ or TNF-α production in CD4+ or CD8+ T cells was found before or after ZEBOV challenges in any of the animals. No animals showed any signs of clinical symptoms after vaccination. Tissue viremia from aerosol challenge mimicked patterns found in IM challenge.
# Citation
Geisbert et al.
2008 (33) Vaccine rVSVΔG-ZEBOV-GP: 1×10 7 PFU Saline placebo
# Time of administration
Pre-exposure: 31 days before lethal ZEBOV challenge Of 9 adult rhesus macaques with clinical evidence of SHIV infection (reduced CD4+ T cell counts and SHIV viremia in 4 of 9), 6 received the rVSVΔG-ZEBOV-GP vaccine and 3 receive placebo. All vaccine recipients and 2 controls were challenged with an IM 4 of the 6 rVSVΔG-ZEBOV-GP-vaccinated SHIVinfected animals and both placebo control animals started to show clinical signs of disease on day 6 after challenge. Disease progressed in 2 of the rVSVΔG-ZEBOV-GP-vaccinated SHIV-infected animals and both of the placebo control animals; these 2 rVSVΔG-ZEBOV-GP-vaccinated animals died on days 9 and 13 and the placebo control animals died on days 9 and 10. Animals that did not survive had the lowest CD4+ counts, suggesting that CD4+ T cells may play a role in mediating protection
# Study Intervention * Population Summary of key findings
The Sudan ebolavirus macaque challenge model was not uniformly lethal.
# Study
# Study design Intervention * Population Summary of key findings
Level & quality of evidence hospital of the treatment unit.
# Sample size
Total: 210 of 650 (32%) of enumerated contacts and contacts of contacts were vaccinated.
# Baseline characteristics
Median age of 33 years. 14% female.
# Citation
Gsell et al. 2017 (27) Design Ring vaccination study from March 17 to April 21, 2016 Location Guinea
# Funding
# No industry funding
Vaccine rVSVΔG-ZEBOV-GP: 2×10 7 PFU
# Population definition
Close contacts and contacts of the close contacts of the EVD index case.
Contacts were individuals who visited or were visited by the index case after the onset of symptoms; had lived in the same household; or were in close physical contact with the patient's body, body fluids, linens, or clothing within the last 21 Ring characteristics 20% of vaccinees were 6-17 years of age and 20% were frontline workers. The delay from onset to confirmation of the index case ranged from 4-7 days, with the exception of a case diagnosed on the day of onset. Mean time from ring inclusion to vaccination ranged from 0.5-5.0 days. Mean cluster size was 414 people (range of 75-715). 73-96% of contacts and contacts of contacts were defined as contacts of contacts and 4-27% of contacts and contacts of contacts were defined as high-risk contacts. There was no significant difference in survival among all groups by day 10: all unvaccinated controls, 1 animal vaccinated at 1 hour, 1 animal vaccinated at 24 hours, and 2 animals vaccinated at both 1 and 24 hours were euthanized due to signs of symptoms consistent with Ebola haemorrhagic fever. Another animal vaccinated at 1 hour was euthanized at day 28 having survived the acute phase of Ebola disease but had developed neurological symptoms and pneumonia. All other animals vaccinated with rVSVΔG-ZEBOV-GP survived. Overall, rVSVΔG-ZEBOV-GP-vaccinated animals showed a 44% survival rate. rVSV RNA was detected in all vaccinated animals as early as 12 hours after vaccination and persisted until at least day 3 after ZEBOV infection, with none being detected by day 6. Protection from the control vaccine was similar (2 of 3 survived following challenge). ZEBOV GP-specific IgM antibody responses were undetectable or very low over the first 9 days after ZEBOV challenge and were not different between survivors and non-survivors. By day 9, IgM levels increased in survivors at about the same time serum IgG could be detected. IFN-α was at low levels in all animals up to 3 days after challenge and increased to higher levels with
# Study
Intervention * Population Summary of key findings no significant difference between groups. By day 6 after challenge, IFN-α decreased in survivors (possibly due to controlling of ZEBOV infection) and increased in non-survivors and unvaccinated controls. IFN-γ production was low in all animals until day 6 after challenge, remaining low in survivors, and significantly increased for nonsurvivors and unvaccinated controls.
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e41f5cc5affe011e92223b472bdfb2efcdd63c37
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cma
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# Background
Head and neck cancer includes a variety of tumours that originate in the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyroid, and salivary glands. Worldwide, it represents the 6th most common type of cancer and accounts for about 6% of all cancers. Smoking, alcohol, age and sex are some of the most common factors for the development of head and neck cancer 1 .
Head and neck cancers are considered among the most complex types of cancers where treatment decisions are made by a multidisciplinary team which includes both oncologists and allied health care professionals such as dietitians, dentists, and speech-language pathologists 2 . The initial evaluation of patient tumour is the most critical step for treating the cancer; it provides information that is essential to making decision on optimal treatment plans. The initial assessment includes indirect mirror and direct endoscopy however the advanced assessment is done by imaging and biopsies. Imaging tools (CT, MRI, PET or PET/CT) are important for determining the local infiltration, regional spread, distant metastases or second primary tumours.
The purpose of this guideline is to outline the diagnosis, and staging recommendations for patients with head and neck cancer in Alberta.
# Search Strategy
The National Guideline Clearinghouse and individual cancer agencies' websites were searched for clinical practice guidelines related to Workup and staging for Head and Neck cancer. A systematic literature review was performed by using the Pubmed, EMBASE, and MEDLINE databases. The detailed literature search strategy is outlined in Appendix A, and the evidence tables are available upon request.
# Target Population
The recommendations outlined in this guideline are intended for adults over the age of 18 years with suspected malignancies arising in the mucosal surfaces of the upper aerodigestive tract, including the oral cavity, pharynx, larynx, and paranasal sinuses. Different principles may apply to pediatric patients or patients with thyroid/salivary gland pathology.
# Recommendations
The following recommendations should be applied in the context of the recommendations outlined in the Alberta Health Services guideline, ' 3. Inquire about HPV vaccination history.
# Physical Exam:
- Physical examination should include: inspection of the neck for lymph nodes, inspection of the facial and scalp skin; inspection of the oral cavity for ulceration of mucosa, swellings, and red or white patches and inspection of the anterior nasal cavities.
# Referral to Specialist:
- For ulcerative lesions or masses that are initially treated as potential infections, or bleeding nasal lesions that are treated with moisturizing ointments and humidification, establish time limit for followup to ensure early referral for specialty care (i.e. if lesion is not resolved or dramatically improved after 3 weeks of therapy, refer for urgent specialty review).
# II.
Workup at Cancer Centre General 6. Once biopsy proven head and neck cancer identified, newly diagnosed cases should be referred to an appropriate head and neck oncologist (with affiliations to a regional cancer centre) to develop an appropriate treatment plan as soon as possible.
- All patients should undergo tumour classification and staging prior to treatment. Staging of head and neck cancers are usually based on two classifications, namely cTNM and pTNM described in detail in the 8 th edition of the AJCC Cancer Staging Manual.
- A complete head and neck examination should be completed and documented (i.e. nose, postnasal space, oral cavity, oropharynx, larynx and hypopharynx, including palpation of neck, oral cavity and tongue base, using endoscopy as appropriate).
- When feasible, radiological investigations should be performed prior to biopsy to avoid the effect of upstaging from the edema caused by biopsy.
- When examination under general anesthesia including endoscopy and biopsy is indicated, that procedure should be performed by the surgeon who is responsible for any future procedures
# Imaging
CT Scan: 11. In all cases, CT of the neck with contrast is recommended for locoregional staging. If tumour extent is unclear on CT, and if clarification would alter management, then further evaluation with MRI is recommended.
# MRI Scan:
- MRI may be particularly helpful for assessing infiltration of surrounding soft tissues (e.g. extrinsic tongue muscles, parapharyngeal space, and masticator space), perineural spread, and intracranial/ intraorbital extension.
# FDG-PET Scan:
- If nodal status is unclear on CT (+/-MRI), and if clarification would alter management, then further evaluation with FDG-PET is recommended.
- In a patient with an unknown primary site of tumour after head and neck examination and CT (+/-MRI), FDG-PET should be performed prior to panendoscopy and biopsy so that sites of biopsy will not lead to a false-positive.
- Chest imaging is recommended for all newly diagnosed head and neck cancers to detect lung metastases and synchronous lung cancers. Both chest CT and PET-CT are superior to chest x-ray in detecting synchronous primary cancers and distant metastases 3 . In cases of N2-N3 disease, patients with a history of smoking and those otherwise at higher risk for second primary tumours and distant metastases (supraglottic and hypopharyngeal cancer), CT of the chest or PET-CT is strongly recommended 3,4 .
- In cases of stage III-IV disease, FDG-PET should be considered for screening for distant metastases and second primary cancers 3 . Interpretation should consider the relatively high false positive rate with PET-CT and the possible need for confirmatory diagnostic tests 5 .
# Diagnostic Biopsy
- It is essential that mucosal lesions of the oral cavity, oropharynx, nasopharynx, hypopharynx and larynx that are clinically suspicious for malignancy, primarily squamous cell carcinoma, be appropriately and adequately biopsied in an expedited manner. The approach and method of biopsy are dependent on the site and size of the lesion, the level of suspicion of malignancy, the resources available and experience of the clinician.
- Oral lesions over 2 cm in maximum dimension, highly suspicious oral lesions and ulcerated or clearly invasive oral lesions should be sampled with an incisional or punch biopsy. The biopsy site should not be in a necrotic or friable area. Generally, a biopsy near the edge of the tumour is ideal. A 4-mm dermatologic punch is a good choice, but scalpel blades or cupped biopsy forceps are acceptable. The biopsy needs to be adequately deep to allow determination of depth of invasion. Excisional biopsies of invasive cancers have a high incidence (62%) of leaving residual cancer requiring repeat excision 6 . This may complicate management but probably does not compromise overall disease control or survival if subsequently appropriately managed. It is suggested that excisional biopsies be reserved for small, superficial lesions that are thought to be benign 7 .
- Incisional biopsies of areas of oral leukoplakia risk false negative results of up to 24-73% in some series mostly due to sampling errors 8 . Small areas of leukoplakia without worrisome clinical features can be excised under local anesthesia. Excisional biopsies of larger or suspicious areas of leukoplakia should be performed under general anesthesia with adequate margins.
- All suspicious lesions of the pharynx and supraglottic larynx require biopsies with forceps. Accessible lesions of the soft palate and tonsils may be biopsied transorally without endoscopy. Suspicious lesions of the nasopharynx, oropharynx (base of tongue), hypopharynx and supraglottic larynx may be biopsied using topical anesthesia and endoscopic guidance (rigid or flexible). This requires the appropriate patient positioning, endoscopes, an experienced Otolaryngologist -Head and Neck Surgeon and often a skilled assistant 9 . When these conditions cannot be met then traditional biopsy under general anesthesia via rigid endoscopy is required.
- Suspected lesions of the tonsils are best sampled by way of an excision of the entire tonsil or tonsils under general anesthesia (diagnostic tonsillectomy). Blind biopsies of the tonsil have a very high false negative rate as cancers often arise deep in the tonsillar crypts and are missed unless they ulcerate through the surface 10 . These tonsillectomies are often done in conjunction with a panendoscopy in the setting of metastatic SCCA in a cervical node without an obvious mucosal lesion on office examination. Larger, ulcerated and clinically obvious cancers of the tonsil may be biopsied with forceps in the clinic.
- For biopsies of the glottis, in most cases, assessment and biopsy under general anesthesia using rigid laryngoscopes is required (suspension laryngoscopy). Larger lesions may be biopsied without magnification however early T1 cancers, leukoplakia, benign or indeterminate lesions of the glottis usually require adjuvant use of a microscope (suspension microlaryngoscopy). Larger or deeply invasive lesions are sampled with cupped laryngeal forceps. Superficial, benign and indeterminate lesions such as leukoplakia and erythroplasia may be suitable for excisional biopsy using either sharp "cold" instruments or a CO2 laser. Endoscopic biopsies of the glottis may sometimes be performed in clinic in selected patients by sub-specialist laryngologists in a highly specialized setting (regional voice clinic). Sensitivity and negative predictive values for in office biopsy techniques are reported from 60 -78% and 74 -87%, respectively. . Lesions involving the anterior commissure of the glottis, bilateral vocal cords or vocal process of the vocal cord should not be excised without prior pathological confirmation and multidisciplinary consultation at a regional cancer centre with discussion of alternative non-surgical options. In performing excisional biopsies of suitable glottic lesions, care must be taken to not violate the vocal ligament or anterior commissure regardless of the instrument used.
- Panendoscopy as a diagnostic tool for the identification of synchronous tumours is inferior in comparison to CT or PET-CT in most cases . Patients at low risk of a secondary lesion have a very low rate of synchronous tumours identified on routine pandendoscopy and esophagoscopy 14,15,17,18 Cancers of the hypopharynx may be an exception in that the incidence of esophageal second primaries is higher and esophagoscopy compares favourably to CT chest 4 .
- Panendoscopy is a useful tool in the workup of patients planned for surgery or potential transoral excision of a head and neck cancer to evaluate feasibility and anatomy.
# Occult Primary
- Fine Needle aspiration cytology of a neck mass or neck node should be performed for occult primaries. When the FNA is non-diagnostic an open biopsy may be required. Special stains including those for lymphoma, EBV and HPV testing should be ordered to help establish the primary tumour.
- PET-CT imaging is superior to panendoscopy in the identification of an occult primary and should be the initial investigation to establish the primary tumour. The PET-CT results may direct subsequent confirmatory biopsies. If PET-CT fails to detect a primary tumour, the patient should be sent for panendoscopy (EUA) for random directed biopsies of potential primary sites including tonsillectomy.
- The role of total mucosal resection for identification of unknown primaries is currently unclear.
|
# Background
Head and neck cancer includes a variety of tumours that originate in the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyroid, and salivary glands. Worldwide, it represents the 6th most common type of cancer and accounts for about 6% of all cancers. Smoking, alcohol, age and sex are some of the most common factors for the development of head and neck cancer 1 .
Head and neck cancers are considered among the most complex types of cancers where treatment decisions are made by a multidisciplinary team which includes both oncologists and allied health care professionals such as dietitians, dentists, and speech-language pathologists 2 . The initial evaluation of patient tumour is the most critical step for treating the cancer; it provides information that is essential to making decision on optimal treatment plans. The initial assessment includes indirect mirror and direct endoscopy however the advanced assessment is done by imaging and biopsies. Imaging tools (CT, MRI, PET or PET/CT) are important for determining the local infiltration, regional spread, distant metastases or second primary tumours.
The purpose of this guideline is to outline the diagnosis, and staging recommendations for patients with head and neck cancer in Alberta.
# Search Strategy
The National Guideline Clearinghouse and individual cancer agencies' websites were searched for clinical practice guidelines related to Workup and staging for Head and Neck cancer. A systematic literature review was performed by using the Pubmed, EMBASE, and MEDLINE databases. The detailed literature search strategy is outlined in Appendix A, and the evidence tables are available upon request.
# Target Population
The recommendations outlined in this guideline are intended for adults over the age of 18 years with suspected malignancies arising in the mucosal surfaces of the upper aerodigestive tract, including the oral cavity, pharynx, larynx, and paranasal sinuses. Different principles may apply to pediatric patients or patients with thyroid/salivary gland pathology.
# Recommendations
The following recommendations should be applied in the context of the recommendations outlined in the Alberta Health Services guideline, ' 3. Inquire about HPV vaccination history.
# Physical Exam:
4. Physical examination should include: inspection of the neck for lymph nodes, inspection of the facial and scalp skin; inspection of the oral cavity for ulceration of mucosa, swellings, and red or white patches and inspection of the anterior nasal cavities.
# Referral to Specialist:
5. For ulcerative lesions or masses that are initially treated as potential infections, or bleeding nasal lesions that are treated with moisturizing ointments and humidification, establish time limit for followup to ensure early referral for specialty care (i.e. if lesion is not resolved or dramatically improved after 3 weeks of therapy, refer for urgent specialty review).
# II.
Workup at Cancer Centre General 6. Once biopsy proven head and neck cancer identified, newly diagnosed cases should be referred to an appropriate head and neck oncologist (with affiliations to a regional cancer centre) to develop an appropriate treatment plan as soon as possible.
7. All patients should undergo tumour classification and staging prior to treatment. Staging of head and neck cancers are usually based on two classifications, namely cTNM and pTNM described in detail in the 8 th edition of the AJCC Cancer Staging Manual.
8. A complete head and neck examination should be completed and documented (i.e. nose, postnasal space, oral cavity, oropharynx, larynx and hypopharynx, including palpation of neck, oral cavity and tongue base, using endoscopy as appropriate).
9. When feasible, radiological investigations should be performed prior to biopsy to avoid the effect of upstaging from the edema caused by biopsy.
10. When examination under general anesthesia including endoscopy and biopsy is indicated, that procedure should be performed by the surgeon who is responsible for any future procedures
# Imaging
CT Scan: 11. In all cases, CT of the neck with contrast is recommended for locoregional staging. If tumour extent is unclear on CT, and if clarification would alter management, then further evaluation with MRI is recommended.
# MRI Scan:
12. MRI may be particularly helpful for assessing infiltration of surrounding soft tissues (e.g. extrinsic tongue muscles, parapharyngeal space, and masticator space), perineural spread, and intracranial/ intraorbital extension.
# FDG-PET Scan:
13. If nodal status is unclear on CT (+/-MRI), and if clarification would alter management, then further evaluation with FDG-PET is recommended.
14. In a patient with an unknown primary site of tumour after head and neck examination and CT (+/-MRI), FDG-PET should be performed prior to panendoscopy and biopsy so that sites of biopsy will not lead to a false-positive.
15. Chest imaging is recommended for all newly diagnosed head and neck cancers to detect lung metastases and synchronous lung cancers. Both chest CT and PET-CT are superior to chest x-ray in detecting synchronous primary cancers and distant metastases 3 . In cases of N2-N3 disease, patients with a history of smoking and those otherwise at higher risk for second primary tumours and distant metastases (supraglottic and hypopharyngeal cancer), CT of the chest or PET-CT is strongly recommended 3,4 .
16. In cases of stage III-IV disease, FDG-PET should be considered for screening for distant metastases and second primary cancers 3 . Interpretation should consider the relatively high false positive rate with PET-CT and the possible need for confirmatory diagnostic tests 5 .
# Diagnostic Biopsy
17. It is essential that mucosal lesions of the oral cavity, oropharynx, nasopharynx, hypopharynx and larynx that are clinically suspicious for malignancy, primarily squamous cell carcinoma, be appropriately and adequately biopsied in an expedited manner. The approach and method of biopsy are dependent on the site and size of the lesion, the level of suspicion of malignancy, the resources available and experience of the clinician.
18. Oral lesions over 2 cm in maximum dimension, highly suspicious oral lesions and ulcerated or clearly invasive oral lesions should be sampled with an incisional or punch biopsy. The biopsy site should not be in a necrotic or friable area. Generally, a biopsy near the edge of the tumour is ideal. A 4-mm dermatologic punch is a good choice, but scalpel blades or cupped biopsy forceps are acceptable. The biopsy needs to be adequately deep to allow determination of depth of invasion. Excisional biopsies of invasive cancers have a high incidence (62%) of leaving residual cancer requiring repeat excision 6 . This may complicate management but probably does not compromise overall disease control or survival if subsequently appropriately managed. It is suggested that excisional biopsies be reserved for small, superficial lesions that are thought to be benign 7 .
19. Incisional biopsies of areas of oral leukoplakia risk false negative results of up to 24-73% in some series mostly due to sampling errors 8 . Small areas of leukoplakia without worrisome clinical features can be excised under local anesthesia. Excisional biopsies of larger or suspicious areas of leukoplakia should be performed under general anesthesia with adequate margins.
20. All suspicious lesions of the pharynx and supraglottic larynx require biopsies with forceps. Accessible lesions of the soft palate and tonsils may be biopsied transorally without endoscopy. Suspicious lesions of the nasopharynx, oropharynx (base of tongue), hypopharynx and supraglottic larynx may be biopsied using topical anesthesia and endoscopic guidance (rigid or flexible). This requires the appropriate patient positioning, endoscopes, an experienced Otolaryngologist -Head and Neck Surgeon and often a skilled assistant 9 . When these conditions cannot be met then traditional biopsy under general anesthesia via rigid endoscopy is required.
21. Suspected lesions of the tonsils are best sampled by way of an excision of the entire tonsil or tonsils under general anesthesia (diagnostic tonsillectomy). Blind biopsies of the tonsil have a very high false negative rate as cancers often arise deep in the tonsillar crypts and are missed unless they ulcerate through the surface 10 . These tonsillectomies are often done in conjunction with a panendoscopy in the setting of metastatic SCCA in a cervical node without an obvious mucosal lesion on office examination. Larger, ulcerated and clinically obvious cancers of the tonsil may be biopsied with forceps in the clinic.
22. For biopsies of the glottis, in most cases, assessment and biopsy under general anesthesia using rigid laryngoscopes is required (suspension laryngoscopy). Larger lesions may be biopsied without magnification however early T1 cancers, leukoplakia, benign or indeterminate lesions of the glottis usually require adjuvant use of a microscope (suspension microlaryngoscopy). Larger or deeply invasive lesions are sampled with cupped laryngeal forceps. Superficial, benign and indeterminate lesions such as leukoplakia and erythroplasia may be suitable for excisional biopsy using either sharp "cold" instruments or a CO2 laser. Endoscopic biopsies of the glottis may sometimes be performed in clinic in selected patients by sub-specialist laryngologists in a highly specialized setting (regional voice clinic). Sensitivity and negative predictive values for in office biopsy techniques are reported from 60 -78% and 74 -87%, respectively. [11][12][13] . Lesions involving the anterior commissure of the glottis, bilateral vocal cords or vocal process of the vocal cord should not be excised without prior pathological confirmation and multidisciplinary consultation at a regional cancer centre with discussion of alternative non-surgical options. In performing excisional biopsies of suitable glottic lesions, care must be taken to not violate the vocal ligament or anterior commissure regardless of the instrument used.
23. Panendoscopy as a diagnostic tool for the identification of synchronous tumours is inferior in comparison to CT or PET-CT in most cases [14][15][16] . Patients at low risk of a secondary lesion have a very low rate of synchronous tumours identified on routine pandendoscopy and esophagoscopy 14,15,17,18 Cancers of the hypopharynx may be an exception in that the incidence of esophageal second primaries is higher and esophagoscopy compares favourably to CT chest 4 .
24. Panendoscopy is a useful tool in the workup of patients planned for surgery or potential transoral excision of a head and neck cancer to evaluate feasibility and anatomy.
# Occult Primary
25. Fine Needle aspiration cytology of a neck mass or neck node should be performed for occult primaries. When the FNA is non-diagnostic an open biopsy may be required. Special stains including those for lymphoma, EBV and HPV testing should be ordered to help establish the primary tumour.
26. PET-CT imaging is superior to panendoscopy in the identification of an occult primary and should be the initial investigation to establish the primary tumour. The PET-CT results may direct subsequent confirmatory biopsies. If PET-CT fails to detect a primary tumour, the patient should be sent for panendoscopy (EUA) for random directed biopsies of potential primary sites including tonsillectomy.
27. The role of total mucosal resection for identification of unknown primaries is currently unclear.
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9936e811f29919173435d0f067fb5824ec1c42d3
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cma
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To assist in the selection and dosing of antithrombotic agents for patients with peripheral artery disease (PAD), considering the risk of vascular events and bleeding.Symptomatic patients with peripheral artery disease often have widespread atherosclerosis and are at risk of both major cardiovascular events (cardiac related deaths, myocardial infarction and stroke) and limb events (acute limb ischemia and amputation). Antithrombotic therapy (see summary table) for the prevention and treatment of atherothrombotic complications in patients with PAD is a key component of their management, in addition to aggressive control of risk factors such as dyslipidemia, hypertension, and diabetes, and through the promotion of smoking cessation and regular exercise. While atherosclerosis is an integral part of the pathophysiology of lower extremity PAD, a large proportion of severe vascular occlusions are now known to be caused by thrombotic occlusive disease in the absence of significant atherosclerotic plaque. PAD is therefore considered a disease of 'atheroembolism', and often requires antiplatelet therapy, with or without anticoagulant, for optimal treatment.# INDICATIONS FOR ANTITHROMBOTIC THERAPY IN PAD:
Symptomatic chronic PAD Symptomatic patients with chronic PAD, as manifested by intermittent claudication with objective evidence of limb atherosclerosis or a previous vascular intervention (including prior bypass surgery, peripheral angioplasty or prior vascular amputation of the lower extremity), benefit from antithrombotic therapy. Single antiplatelet therapy (ASA or clopidogrel) lowers the risk for major adverse cardiovascular events (MACE) and has long been the standard of care of patients with PAD. In most studies, the dose of ASA varies between 80 and 160 mg. For patients allergic or intolerant to ASA, the use of clopidogrel is recommended. The CAPRIE study suggests that clopidogrel may be marginally better than ASA in reducing cardiovascular events in the subgroup of patients with PAD. Ticagrelor has no benefit over clopidogrel in preventing MACE or major adverse limb events (MALE), such as hospitalization for acute limb ischemia, and is discontinued at a higher frequency due to higher rates of side effects.
In the CHARISMA study, adding clopidogrel 75 mg to ASA 75-162 mg did not result in a significant difference in MACE or major bleeding compared to the use of ASA alone in those at high risk of or with established atherosclerosis. While the combination of ASA and clopidogrel led to a 37% lower rate of myocardial infarction in the subgroup with established PAD, there was no significant effect on the risk of other vascular or limb events or of major bleeding. More recently, a subanalysis of the PEGASUS trial reported that the combination of ticagrelor with ASA decreased both MACE and MALE compared with ASA alone in post-MI patients with concomitant PAD, albeit at the cost of excess bleeding; results specific to PAD patients are not definitive due to relatively small patient numbers. In the TRA 2P-TIMI trial, the addition of Vorapaxar, a platelet thrombin receptor antagonist, to a second antiplatelet therapy (primarily ASA) resulted in a reduced rate of acute limb revascularization and amputations in the subgroup of patients with PAD. However, there was no difference in the rates of cardiovascular death, stroke and myocardial infarction, and this combination was associated with an increased risk of severe bleeding events and intracranial hemorrhages. Overall, while dual antiplatelet therapy (DAPT) suggests benefit over single antiplatelet therapy in reducing MACE and MALE, the benefit is marginal and is associated with increased bleeding complications. Therefore, while DAPT can be considered in PAD patients with acute coronary syndrome or post-coronary percutaneous interventions, it is uncommonly utilized in PAD patients in the absence of recent coronary events or peripheral revascularization.
The WAVE trial showed that the addition of warfarin (INR 2-3) to antiplatelet therapy does not reduce major adverse cardiovascular events or severe limb ischemia patients in with chronic PAD and is associated with a 3.4-fold increase in life-threatening bleeding, including increased fatal and intracranial bleeding. Full dose anticoagulation should therefore not be added to antiplatelet therapy for the purpose of decreasing arterial ischemic events. There have been no trials evaluating MACE, MALE, or major bleeding outcomes with the combination of full dose direct oral anticoagulants (DOACs) and ASA in patients with chronic PAD. In patients with PAD who are on oral anticoagulant therapy with warfarin or a full dose DOAC for another indication (i.e. atrial fibrillation), the addition of an antiplatelet agent is usually not required. While not specifically evaluated in the PAD literature, robust evidence for patients with stable coronary artery disease requiring full dose anticoagulation shows demonstrable harm with the addition of single antiplatelet therapy. Therefore, we caution against the addition of an antiplatelet agent in fully anticoagulated patients with PAD unless it is short term or there has been a recent (<1 year) coronary or peripheral event (with or without revascularization).
In the COMPASS Trial, the combination of low dose rivaroxaban (2.5 mg bid) and ASA as compared to ASA alone reduced both MACE and MALE in patients with chronic stable PAD, conferring a 28% relative risk reduction in cardiovascular death, stroke and myocardial infarction as well as a 46% relative risk reduction in severe limb ischemia leading to an intervention (including major limb amputations). While a significant increase in major bleeding was observed, there was no increase in fatal or symptomatic bleeding into a critical organ (e.g. intracranial hemorrhage). Most major bleeding events were gastrointestinal. Of note, patients with a high risk of bleeding, recent stroke within 1 month, a history of hemorrhagic stroke, or estimated glomerular filtration rate of less than 15 mL/min, and severe heart failure (NYHA III/IV or EF<30%) were excluded from this study. While rivaroxaban alone at 5 mg bid outperformed ASA alone in preventing MALE, it did not reduce MACE and was similarly associated with increased major bleeding, including intracranial hemorrhage.
Patients at particularly high risk of ischemic vascular events derive the greatest benefit with combination low-dose rivaroxaban and aspirin. PAD patients with a high-risk limb presentation (HRLP), such as previous revascularization, previous amputation, or Fontaine III/IV status, as well as patients with high-risk comorbidities (HRCM), such as polyvascular disease, diabetes, renal insufficiency (eGFR <60) or heart failure, seem to have the highest risk of vascular events when followed over time. Treatment with rivaroxaban 2.5mg BID in addition to aspirin, as compared to aspirin alone, yields an absolute risk reduction in MACE or MALE including major amputation of 4.6% for patients with HRLP, 4.4% for patients with HRCM, and 5.2% for patients with both HRLP and HRCM. This is in contrast to a 1.0% absolute risk reduction for patients with neither HRLP or HRCM. Absolute risk increase of major bleeding was <1.0% for all groups. Therefore patients with these HRLP or HRCM should be considered for rivaroxaban 2.5mg BID in addition to aspirin.
|
To assist in the selection and dosing of antithrombotic agents for patients with peripheral artery disease (PAD), considering the risk of vascular events and bleeding.Symptomatic patients with peripheral artery disease often have widespread atherosclerosis and are at risk of both major cardiovascular events (cardiac related deaths, myocardial infarction [MI] and stroke) and limb events (acute limb ischemia and amputation). Antithrombotic therapy (see summary table) for the prevention and treatment of atherothrombotic complications in patients with PAD is a key component of their management, in addition to aggressive control of risk factors such as dyslipidemia, hypertension, and diabetes, and through the promotion of smoking cessation and regular exercise. While atherosclerosis is an integral part of the pathophysiology of lower extremity PAD, a large proportion of severe vascular occlusions are now known to be caused by thrombotic occlusive disease in the absence of significant atherosclerotic plaque. PAD is therefore considered a disease of 'atheroembolism', and often requires antiplatelet therapy, with or without anticoagulant, for optimal treatment.# INDICATIONS FOR ANTITHROMBOTIC THERAPY IN PAD:
Symptomatic chronic PAD Symptomatic patients with chronic PAD, as manifested by intermittent claudication with objective evidence of limb atherosclerosis or a previous vascular intervention (including prior bypass surgery, peripheral angioplasty or prior vascular amputation of the lower extremity), benefit from antithrombotic therapy. Single antiplatelet therapy (ASA or clopidogrel) lowers the risk for major adverse cardiovascular events (MACE) and has long been the standard of care of patients with PAD. In most studies, the dose of ASA varies between 80 and 160 mg. For patients allergic or intolerant to ASA, the use of clopidogrel is recommended. The CAPRIE study suggests that clopidogrel may be marginally better than ASA in reducing cardiovascular events in the subgroup of patients with PAD. Ticagrelor has no benefit over clopidogrel in preventing MACE or major adverse limb events (MALE), such as hospitalization for acute limb ischemia, and is discontinued at a higher frequency due to higher rates of side effects.
In the CHARISMA study, adding clopidogrel 75 mg to ASA 75-162 mg did not result in a significant difference in MACE or major bleeding compared to the use of ASA alone in those at high risk of or with established atherosclerosis. While the combination of ASA and clopidogrel led to a 37% lower rate of myocardial infarction in the subgroup with established PAD, there was no significant effect on the risk of other vascular or limb events or of major bleeding. More recently, a subanalysis of the PEGASUS trial reported that the combination of ticagrelor with ASA decreased both MACE and MALE compared with ASA alone in post-MI patients with concomitant PAD, albeit at the cost of excess bleeding; results specific to PAD patients are not definitive due to relatively small patient numbers. In the TRA 2P-TIMI trial, the addition of Vorapaxar, a platelet thrombin receptor antagonist, to a second antiplatelet therapy (primarily ASA) resulted in a reduced rate of acute limb revascularization and amputations in the subgroup of patients with PAD. However, there was no difference in the rates of cardiovascular death, stroke and myocardial infarction, and this combination was associated with an increased risk of severe bleeding events and intracranial hemorrhages. Overall, while dual antiplatelet therapy (DAPT) suggests benefit over single antiplatelet therapy in reducing MACE and MALE, the benefit is marginal and is associated with increased bleeding complications. Therefore, while DAPT can be considered in PAD patients with acute coronary syndrome or post-coronary percutaneous interventions, it is uncommonly utilized in PAD patients in the absence of recent coronary events or peripheral revascularization.
The WAVE trial showed that the addition of warfarin (INR 2-3) to antiplatelet therapy does not reduce major adverse cardiovascular events or severe limb ischemia patients in with chronic PAD and is associated with a 3.4-fold increase in life-threatening bleeding, including increased fatal and intracranial bleeding. Full dose anticoagulation should therefore not be added to antiplatelet therapy for the purpose of decreasing arterial ischemic events. There have been no trials evaluating MACE, MALE, or major bleeding outcomes with the combination of full dose direct oral anticoagulants (DOACs) and ASA in patients with chronic PAD. In patients with PAD who are on oral anticoagulant therapy with warfarin or a full dose DOAC for another indication (i.e. atrial fibrillation), the addition of an antiplatelet agent is usually not required. While not specifically evaluated in the PAD literature, robust evidence for patients with stable coronary artery disease requiring full dose anticoagulation shows demonstrable harm with the addition of single antiplatelet therapy. Therefore, we caution against the addition of an antiplatelet agent in fully anticoagulated patients with PAD unless it is short term or there has been a recent (<1 year) coronary or peripheral event (with or without revascularization).
In the COMPASS Trial, the combination of low dose rivaroxaban (2.5 mg bid) and ASA as compared to ASA alone reduced both MACE and MALE in patients with chronic stable PAD, conferring a 28% relative risk reduction in cardiovascular death, stroke and myocardial infarction as well as a 46% relative risk reduction in severe limb ischemia leading to an intervention (including major limb amputations). While a significant increase in major bleeding was observed, there was no increase in fatal or symptomatic bleeding into a critical organ (e.g. intracranial hemorrhage). Most major bleeding events were gastrointestinal. Of note, patients with a high risk of bleeding, recent stroke within 1 month, a history of hemorrhagic stroke, or estimated glomerular filtration rate of less than 15 mL/min, and severe heart failure (NYHA III/IV or EF<30%) were excluded from this study. While rivaroxaban alone at 5 mg bid outperformed ASA alone in preventing MALE, it did not reduce MACE and was similarly associated with increased major bleeding, including intracranial hemorrhage.
Patients at particularly high risk of ischemic vascular events derive the greatest benefit with combination low-dose rivaroxaban and aspirin. PAD patients with a high-risk limb presentation (HRLP), such as previous revascularization, previous amputation, or Fontaine III/IV status, as well as patients with high-risk comorbidities (HRCM), such as polyvascular disease, diabetes, renal insufficiency (eGFR <60) or heart failure, seem to have the highest risk of vascular events when followed over time. Treatment with rivaroxaban 2.5mg BID in addition to aspirin, as compared to aspirin alone, yields an absolute risk reduction in MACE or MALE including major amputation of 4.6% for patients with HRLP, 4.4% for patients with HRCM, and 5.2% for patients with both HRLP and HRCM. This is in contrast to a 1.0% absolute risk reduction for patients with neither HRLP or HRCM. Absolute risk increase of major bleeding was <1.0% for all groups. Therefore patients with these HRLP or HRCM should be considered for rivaroxaban 2.5mg BID in addition to aspirin.
Acknowledging this, Health Canada labelling has been recently updated for rivaroxaban 2.5mg BID in combination with ASA for the treatment of patients with symptomatic PAD at demonstrated high risk of MALE or MACE, in addition to the initial indication for CAD with or without PAD.
# Asymptomatic PAD:
There is no evidence that supports the use of antiplatelet agents in patients with lone asymptomatic PAD or a reduced ABI without symptoms. This absence of a beneficial effect is akin to the role of ASA in primary prevention where the reduced risk of cardiovascular events is counterbalanced by an increased risk of bleeding.
# Peripheral limb revascularization:
For patients who undergo endovascular or open revascularization, rivaroxaban 2.5mg BID in combination with aspirin should be utilized unless there is unduly high bleeding risk. Clopidogrel can be added in addition to low dose rivaroxaban and aspirin for those who undergo high-risk endovascular stenting. If clopidogrel is added to low dose rivaroxaban and aspirin, it should be continued for a maximum of 30 days unless other indications (i.e. coronary revascularization) arise.
A recently published large, randomized trial, VOYAGER PAD, randomized 6564 adults who underwent a successful infrainguinal endovascular or surgical revascularization procedure for symptomatic PAD to either ASA and low dose rivaroxaban (2.5mg PO bid) or ASA alone. At 3 years, patients treated with ASA and low dose rivaroxaban had a 13% relative risk reduction in the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes when compared to ASA alone. Of note, incidence of all individual components of the primary outcome as well as unplanned index limb revascularization for recurrent ischemia were lowered on ASA and low-dose rivaroxaban, but all-cause mortality was unchanged. There was a nonsignificant 0.78% absolute risk increase in TIMI major bleeding and a significant 1.22% absolute risk increase of ISTH major bleeding on ASA and rivaroxaban. As with COMPASS, there was no excess in severe bleeding, including fatal or intracranial hemorrhage. There was no significant heterogeneity in primary efficacy or bleeding outcomes based on open or endovascular revascularization. Within VOYAGER PAD, the addition of clopidogrel did not affect the efficacy of combination ASA and low-dose rivaroxaban in preventing vascular events compared to ASA alone. Use of clopidogrel for greater than 30 days was found to confer a numerically increased bleeding risk compared to shorter courses of clopidogrel. It is pertinent to note that most of the procedures within VOYAGER PAD were endovascular (65%) and were performed for claudication symptoms (77%), with a smaller proportion for chronic limb ischemia (23%). Patients with acute limb ischemia were not well represented.
If ineligible for rivaroxaban (i.e. drug interaction) following endovascular revascularization, dual antiplatelet therapy with aspirin and clopidogrel should be utilized for 1 to 3 months. If ineligible for rivaroxaban following open revascularization, a single antiplatelet agent or full dose oral anticoagulation can be considered. While the overall trial showed no benefit of high intensity warfarin when compared with ASA therapy, a subgroup analysis of the DUTCH BOA trial suggests that oral anticoagulation is more effective in preventing infra-inguinal vein-graft occlusion (but with a significant excess of life-threatening bleeding) while ASA therapy is more effective in preventing nonvenous graft occlusion. Addition of clopidogrel or ticagrelor to ASA has not shown clear benefit in optimizing limb patency, but studies addressing DAPT in this setting are small. It is not clear whether complicated distal bypasses or bypasses with synthetic grafts might benefit from temporary DAPT.
Patients presenting with acute limb ischemia should be treated with heparin in an emergent manner; thereafter, there is clinical uncertainty as to the optimal acute term antiplatelet +/-anticoagulant regimen to use. A recent survey of Canadian vascular surgeons demonstrated that ASA combined with full-dose anticoagulation is the most commonly chosen post-operative antithrombotic regimen when concerned for high risk of postoperative graft/stent re-thrombosis. Most acknowledged that clinical equipoise on the topic persists. Patients with acute limb ischemia were not well represented within the VOYAGER PAD trial, though one can consider rivaroxaban 2.5mg BID in combination with aspirin as a minimum in patients requiring urgent/emergent revascularization.
# DOSING:
• The standard daily dose of ASA is 81 mg and the standard dose of clopidogrel is 75 mg.
• The standard dose of ticagrelor is 60 or 90 mg bid.
• Low-dose rivaroxaban dosing is 2.5 mg bid, when used together with low dose aspirin (approved by Health Canada).
# ADVERSE EFFECTS:
The main adverse effect of ASA, seen more at higher doses, is bleeding. While most bleeding occurs within the gastrointestinal tract, there is an increased risk of intracranial bleeding as well. The riskbenefit ratio is generally acceptable in patients with symptomatic PAD. The main adverse effect of
# Indications
# Antithrombotic options Comments
Asymptomatic PAD Lack of evidence for a proven net-benefit of antiplatelet or anticoagulant therapy.
Manage cardiovascular risk factors. Assess for other clinical indications for antithrombotic therapy (e.g. CAD). Chronic Symptomatic PAD Antiplatelet monotherapy (aspirin or clopidogrel) or dual pathway inhibition with vascular dose rivaroxaban + ASA DAPT may be indicated in patients with acute coronary syndrome or coronary stent implantation.
# Elective revascularization
Endovascular ± Stents DAPT for 1-3 months in those undergoing stent implantation, thereafter dual pathway inhibition with vascular dose rivaroxaban + ASA can be considered.
The VOYAGER PAD trial showed lower rates of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, death from cardiovascular causes and unplanned index limb revascularization for recurrent ischemia with ASA and low dose rivaroxaban when compared to ASA alone. Adding clopidogrel to this regimen does not seem to further improve outcomes.
# Surgical Revascularization
Aspirin or clopidogrel or dual pathway inhibition with vascular dose rivaroxaban + ASA. In those with high risk bypass, warfarin alone or DAPT may be considered.
# Emergent Revascularization Acute Limb Ischemia or Critical Limb Ischemia
Optimal antithrombotic management is unclear, and more studies are needed.
Options include either single or dual antiplatelet therapy, full dose anticoagulation or dual pathway inhibition with vascular dose rivaroxaban + ASA In those with high risk of adverse limb event, intensifying antithrombotic therapy (e.g., full dose anticoagulation with warfarin or DOACs) in the subacute period (1-3 months) could be considered in those at low risk of bleeding. ASA, acetylsalicylic acid; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DOACs, direct oral anticoagulants; PAD: peripheral artery disease clopidogrel is also bleeding, although the rate of severe gastrointestinal bleeding is less than that with ASA. While the combination of ASA and low dose rivaroxaban increases the risk of major bleeding (mostly gastrointestinal), there is no difference in the risk of critical organ (i.e., intracranial) or fatal bleeds when compared to ASA alone. The combination of full dose anticoagulant and antiplatelet confers further increased bleeding risk.
# PERIPROCEDURAL MANAGEMENT:
There is little data on the thrombotic risk in patients with PAD who have antiplatelet therapy interrupted for a surgical or other invasive procedure. The POISE-2 study, which randomized patients already taking ASA and undergoing non-cardiac surgery to either continuing or discontinuing their antiplatelet therapy, reported that continuation does not decrease perioperative MACE but comes at a price of increased major bleeding. A subgroup analysis of patients in POISE-2 undergoing vascular surgery found that withdrawal of ASA therapy did not increase vascular occlusive complications. It is, therefore, reasonable to continue ASA if the procedure is associated with a low risk of bleeding and to stop ASA before the procedure if the bleeding risk of the procedure is anticipated to be high. For patients on clopidogrel for PAD, clopidogrel should be discontinued 5 -7 days before an invasive procedure. After a procedure, the highest risk of major life-threatening bleeding is 2 days post procedure. A significant reduction in the risk of bleeding occurs by post-procedure day 8 and resumption of antiplatelet therapy is often indicated at this time. However, in high risk patients, physicians may elect to resume antiplatelet therapy before day 8 after weighing the risks of a thrombotic event against the risk of major bleeding.
There is strikingly little data on the periprocedural management of low-dose rivaroxaban at 2.5mg BID. While no clinical investigations have been specifically performed to address this question, discontinuing low-dose rivaroxaban 12-24 hours before most surgeries is likely sufficient based on pharmacokinetic data.
Full dose anticoagulation should be managed according to thrombotic risk, surgical bleeding risk, and renal function, as outlined in the Thrombosis Canada Perioperative Management Clinical Guides.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES
# Date of Version: 17September2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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- Mental health care is an essential medical service that must be maintained during any pandemic. 2. Older adults living in LTC facilities have the right to mental health, medical care and social services, regardless of their age, the presence of dementia, or a diagnosis of other mental health problems and illnesses. 3. LTC facilities must be provided with the technology and resources necessary for provision of essential virtual medical services and for the maintenance of family and social connections when in person visits are restricted. 4. Infection control measures intended to reduce the spread of infectious diseases must also balance the impact of these measures on the quality of life and dignity of LTC residents. 5. Supporting the mental health of LTC staff is critical to effectively managing pandemics in LTC.
# INTRODUCTION:
One of the many tragedies of the COVID-19 pandemic has been the significant mortality and psychosocial consequences disproportionately experienced by older persons, particularly those living in long-term care (LTC) facilities. Throughout the pandemic, Canada has consistently had one of the highest global proportion of all COVID-19 deaths occurring among LTC residents. (1)(2)(3) While many recommendations related to improving care for LTC residents during COVID-19 have been created both nationally (4)(5)(6)(7)(8) and internationally (9,10) , none have focussed on the mental health implications associated with COVID-19 in LTC. Mental health disorders including dementia, depression, and anxiety (11,12) are more prevalent in LTC settings than among older adults living in the community. Despite this high need for mental health supports among LTC residents, their access to mental health care was poor even prior to the pandemic (13,14) .
Several factors have contributed to a potential worsening of the mental health of LTC residents during COVID-19. Ageism (15) , predating COVID-19, is contributing to the adverse mental health impacts related to COVID-19 in LTC in Canada. Older adults with mental illness and dementia are particularly susceptible to negative consequences of ageism (16,17) . The COVID-19 pandemic has identified long-standing consequences of ageism in LTC due in part to measures implemented to manage COVID-19 in this setting (9,18) . Furthermore, longstanding staff shortages, limited staff education about dementia and mental health, and poor access to medical and psychiatric specialized services in LTC have all contributed to the current crisis in LTC (19) . While this serious problem has received media attention (20) , these concerns have not been reflected adequately in recommendations meant to address and mitigate the impact of COVID-19 in LTC. Already concerns have arisen that quality of care in LTC facilities has deteriorated further with reports of increased use of antipsychotics and restraints to managed increased occurrence of behavioural symptoms of people with dementia in LTC or to prevent LTC residents from wandering within LTC facilities to potentially prevent the spread of COVID-19 (21) . This position paper highlights the mental health care needs of older persons living in LTC settings during COVID-19 and other similar pandemics.
# METHODS:
The Canadian Academy of Geriatric Psychiatry (CAGP) and Canadian Coalition for Seniors Mental Health (CCMSH) established a working group to develop a position statement on mental health care for older adults in long-term care settings. A call for expressions of interest to participate in the working group was distributed to current CAGP members. A working group planning committee initially met in July, 2020 to identify the scope and anticipated outputs for this project. The final working group consists of 14 individuals (Appendix A) representing geriatric psychiatrists and geriatric psychiatry trainees from different provinces, care settings and career stages. The working group met by videoconference a total of 4 times to prepare the position statement. The working group drafted position statements and working group members contributed to reviewing the evidence related to each position statement. The final position statements and accompanying evidence were arrived at by consensus.
# POSITION STATEMENTS:
Statement 1: Mental health care in LTC settings is an essential service.
While access to medical services may need to be adapted during COVID-19 and other outbreaks in keeping with public health requirements, mental health care in LTC settings is an essential service. This includes access to outpatient, outreach, inpatient and specialized mental health treatments such as electroconvulsive therapy (ECT), within the limits of necessary infection control practices.
During the initial outbreak of COVID-19 in Canada, preparations for an anticipated influx of COVID-19 patients into acute care led to the cancellation of many medical services and surgical procedures that were deemed non-essential at the time. In addition, many hospital-based outpatient programs and procedures such as ECT were suspended or severely curtailed to prevent introduction of the virus (22) . Medical services provided directly in LTC were also reduced to those deemed essential. As a result, many individuals with mental health conditions in LTC settings had mental health assessments or treatments delayed or cancelled during the first six months of the COVID pandemic in Canada.
While mental health assessments or treatments can be delayed for some individuals on a shortterm basis due to necessary infection control practices, many individuals with mental problems and illnesses in LTC facilities do require urgent access to ongoing, consistent and reliable mental health services. These services may include outpatient visits, outreach services, inpatient admission, and the ability to initiate or continue hospital-based mental health treatments such as ECT (23) . COVID-19 has disrupted mental health services in most countries (24) . While COVIDrelated restrictions to health care provider visits have disrupted mental health services in most LTC facilities, the impact of COVID-19 on access to mental health services in LTCFs is currently unknown. Therefore, health systems need to provide the necessary safeguards and processes to allow ongoing mental health care for older adults in LTC while at the same time protecting long-term care residents and the community from the very real risks associated with COVID-19 infections.
# Statement 2: Factors such as age, the presence of dementia, or a diagnosis of mental health problems or illnesses are not reasons to exclude individuals from having access to resources such as emergency departments or inpatient hospitalization.
The COVID-19 pandemic has challenged healthcare organizations to prepare for increased demands on acute care. Crisis triage protocols have been developed, but often use survivability to determine allocation of health care resources (25) . This approach may stigmatize older adults, and those with chronic illness or disability (26) . Older adults who contract COVID-19 have higher mortality rates, especially in the presence of chronic medical conditions (26) . Long-term care (LTC) residents have a high burden of such illnesses and the presence of frailty and dementia further compounds their vulnerability (27,28) . On admission to LTC, advanced care planning and goals of care discussions should occur between individuals and/or their substitute decision makers (SDMs) and health-care teams. Furthermore, these discussions should be routinely revisited (29) . Individuals and/or SDMs should be provided the best information to make informed choices about whether or not to remain in the LTC setting or be transferred to an acute care setting for treatment and about the level of care that is to be received. Individuals and their families must be supported through this process and be able to express their wishes, while also being made aware of the significantly lowered survival rates among older adults with a high burden of medical illness and frailty who become infected with COVID-19. The presence or absence of cognitive impairment should not in itself preclude access to treatment but should factor into decisions about goals of care. It is essential that stigma, presumed decreased quality of life, and ageism do not influence these decisions.
# Statement 3: Restrictions on in-person visits to LTC must consider the potential effects of these restrictions on the mental health, quality of life, and dignity of LTC residents and their families.
While some restrictions on LTC visits will be required during infectious disease outbreaks, the least restrictive approaches to visitation permitted during pandemics should be made available to all LTC residents. Restrictions intended to prevent the spread of COVID-19 have significant impacts on the social networks of individuals and plans to minimize potential negative impacts of social isolation need to be considered in conjunction with any restrictions to visits in LTC.
Plans to minimize the negative impacts of isolation on these individuals and their families should be in place, including adherence to compassionate practices for ensuring social connection and care (30) . This should include offering at least weekly contact with a family member through virtual means or a safe in-person visit with appropriate personal protective equipment. Ideally, patients would be able to receive visits in accordance with their needs and not be limited to an arbitrary number. Most effective non-pharmacological interventions for dementia in LTC facilities, including one-to-one visits provided by family members or other individuals, require 2 to 3 interactions per week for sustained benefits on mood and behaviors to be observed between interactions (31) . Specific plans for all infectious outbreaks in LTC need to include not only infection prevention measures, but also a plan to maintain nursing care, social contact, and activities that support the mental health of the residents and prevention of unnecessary physical and cognitive decline. While these measures are often implemented during infectious disease outbreak in LTC facilities, during COVID-19 these restrictions occurred for prolonged periods of time and had significant impacts for the residents of LTC. These included loneliness, anxiety, feelings of insecurity, suicidal thoughts as well as physical and cognitive decline (13) .
Caregivers have also experienced significant stress when they could no longer be physically present to support their family members in LTC facilities. This was compounded in many situations by a lack of information and communication from LTC facilities about their loved ones. LTC facilities should implement processes to provide LTC residents, their families and caregivers, and staff with timely information related to the COVID-19. LTC facilities may consider providing access to electronic charts or secure communications for family members. All LTC facilities should have LTC staff who are key contacts and can provide timely information to LTC residents, their families and caregivers.
# Statement 4: Appropriate communication technology and human resources must be available to allow communication between LTC residents and individuals located outside a resident's LTC facility.
Access to virtual communication technology (e.g. phone, tablet, or computer-based videoconferencing) has been identified as critical to ensuring that LTC residents are able to communicate with families, friends, and health service providers who are unable to visit an individual in person at a LTC (32,33) . Utilization of telemedicine (services delivered by physicians) and telehealth services (delivered by other health care providers) have been identified as key to maintaining access to health care during COVID-19 (34) to and reducing disease transmission (35) . Older adults in LTC facilities may suffer the effects of "double burden of exclusion" by having restrictions to in-person visits and limited access to technology needed for other methods of communication (36) . Unfortunately, many LTC facilities have limited access to the technology, expertise and human resources necessary to support this form of communication at all or as frequently as would be optimal for an individual's needs. (33) Each LTC facility should have the infrastructure to support virtual visits with family and health care professionals. At a minimum, this should include high-speed internet connection, and the provision of portable devices (e.g. tablets or laptops) for LTC residents who does not have access to their own personal device. All LTC staff should have basic knowledge of facilitating visits with families using commonly used platforms. The unique needs of older adults with dementia, mental illnesses, and co-morbid sensory impairments must be accommodated in these visits. Each LTC facility should have two or more staff per resident care unit trained in facilitating secure and private virtual health care visits that follow required privacy regulations. Interprofessional teams based outside of LTC facilities should also receive training in conducting virtual assessments and be provided with the virtual technology necessary to complete assessments.
# Statement 5: Public health measures limiting access to in-person visits, restrictions of movement within LTC facilities, and cessation of LTC social programming must consider the risks and benefits to specific individuals in LTCs.
LTC facilities did not allow any visitors in the early stages of the COVID-19 pandemic, which resulted in an overwhelming response from LTC residents, their families and caregivers about the negative impact of these restrictions (37) . Early studies examining the reintroduction of visitors in LTC through carefully implemented policies, have demonstrated success and show that these visits have not led to a significant increase in the rates of COVID-19 infection (38) . There are emerging recommendations on the re-integration of family caregivers into LTC, which require rapid dissemination to adopt evidence-based visitation policies that provide a better balance of infection control measures with quality of life (39) . Failure to utilize family presence in LTC facilities to support older adults exacerbates the current gaps in the LTC workforce. It is estimated that approximately 750,000 Canadians provide care to a family member in a LTC setting with over 20% of them providing over 10 hours per week of care including personal care (40) . LTC residents have discussed their experiences over the last six months with some describing their experience as "devastating, emotional, terror awakened, muzzled, trapped, broken-spirited and boredom" (37) . Research into the impact of these restrictions in LTC facilities should include direct interviews with residents and family caregivers (37) .
As new policies for the integration of family caregivers at LTC facilities are developed, they should follow a person-centered approach. Processes must be in place for exceptional circumstances where family caregivers are required as part of an individual's mental health care plan. Geriatric psychiatrists and LTC mental health service providers should be consulted in the development of these policies and be included in the review of such exceptional circumstances. While mental health conditions are common in LTC settings (11) , access to mental health and psychiatric services in LTC is limited (14) . Canada has shortage of geriatric psychiatrists which is unlikely to improve substantially in coming years (41) . Research has suggested that COVID-19 has resulted in an increase in behavioural symptoms of dementia in LTC resulting in an even greater need for mental health care (42,43) . It is therefore important that all LTC facilities have adequately trained staff and sufficient resources to assess and treat common mental health conditions, during COVID-19 and similar periods of infectious disease outbreaks when access to mental health resources is even more limited.
Staff training approaches are among the best supported interventions for addressing behavioural symptoms of dementia in LTC settings (31) . Guidelines recommend that all LTC facilities provide staff with training in the assessment and management of common mental health disorders (44,45) such as delirium and depression (44) , management of neuropsychiatric symptoms, and responding to emergent mental health crises (46) . These training programs require access to trainers (often associated with geriatric mental health programs) as well as resources to allow staff to attend these courses as part of their paid employment while ensuring an adequate number of staff are available to support the ongoing needs of LTC residents. Some LTC homes may have mental health champions or embedded mental health resources provided by either the LTC facility or through partnerships with provincial mental health programs. Mental health care provided by LTC staff can be supplemented by regional outreach programs or telemedicine (47) . Statement 7: Governments, LTC, and mental health service providers must ensure that staff working in LTC during the COVID-19 pandemic have adequate access to mental health supports and programs to support staff wellness.
Staff working in LTC settings were experiencing significant stress and devaluation due to chronic understaffing of LTC facilities prior to COVID-19. COVID-19 has contributed additional stressors related to a worsening of staffing shortages, initial shortages of PPE and ongoing risks of staff contracting COVID-19 and the high death rates in COVID-19 affected facilities (48,49) . Each individual may respond to the new stressors associated with COVID-19 differently (50) . To mitigate these negative sequelae, LTC facilities must promote and maintain the mental health and wellbeing of frontline staff by ensuring measures are taken to adequately support staff and ensure their safety and recognize the value of their work (49) . This includes access to appropriate personal protective equipment, and educational programs to ensure its proper use (5) . Psychoeducation on caregiver burnout, stress management, anxiety and depressive disorders should be incorporated in job training at long-term care facilities, and regularly reviewed to promote staff resilience. Sick leave and employee assistance programs should be made available to staff working in facilities impacted by COVID-19. Other recommendations related to supporting LTC staff have included clear guidance from LTC facility leadership, optimizing human health resource planning, and adoption of clinical practices to minimize the impact of COVID-19 in LTC (49) . Statement 8: Measures of mental health and quality of life in LTC facilities must be systematically evaluated during COVID-19, and strategies implemented to understand and remediate adverse mental health outcomes when they are identified.
Mental health and quality of life must be systematically evaluated to assess the effects of the COVID-19 pandemic on LTC residents. This monitoring will help identify early signs of worsening of mental health symptoms within individual LTC residents and facilities and identify individuals and facilities which may require additional supports or resources, similar to how LTC with COVID-19 outbreaks are currently triaged for additional supports based on their needs.
While mortality and infection rates may reflect the most important measures for monitoring of the impact of COVID-19 in other settings, they capture only part of the effects of COVID-19 in LTC. One of the most dramatic effects of COVID-19 in LTCs has been the increase in social isolation of residents due to restrictions on visitors and residents' ability to leave their care home. Social isolation has adverse mental health outcomes such as worsening of depression, cognitive decline and behavioural symptoms of dementia. (51) Measurement is the basis of monitoring quality of care, overall health status, and identifies opportunities for improving quality of care amidst the COVID-19 pandemic. Monitoring quality of life, functioning, and mental health can be done without creating new or onerous data collection. For example, the Minimum Dataset Resident Assessment Instrument (MDS-RAI) is a routine measure used in many LTC facilities, which includes quality indicators measuring depression (52) , behavioural symptoms (53) , and cognition (54) . Incorporating these and other relevant measures of long-term care resident health status as part of COVID-19 related outcomes would provide a more accurate picture of the effects of COVID-19 in long term care.
# CONCLUSION
All Canadians have been affected by the COVID-19 pandemic and none more so than LTC residents. As LTC residents, their families and those caring for them continue to be affected by the COVID-19 epidemic we anticipate that the mental health of LTC residents, their families and LTC staff will continue to be significantly impacted. Our position statements provide actionable strategies and priorities to minimize the impact of COVID-19 on the mental health of individuals in LTC. Collectively we can learn from our actions in the past and make plans for a future that better meet the mental needs of individuals in LTC during COVID-19.
Appendix A
|
#
1. Mental health care is an essential medical service that must be maintained during any pandemic. 2. Older adults living in LTC facilities have the right to mental health, medical care and social services, regardless of their age, the presence of dementia, or a diagnosis of other mental health problems and illnesses. 3. LTC facilities must be provided with the technology and resources necessary for provision of essential virtual medical services and for the maintenance of family and social connections when in person visits are restricted. 4. Infection control measures intended to reduce the spread of infectious diseases must also balance the impact of these measures on the quality of life and dignity of LTC residents. 5. Supporting the mental health of LTC staff is critical to effectively managing pandemics in LTC.
# INTRODUCTION:
One of the many tragedies of the COVID-19 pandemic has been the significant mortality and psychosocial consequences disproportionately experienced by older persons, particularly those living in long-term care (LTC) facilities. Throughout the pandemic, Canada has consistently had one of the highest global proportion of all COVID-19 deaths occurring among LTC residents. (1)(2)(3) While many recommendations related to improving care for LTC residents during COVID-19 have been created both nationally (4)(5)(6)(7)(8) and internationally (9,10) , none have focussed on the mental health implications associated with COVID-19 in LTC. Mental health disorders including dementia, depression, and anxiety (11,12) are more prevalent in LTC settings than among older adults living in the community. Despite this high need for mental health supports among LTC residents, their access to mental health care was poor even prior to the pandemic (13,14) .
Several factors have contributed to a potential worsening of the mental health of LTC residents during COVID-19. Ageism (15) , predating COVID-19, is contributing to the adverse mental health impacts related to COVID-19 in LTC in Canada. Older adults with mental illness and dementia are particularly susceptible to negative consequences of ageism (16,17) . The COVID-19 pandemic has identified long-standing consequences of ageism in LTC due in part to measures implemented to manage COVID-19 in this setting (9,18) . Furthermore, longstanding staff shortages, limited staff education about dementia and mental health, and poor access to medical and psychiatric specialized services in LTC have all contributed to the current crisis in LTC (19) . While this serious problem has received media attention (20) , these concerns have not been reflected adequately in recommendations meant to address and mitigate the impact of COVID-19 in LTC. Already concerns have arisen that quality of care in LTC facilities has deteriorated further with reports of increased use of antipsychotics and restraints to managed increased occurrence of behavioural symptoms of people with dementia in LTC or to prevent LTC residents from wandering within LTC facilities to potentially prevent the spread of COVID-19 (21) . This position paper highlights the mental health care needs of older persons living in LTC settings during COVID-19 and other similar pandemics.
# METHODS:
The Canadian Academy of Geriatric Psychiatry (CAGP) and Canadian Coalition for Seniors Mental Health (CCMSH) established a working group to develop a position statement on mental health care for older adults in long-term care settings. A call for expressions of interest to participate in the working group was distributed to current CAGP members. A working group planning committee initially met in July, 2020 to identify the scope and anticipated outputs for this project. The final working group consists of 14 individuals (Appendix A) representing geriatric psychiatrists and geriatric psychiatry trainees from different provinces, care settings and career stages. The working group met by videoconference a total of 4 times to prepare the position statement. The working group drafted position statements and working group members contributed to reviewing the evidence related to each position statement. The final position statements and accompanying evidence were arrived at by consensus.
# POSITION STATEMENTS:
Statement 1: Mental health care in LTC settings is an essential service.
While access to medical services may need to be adapted during COVID-19 and other outbreaks in keeping with public health requirements, mental health care in LTC settings is an essential service. This includes access to outpatient, outreach, inpatient and specialized mental health treatments such as electroconvulsive therapy (ECT), within the limits of necessary infection control practices.
During the initial outbreak of COVID-19 in Canada, preparations for an anticipated influx of COVID-19 patients into acute care led to the cancellation of many medical services and surgical procedures that were deemed non-essential at the time. In addition, many hospital-based outpatient programs and procedures such as ECT were suspended or severely curtailed to prevent introduction of the virus (22) . Medical services provided directly in LTC were also reduced to those deemed essential. As a result, many individuals with mental health conditions in LTC settings had mental health assessments or treatments delayed or cancelled during the first six months of the COVID pandemic in Canada.
While mental health assessments or treatments can be delayed for some individuals on a shortterm basis due to necessary infection control practices, many individuals with mental problems and illnesses in LTC facilities do require urgent access to ongoing, consistent and reliable mental health services. These services may include outpatient visits, outreach services, inpatient admission, and the ability to initiate or continue hospital-based mental health treatments such as ECT (23) . COVID-19 has disrupted mental health services in most countries (24) . While COVIDrelated restrictions to health care provider visits have disrupted mental health services in most LTC facilities, the impact of COVID-19 on access to mental health services in LTCFs is currently unknown. Therefore, health systems need to provide the necessary safeguards and processes to allow ongoing mental health care for older adults in LTC while at the same time protecting long-term care residents and the community from the very real risks associated with COVID-19 infections.
# Statement 2: Factors such as age, the presence of dementia, or a diagnosis of mental health problems or illnesses are not reasons to exclude individuals from having access to resources such as emergency departments or inpatient hospitalization.
The COVID-19 pandemic has challenged healthcare organizations to prepare for increased demands on acute care. Crisis triage protocols have been developed, but often use survivability to determine allocation of health care resources (25) . This approach may stigmatize older adults, and those with chronic illness or disability (26) . Older adults who contract COVID-19 have higher mortality rates, especially in the presence of chronic medical conditions (26) . Long-term care (LTC) residents have a high burden of such illnesses and the presence of frailty and dementia further compounds their vulnerability (27,28) . On admission to LTC, advanced care planning and goals of care discussions should occur between individuals and/or their substitute decision makers (SDMs) and health-care teams. Furthermore, these discussions should be routinely revisited (29) . Individuals and/or SDMs should be provided the best information to make informed choices about whether or not to remain in the LTC setting or be transferred to an acute care setting for treatment and about the level of care that is to be received. Individuals and their families must be supported through this process and be able to express their wishes, while also being made aware of the significantly lowered survival rates among older adults with a high burden of medical illness and frailty who become infected with COVID-19. The presence or absence of cognitive impairment should not in itself preclude access to treatment but should factor into decisions about goals of care. It is essential that stigma, presumed decreased quality of life, and ageism do not influence these decisions.
# Statement 3: Restrictions on in-person visits to LTC must consider the potential effects of these restrictions on the mental health, quality of life, and dignity of LTC residents and their families.
While some restrictions on LTC visits will be required during infectious disease outbreaks, the least restrictive approaches to visitation permitted during pandemics should be made available to all LTC residents. Restrictions intended to prevent the spread of COVID-19 have significant impacts on the social networks of individuals and plans to minimize potential negative impacts of social isolation need to be considered in conjunction with any restrictions to visits in LTC.
Plans to minimize the negative impacts of isolation on these individuals and their families should be in place, including adherence to compassionate practices for ensuring social connection and care (30) . This should include offering at least weekly contact with a family member through virtual means or a safe in-person visit with appropriate personal protective equipment. Ideally, patients would be able to receive visits in accordance with their needs and not be limited to an arbitrary number. Most effective non-pharmacological interventions for dementia in LTC facilities, including one-to-one visits provided by family members or other individuals, require 2 to 3 interactions per week for sustained benefits on mood and behaviors to be observed between interactions (31) . Specific plans for all infectious outbreaks in LTC need to include not only infection prevention measures, but also a plan to maintain nursing care, social contact, and activities that support the mental health of the residents and prevention of unnecessary physical and cognitive decline. While these measures are often implemented during infectious disease outbreak in LTC facilities, during COVID-19 these restrictions occurred for prolonged periods of time and had significant impacts for the residents of LTC. These included loneliness, anxiety, feelings of insecurity, suicidal thoughts as well as physical and cognitive decline (13) .
Caregivers have also experienced significant stress when they could no longer be physically present to support their family members in LTC facilities. This was compounded in many situations by a lack of information and communication from LTC facilities about their loved ones. LTC facilities should implement processes to provide LTC residents, their families and caregivers, and staff with timely information related to the COVID-19. LTC facilities may consider providing access to electronic charts or secure communications for family members. All LTC facilities should have LTC staff who are key contacts and can provide timely information to LTC residents, their families and caregivers.
# Statement 4: Appropriate communication technology and human resources must be available to allow communication between LTC residents and individuals located outside a resident's LTC facility.
Access to virtual communication technology (e.g. phone, tablet, or computer-based videoconferencing) has been identified as critical to ensuring that LTC residents are able to communicate with families, friends, and health service providers who are unable to visit an individual in person at a LTC (32,33) . Utilization of telemedicine (services delivered by physicians) and telehealth services (delivered by other health care providers) have been identified as key to maintaining access to health care during COVID-19 (34) to and reducing disease transmission (35) . Older adults in LTC facilities may suffer the effects of "double burden of exclusion" by having restrictions to in-person visits and limited access to technology needed for other methods of communication (36) . Unfortunately, many LTC facilities have limited access to the technology, expertise and human resources necessary to support this form of communication at all or as frequently as would be optimal for an individual's needs. (33) Each LTC facility should have the infrastructure to support virtual visits with family and health care professionals. At a minimum, this should include high-speed internet connection, and the provision of portable devices (e.g. tablets or laptops) for LTC residents who does not have access to their own personal device. All LTC staff should have basic knowledge of facilitating visits with families using commonly used platforms. The unique needs of older adults with dementia, mental illnesses, and co-morbid sensory impairments must be accommodated in these visits. Each LTC facility should have two or more staff per resident care unit trained in facilitating secure and private virtual health care visits that follow required privacy regulations. Interprofessional teams based outside of LTC facilities should also receive training in conducting virtual assessments and be provided with the virtual technology necessary to complete assessments.
# Statement 5: Public health measures limiting access to in-person visits, restrictions of movement within LTC facilities, and cessation of LTC social programming must consider the risks and benefits to specific individuals in LTCs.
LTC facilities did not allow any visitors in the early stages of the COVID-19 pandemic, which resulted in an overwhelming response from LTC residents, their families and caregivers about the negative impact of these restrictions (37) . Early studies examining the reintroduction of visitors in LTC through carefully implemented policies, have demonstrated success and show that these visits have not led to a significant increase in the rates of COVID-19 infection (38) . There are emerging recommendations on the re-integration of family caregivers into LTC, which require rapid dissemination to adopt evidence-based visitation policies that provide a better balance of infection control measures with quality of life (39) . Failure to utilize family presence in LTC facilities to support older adults exacerbates the current gaps in the LTC workforce. It is estimated that approximately 750,000 Canadians provide care to a family member in a LTC setting with over 20% of them providing over 10 hours per week of care including personal care (40) . LTC residents have discussed their experiences over the last six months with some describing their experience as "devastating, emotional, terror awakened, muzzled, trapped, broken-spirited and boredom" (37) . Research into the impact of these restrictions in LTC facilities should include direct interviews with residents and family caregivers (37) .
As new policies for the integration of family caregivers at LTC facilities are developed, they should follow a person-centered approach. Processes must be in place for exceptional circumstances where family caregivers are required as part of an individual's mental health care plan. Geriatric psychiatrists and LTC mental health service providers should be consulted in the development of these policies and be included in the review of such exceptional circumstances. While mental health conditions are common in LTC settings (11) , access to mental health and psychiatric services in LTC is limited (14) . Canada has shortage of geriatric psychiatrists which is unlikely to improve substantially in coming years (41) . Research has suggested that COVID-19 has resulted in an increase in behavioural symptoms of dementia in LTC resulting in an even greater need for mental health care (42,43) . It is therefore important that all LTC facilities have adequately trained staff and sufficient resources to assess and treat common mental health conditions, during COVID-19 and similar periods of infectious disease outbreaks when access to mental health resources is even more limited.
Staff training approaches are among the best supported interventions for addressing behavioural symptoms of dementia in LTC settings (31) . Guidelines recommend that all LTC facilities provide staff with training in the assessment and management of common mental health disorders (44,45) such as delirium and depression (44) , management of neuropsychiatric symptoms, and responding to emergent mental health crises (46) . These training programs require access to trainers (often associated with geriatric mental health programs) as well as resources to allow staff to attend these courses as part of their paid employment while ensuring an adequate number of staff are available to support the ongoing needs of LTC residents. Some LTC homes may have mental health champions or embedded mental health resources provided by either the LTC facility or through partnerships with provincial mental health programs. Mental health care provided by LTC staff can be supplemented by regional outreach programs or telemedicine (47) . Statement 7: Governments, LTC, and mental health service providers must ensure that staff working in LTC during the COVID-19 pandemic have adequate access to mental health supports and programs to support staff wellness.
Staff working in LTC settings were experiencing significant stress and devaluation due to chronic understaffing of LTC facilities prior to COVID-19. COVID-19 has contributed additional stressors related to a worsening of staffing shortages, initial shortages of PPE and ongoing risks of staff contracting COVID-19 and the high death rates in COVID-19 affected facilities (48,49) . Each individual may respond to the new stressors associated with COVID-19 differently (50) . To mitigate these negative sequelae, LTC facilities must promote and maintain the mental health and wellbeing of frontline staff by ensuring measures are taken to adequately support staff and ensure their safety and recognize the value of their work (49) . This includes access to appropriate personal protective equipment, and educational programs to ensure its proper use (5) . Psychoeducation on caregiver burnout, stress management, anxiety and depressive disorders should be incorporated in job training at long-term care facilities, and regularly reviewed to promote staff resilience. Sick leave and employee assistance programs should be made available to staff working in facilities impacted by COVID-19. Other recommendations related to supporting LTC staff have included clear guidance from LTC facility leadership, optimizing human health resource planning, and adoption of clinical practices to minimize the impact of COVID-19 in LTC (49) . Statement 8: Measures of mental health and quality of life in LTC facilities must be systematically evaluated during COVID-19, and strategies implemented to understand and remediate adverse mental health outcomes when they are identified.
Mental health and quality of life must be systematically evaluated to assess the effects of the COVID-19 pandemic on LTC residents. This monitoring will help identify early signs of worsening of mental health symptoms within individual LTC residents and facilities and identify individuals and facilities which may require additional supports or resources, similar to how LTC with COVID-19 outbreaks are currently triaged for additional supports based on their needs.
While mortality and infection rates may reflect the most important measures for monitoring of the impact of COVID-19 in other settings, they capture only part of the effects of COVID-19 in LTC. One of the most dramatic effects of COVID-19 in LTCs has been the increase in social isolation of residents due to restrictions on visitors and residents' ability to leave their care home. Social isolation has adverse mental health outcomes such as worsening of depression, cognitive decline and behavioural symptoms of dementia. (51) Measurement is the basis of monitoring quality of care, overall health status, and identifies opportunities for improving quality of care amidst the COVID-19 pandemic. Monitoring quality of life, functioning, and mental health can be done without creating new or onerous data collection. For example, the Minimum Dataset Resident Assessment Instrument (MDS-RAI) is a routine measure used in many LTC facilities, which includes quality indicators measuring depression (52) , behavioural symptoms (53) , and cognition (54) . Incorporating these and other relevant measures of long-term care resident health status as part of COVID-19 related outcomes would provide a more accurate picture of the effects of COVID-19 in long term care.
# CONCLUSION
All Canadians have been affected by the COVID-19 pandemic and none more so than LTC residents. As LTC residents, their families and those caring for them continue to be affected by the COVID-19 epidemic we anticipate that the mental health of LTC residents, their families and LTC staff will continue to be significantly impacted. Our position statements provide actionable strategies and priorities to minimize the impact of COVID-19 on the mental health of individuals in LTC. Collectively we can learn from our actions in the past and make plans for a future that better meet the mental needs of individuals in LTC during COVID-19.
#
Appendix A
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This commentary summarizes the Canadian Thoracic Society (CTS) position statement on managing asthma during the coronavirus disease 2019 (COVID-19) pandemic 1 in an easy, frequently asked question (FAQ) format. The full asthma position statement as well as other valuable clinical tools, including links to online self-management tools, can be found at the CTS website. 2 In general, asthma maintenance and exacerbation management should continue according to national and international guidelines during the COVID-19 pandemic; however, treatment decisions should be individualized on the basis of patient characteristics. Optimal asthma control is expected to be ABBREVIATIONS: COVID-19 = coronavirus disease 2019; CTS = Canadian Thoracic Society#
FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: C. L. reports grants and personal fees from AstraZeneca Canada Ltd. (AZ), grants and personal fees from Boehringer Ingelheim Canada Ltd, grants and personal fees from Novartis, personal fees from GlaxoSmithKline Canada Ltd (GSK), and grants and personal fees from Pfizer, outside the submitted work. C. L. Y. reports grants and personal fees from Covis and Novartis, outside the submitted work. F. M. D. reports unrestricted grants from Novartis, Teva, and Trudell Medical; grants from GSK the best protection against a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exacerbation. The pandemic is a rapidly evolving situation. Healthcare professionals are advised to monitor the national/ international society websites, including that of the CTS, for resources and links to asthma action plans and tutorial videos for children and adults on the proper use of inhalers and puffers as well as updates on COVID-19 and lung diseases. A link to recommendations regarding the clinical treatment of patients in the event of a salbutamol metered dose inhaler shortage can also be found on the CTS website. 2 Are Patients With Asthma More at Risk of Acquiring SARS-CoV-2 Infection?
No. Most studies to date suggest that patients with asthma have no greater risk of acquiring COVID-19 than the general population. In the largest studies published to date, with 44,672 patients (China) and 5,700 patients (United States), respectively, the prevalence of asthma in the COVID-19 population was below or approximated the expected general population prevalence; patients with asthma were not overrepresented. Are Patients With Asthma at Risk of Experiencing an Exacerbation Triggered by SARS-CoV-2 (COVID-19)?
Probably yes, but there is no direct evidence. Viral respiratory tract infections are a common cause of asthma exacerbations. 10 Exacerbations requiring ED visits and hospitalizations increase annually at times when viral infections increase, typically week 38 on the calendar. 11 Nonpandemic coronaviruses have been associated with asthma exacerbations. 12,13 Is Asthma a Chronic Medical Condition That Is Associated With a Higher Risk of Severe Illness or Death From COVID-19?
Possibly yes, but there is no direct evidence to answer this question. The Centers for Disease Control and Prevention identify people with asthma as a group that may be at higher risk for severe illness from COVID-19. 14 Although comorbid illness is common in people who are admitted to hospital and in people who die of COVID-19, asthma has not been identified as an independent risk factor for severe illness or death. Regarding severe illness leading to hospitalization, two studies from China, one from Korea, and one from the United States did not find that hospitalized patients with asthma were overrepresented in the COVID-19 populations studied. 9, Regarding the risk of death from COVID-19, the Chinese Centre for Disease Control and Prevention reported a higher than average case-fatality rate for patients with "chronic respiratory disease" but did not evaluate asthma as an independent risk factor. 8 In contrast, a report from Italy reporting 481 deaths and one from China reporting 54 deaths did not identify asthma as a comorbid risk factor. 18,19 Should Patients With Asthma Change Treatment During the COVID-19 Pandemic?
No. Patients with asthma should restart or continue their prescribed inhaled corticosteroid or inhaled corticosteroid plus long-acting b 2 -agonist maintenance therapy to improve disease control and to reduce the severity of exacerbations, including exacerbations that may be caused by SARS-CoV-2.
# Is It Safe to Continue Using Corticosteroids (Prednisone) During the COVID-19 Pandemic?
So far, yes. There is no evidence of harm caused by using prednisone to treat asthma exacerbations during the pandemic. The brief course of prednisone used to treat acute asthma exacerbation is not expected to compromise the immune system enough to increase chances of acquiring SARS-CoV-2 and/or developing COVID-19. Patients should use prednisone to treat severe asthma exacerbations, whether or not the exacerbation is triggered by SARS-CoV-2.
# Is It Safe to Use Inhaled Steroids?
Yes. There is no evidence that inhaled corticosteroids increase the risk of acquiring COVID-19 or that inhaled corticosteroids increase the severity of infection. Most importantly, inhaled corticosteroids are key to maintaining disease control in most patients with asthma, and well-controlled asthma is probably the best protection against a SARS-CoV-2-induced asthma exacerbation.
# Should Patients Continue to Use Biologics to Manage Severe Asthma?
Yes. Biologics are not expected to adversely affect the immune response to viral infection. In fact, omalizumab may protect against virus-induced exacerbations. 20 Patients should continue using anti-IgE, anti-IL-5, and anti-IL-4/IL-13 monoclonal antibodies during the COVID-19 pandemic because they reduce the frequency of severe asthma exacerbations and, therefore, the likelihood of entering the health-care system. (Note: Anti-IL-4/IL-13 monoclonal antibody therapy is not currently approved in Canada for the management of severe asthma.) Should Patients With Asthma Use Nebulizers Inside of Health-Care Facilities?
No, except for patients who are unable to use a metered dose inhaler with a spacing device or a dry powder device. Nebulizers may increase the risk of aerosol spread of viral particles and the risk of infection for health-care workers and caregivers. 21 The recommendation to avoid nebulization applies to all patients, not only to patients who have confirmed or suspected COVID-19. Patients should continue using or switch to metered dose inhalers with spacing devices, or dry powder inhalers, to administer inhaled corticosteroids and short-acting bronchodilators. For patients unable to use a metered dose inhaler with spacing devices, or a dry powder inhaler, nebulizers may be used cautiously in compliance with applicable contact and droplet infection control standards.
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This commentary summarizes the Canadian Thoracic Society (CTS) position statement on managing asthma during the coronavirus disease 2019 (COVID-19) pandemic 1 in an easy, frequently asked question (FAQ) format. The full asthma position statement as well as other valuable clinical tools, including links to online self-management tools, can be found at the CTS website. 2 In general, asthma maintenance and exacerbation management should continue according to national and international guidelines during the COVID-19 pandemic; however, treatment decisions should be individualized on the basis of patient characteristics. Optimal asthma control is expected to be ABBREVIATIONS: COVID-19 = coronavirus disease 2019; CTS = Canadian Thoracic Society#
FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: C. L. reports grants and personal fees from AstraZeneca Canada Ltd. (AZ), grants and personal fees from Boehringer Ingelheim Canada Ltd, grants and personal fees from Novartis, personal fees from GlaxoSmithKline Canada Ltd (GSK), and grants and personal fees from Pfizer, outside the submitted work. C. L. Y. reports grants and personal fees from Covis and Novartis, outside the submitted work. F. M. D. reports unrestricted grants from Novartis, Teva, and Trudell Medical; grants from GSK the best protection against a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exacerbation. [3][4][5][6] The pandemic is a rapidly evolving situation. Healthcare professionals are advised to monitor the national/ international society websites, including that of the CTS, for resources and links to asthma action plans and tutorial videos for children and adults on the proper use of inhalers and puffers as well as updates on COVID-19 and lung diseases. A link to recommendations regarding the clinical treatment of patients in the event of a salbutamol metered dose inhaler shortage can also be found on the CTS website. 2 Are Patients With Asthma More at Risk of Acquiring SARS-CoV-2 Infection?
No. Most studies to date suggest that patients with asthma have no greater risk of acquiring COVID-19 than the general population. In the largest studies published to date, with 44,672 patients (China) and 5,700 patients (United States), respectively, the prevalence of asthma in the COVID-19 population was below or approximated the expected general population prevalence; patients with asthma were not overrepresented. [7][8][9] Are Patients With Asthma at Risk of Experiencing an Exacerbation Triggered by SARS-CoV-2 (COVID-19)?
Probably yes, but there is no direct evidence. Viral respiratory tract infections are a common cause of asthma exacerbations. 10 Exacerbations requiring ED visits and hospitalizations increase annually at times when viral infections increase, typically week 38 on the calendar. 11 Nonpandemic coronaviruses have been associated with asthma exacerbations. 12,13 Is Asthma a Chronic Medical Condition That Is Associated With a Higher Risk of Severe Illness or Death From COVID-19?
Possibly yes, but there is no direct evidence to answer this question. The Centers for Disease Control and Prevention identify people with asthma as a group that may be at higher risk for severe illness from COVID-19. 14 Although comorbid illness is common in people who are admitted to hospital and in people who die of COVID-19, asthma has not been identified as an independent risk factor for severe illness or death. Regarding severe illness leading to hospitalization, two studies from China, one from Korea, and one from the United States did not find that hospitalized patients with asthma were overrepresented in the COVID-19 populations studied. 9,[15][16][17] Regarding the risk of death from COVID-19, the Chinese Centre for Disease Control and Prevention reported a higher than average case-fatality rate for patients with "chronic respiratory disease" but did not evaluate asthma as an independent risk factor. 8 In contrast, a report from Italy reporting 481 deaths and one from China reporting 54 deaths did not identify asthma as a comorbid risk factor. 18,19 Should Patients With Asthma Change Treatment During the COVID-19 Pandemic?
No. Patients with asthma should restart or continue their prescribed inhaled corticosteroid or inhaled corticosteroid plus long-acting b 2 -agonist maintenance therapy to improve disease control and to reduce the severity of exacerbations, including exacerbations that may be caused by SARS-CoV-2.
# Is It Safe to Continue Using Corticosteroids (Prednisone) During the COVID-19 Pandemic?
So far, yes. There is no evidence of harm caused by using prednisone to treat asthma exacerbations during the pandemic. The brief course of prednisone used to treat acute asthma exacerbation is not expected to compromise the immune system enough to increase chances of acquiring SARS-CoV-2 and/or developing COVID-19. Patients should use prednisone to treat severe asthma exacerbations, whether or not the exacerbation is triggered by SARS-CoV-2.
# Is It Safe to Use Inhaled Steroids?
Yes. There is no evidence that inhaled corticosteroids increase the risk of acquiring COVID-19 or that inhaled corticosteroids increase the severity of infection. Most importantly, inhaled corticosteroids are key to maintaining disease control in most patients with asthma, and well-controlled asthma is probably the best protection against a SARS-CoV-2-induced asthma exacerbation.
# Should Patients Continue to Use Biologics to Manage Severe Asthma?
Yes. Biologics are not expected to adversely affect the immune response to viral infection. In fact, omalizumab may protect against virus-induced exacerbations. 20 Patients should continue using anti-IgE, anti-IL-5, and anti-IL-4/IL-13 monoclonal antibodies during the COVID-19 pandemic because they reduce the frequency of severe asthma exacerbations and, therefore, the likelihood of entering the health-care system. (Note: Anti-IL-4/IL-13 monoclonal antibody therapy is not currently approved in Canada for the management of severe asthma.) Should Patients With Asthma Use Nebulizers Inside of Health-Care Facilities?
No, except for patients who are unable to use a metered dose inhaler with a spacing device or a dry powder device. Nebulizers may increase the risk of aerosol spread of viral particles and the risk of infection for health-care workers and caregivers. 21 The recommendation to avoid nebulization applies to all patients, not only to patients who have confirmed or suspected COVID-19. Patients should continue using or switch to metered dose inhalers with spacing devices, or dry powder inhalers, to administer inhaled corticosteroids and short-acting bronchodilators. For patients unable to use a metered dose inhaler with spacing devices, or a dry powder inhaler, nebulizers may be used cautiously in compliance with applicable contact and droplet infection control standards.
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The BC Centre on Substance Use (BCCSU) is a provincially networked organization with a mandate to develop, help implement, and evaluate evidence-based approaches to substance use and addiction. The BCCSU seeks to improve the integration of best practices and care across the continuum of substance use through the collaborative development of evidence-based policies, guidelines, and standards. With the support of the Province of BC, the BCCSU aims to transform substance use policies and care by translating research into education and care guidance, thereby serving all British Columbians. The BCCSU seeks to achieve these goals through integrated activities of its three core functions: research and evaluation, education and training, and clinical care guidance.-Leading an innovative multidisciplinary program of research, monitoring, evaluation and quality improvement activities to guide health system improvements in the area of substance use. Education and Training -Strengthening addiction medicine education activities across disciplines, academic institutions, and health authorities, and training the next generation of interdisciplinary leaders in addiction medicine. Clinical Care Guidance -Developing and helping implement evidence-based clinical practice guidelines, treatment pathways, and other practice support documents.# Disclaimer for Health Care Providers
The recommendations in this guideline represent the view of the provincial guideline committee, arrived at after careful consideration of the available scientific evidence and following external expert peer review. The application of the recommendations in this guideline does not override the responsibility of health care professionals to make decisions that are appropriate to the needs, preferences, and values of an individual patient, in consultation with that patient and their family members or guardian(s), and, when appropriate, external experts (e.g., specialty consultation). When exercising clinical judgment in the treatment of high-risk drinking and alcohol use disorder, BC health care professionals are expected to take this guideline fully into account while upholding their duty to adhere to the fundamental principles and values of the Canadian Medical Association Code of Ethics, especially compassion, beneficence, non-maleficence, respect for persons, justice and accountability, as well as the required standards for good clinical practice as set by the College of Physicians and Surgeons of British Columbia and any other relevant provincial regulatory body. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
# Legal Disclaimer
While the individuals and groups involved in the production of this document have made every effort to ensure the accuracy of the information contained in this treatment guideline, please note that the information is provided "as is". The Ministry of Health (MoH), the Ministry of Mental Health and Addictions (MMHA), and the BCCSU make no representation or warranty of any kind, either expressed or implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest extent possible under applicable law, the MoH, MMHA, and the BCCSU disclaims and will not be bound by any express, implied or statutory representation or warranty (including, without limitation, representations or warranties of title or non-infringement).
The Guideline is intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guideline is not intended as a substitute for the advice or professional judgment of a health care professional, nor is it intended to be the only approach to the management of a clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional. 3 Mindfulness-Based Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
# Table of Contents
Executive
# Psychosocial Treatment Interventions and
Co-occurring Mental Health Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 7.2.5 Psychosocial Treatment Interventions in Youth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 7.2.6 Psychosocial Treatment Interventions in Pregnant Individuals . . . . . . . . . . . . . . . . . . . . . . . . 83 7.2.7 Duration of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 7.2.8 Accessibility and Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 7.2.9 Section Summary and Recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 7.3 Combining Pharmacotherapy and Psychosocial Treatment Interventions . . . . . . . . . . . 85 8. Community-Based Supports and Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Supportive Recovery Housing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 8.3 Psychosocial Support Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 9. Managed Alcohol Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Appendix 1: Alcohol Use Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Step The 5As Model for Brief Alcohol Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Appendix 3: Withdrawal Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 A. Assessment Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 B. Selecting the Appropriate Care Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alternative Pharmacotherapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Appendix 5: Motivational Interviewing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Principles of Motivational Interviewing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Indigenous Peoples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sex and Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Youth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pregnant Individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Co-occurring Mental Health and Substance Use Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Co-occurring Alcohol Use and Mental Health Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Co-occurring Substance Use Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 1 Summary 2 Summary of Principles of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Table 3 Summary of Canada's Low-Risk Alcohol Drinking Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Table 4 Age-Specific Thresholds for NIAAA Screening Tool . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Table 5 Comparison of Pharmacotherapy Options for Outpatient Management of Alcohol Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Table 6 Comparison of First-Line Pharmacotherapies for AUD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Table 7 Comparison of Select Alternative AUD Pharmacotherapy Options . . . . . . . . . . . . . . . . . . . . . . . 72 Table 8 Comparison of Selected Alcohol Use Screening Tools (Adults) . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Table 9 Comparison of Selected Alcohol Use Screening Tools (Youth) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Table 10
# List of Tables
# Executive Summary
Despite the relatively high prevalence of high-risk drinking, alcohol use disorder (AUD), and alcohol-related harms in British Columbia (BC), these conditions frequently go unrecognized and untreated in the health care system. Research has shown that primary care providers can play an important role in the early detection and treatment of high-risk drinking and AUD, and in connecting patients and families with specialized care services and recovery-oriented supports in their communities. However, the lack of an evidence-based guideline for the clinical management of high-risk drinking and AUD has resulted in low awareness and use of the full range of available treatment interventions among primary care providers in BC.
To address this gap, the BCCSU convened a provincial guideline committee to review the research evidence and reach consensus on recommendations for the clinical management of high-risk drinking and AUD. A set of 13 recommendations were derived by the committee, spanning the identification and clinical management of high-risk drinking and AUD in youth (aged 12-25 years) and adult patient populations, with a focus on primary care practice. The purpose of this guideline is to support health care providers with the implementation of evidence-based prevention, harm reduction, and treatment interventions for high-risk drinking and AUD in their scope of practice.
Specifically, this guideline aims to:
- Describe principles of care and general considerations for screening, intervention, management and continuing care of high-risk drinking and AUD
- Review strategies for alcohol use screening and brief intervention for adult and youth patients who are drinking above recommended low-risk limits
- Recommend a clinical algorithm for alcohol withdrawal management, where an individual's risk of developing severe complications is used to triage that individual to an appropriate care setting and management approach
- Provide guidance on outpatient withdrawal management, with attention to limiting or avoiding use of benzodiazepines where appropriate and indicated
- Recommend strategies for continuing AUD care supported by evidence, including use of pharmacotherapy, psychosocial treatment interventions, and specialist-led and community-based services and supports
- Provide advice for managing transitions along the continuum of care, with an emphasis on optimizing engagement and continuity of care where multiple referral partners are involved This guideline is intended to be a resource for physicians, nurses and nurse practitioners, pharmacists, allied health professionals, and all other clinical and non-clinical personnel involved in the care of individuals and families affected by alcohol use. This guideline is also intended to be used by policymakers and healthcare administrators in the development of strategies to address unmet alcohol treatment and care needs in BC in an evidence-based, cost-effective manner.
# Quality of Evidence
# Strength of Recommendation
# Screening and Brief Intervention 1
Clinicians should provide education about Canada's Low-Risk Alcohol Drinking Guidelines to all adult and youth patients.
# LOW STRONG 2
All adult and youth patients should be screened annually for alcohol use above low-risk limits.
# MODERATE STRONG 3
All patients who are drinking alcohol above low-risk limits but do not have an alcohol use disorder (AUD) b should receive a brief counselling intervention.
# MODERATE STRONG
Withdrawal Management 4
Clinicians should use the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) to assess the risk of severe complications of alcohol withdrawal in patients with AUD, in order to select the most appropriate withdrawal management pathway.
# MODERATE STRONG 5
Patients at low risk of severe complications of alcohol withdrawal (PAWSS<4) who have no other concurrent conditions that would require inpatient management should be offered outpatient withdrawal management.
HIGH STRONG
Clinicians should consider prescribing non-benzodiazepine medications, such as gabapentin, carbamazepine, or clonidine, for the outpatient management of patients at low risk of severe complications of alcohol withdrawal.
# MODERATE STRONG 7
Patients at high risk of severe complications of withdrawal (PAWSS≥4) should be referred to an inpatient facility (i.e., withdrawal management facility or hospital) where they can receive a benzodiazepine treatment regimen under close observation, and emergency care can be administered immediately if needed.
HIGH STRONG
All patients who complete withdrawal management should be connected to continuing AUD care.
# LOW STRONG
Continuing Care 9
Adult patients with moderate to severe AUD should be offered naltrexone or acamprosate as a first-line pharmacotherapy to support achievement of patient-identified treatment goals.
A. Naltrexone is recommended for patients who have a treatment goal of either abstinence or a reduction in alcohol consumption.
B. Acamprosate is recommended for patients who have a treatment goal of abstinence.
# MODERATE STRONG 1 Introduction to the Guideline
This introduction describes the overall structure, scope and intended use of the guideline, and provides a brief overview of methods used to conduct the systematic review of the literature, develop recommendations for clinical practice, and assess quality of evidence and strength for each recommendation.
# Guideline Structure
This guideline consists of nine main sections, appendices, and a supplemental section. A brief description of each is provided below.
# Introduction:
This section provides a brief overview of the scope, intended use, and the methods used to develop the guideline.
# Background and Rationale:
This section outlines the risks, harms, and costs attributable to alcohol use in British Columbia, Canada, and globally that collectively underscore the need for an evidence-based guideline on the clinical management of high-risk drinking and alcohol use disorder.
# Working with Patients and Families Affected by Alcohol Use:
This section sets out general principles of care for working with patients and families affected by alcohol use, high-risk drinking, and alcohol use disorder. Overarching frameworks such as the social determinants of health, harm reduction, trauma-and violence-informed care, and Indigenous cultural safety are discussed, as well as models for providing care, including longitudinal care, continuum of care, and comprehensive medical management models. The section concludes with a review of the principles of patient-centred, recovery-oriented care, and best practices for the involvement of family in patients' treatment and recovery plans.
# Screening and Brief Intervention:
This section reviews the evidence and makes recommendations on the use of universal alcohol use screening and brief counselling interventions to reduce drinking in adult and youth patients exceeding low-risk drinking limits. Clinical signs and diagnosis of alcohol use disorder are also discussed.
# Withdrawal Management:
This section provides an overview of the pathophysiology, signs, and symptoms of alcohol withdrawal, and reviews the evidence for use of a simple scale to predict patients' risk of developing severe complications of alcohol withdrawal in order to determine an appropriate management plan. Recommendations are made for use of pharmacotherapy and supportive care to manage mild to severe alcohol withdrawal in outpatient and inpatient care settings. Medications reviewed include benzodiazepines, carbamazepine, gabapentin, and alpha-adrenergic agonists (i.e., clonidine).
# Continuing Care -Pharmacotherapy:
This section reviews the evidence and makes recommendations for use of pharmacotherapy as part of continuing care plans for alcohol use disorder, with special consideration of patients' treatment and recovery goals. Naltrexone, acamprosate, topiramate, gabapentin, and disulfiram are reviewed in depth. A brief review of emerging therapies, including baclofen, ondansetron, and combination therapy, is also included.
# Continuing Care -Psychosocial Treatment Interventions:
This section reviews the evidence and makes recommendations on the use of psychosocial treatment interventions as part of continuing care plans for alcohol use disorder. Primary care-led approaches, such as motivational interviewing and contingency management, and specialist-led approaches, such as cognitive-behavioural therapy, family-based therapy, and mindfulness-based interventions, are covered.
# Community-Based Programs and Supports:
This section reviews the evidence and makes recommendations on referring patients and families to community-based programs and supports for alcohol use disorder, including peer-support groups (e.g., Alcoholics Anonymous, SMART © Recovery), intensive outpatient programs, and inpatient treatment programs.
# Managed Alcohol Programs:
A brief overview of the evidence for the use of managed alcohol programs in outpatient and inpatient settings is provided in the section. Making an explicit recommendation on managed alcohol programs was outside the scope of this guideline, however, the committee wishes to acknowledge the important role of this intervention in reducing harm for certain patients with severe alcohol use disorder.
# Appendices:
The appendices include practical guidance, instructions, medication protocols, and external resources to support health care providers with implementing guideline recommendations in their practice.
The following topics are covered: Alcohol Use Screening, Brief Intervention for High-Risk Drinking, Withdrawal Management, AUD Pharmacotherapy, and Motivational Interviewing. Guidance for youth and pregnant patients is provided where appropriate.
Supplemental Content: Supplemental guidance and resources for working with specific patient populations, including Indigenous peoples, 2SLGBTQ+ populations, youth, pregnant patients, older adults, and patients with co-occurring mental health and substance use disorders is provided in this supplement.
# Scope of the Guidelines
The scope of these guidelines is the identification and clinical management of high-risk drinking and alcohol use disorder (AUD) in adults (individuals aged 25 years and older) and youth (individuals aged 11-25 years). The intended use is to support routine screening to identify high-risk alcohol use and diagnose AUD, and to promote the use of evidence-based prevention, risk and harm reduction, and treatment interventions within primary care and other clinical settings in British Columbia.
Specifically, these guidelines aim to:
- Describe principles of care and general considerations for screening, intervention, management, and continuing care for adult and youth patients who are drinking above recommended low-risk limits and meet diagnostic criteria for an AUD.
- Review strategies for alcohol use screening and brief intervention for adult and youth patients who are drinking above recommended low-risk limits.
- Recommend a clinical algorithm for alcohol withdrawal management, where an individual's risk of developing severe complications is used to triage that individual to an appropriate care setting and management approach.
- Provide guidance on outpatient withdrawal management, with attention to limiting or avoiding use of benzodiazepines where appropriate and indicated.
- Recommend strategies for continuing AUD care supported by evidence, including use of pharmacotherapy, psychosocial treatment interventions, and specialist-led and community-based services and supports.
- Provide advice for managing transitions along the continuum of care, with an emphasis on optimizing engagement and continuity of care where multiple referral partners are involved.
# Objective and Purpose
The objective of this guideline is to provide recommendations, supported by current and rigorously reviewed evidence, for the full spectrum of medical and psychosocial interventions available to treat patients with high-risk drinking and AUD. In doing so, the guideline aims to provide comprehensive education and clinical care guidance to health care providers spanning the addiction care continuum in the province, which will, in turn, improve access to evidence-based treatment for patients and families, and reduce the significant harms associated with alcohol use in British Columbia.
# Intended Audience
The guideline is intended to be a resource for physicians, nurses and nurse practitioners, pharmacists, allied health care professionals, and all other clinical and non-clinical personnel with and without specialized training in addiction medicine, who are involved in the care and management of individuals, families, and communities affected by alcohol use. In addition, this guideline is intended to be a resource for policy makers and health care administrators in the development of strategies and programs to best address unmet alcohol treatment and care needs within British Columbia in an evidence-based, cost-effective manner.
# Care Settings
While this guideline focuses on the clinical management of AUD in primary care settings (e.g., family practice clinics, community health centres, walk-in clinics, student health services), the recommendations also apply more broadly to other care settings and environments that may represent an individual's first contact with the health care system. Depending on the circumstances, an individual experiencing alcohol-related issues or consuming alcohol in a high-risk manner may be identified through routine intake, assessment, and monitoring procedures at a number of other care settings, including: emergency and assessment rooms, acute care settings (e.g., general, surgical, trauma or intensive care wards), sexual health services, trauma and anti-violence services, prenatal care clinics, and specialized mental health and addiction services (e.g., inpatient addiction medicine consult teams, outpatient rapid access addiction medicine clinics, community mental health and substance use programs). Clinical care teams and staff in these health care settings are encouraged to adapt and apply guideline recommendations as needed for their practice, supporting individuals and families affected by alcohol use in seeking help and accessing evidence-based treatment and services at multiple points of entry in the provincial health care system. 3
# Patient Populations
The recommendations made in this guideline are applicable to the general adult patient population, which can include individuals who are drinking within recommended limits for low-risk drinking, those who are exceeding low-risk alcohol drinking limits, individuals diagnosed with AUD of any severity (mild, moderate, severe), 2 as well as individuals in recovery from an AUD. While much of the evidence reviewed in this guideline pertains to the general adult population, it is the consensus of the guideline committee that guideline recommendations are equally relevant and applicable to youth.
Additionally, while this guideline offers a brief overview of the available evidence for the clinical management of high-risk drinking and AUD in pregnant individuals c , the importance of specialist consultation in these cases is emphasized, as is the urgent need for more research in this area. For additional clinical guidance on the management of alcohol use during pregnancy and postpartum, clinicians can refer to the Alcohol Use and Pregnancy Consensus Clinical Guidelines 4 issued by the Society of Obstetricians and Gynaecologists of Canada.
In partnership with Perinatal Services BC, the BCCSU will be releasing guidance for the Clinical Management of High-Risk Drinking and Alcohol Use Disorder in Pregnancy, which will be available at the following link once published: /.
The guideline committee also recognizes the need to develop and implement best practices for identifying, treating, and managing high-risk drinking and AUD in specific populations, including Indigenous peoples, women and girls, men and boys, 2SLGBTQ+ folks d , pregnant individuals, adolescents (age and young adults (age , older adults (age 65 and over), and individuals with co-occurring mental health disorders. A brief overview on working with these specific patient populations, including links to additional resources, has been included as a Supplement.
# Methods
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The BC Centre on Substance Use (BCCSU) is a provincially networked organization with a mandate to develop, help implement, and evaluate evidence-based approaches to substance use and addiction. The BCCSU seeks to improve the integration of best practices and care across the continuum of substance use through the collaborative development of evidence-based policies, guidelines, and standards. With the support of the Province of BC, the BCCSU aims to transform substance use policies and care by translating research into education and care guidance, thereby serving all British Columbians. The BCCSU seeks to achieve these goals through integrated activities of its three core functions: research and evaluation, education and training, and clinical care guidance.-Leading an innovative multidisciplinary program of research, monitoring, evaluation and quality improvement activities to guide health system improvements in the area of substance use. Education and Training -Strengthening addiction medicine education activities across disciplines, academic institutions, and health authorities, and training the next generation of interdisciplinary leaders in addiction medicine. Clinical Care Guidance -Developing and helping implement evidence-based clinical practice guidelines, treatment pathways, and other practice support documents.# Disclaimer for Health Care Providers
The recommendations in this guideline represent the view of the provincial guideline committee, arrived at after careful consideration of the available scientific evidence and following external expert peer review. The application of the recommendations in this guideline does not override the responsibility of health care professionals to make decisions that are appropriate to the needs, preferences, and values of an individual patient, in consultation with that patient and their family members or guardian(s), and, when appropriate, external experts (e.g., specialty consultation). When exercising clinical judgment in the treatment of high-risk drinking and alcohol use disorder, BC health care professionals are expected to take this guideline fully into account while upholding their duty to adhere to the fundamental principles and values of the Canadian Medical Association Code of Ethics, especially compassion, beneficence, non-maleficence, respect for persons, justice and accountability, as well as the required standards for good clinical practice as set by the College of Physicians and Surgeons of British Columbia and any other relevant provincial regulatory body. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
# Legal Disclaimer
While the individuals and groups involved in the production of this document have made every effort to ensure the accuracy of the information contained in this treatment guideline, please note that the information is provided "as is". The Ministry of Health (MoH), the Ministry of Mental Health and Addictions (MMHA), and the BCCSU make no representation or warranty of any kind, either expressed or implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest extent possible under applicable law, the MoH, MMHA, and the BCCSU disclaims and will not be bound by any express, implied or statutory representation or warranty (including, without limitation, representations or warranties of title or non-infringement).
The Guideline is intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guideline is not intended as a substitute for the advice or professional judgment of a health care professional, nor is it intended to be the only approach to the management of a clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional. 3 Mindfulness-Based Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
# Table of Contents
Executive
# Psychosocial Treatment Interventions and
Co-occurring Mental Health Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 7.2.5 Psychosocial Treatment Interventions in Youth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 7.2.6 Psychosocial Treatment Interventions in Pregnant Individuals . . . . . . . . . . . . . . . . . . . . . . . . 83 7.2.7 Duration of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 7.2.8 Accessibility and Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 7.2.9 Section Summary and Recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 7.3 Combining Pharmacotherapy and Psychosocial Treatment Interventions . . . . . . . . . . . 85 8. Community-Based Supports and Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Supportive Recovery Housing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 8.3 Psychosocial Support Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 9. Managed Alcohol Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Appendix 1: Alcohol Use Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Step The 5As Model for Brief Alcohol Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Appendix 3: Withdrawal Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 A. Assessment Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 B. Selecting the Appropriate Care Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alternative Pharmacotherapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Appendix 5: Motivational Interviewing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Principles of Motivational Interviewing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Indigenous Peoples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sex and Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Youth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pregnant Individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Co-occurring Mental Health and Substance Use Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Co-occurring Alcohol Use and Mental Health Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Co-occurring Substance Use Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 1 Summary 2 Summary of Principles of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Table 3 Summary of Canada's Low-Risk Alcohol Drinking Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Table 4 Age-Specific Thresholds for NIAAA Screening Tool . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Table 5 Comparison of Pharmacotherapy Options for Outpatient Management of Alcohol Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Table 6 Comparison of First-Line Pharmacotherapies for AUD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Table 7 Comparison of Select Alternative AUD Pharmacotherapy Options . . . . . . . . . . . . . . . . . . . . . . . 72 Table 8 Comparison of Selected Alcohol Use Screening Tools (Adults) . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Table 9 Comparison of Selected Alcohol Use Screening Tools (Youth) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Table 10
# List of Tables
# Executive Summary
Despite the relatively high prevalence of high-risk drinking, alcohol use disorder (AUD), and alcohol-related harms in British Columbia (BC), these conditions frequently go unrecognized and untreated in the health care system. Research has shown that primary care providers can play an important role in the early detection and treatment of high-risk drinking and AUD, and in connecting patients and families with specialized care services and recovery-oriented supports in their communities. However, the lack of an evidence-based guideline for the clinical management of high-risk drinking and AUD has resulted in low awareness and use of the full range of available treatment interventions among primary care providers in BC.
To address this gap, the BCCSU convened a provincial guideline committee to review the research evidence and reach consensus on recommendations for the clinical management of high-risk drinking and AUD. A set of 13 recommendations were derived by the committee, spanning the identification and clinical management of high-risk drinking and AUD in youth (aged 12-25 years) and adult patient populations, with a focus on primary care practice. The purpose of this guideline is to support health care providers with the implementation of evidence-based prevention, harm reduction, and treatment interventions for high-risk drinking and AUD in their scope of practice.
Specifically, this guideline aims to:
• Describe principles of care and general considerations for screening, intervention, management and continuing care of high-risk drinking and AUD
• Review strategies for alcohol use screening and brief intervention for adult and youth patients who are drinking above recommended low-risk limits
• Recommend a clinical algorithm for alcohol withdrawal management, where an individual's risk of developing severe complications is used to triage that individual to an appropriate care setting and management approach
• Provide guidance on outpatient withdrawal management, with attention to limiting or avoiding use of benzodiazepines where appropriate and indicated
• Recommend strategies for continuing AUD care supported by evidence, including use of pharmacotherapy, psychosocial treatment interventions, and specialist-led and community-based services and supports
• Provide advice for managing transitions along the continuum of care, with an emphasis on optimizing engagement and continuity of care where multiple referral partners are involved This guideline is intended to be a resource for physicians, nurses and nurse practitioners, pharmacists, allied health professionals, and all other clinical and non-clinical personnel involved in the care of individuals and families affected by alcohol use. This guideline is also intended to be used by policymakers and healthcare administrators in the development of strategies to address unmet alcohol treatment and care needs in BC in an evidence-based, cost-effective manner.
# Quality of Evidence
# Strength of Recommendation
# Screening and Brief Intervention 1
Clinicians should provide education about Canada's Low-Risk Alcohol Drinking Guidelines to all adult and youth patients.
# LOW STRONG 2
All adult and youth patients should be screened annually for alcohol use above low-risk limits.
# MODERATE STRONG 3
All patients who are drinking alcohol above low-risk limits but do not have an alcohol use disorder (AUD) b should receive a brief counselling intervention.
# MODERATE STRONG
Withdrawal Management 4
Clinicians should use the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) to assess the risk of severe complications of alcohol withdrawal in patients with AUD, in order to select the most appropriate withdrawal management pathway.
# MODERATE STRONG 5
Patients at low risk of severe complications of alcohol withdrawal (PAWSS<4) who have no other concurrent conditions that would require inpatient management should be offered outpatient withdrawal management.
HIGH STRONG
# 6
Clinicians should consider prescribing non-benzodiazepine medications, such as gabapentin, carbamazepine, or clonidine, for the outpatient management of patients at low risk of severe complications of alcohol withdrawal.
# MODERATE STRONG 7
Patients at high risk of severe complications of withdrawal (PAWSS≥4) should be referred to an inpatient facility (i.e., withdrawal management facility or hospital) where they can receive a benzodiazepine treatment regimen under close observation, and emergency care can be administered immediately if needed.
HIGH STRONG
# 8
All patients who complete withdrawal management should be connected to continuing AUD care.
# LOW STRONG
Continuing Care 9
Adult patients with moderate to severe AUD should be offered naltrexone or acamprosate as a first-line pharmacotherapy to support achievement of patient-identified treatment goals.
A. Naltrexone is recommended for patients who have a treatment goal of either abstinence or a reduction in alcohol consumption.
B. Acamprosate is recommended for patients who have a treatment goal of abstinence.
# MODERATE STRONG 1 Introduction to the Guideline
This introduction describes the overall structure, scope and intended use of the guideline, and provides a brief overview of methods used to conduct the systematic review of the literature, develop recommendations for clinical practice, and assess quality of evidence and strength for each recommendation.
# Guideline Structure
This guideline consists of nine main sections, appendices, and a supplemental section. A brief description of each is provided below.
# Introduction:
This section provides a brief overview of the scope, intended use, and the methods used to develop the guideline.
# Background and Rationale:
This section outlines the risks, harms, and costs attributable to alcohol use in British Columbia, Canada, and globally that collectively underscore the need for an evidence-based guideline on the clinical management of high-risk drinking and alcohol use disorder.
# Working with Patients and Families Affected by Alcohol Use:
This section sets out general principles of care for working with patients and families affected by alcohol use, high-risk drinking, and alcohol use disorder. Overarching frameworks such as the social determinants of health, harm reduction, trauma-and violence-informed care, and Indigenous cultural safety are discussed, as well as models for providing care, including longitudinal care, continuum of care, and comprehensive medical management models. The section concludes with a review of the principles of patient-centred, recovery-oriented care, and best practices for the involvement of family in patients' treatment and recovery plans.
# Screening and Brief Intervention:
This section reviews the evidence and makes recommendations on the use of universal alcohol use screening and brief counselling interventions to reduce drinking in adult and youth patients exceeding low-risk drinking limits. Clinical signs and diagnosis of alcohol use disorder are also discussed.
# Withdrawal Management:
This section provides an overview of the pathophysiology, signs, and symptoms of alcohol withdrawal, and reviews the evidence for use of a simple scale to predict patients' risk of developing severe complications of alcohol withdrawal in order to determine an appropriate management plan. Recommendations are made for use of pharmacotherapy and supportive care to manage mild to severe alcohol withdrawal in outpatient and inpatient care settings. Medications reviewed include benzodiazepines, carbamazepine, gabapentin, and alpha-adrenergic agonists (i.e., clonidine).
# Continuing Care -Pharmacotherapy:
This section reviews the evidence and makes recommendations for use of pharmacotherapy as part of continuing care plans for alcohol use disorder, with special consideration of patients' treatment and recovery goals. Naltrexone, acamprosate, topiramate, gabapentin, and disulfiram are reviewed in depth. A brief review of emerging therapies, including baclofen, ondansetron, and combination therapy, is also included.
# Continuing Care -Psychosocial Treatment Interventions:
This section reviews the evidence and makes recommendations on the use of psychosocial treatment interventions as part of continuing care plans for alcohol use disorder. Primary care-led approaches, such as motivational interviewing and contingency management, and specialist-led approaches, such as cognitive-behavioural therapy, family-based therapy, and mindfulness-based interventions, are covered.
# Community-Based Programs and Supports:
This section reviews the evidence and makes recommendations on referring patients and families to community-based programs and supports for alcohol use disorder, including peer-support groups (e.g., Alcoholics Anonymous, SMART © Recovery), intensive outpatient programs, and inpatient treatment programs.
# Managed Alcohol Programs:
A brief overview of the evidence for the use of managed alcohol programs in outpatient and inpatient settings is provided in the section. Making an explicit recommendation on managed alcohol programs was outside the scope of this guideline, however, the committee wishes to acknowledge the important role of this intervention in reducing harm for certain patients with severe alcohol use disorder.
# Appendices:
The appendices include practical guidance, instructions, medication protocols, and external resources to support health care providers with implementing guideline recommendations in their practice.
The following topics are covered: Alcohol Use Screening, Brief Intervention for High-Risk Drinking, Withdrawal Management, AUD Pharmacotherapy, and Motivational Interviewing. Guidance for youth and pregnant patients is provided where appropriate.
Supplemental Content: Supplemental guidance and resources for working with specific patient populations, including Indigenous peoples, 2SLGBTQ+ populations, youth, pregnant patients, older adults, and patients with co-occurring mental health and substance use disorders is provided in this supplement.
# Scope of the Guidelines
The scope of these guidelines is the identification and clinical management of high-risk drinking and alcohol use disorder (AUD) in adults (individuals aged 25 years and older) and youth (individuals aged 11-25 years). The intended use is to support routine screening to identify high-risk alcohol use and diagnose AUD, and to promote the use of evidence-based prevention, risk and harm reduction, and treatment interventions within primary care and other clinical settings in British Columbia.
Specifically, these guidelines aim to:
• Describe principles of care and general considerations for screening, intervention, management, and continuing care for adult and youth patients who are drinking above recommended low-risk limits and meet diagnostic criteria for an AUD.
• Review strategies for alcohol use screening and brief intervention for adult and youth patients who are drinking above recommended low-risk limits.
• Recommend a clinical algorithm for alcohol withdrawal management, where an individual's risk of developing severe complications is used to triage that individual to an appropriate care setting and management approach.
• Provide guidance on outpatient withdrawal management, with attention to limiting or avoiding use of benzodiazepines where appropriate and indicated.
• Recommend strategies for continuing AUD care supported by evidence, including use of pharmacotherapy, psychosocial treatment interventions, and specialist-led and community-based services and supports.
• Provide advice for managing transitions along the continuum of care, with an emphasis on optimizing engagement and continuity of care where multiple referral partners are involved.
# Objective and Purpose
The objective of this guideline is to provide recommendations, supported by current and rigorously reviewed evidence, for the full spectrum of medical and psychosocial interventions available to treat patients with high-risk drinking and AUD. In doing so, the guideline aims to provide comprehensive education and clinical care guidance to health care providers spanning the addiction care continuum in the province, which will, in turn, improve access to evidence-based treatment for patients and families, and reduce the significant harms associated with alcohol use in British Columbia.
# Intended Audience
The guideline is intended to be a resource for physicians, nurses and nurse practitioners, pharmacists, allied health care professionals, and all other clinical and non-clinical personnel with and without specialized training in addiction medicine, who are involved in the care and management of individuals, families, and communities affected by alcohol use. In addition, this guideline is intended to be a resource for policy makers and health care administrators in the development of strategies and programs to best address unmet alcohol treatment and care needs within British Columbia in an evidence-based, cost-effective manner.
# Care Settings
While this guideline focuses on the clinical management of AUD in primary care settings (e.g., family practice clinics, community health centres, walk-in clinics, student health services), the recommendations also apply more broadly to other care settings and environments that may represent an individual's first contact with the health care system. Depending on the circumstances, an individual experiencing alcohol-related issues or consuming alcohol in a high-risk manner may be identified through routine intake, assessment, and monitoring procedures at a number of other care settings, including: emergency and assessment rooms, acute care settings (e.g., general, surgical, trauma or intensive care wards), sexual health services, trauma and anti-violence services, prenatal care clinics, and specialized mental health and addiction services (e.g., inpatient addiction medicine consult teams, outpatient rapid access addiction medicine clinics, community mental health and substance use programs). Clinical care teams and staff in these health care settings are encouraged to adapt and apply guideline recommendations as needed for their practice, supporting individuals and families affected by alcohol use in seeking help and accessing evidence-based treatment and services at multiple points of entry in the provincial health care system. 3
# Patient Populations
The recommendations made in this guideline are applicable to the general adult patient population, which can include individuals who are drinking within recommended limits for low-risk drinking, those who are exceeding low-risk alcohol drinking limits, individuals diagnosed with AUD of any severity (mild, moderate, severe), 2 as well as individuals in recovery from an AUD. While much of the evidence reviewed in this guideline pertains to the general adult population, it is the consensus of the guideline committee that guideline recommendations are equally relevant and applicable to youth.
Additionally, while this guideline offers a brief overview of the available evidence for the clinical management of high-risk drinking and AUD in pregnant individuals c , the importance of specialist consultation in these cases is emphasized, as is the urgent need for more research in this area. For additional clinical guidance on the management of alcohol use during pregnancy and postpartum, clinicians can refer to the Alcohol Use and Pregnancy Consensus Clinical Guidelines 4 issued by the Society of Obstetricians and Gynaecologists of Canada.
In partnership with Perinatal Services BC, the BCCSU will be releasing guidance for the Clinical Management of High-Risk Drinking and Alcohol Use Disorder in Pregnancy, which will be available at the following link once published: http://www.bccsu.ca/clinical-care-guidance/.
The guideline committee also recognizes the need to develop and implement best practices for identifying, treating, and managing high-risk drinking and AUD in specific populations, including Indigenous peoples, women and girls, men and boys, 2SLGBTQ+ folks d , pregnant individuals, adolescents (age [11][12][13][14][15][16][17][18] and young adults (age [19][20][21][22][23][24][25], older adults (age 65 and over), and individuals with co-occurring mental health disorders. A brief overview on working with these specific patient populations, including links to additional resources, has been included as a Supplement.
# Methods
# Funding
Guideline development activities were entirely supported by internal funding from the BC Ministry of Health to the BCCSU, without support from the pharmaceutical industry or associated stakeholders.
# Committee Membership
An interdisciplinary committee of 39 individuals was assembled in March 2018, including representation from each regional Health Authority in BC, the Provincial Health Services Authority, the First Nations Health Authority, and the BC Ministry of Health, with expertise spanning addiction medicine, psychiatry, family practice, social work, nursing, pharmacy, recovery-oriented systems of care, health care administration and policy, and people and family members with lived experience.
# Conflict of Interest Policy
In keeping with Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts, 5 committee members were asked to disclose all sources and amounts of direct and indirect remuneration from industry, for-profit enterprises, and other entities (i.e., direct financial conflicts) that could potentially introduce real or perceived risk of bias. In addition, committee members were asked to report indirect conflicts of interest, such as academic advancement, clinical revenue, and professional or public standing that could potentially influence interpretation of evidence and formulation of recommendations.
Twenty-three committee members disclosed special interests in relation to the guideline content, mainly pertaining to expertise (e.g., addiction medicine clinician), clinical practice, or past or current research on treatment interventions or approaches reviewed in the guideline. On review, none of the disclosed potential c While the majority of pregnant individuals identify as women, this term does not reflect the identities and experience of all pregnant people, some of whom may not identify as female or as women. The BCCSU has adopted the practice of using gender-neutral language in pregnancyrelated guidance to support inclusivity of sex-and gender-diverse patient populations. Asking patients how they choose to identify themselves and using their correct or chosen pronouns (e.g., they/them/theirs, she/her/hers, he/him/his) is an important component of person-centred care. d The acronym 2SLGBTQ+ has been used in this guideline to describe Two-Spirit, lesbian, gay, bisexual, transgender, queer, and other gender and sexually diverse individuals. The BCCSU has adopted the practice of placing "2S" for "Two-Spirit" at the beginning of this acronym to acknowledge Indigenous ways of knowing gender and sexuality and the long history of gender and sexual diversity in Indigenous cultures. It is important to note that not all Indigenous LGBTQ+ people identify as Two-Spirit, and that not all Indigenous cultures perceive the Two-Spirit identity in the same way. Asking patients how they prefer to identify themselves rather than assuming their gender identity or sexuality is an important component of person-centred care.
indirect conflicts of interest or bias were deemed to be of sufficient relevance or weight to warrant exclusion from the committee.
No committee members disclosed direct monetary or non-monetary support from pharmaceutical industry sources within the past five years. Three committee members disclosed potential direct conflicts of interest involving current and past employment at private or mixed private-/public-pay addiction treatment facilities.
One committee member disclosed a potential direct conflict of interest in that their spouse is employed in beverage alcohol production. To mitigate any real, potential or perceived risk of bias, these four committee members were recused from the final review and approval of the guideline.
No other committee member met the criteria of current or past employment (either self or a family member), investment interests, grants-in-aid of research, non-monetary research or program support (e.g., equipment, travel, staff salary, facilities), or intellectual property holdings with a commercial entity that could potentially be impacted by guideline recommendations. Thus, the remaining 35 members reviewed and granted final approval of the guideline contents and clinical recommendations.
# Guideline Development Process
Consistent with best practices for guideline development, the BCCSU used the AGREE-II instrument 6 throughout development and revision phases to ensure the guideline met international standards for transparency, high quality, and methodological rigour.
# Guideline Development Process
Between April 2018 and April 2019, the guideline committee conferred through email, teleconferences, and three face-to-face meetings. At the first committee meeting, evidence gathered through scoping activities performed by the BCCSU medical writing team was reviewed, and the outline, scope, and contents of the guideline were provisionally approved by committee consensus. The committee also provided feedback and suggestions for literature search strategies and parameters (e.g., keywords, search limits, inclusion/exclusion criteria).
Three working groups were struck and assigned core sections of the guideline: (1) Screening and Brief Intervention, (2) Withdrawal Management, and (3) Continuing Care. Between May and October 2018, each working group conferred over email and teleconference, and held three in-person meetings to develop and approve literature search strategies, review evidence summaries, and draft guideline contents and recommendations.
# Literature Search Strategy
The guideline evidence review and recommendations are based on a limited but systematic review of the literature, and used a traditional hierarchy to identify relevant research evidence, whereby meta-analyses of randomized clinical trials were given the most weight, followed by individual clinical trials, observational reports, and expert opinion. 1,7 An information specialist performed the literature search using a peer-reviewed search strategy for the following databases: Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials via Ovid; and CINAHL and PsycINFO via EbscoHost. Search date limits varied by topic and were informed by the most recent high-quality systematic review or meta-analysis available. Studies were excluded if they did not meet inclusion criteria established a priori or if they were already included in highquality systematic reviews and meta-analyses. For more detail on the literature search strategy please refer to the Methodology Supplement.
# Study Selection and Critical Appraisal
Two medical writers independently screened and identified eligible studies. Discordance between reviewers on inclusion or exclusion of individual studies was resolved through discussion with no need for arbitration. One reviewer used validated assessment tools (i.e., AMSTAR-2, Cochrane Risk of Bias Tool, Downs and Black checklist) to evaluate study quality. The second reviewer verified the assessments. The writers then prepared an evidence synthesis for review by each of the working groups.
# Development and Approval of Recommendations
After reviewing prepared evidence summaries, the working groups used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool 1 to develop and score recommendations. Using the GRADE system, the quality of evidence to support each recommendation can be assigned a rank of high, moderate, low, or very low, based on the committee's confidence in the estimates of effect. Initial estimates of quality are based on traditional hierarchy of evidence, whereby meta-analyses of randomized clinical trials were assigned a high score, followed by individual clinical trials, quasi-or non-randomized trials, observational studies and reports, and expert opinion, which is assigned the lowest score. The final quality ratings are reflective of the confidence in the estimated effect of an intervention as reported in the literature with consideration of biases and limitations of the evidence base as identified by the committee. Factors that lowered confidence in the estimated effect of an intervention included risk of bias, inconsistency across the RCTs, indirectness, and publication bias. Factors that increased confidence included large effect sizes and an observed dose-response effect.
To determine strength of recommendations, the GRADE system takes into account the quality of evidence as well as additional factors such as clinician, patient, and policy-maker's values and preferences, costs and cost-effectiveness, risk-benefit ratios, and feasibility. 8 It is the consensus of this guideline committee that all recommendations are strong, which implies that all patients in the given situation would want the recommended course of action, and that only a small proportion of patients would not.
Once approved by respective working groups, the draft guideline and graded recommendations were compiled and circulated to the full committee. A committee meeting was held in October 2018 to review and provide feedback on guideline contents and recommendations. Following the meeting, the committee was given four weeks to submit written feedback on the draft guideline. Feedback was collated and incorporated into a revised draft for external review.
# External Review and Stakeholder Consultation
The draft guideline was circulated for review and comment to relevant experts and stakeholders as identified by the committee. As per policy, all external reviewers completed disclosure of interest forms prior to review.
A second and final committee meeting was held in April 2019, where feedback from the external reviewers was reviewed by the co-chairs and the committee, and incorporated into the guideline by majority consensus.
# Update Schedule
In order to ensure that advancements in the field reach the intended audience in a timely and effective manner, the guideline committee will reconvene two years after publication to review and update the guideline, with a revised guideline to be published on an approximate three-year cycle.
# Background and Rationale
Alcohol use disorders (AUD) and high-risk drinking e are common in Canada. 9 It is estimated that up to 18% of all Canadians aged 15 or older have met the clinical criteria for an AUD during their lifetime, 10 while 19.5% of Canadians aged 12 or older currently drink in excess of recommended daily or weekly limits. 11 Nearly 200 disease or injury conditions are wholly or in part attributable to alcohol use, with the total global burden of disease estimated to be two to three times higher than that of all illicit substances combined. 12,13 Globally, alcohol was responsible for an estimated 3 million deaths (5% of all deaths) in 2016, 13 and for the total population aged 15-49 years, was the leading risk factor for premature death and disability. 14 National statistics indicate that alcohol use is linked to 7.7% of all deaths and 8.0% of all potential years of life lost for individuals aged 0 to 64 years. 15 In British Columbia (BC), there were nearly 28 alcohol-related deaths per 100,000 people in 2017. 16 In the context of the North American opioid overdose crisis, which claimed approximately 31 lives per 100,000 people in BC in 2018, alcohol was present in over 25% of overdose deaths that occurred in the province between 2016 and 2018. 17 Economic, health care, and social costs associated with alcohol are equally substantive. In 2014, the overall annual economic cost of substance use in Canada was estimated to be over $38 billion. 18 Alcohol use was associated with the greatest proportion of these costs (lost productivity, health care, criminal justice, other direct costs), accounting for about $14.6 billion or 38% of the total, followed by tobacco ($12 billion; 31%), and all other substances f ($11.8 billion; 30.7%). 18 Alcohol use can also cause harm to others, for example, interpersonal conflict and financial problems, workplace accidents, traffic accidents and deaths. 19 As well, alcohol is often associated with incidents of intimate partner and stranger violence, as well as theft and property crime. 18,[20][21][22] In the 2015/16 fiscal year, approximately 56,600 Canadians were hospitalized for alcohol-related conditions, and 21% of whom were hospitalized two or more times in that year. 23 The total number of hospitalizations directly related to alcohol (77,000; 212 admissions/day) exceeded hospitalization rates for heart attacks (75,000; 205 admissions/day) in that year. 23 In British Columbia, annual per capita consumption rates of pure ethanol have increased from 8.25 L in 2002 to 9.39 L in 2017 g, 24 an upward trend that has been correlated with the privatization of alcohol sales and increased availability of and access to alcohol in the province. 25 In parallel, hospitalization rates for alcohol-related conditions increased from 383 to 557 per 100,000 individuals from 2002 to 2017, surpassing those for tobacco-related conditions in 2017 (517 per 100,000 individuals) in BC. 16 Similarly, the number of primary care visits for alcohol-related conditions increased by 53% between 2001 and 2011. 26 Despite the significant burden of disease, social harms, and economic costs attributed to alcohol in Canada, high-risk drinking and AUD frequently go unrecognized and untreated in the health care system. Although Canadian statistics are lacking, in the United States, national surveys indicate that fewer than 8% of individuals with AUD had received treatment in the past 12 months. 27 European countries report similarly low rates, with less than 20% of people with AUD receiving any kind of treatment. 28 These trends underscore the importance of bridging the gap between research and clinical practice, particularly in primary care, to generate meaningful improvements in health and wellbeing for individuals, families, and communities impacted by alcohol use. Recent research has highlighted the important role that primary care providers can have in early detection and intervention for high-risk drinking, outpatient withdrawal management, and treatment of AUD, and connecting patients and families with specialized services and community-based supports. 29 Although high-risk drinking and AUD can be readily identified using simple screening tools, alcohol use screening is not widely implemented in clinical practice. 30 This is a critical missed opportunity to intervene early, at a point where many individuals, including adolescents and young adults, may respond positively to brief counselling interventions alone, by changing their behaviour to reduce their risk of alcohol-related harms. 30 These opportunities for early intervention, treatment, and support are missed if providers rely on case identification alone.
Screening can also serve an important role in identifying individuals with mild to severe AUD who would benefit from more intensive treatment approaches, including pharmacotherapy, psychosocial treatment interventions, as well as community-based recovery-oriented and psychosocial support services. Very few individuals who would benefit are receiving evidence-based treatment for AUD, including safe and effective pharmacotherapies for managing alcohol withdrawal, reducing alcohol consumption, and preventing relapse. 31,32 In the majority of cases, the care needs of individuals with AUD can be met in an outpatient primary care setting. 33 For patients who identify cessation or reduction of alcohol use as a treatment goal, there are two first-line medications currently approved in Canada: naltrexone and acamprosate and both are critically underutilized. 32 Although national statistics are lacking, a study in Ontario found that over a one-year period, only 37 of 10,394 (0.4%) public drug plan beneficiaries diagnosed with an AUD filled a prescription for naltrexone or acamprosate in the year following their diagnosis. 34 Similarly, a 2018 report from Manitoba found that only 493 of 53,625 individuals (0.9%) diagnosed with an AUD had a prescription dispensed for naltrexone, acamprosate, or disulfiram within one year. 35 The cumulative result of these missed opportunities is a system where patients and providers alike are often constrained to managing the negative consequences of alcohol use rather than preventing or reducing harm through early intervention and treatment.
BC is in urgent need of a paradigm shift in the clinical management of AUD. To move this agenda forward, this committee sought to address the lack of evidence-based practice recommendations available to health care providers. An expert panel was convened to review the literature and develop a consensus guideline for the optimal screening, diagnosis, treatment, and care of individuals with AUD. What follows is a summary of the research evidence used to derive the clinical recommendations proposed by the committee. It is anticipated that health professionals, policymakers, and educators will use this document to inform clinical practice and health promotion activities directed towards reducing alcohol-related harms within the province.
# Working with Patients and Families Affected by Alcohol Use
In developing this guideline, the committee identified several overarching principles of care that apply to all recommendations and, more broadly, to establishing positive partnerships with patients and families experiencing alcohol-related harms. Underlying these principles is the importance of considering the social determinants of health, and incorporating harm reduction, trauma-and violence-informed, and culturally safe approaches as the standard of care for patients and families affected by alcohol use. To implement these principles in practice, the committee endorses a longitudinal and comprehensive clinical management strategy, and the use of patientcentred, recovery-oriented, and family-oriented approaches to optimize health, wellness, and social outcomes of patients and families.
# Principles of Care
The following principles of care are intended to serve as a general framework to support clinicians, care teams, and programs in the integration of care for high-risk drinking and AUD in their clinical practice. Clinicians and care teams are encouraged to review and adapt these principles of care as needed to fit their local context and resources available.
These principles of care identified here should not be considered an exhaustive list. There may be additional factors clinicians should take into account in different practice settings, or when working with specific patients, families, communities, and populations. In recognition of this, a brief overview of additional considerations when working with Indigenous peoples, 2SLGBTQ+ populations, pregnant individuals, youth, older adults, and individuals with co-occurring mental health and substance use disorders, as well as sex-and gender-specific care, can be found in the Supplement.
# Table 2 Summary of Principles of Care 1
Alcohol use, high-risk drinking, and AUD should be viewed within a larger societal framework that is shaped by inequities in the social determinants of health. Clinicians should aim to address disparities in the social determinants of health by connecting patients with resources that meet these needs (e.g., housing, food/nutrition, financial assistance, employment).
# 2
Clinicians should be familiar with and incorporate the principles of harm reduction, trauma-and violence-informed care, and Indigenous cultural safety in the care and clinical management of patients with AUD.
# 3
AUD is understood to be a chronic, relapsing condition. As with other chronic disorders, a longitudinal care approach is recommended.
# 4
Patients should be offered a full range of evidence-based pharmacotherapies, psychosocial treatment interventions, and recovery supports to support achievement of their treatment goals.
# 5
A stepped and integrated approach to management of AUD is recommended, where mode of treatment is regularly adjusted to meet patient needs, circumstances, and preferences over time.
# 6
AUD should be managed within a broader framework of comprehensive medical care and support, including routine and ongoing medical, mental health, and psychosocial assessments.
# 7
Treatment plans should be individually tailored, patient-centered, and recovery-oriented, with the understanding that "recovery" can look different to each person.
# 8
Family and social circle h involvement in treatment planning and decision-making should be encouraged whenever possible, and when deemed appropriate by the patient and their care team.
h This guideline uses the term "family" to encompass all relations that are important to the patient within their social circle, which may include romantic partners, close friends, and other people of significance who may or may not be legally recognized as family.
# Overarching Frameworks
The Social Determinants of Health
The social determinants of health have been defined as "the economic and social conditions that shape the health of individuals, communities, and jurisdictions as a whole. " 36 At a population level, this can be understood as the quantity and quality of resources a society makes available to all of its members, which include, but are not limited to: conditions of childhood; access to income; education and literacy; food, housing, and employment; working conditions; and health and social services. 36,37 Distribution of these resources tends to occur along a social gradient, 38 and is shaped by factors such as socioeconomic class and income; sex, gender identity, and sexuality; Indigeneity; race and ethnicity; refugee, migrant or immigrant status; and disability status, among others. 37,39 These factors are often interrelated and intersectional -meaning that most people occupy multiple social positions by nature of their unique identity, and that these factors interact with and impact each other. 40 People who belong to marginalized groups and/or occupy the lowest socioeconomic classes experience the most significant barriers to accessing resources, and, in turn, have the poorest health outcomes. 39 Alcohol use, high-risk drinking, and AUD should also be viewed within this larger social context. Higher prevalence rates of high-risk drinking and AUD are observed among individuals who report adverse early childhood experiences, 41 lower socioeconomic status, 42 living in poorer neighbourhoods, 43 and who identify as a racial, ethnic, sex, and/or gender minority. 44 Clinicians, care teams, and staff should have a basic understanding of how the unequal distribution of power, opportunity, and resources in Canadian society impacts the social determinants of health for individuals. 39 Clinicians providing care to individuals, groups, and those communities at risk of discrimination and marginalization above and beyond that related to alcohol and other substance use should endeavour to remove barriers to accessing care that patients may experience. Additionally, clinicians should aim to address inequities that may exist in the social determinants of health by connecting patients with resources to meet their social and survival needs (e.g., housing, food/nutrition, financial assistance, employment).
# Harm Reduction
Harm reduction has been defined as "Policies, programmes and practices that aim to minimise negative health, social and legal impacts associated with drug use, drug policies and drug laws. Harm reduction […] focuses on positive change and on working with people without judgement, coercion, discrimination, or requiring that they stop using drugs as a precondition of support. " 45 Although most often associated with the use of illegal substances, harm reduction approaches can also be applied to any behaviour that increases risk of adverse health, social, or legal consequences for an individual, including alcohol use. 46 At its core, a harm reduction approach to alcohol use supports any steps taken by patients to improve their health and wellbeing, and seeks to meet the patients "where they are at" in terms of willingness and ability to change. 46 Although it is understood that the only way to fully avoid all negative consequences associated with alcohol is abstinence, it is also recognized that not all patients are able or willing to discontinue or substantially reduce their drinking, even if it is recommended by their health care provider. 46 In these cases, clinicians are encouraged to adopt strategies to minimize alcohol-related harms rather than imposing abstinence from alcohol as the only desirable outcome of treatment. (Also see Setting Patient-Centred Treatment Goals). Harm reduction strategies could include promoting safer alcohol use strategies (e.g., reducing drinking [total consumption or drinking days per week], not drinking and driving, reducing use of non-beverage alcohol), optimizing engagement and retention in care, and connecting patients with resources to address inequities in the social determinants of health (e.g., housing, legal services, financial assistance, employment programs). [47][48][49][50] For some patients, a reduction in drinking can lead to clinically significant improvements in health and quality of life, [51][52][53] while for others, treatment goals can change from reduced drinking to abstinence over time with continued engagement in care. 50 This guideline also recognizes the growing body of evidence supporting managed alcohol programs as a harm reduction approach for individuals with severe AUD (see Managed Alcohol Programs).
# Trauma-and Violence-Informed Practice
The goal of trauma-and violence-informed practice is to create a safe and respectful environment that minimizes the potential for harm and re-traumatization of patients. 54 Embedding trauma and violence-informed approaches into all aspects of clinical practice can create universal trauma precautions, which provide positive supports for all patients and families, regardless of whether they have experienced trauma or violence in their lives. 55 Universal trauma precautions can also aid clinicians, care teams, and staff in developing a consistent approach to working with people who have potentially experienced trauma and violence. 55 The key principles of traumaand violence-informed practice are trauma awareness; safety and trustworthiness; choice, collaboration and connection; and strengths-based approaches and skill building. 54 While a universal approach to trauma-and violence-informed practice is recommended, it is recognized that some patient populations are more likely to have experienced trauma and violence than others. For example, Indigenous peoples, women, and 2SLGBTQ+ populations are more likely to have experienced trauma and violence as a result of racism, discrimination, and social inequity compared to other patient populations. 56,57 In the context of alcohol use, research has shown that individuals with AUD are more likely to have experienced past trauma or have a diagnosis of post-traumatic stress disorder compared to the general population. 27,58,59 Accordingly, this guideline strongly recommends that clinicians and care teams be familiar with and adhere to the principles of trauma-informed practice when working with patients and families affected by alcohol.
The Centre of Excellence in Women's Health's Trauma-Informed Practice (TIP) Guide 54 and New Terrain toolkit 57 It is important to note that disclosure of violence and trauma is not the goal of trauma and violence-informed practice; health care providers do not necessarily need to know an individual's past experiences to provide appropriate support. Additionally, trauma-and violence-informed care is not intended to treat trauma. Clinicians should be familiar with specialized treatment and support services for individuals who have experienced trauma as well as crisis services in their community, and provide information and referrals to patients, should the need arise.
# Indigenous Cultural Safety
It is well documented that the Indigenous peoples of Canada have inequities in the social determinants of health that are a direct result of colonization. Decades of federal policies with the sole purpose of eradicating Indigenous identities, families, communities, culture, and traditional ways of life (i.e., genocide) have resulted in direct and intergenerational trauma, and institutionalised racism and discrimination. [62][63][64] These factors manifest as an overall increased risk of premature morbidity and mortality among Indigenous peoples in Canada relative to non-Indigenous Canadians. [65][66][67] Epidemiological data that show higher prevalence rates of high-risk substance use, substance use disorders, and substance-related harms among Indigenous peoples 65,68 must also be interpreted within this broader context. More specifically, it is emphasized that Indigenous peoples are not, by nature of their genetic background and cultural identity, a "high-risk" population. Rather, health and social inequities faced by Indigenous peoples have created conditions where some individuals use alcohol and other substances to cope with racism, discrimination, poverty, trauma, violence, or other sources of distress in their daily lives. 69,70 Despite this, racism and harmful stereotypes about Indigenous peoples, particularly around alcohol and other substance use, [71][72][73] persist within the Canadian health care system and can act as a deterrent to seeking out and staying engaged in care in this population. [74][75][76] If the mainstream Canadian health care system is to be effective in addressing health and social inequities experienced by Indigenous peoples, health care providers must make a meaningful commitment to providing culturally safe and culturally appropriate care. 77 Indigenous cultural safety is an approach that moves beyond the concept of cultural sensitivity i to consider how social and historical contexts, institutional discrimination, structural and interpersonal power imbalances, and past, current, and ongoing colonization shape health and health care experiences of Indigenous peoples. 79 It requires health care providers to be knowledgeable of the colonial history of Canada and the roots of historical, ongoing, and intergenerational trauma among Indigenous peoples, and to practice cultural humility: to be continually self-reflective of personal biases and aware of their position of power and the effects that this power dynamic may have on their Indigenous patients. 78 Establishing a trusting, respectful and collaborative therapeutic relationship with patients is a cornerstone of treating substance use disorders in clinical practice, and this guideline strongly recommends that all health care professionals and staff undertake Indigenous cultural safety training to improve their ability to establish safe, positive partnerships with Indigenous patients and families. i Cultural sensitivity respects cultural differences and involves communicating and behaving in ways that are considered polite and respectful by the person of the other culture. 78
# Models of Care
# Longitudinal Care Model
For most patients, AUD is a chronic, relapsing condition, yet traditionally, approaches to care and management of AUD have emphasized short-term and high-intensity treatment; for example, referring patients to inpatient withdrawal management or inpatient treatment programs without a plan for continuing care after discharge or completion. In recent years, however, there has been increased recognition that, like other chronic health conditions (e.g., diabetes, hypertension, heart disease), AUD can be safely and effectively managed in outpatient primary care settings using a longitudinal care approach. 80 A pre-existing therapeutic relationship (or the development of one over time) can improve engagement and retention in care.
# Integrated Continuum of Care Model
As noted above, AUD is understood to be a chronic, relapsing condition. This underscores the importance of using a continuum of care approach, where patients with AUD (and their families, if involved in care) are offered a range of evidence-based pharmacotherapies, psychosocial treatment interventions, and recovery support services to reduce harm, prevent relapse, and support long-term recovery, with the understanding that patients with AUD may need to try multiple approaches of varying intensities along this continuum of care. 81 Further, it is recognized that individual patient needs, circumstances, and goals may change over time, and this guideline supports the use of a stepped and integrated approach, where the mode of treatment is continually adjusted to meet these needs. A stepped approach may include treatment intensification, transitions between different treatment options, and strategies to de-intensify treatment at the patient's discretion. Patients can opt to re-initiate pharmacotherapy, psychosocial treatment, or recovery supports at any time if their needs and circumstances change.
Primary care providers and care teams should ensure that patients with AUD and their families are aware of the range of specialist-led and community-based programs and services that are available to them, and regularly assess interest or readiness in accessing these services. To support continuity of and transitions in care across the continuum, primary care providers and care teams should establish fully functioning referral pathways. Establishing protocols for communication and sharing information (with the patient's consent) between the primary care team and referral partners is strongly encouraged.
# Comprehensive Medical Management
As is the standard of care for any complex or chronic medical condition, all primary care clinicians and care teams should provide medical management to patients with AUD. By definition, medical management includes, but is not limited to: providing non-judgmental support and advice; assessing motivation and exploring barriers to change; developing and regularly reviewing a treatment and recovery plan with the patient; promoting alternative strategies for managing stress; and providing referrals to specialized medical care, recovery support, and social services when requested or appropriate. 82 Management of AUD in primary care also permits the provision of more comprehensive care, which may include, but is not limited to: screening and clinical management of co-occurring substance use and mental health disorders, concurrent medical conditions, and alcohol-related sequelae (e.g., liver disease, gastrointestinal disorders, cardiovascular disease, dementia), preventive health care (e.g., vaccinations, general health screening), sexual and reproductive health services (e.g., sexually-transmitted infection screening, contraceptive counselling, family planning), chronic disease management (e.g., arthritis, diabetes, cardiovascular disease), and referrals to specialist care.
# Approaches to Care
Patient-Centred Care
Research suggests that incorporating patient-centred approaches in the clinical management of AUD can improve retention in care, treatment satisfaction, and health outcomes. 83 In addition to recognizing the unique needs, values, and preferences of each individual, patient-centred care involves listening to, informing, and empowering patients as experts in their own care. 84 Practical strategies for incorporating patient-centred care in the clinical management of AUD include collaboratively developing treatment plans, encouraging patients to set treatment goals that are realistic and meaningful to them (and not imposing goals on them), using a shared decision-making framework to select treatment options or interventions, and being open to and respectful of patient agency and choice. 85 Awareness of and active efforts to address stigma experienced by individuals with AUD are important elements of patient-centred care. Primary care clinicians and care teams should be aware of the language they use and its potential to stigmatize individuals who use alcohol and other substances. Clinicians and staff involved in substance use care should strive, at all times, to use "person-first" language and current medical terminology (i.e., person with an alcohol use disorder) when interacting with patients, families, colleagues, health care professionals, and staff. 86 While patients may choose to refer to themselves and their health conditions using language that they are most comfortable with, clinicians, other health care professionals, and non-clinical staff should also avoid using non-diagnostic, outdated, or "slang" terms (e.g., "alcoholic", "addict", "[alcohol] abuse", "clean/dirty") in conversation and when charting. Use of such terms by health care providers has been shown to be stigmatizing to some patients, 87,88 and stigma (both experienced and anticipated) has been associated with a reduced likelihood of accessing and staying in care. [89][90][91] Clinicians are encouraged to review Respectful Language And Stigma: Regarding People Who Use Substances, 92 a resource jointly developed by the BC Centre for Disease Control, PHSA, and Toward the Heart, for more information.
# Recovery-Oriented Care
The continuum of care for AUD is considered to be inclusive of recovery and recovery-oriented services.
Recovery-oriented care recognizes that there are multiple pathways to recovery, and strives to respect the choices, autonomy, dignity, and self-determination of individuals in defining their personal recovery goals and pathway. 93 Recovery-oriented care emphasizes holistic, client-centered, strengths-based approaches, and can encompass both abstinence-oriented and harm reduction management strategies. 93 This guideline suggests adoption of the United States-based SAMHSA's Working Definition of Recovery 94 as an overarching framework and for the purpose of developing patient-centred, recovery-oriented treatment plans:
" A process of change through which individuals improve their health and wellness, live a self-directed life, and strive to reach their full potential. "
Recognizing and validating how individuals choose to define their recovery is an important component of recovery-oriented care. Treatment and recovery plans should be developed in partnership with patients and families, and include goals that patients have identified as important to them. In some cases, patient-identified goals may not be directly related to alcohol use, such as improved health and wellness, having a safe and stable place to live, finding a sense of purpose through volunteer, educational or employment activities, strengthening relationships with family and friends, or building social support networks. 94 There is a diversity of recovery-oriented services in BC that can provide additional care, support, and guidance to individuals and families affected by AUD, in a manner that is complementary to the clinical management approaches delivered in primary care. It is recognized, however, that recovery-oriented services and the health care system have traditionally operated independently of one another, and there is a need to improve collaboration and communication between multiple service providers and programs that may be involved in an individual's care. This guideline emphasizes the importance of establishing functional referral networks and streamlined communication pathways between these two sectors as part of a broader provincial strategy to build an integrated continuum of substance use care in BC.
# Family and Social Circle Involvement in Care
This guideline uses the term "family" to encompass all relationships that are important to the patient, which may include romantic partners, close friends, and other people of significance who may or may not be legally recognized as family. Family members can have an important role as partners in an individual patient's care, and this guideline recommends the inclusion of family members in decision-making processes and care at all levels, when deemed appropriate by patients and their care teams. Research has shown that families can have a pivotal role in improving treatment outcomes and sustaining benefits of treatment among youth and adults with AUD, by providing additional support and structure, and promoting resilience. [95][96][97][98] If a patient determines family involvement would be a positive element in their treatment plan, clinicians are encouraged to educate family members about available treatment options and resources, and provide as much patient-specific information as possible within the boundaries of confidentiality requirements.
As with all medical care, confidentiality requirements must be met when treating individuals with AUD. This includes maintaining confidentiality from family members unless patients have granted consent for their medical information to be shared with their family. 99 However, it is also emphasized that health care providers should avoid making assumptions about privacy, and routinely ask patients if they prefer to include family members or friends as supportive partners in their care. If aspects of care are being kept confidential from family members, the challenges and logistics of this should be discussed with the patient. While information cannot be shared with family members without a patient's consent, family members can share relevant information with health care providers without violating that patient's privacy or confidentiality.
It is important to note that, in some cases, family involvement may not be in the best interest of the patient. Factors such as partner or parental substance use, familial abuse and violence, or dysfunctional family relationships can act as barriers to engagement and retention in treatment as well as to achieving long-term recovery. [95][96][97][98] Patients should be given full discretion on whether and how they wish to include family members in their care, and if they opt not to involve family members, this decision should be respected.
In the case of youth (aged [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], parental participation in treatment should be actively encouraged, if appropriate, and family members should be supported with sufficient education and information about alcohol use and AUD.
Offering or providing referrals to group or individual sessions for parents and/or caregivers is recommended.
A family history should be taken, when possible, to identify and treat any mental health or substance use issues requiring treatment in the youth's family. It should also be noted that, like adults, not all youth have healthy or positive relationships with their family members. Decisions to involve family members in care should be guided by the patient's wishes and an understanding of the family dynamic.
Regardless of their level of involvement in a patient's care, family members and caregivers often require support for their own health and wellness. Several resources exist for family members impacted by alcohol and AUD, including From Grief to Action's Coping Kit: A guide for family members; Parents Forever, a support group for parents of adults with substance use issues in Vancouver, BC; Al-Anon and Alateen Family Groups across BC; and Here to Help's resources for family members. Family members can also be referred to external specialist-led and community-based services and supports. Clinicians should be mindful of any concerns that patients may have about privacy, confidentiality, or perceived conflicts of interest if patients and family members are referred to the same specialist-led or community-based programs.
4 Screening and Brief Intervention
# Providing Information and Education on Low-Risk Drinking to Patients
Alcohol use screening often relies on an assessment of a patient's alcohol use in comparison to an accepted standard for high-versus low-risk drinking. While alcohol use that exceeds recommended daily or weekly limits does not automatically equate to "high-risk" for every individual in every circumstance, alcohol-related harms rarely occur when drinking remains below recommended low-risk standards. 100 This guideline endorses the adoption and use of Canada's Low-Risk Alcohol Drinking Guidelines 9 as an educational resource and discussion tool in primary care practice. Although the Low-Risk Alcohol Drinking Guidelines were released in 2011, public awareness and knowledge of these guidelines remain low. Several provincial and national surveys of the general public have reported that fewer than 20% of respondents are aware that the Low-Risk Alcohol Drinking Guidelines exist, and fewer still are able to correctly identify standard drink sizes or recall age-and sex-specific limits for low-risk drinking. [101][102][103][104][105] While some studies suggest that mass media campaigns aimed at increasing knowledge of national low-risk drinking guidelines can lead to short-term reductions in alcohol consumption, 106,107 others have found that without personalized context, some individuals may perceive low-risk guidelines as not realistic or relevant to their lives, particularly when they are drinking above low-risk limits. 101,108 By providing patients with information and education about the Low-Risk Alcohol Drinking Guidelines, primary care providers can play an important role in promoting awareness, as well as work with patients to understand how the low-risk limits may apply to their health and daily life. Introducing the topic in a general and conversational way can also help build rapport and comfort in talking about personal use in subsequent steps in the screening and intervention pathway. For example: "Have you heard about Canada's Low-Risk Alcohol Drinking Guidelines? I talk to all of my patients about these guidelines. They contain important information about safer alcohol use that everyone needs to know. "
# Overview of Canada's Low-Risk Alcohol Drinking Guidelines
Canada's Low-Risk Alcohol Drinking Guidelines provide information on the risks and benefits associated with alcohol consumption, and evidence-based guidance on estimated levels of consumption that would be considered lower-risk in adult men and women. 9 The evidence used to derive approximate levels of alcohol consumption that would be considered "low-risk" is based on large prospective population-based studies that have shown that long-term alcohol consumption is associated with increased risk of harm, including premature mortality. 100 Observational cohort studies have found that average long-term alcohol consumption levels as low as one or two standard drinks per day are directly or indirectly linked to increased risk of at least eight different types of cancer (i.e., oral, pharynx, larynx, oesophageal, liver, breast, colon and rectal cancers) as well as numerous other serious medical conditions (e.g., epilepsy, haemorrhagic stroke, cardiac dysrhythmias, liver cirrhosis, and hypertension). 15,[109][110][111][112][113][114] In addition, there are a number of serious medical conditions directly attributed to long-term alcohol consumption, including AUD, alcohol-related psychosis, nervous system degeneration, polyneuropathy, myopathy, cardiomyopathy, gastritis, liver diseases (e.g., hepatitis), and pancreatitis. 9,15,100,[112][113][114] From this literature, the authors of the Low-Risk Alcohol Drinking Guidelines derived a threshold level of average daily and weekly alcohol consumption for adult men and women where the overall net risk of premature death was equivalent to that of an individual who had never consumed alcohol in their lifetime (Table 3). The Low-Risk Alcohol Drinking Guidelines also make recommendations for specific populations and scenarios in which either abstinence from or extreme caution with alcohol use is advised, including alcohol use among youth (see Table 3), during pregnancy, in association with high-risk activities (e.g., driving motor vehicles), and in combination with medication and/or other substances.
At least half of all alcohol consumed in Canada is in excess of levels deemed low-risk 115 and the authors estimate that if all Canadians who drink alcohol were to adhere to the low-risk limits, there would be a reduction in alcohol-related deaths of approximately 4,600 per year. 9 Recognizing that the Low-Risk Alcohol Drinking Guidelines are less likely to have any significant impact on population health if disseminated in isolation, the authors encourage their adoption and use as part of a more comprehensive public health strategy to address alcohol-related harms, for example, to support the implementation of a continuum of evidence-based interventions in clinical practice. 9 To support discussions about the Low-Risk Alcohol Drinking Guidelines, the Canadian Centre on Substance Use and Addiction (CCSA) has created a number of patient education and decision-making tools, including tailored materials for women and youth, and guidance for clinicians on how to talk to their patients about alcohol-related risks and harms. These materials can be accessed on their website: www.ccsa.ca/Eng/topics/alcohol/drinking-guidelines/Pages/default.aspx.
# Section Summary and Recommendation
This guideline strongly recommends that clinicians provide education to their patients about Canada's Low-Risk Drinking Guidelines to both enhance awareness and knowledge of alcohol use among their patients and as an introduction to alcohol use screening. Although research evidence is limited, increased awareness and knowledge of safer alcohol consumption guidelines can lead to reductions in alcohol consumption, 106,107 particularly when delivered in a personalized manner. 101,108 Recommendation 1 Awareness of Canada's Low Risk Alcohol Drinking Guidelines
Clinicians should provide education about Canada's Low-Risk Alcohol Drinking Guidelines to all adult and youth patients.
# Quality of Evidence: LOW Strength of Recommendation: STRONG
# Remarks
• This recommendation has been graded as strong despite limited research evidence. It is the consensus of the committee that all patients could potentially benefit from increased knowledge and awareness of Canada's Low-Risk Alcohol Drinking Guidelines.
• Cultural safety is critical when talking to Indigenous patients and families about alcohol use. Some patients may have experienced stigma and discrimination, or been subject to harmful stereotypes about Indigenous peoples and alcohol in the health care system in the past. Using culturally safe approaches can minimize unintended harms and strengthen the therapeutic relationship.
• Clinicians should be mindful that some patients may be in recovery or abstinent from alcohol for personal reasons, such as a family history of alcohol-related issues. These types of disclosures should be handled with sensitivity and support to avoid causing distress or other unintended consequences in patients.
# Alcohol Use Screening
Despite its high prevalence in primary care and other clinical settings, high-risk drinking often goes unrecognized and untreated. 116 Implementation of routine and universal alcohol screening in primary care practice has increasingly been advocated as an important public health strategy for early identification of high-risk drinking and secondary prevention of AUD. [117][118][119] The underlying rationale of universal screening is to capitalize on both patterns of practice that are already in place and the longitudinal model of care in the primary care setting. Patients can be routinely asked about alcohol use during new client intakes, general assessments, annual preventive screening, and in specific disease management clinics (e.g., hypertension, diabetes). Thus, screening could occur when alcohol use is not the primary reason for presentation, facilitating early intervention and connection to care among patients not actively seeking treatment for alcohol-related problems or concerns.
Introducing alcohol use screening tools in a non-judgmental, conversational manner can foster trust, and in turn, improve the accuracy of self-reported alcohol use. Seeking the patient's consent and providing context prior to asking screening questions may also aid in building rapport, for example: "Now that we've talked about some of the effects alcohol can have on our health, would you mind if I ask you some questions about your alcohol use?" Establishing trust and safety in these initial conversations is particularly important for patients who may otherwise tend to underreport substance use, such as pregnant individuals j , adolescents, older adults, or patients with co-occurring disorders where alcohol use may be associated with greater risk of harm.
j While the majority of pregnant individuals identify as women, this term does not reflect the identities and experience of all pregnant people. Gender-neutral language has been used in this guideline where possible. Respect for individual identities and use of corresponding or chosen pronouns is an important component of patient-centred care.
# Box 1 Terminology Used to Assess Screening Tools Sensitivity
The proportion of individuals correctly identified as having the condition, or "true positives".
# Specificity
The proportion of individuals correctly identified as not having the condition, or "true negatives".
# Remarks
Sensitivity and specificity can vary according to the cut-point used for the scale, the population being assessed, the setting, and the experience of the assessor. A general rule when assessing the usefulness of a screening or diagnostic tool is for both sensitivity and specificity to be greater than 0.75 or 75%. 120 Regardless of the screening tool used, it is emphasized that screening alone does not improve outcomes. Provider and staff education, training, and the development of clinical pathways and processes that support early intervention among individuals who meet criteria for high-risk drinking are also needed, along with a plan for required diagnostic follow-up and treatment for individuals who are diagnosed with an AUD.
# Screening Adult Patients
A number of standardized alcohol use screening instruments are available that have been validated in a range of clinical care settings, including the Alcohol Use Disorders Identification Test (AUDIT), the condensed AUDIT-Consumption (AUDIT-C) test, and the Cut-down, Annoyed, Guilty, Eye Opener (CAGE) questionnaire (see Appendix 1). However, provider-level barriers, including time constraints, unfamiliarity with the instruments, and the requirement to calculate item and overall scores have been cited as impediments to the uptake and use of such screening tools in primary care settings. An approach specifically tailored for the primary care setting is "single-question" alcohol screening (SASQ), as it takes minimal time to administer, is easily recalled, and requires no scoring. 121 Single Alcohol Screening Question (SASQ)
SASQ screening is typically structured around sex-and age-specific recommendations for low-risk alcohol consumption. To normalize alcohol use and support disclosure, patients are asked to estimate how many times in the past year their drinking exceeded low-risk limits, however, frequency is not factored in to the screening result. For example, any response greater than "never" or "zero times" to the question below would be considered a positive screening result for high-risk drinking, warranting additional follow-up:
" In the past year, how often have you consumed more than 3 drinks (for adult women) or 4 drinks (for adult men) on any one occasion?"
Although less sensitive than structured screening instruments for the detection of high-risk drinking behaviours, 122 studies have found that the sensitivity of single question screening ranges from 60-90% versus reference standards (e.g., AUDIT, AUDIT-C, or clinical diagnostic interview), [123][124][125][126] and systematic reviews have concluded that this is a valid option in clinical settings where time and patient interactions are limited. 121,127
# Screening Adolescent Patients
For adolescents aged 11-18, there are also validated screening tools available, including AUDIT, AUDIT-C, and the six-question Car, Relax, Alone, Forget, Friends, Trouble (CRAFFT) instrument which is specifically for screening adolescents (see Appendix 1), but as described above, a simplified 1-or 2-question screening approach may be preferred in primary care due to brevity and ease of recall. [128][129][130] U.S. National Institute on Alcohol Abuse and Alcoholism (N IAAA) Screening Tool
The U.S. NIAAA developed a two-question tool for screening adolescents aged 11 to 18 years that consists of the following questions 131 :
1. "Have any of your friends consumed alcohol in the past year?" 2. "Have you consumed any alcohol in the past year?"
These questions were empirically derived from extensive analyses of national survey data, and have the strongest evidence base for predicting current or downstream alcohol-related problems in adolescents. 131 For adolescents aged 11-14, it is recommended to first ask about alcohol use among friends as a less-threatening introduction to the topic, followed by personal use questions (i.e., question 1 then 2), with the order reversed for adolescents aged 15 to 18 (i.e., question 2 then 1). 132 To assess risk and triage youth appropriately, the NIAAA tool recommends asking all youth aged 11 to 18 years who screen positive for personal use ("yes" to question 2) to estimate the number of days they have consumed alcohol over the past year. 133,134 Self-reported drinking days that exceed age-specific thresholds shown below (Table 4) signal that the patient may be at increased risk of alcohol-related problems, including AUD. 135 Prospective evaluations of the NIAAA tool incorporating these age-specific cut-points have concluded that it is an accurate and reliable method for screening and triaging adolescents for more intensive interventions in primary care settings. 136,137 However, these studies also noted the advantages of having a simplified version of the tool that could be used to stratify adolescents of any age into low-versus high-risk categories.
To date, several studies have been conducted investigating a simplified version of the NIAAA tool for triaging adolescents based on current or future risk of alcohol-related harms. In an urban primary care setting, researchers found that utilizing a threshold of ≥ 2 drinking days per year for adolescents aged 12-17 (n=525) conferred high sensitivity (96%) and specificity (85%) for identifying individuals who met DSM-5 criteria for AUD. 136 The simplified NIAAA screening tool was subsequently evaluated in six rural primary care clinics, where researchers determined a threshold of ≥3 drinking days per year had a 91% sensitivity and 93% specificity for detection of AUD among youth aged 12-17 (n=942). 137 Further research is underway to improve the precision and accuracy of cut-points for the risk-based triage of adolescents, and as illustrated by these findings, local context may play an important role. In the interim, adopting the age-specific cut-points as described in Table 4 is advised.
# Screening Pregnant Patients
As noted above, alcohol use screening is recommended for all individuals of childbearing capacity, whether they are intending to become pregnant or not. Universal screening of all primary care patients allows for timely intervention prior to pregnancy and secondary prevention of maternal and fetal harms associated with alcohol use. 138 Prior to screening, it is crucial to secure the patient's consent, and to review confidentiality and other rights of the patient involved, congruent with the standards of medical practice. 4 Alcohol use screening should be conducted at the first prenatal visit or during the first trimester, and as needed in subsequent visits. 4 Although not explicitly validated for use in pregnant patients, SASQ has been recommended as the first step in alcohol use screening in this population by the Society of Obstetricians and Gynaecologists of Canada 4 and the U.S. Preventive Health Services Task Force. 127 As with non-pregnant patients, a simplified approach to alcohol use screening may be preferred in the prenatal care context, and the general consensus among experts is that these questions are sufficiently sensitive and specific for identifying individuals and pregnancies that may be at increased risk. 138 When combined with supportive, non-judgmental dialogue, the SASQ format -asking open-ended rather than yes/no questions, and assessing alcohol use patterns over the past year -can encourage an open discussion about alcohol use and strategies to reduce maternal and fetal risks. 4 As well, individuals may be more likely to report pre-pregnancy or lifetime use than they are to report use during pregnancy because of the risks and stigma involved in disclosure. 138 Individuals who disclose alcohol use during pregnancy should undergo further assessment to determine frequency and amount of alcohol consumption, and to differentiate high-risk use from individuals with an AUD (see Diagnosis of Alcohol Use Disorder).
# Frequency of Alcohol Use Screening
Several systematic reviews have concluded that there is insufficient research evidence to recommend an optimal screening/rescreening interval for alcohol use in adults and youth. 127 In the absence of robust evidence, most public health agencies, including the Canadian Task Force on Preventive Health Care 139 and the Canadian Paediatric Society, 140,141 recommend screening adults and youth on an annual basis. This is for reasons of convenience -alcohol screening can be combined with other components of a routine medical exam or preventive health screening -and to detect changes, as an individual's alcohol use can shift from low-to high-risk over a one-year period. In line with this, a U.S. study found that use of annual substance use screening intervals identifies a modest number of incident cases of high-risk use in adult primary care patients. 142 Of 1014 patients who initially screened negative for high-risk alcohol or drug use, 34 (3.4%) screened positive for high-risk use when screened again one year later, with the majority (23/34) meeting criteria for high-risk alcohol use. 142
# Clinical Indications for Alcohol Use Screening
This guideline recommends universal screening of all adult and youth patients in primary care. However, there are a number of common clinical scenarios that should trigger alcohol screening regardless of whether or when a patient was last screened. These include: Additionally, patients presenting to care because they are concerned about their alcohol use or suspect they have an AUD can undergo a full diagnostic interview immediately.
# Section Summary and Recommendation
Based on known risks and harms of high-risk drinking, and the benefits of early identification, intervention, and treatment, this guideline recommends universal alcohol use screening for all adult and adolescent patients seen in primary care.
The committee endorses the use of single-question alcohol screening (SASQ) for adult patients (including pregnant individuals) and the NIAAA tool for youth. Simplified screening tools have several advantages in primary care, 121 while still achieving acceptable sensitivity and specificity for detection of high-risk drinking compared to more complex screening tools. 121,[123][124][125][126] There is a lack of evidence regarding optimal screening-rescreening intervals in adults and youth. Given the advantages of early detection and intervention to reduce or prevent alcohol-related harms, it is the consensus of this committee that the benefits of annual screening, as recommended by national public health agencies, would likely outweigh any disadvantages of this approach.
k Abbreviations: GGT -gamma-glutamyl transpeptidase, AST -aspartate aminotransferase, ALT -alanine transaminase, MCV -mean cell corpuscular volume, CBC -complete blood count.
# Recommendation 2 Universal Screening for Drinking Alcohol Above Low-Risk Limits
All adult and youth patients should be screened annually for alcohol use above low-risk limits.
# Quality of Evidence: MODERATE Strength of Recommendation: STRONG
# Remarks
• Screening alone does not improve outcomes. As a standard component of screening, all patients should be provided with individually tailored feedback about their results, regardless of the screening tool used.
# Diagnosis of Alcohol Use Disorder
Patients who screen positive for drinking above low-risk limits should undergo further assessment, and if appropriate, a structured interview using the DSM-5 criteria to confirm the diagnosis and severity of AUD (see Table 10). Confirmation or exclusion of an AUD, and an assessment of AUD severity and the patient's risk of complications, determines subsequent steps in the treatment pathway.
Patients who are drinking above low-risk limits but do not have an AUD should be administered a brief counselling intervention and encouraged to reduce their alcohol consumption (see Brief Interventions).
Brief intervention alone is not effective for individuals with AUD. 143 Patients who are diagnosed with an AUD should undergo a more comprehensive assessment, including, as appropriate and indicated: a detailed medical, mental health and substance use history; physical examination; laboratory investigations; and risk assessment for developing severe complications of withdrawal (i.e., seizures, delirium tremens). All patients should be offered evidence-based treatment for AUD (see Withdrawal Management, Pharmacotherapy, Psychosocial Treatment Interventions).
# Brief Interventions for Drinking Above Low-Risk Alcohol Limits
# Theory and Practice
Identification of patients who are drinking above recommended low-risk alcohol limits through screening provides the opportunity for clinicians to conduct a brief intervention (BI) to support behavioural change to reduce alcohol consumption. BI approaches vary in a range of components, such as the duration and number of clinician-patient interactions involved, but they all consist of a brief or ultra-brief variant of motivational interviewing (MI), an evidence-based psychosocial treatment intervention.
Motivational interviewing (MI) is a counselling approach that helps patients develop motivation to change, and creates a therapeutic alliance that is predominantly a partnership, rather than an expert/patient dynamic. 144 The general principles of MI are to express empathy, support self-efficacy, avoid argumentation, roll with resistance, and develop understanding of any discrepancy between current behaviour and future goals. 145 BI approaches that adhere to the principals of MI are typically structured using the FRAMES approach, 144 an mnemonic device that stands for Feedback, Responsibility, Advice, Menu, Empathic, and Self-efficacy (see Appendix 2). 144,146 An example that has been well studied in primary care is the "5 As" model for behavioural change. 147 The 5As model was originally developed to facilitate the adoption of universal screening and brief intervention for tobacco cessation, but has been adapted for a number of other conditions, including alcohol use. 48,148 The 5As stand for Ask, Advise, Assess, Assist, and Arrange (see Box 2). Ease of recall and brevity are practice-relevant strengths of this approach. The 5As can also be easily adapted to specific clinical settings and patient populations (e.g., question order and format can be modified as needed), and other members of the primary care team can administer the 5As if physician time is limited.
# Box 2
The 5As Model for Delivering Alcohol Use Brief Interventions 48,148 Ask Screen and document alcohol use for every patient. Identify individuals who are drinking above low-risk limits.
# Advise
In a clear, strong, and personalized manner, advise individuals that they are drinking above low-risk limits, and may be at risk of alcohol-related harms.
# Assess
Is the individual willing to make a change at this time? Confirming/excluding a diagnosis of AUD is advised, as BI alone is not effective for individuals with an AUD.
# Assist
For the patient willing to reduce or stop alcohol use, develop a treatment plan using a shared decision-making framework. Provide supportive counselling and advice, and referrals to community resources.
# Arrange
Schedule a follow-up visit, preferably within a week of the planned "change date".
Patients who are pre-contemplative or ambivalent about reducing their drinking can be reassessed at subsequent appointments to determine whether their alcohol use and related circumstances have changed.
Additional guidance on delivering brief alcohol interventions can be found in Appendix 2.
# Brief Intervention
There is a robust evidence base to support the use of BI for high-risk drinking in adults and youth (aged 11-25 years). 128,149 Several high-quality systematic reviews have demonstrated that BI results in clinically meaningful reductions in high-risk drinking behaviours, including heavy episodic drinking, high daily or weekly levels of alcohol consumption, and drinking that exceeds recommended alcohol consumption limits, and have concluded that overall, there is a moderate beneficial effect of BI. 143,[150][151][152][153] For example, a 2018 meta-analysis (69 RCTs, n=33,642) reported moderate-quality evidence that alcohol-related BIs administered in primary care and emergency settings led to sustained reductions in alcohol use up to one year later: on average, participants consumed 1.5 fewer drinks l per week than participants who received minimal or no intervention.
Although a 2012 systematic review reported larger effect sizes with multi-contact brief interventions, (i.e., multiple 10-15 minute BI sessions delivered over a timespan of up to 1 year); 117 other reviews have found that extending the duration and frequency of brief interventions does not appear to confer significant advantages. 143,154 A consistent finding across multiple reviews is that even a single, 5-minute session incorporating the core principles of MI is likely to be effective in reducing alcohol consumption among individuals at higher risk of alcohol-related harms. 149 A 2016 meta-analysis of 52 RCTs (n=29,891) found that provider type did not impact outcomes, with some evidence that BI delivered by nurses was more effective than physician-, counsellor-or peer-delivered BIs in reducing the quantity of alcohol consumed by individuals with high-risk drinking patterns. 155 Thus, if physician and nurse practitioner time is limited, delegation of screening and BI to other trained members of the care team or staff can be considered.
# Brief Intervention in Adolescent Patients
A 2018 systematic review (13 studies, n=7,060) of BI for high-risk drinking in adolescent primary care patient populations concluded that both indicated and universal (i.e., preventative) delivery of alcohol-focused BI can result in clinically important changes in alcohol-related outcomes. 156 However, authors also noted limitations of the current evidence base, and specifically the lack of research on best practices for delivery, communication methods, and intervention-specific components that could influence "real-world" effectiveness of BI in this population. 156 In the Canadian context, key messages for youth from the Low-Risk Alcohol Drinking Guidelines that could be adapted into BI are to advise youth that if possible, they should try to delay drinking until they are of legal age (≥19 years of age). 9 If youth do decide to drink, strategies for reducing harm can be discussed, such as ensuring that drinking occurs in a safe environment, and limiting that to one to two drinks at a time, one to two times per week (Also see Table 3). 9
# Brief Intervention in Pregnant Patients
A 2009 systematic review (4 RCTs; n=715) of clinical trials examining the effectiveness of psychosocial interventions found that BI might motivate pregnant patients to reduce or discontinue alcohol use, but noted that due to insufficient and heterogeneous data, a meta-analysis could not be performed. 157 A number of individual studies have reported significant results in favour of BI in this population. For example, a randomized study that compared BI to assessment only (n=162) found that pregnant individuals who received a BI were five times more likely to discontinue alcohol use throughout their pregnancy than those who received assessment only. 158 Perinatal outcomes were also improved in the BI group: infant mortality rate was three times lower, and infants had greater birth length and weight in the BI group than the assessment-only group. 158 As with the general patient population, the most frequently studied form of BI in this population is MI, including the 5As model. 4,159,160 However, research has also shown that simply asking pregnant patients about their alcohol use, discussing potential risks, and offering brief, nonjudgmental advice may help modify drinking behaviour. 4,161
# Section Summary and Recommendation
Based on available evidence, this guideline recommends that clinicians administer a brief intervention (BI) to all adult and youth patients who screen positive for high-risk drinking. Several high-quality systematic reviews have found that BI results in clinically meaningful reductions in alcohol consumption, and concluded that overall, there is moderate quality evidence for the beneficial effect of BI. 30,127,143,162 The committee endorses the use of short, practice-friendly motivational interviewing (MI)-based approaches, for example, the 5As model to support behavioural change, 48,148 as these approaches have been well-studied and are likely familiar to many primary care providers.
Involving interprofessional staff or teams in the screening and brief intervention pathway is recommended if clinician time is limited and to ensure that all patients are screened and triaged appropriately. Research has shown that BI delivered by nurses, counsellors, or peer support staff is as effective as physician-delivered BI in supporting patients to reduce drinking and alcohol-related harms. 155
# Recommendation 3 Brief Intervention for Drinking Alcohol Above Low-Risk Limits
All patients who are drinking alcohol above low-risk limits but do not have an AUD should receive a brief counselling intervention to reduce drinking.
# Quality of Evidence: MODERATE Strength of Recommendation: STRONG
# Remarks
• Clinicians should have access to appropriate training, education and resources for delivering BI.
# Implementing Screening and Brief Intervention in Practice
Implementation of universal screening and BI for alcohol use has been recommended by a range of national and international organizations, including the Canadian National Alcohol Strategy Working Group, the Canadian Task Force on Preventive Health Care, the Canadian Paediatric Society, the US Preventive Services Task Force, the American Academy of Pediatrics, and the WHO. 118,[139][140][141]146,163,164 However, real-world implementation of universal alcohol screening and brief intervention has proven challenging, with reported rates of uptake as low as 2% for alcohol use screening and 1% for BI. 165 Barriers most often cited by primary care providers include a lack of time, education, training, and resources; personal discomfort and unease around how to communicate with patients; stigma manifesting in beliefs that patients will not change their behaviour; and fear of offending patients with questions about alcohol consumption. 166 These barriers may also underpin discrepancies between efficacy and effectiveness studies, including recent trials that reported modest or no differences in alcohol consumption following widespread implementation of universal alcohol use screening and BI in private and publicly-funded care systems. [167][168][169][170] In these studies, the authors specifically cited low rates of provider compliance in administering BI as per recommendations as contributing factors, and suggest that organizational or system-level factors, such as provider incentives, educating providers about the risks of high-risk drinking and effectiveness of BI, and providing training for delegated staff (e.g., nurses, allied health professionals) could facilitate wider implementation and improve effectiveness in the primary care context. [167][168][169][170] In the United States, funding for screening, brief intervention, and referral to treatment (SBIRT) initiatives has been prioritized by the National Institutes of Health for over a decade, and robust evaluations of large-scale implementation projects are available. Through this work, a number of similar themes have emerged among successful programs. These "best practices" for successful uptake and implementation of substance use SBIRT are summarized below (Box 3). • Identify a "practice champion"
• Ensure buy-in from leadership and senior staff
• Involve all members of the care team and clinic staff
• Clearly define and communicate each step of the SBIRT pathway to all team members
• Develop functional referral pathways with external partners and programs
• Institute ongoing and regular opportunities for staff training/re-training in SBIRT
• Align the SBIRT pathway within the primary care clinic flow such that disruptions are minimal and change is readily adopted
• Use a pre-screening instrument if available
• Integrate SBIRT into the electronic health record
# Withdrawal Management
Withdrawal management is defined as a set of pharmacological, psychosocial, and supportive care interventions that aim to manage withdrawal symptoms and/or syndromes that occur when an individual with a substance use disorder stops using that substance. 175 For individuals with AUD, medically supervised withdrawal management can prevent potentially life-threatening complications that can emerge if the patient is left untreated. 175 Withdrawal management for alcohol may be recommended for a number of reasons. Some patients may have a treatment goal of abstinence and thus, completion of withdrawal management would be the first step in their treatment plan. Most AUD pharmacotherapies do not address alcohol withdrawal symptoms, and none have been shown to prevent severe complications of withdrawal (i.e., seizures, delirium tremens). 176 Research has also shown that completion of withdrawal management prior to starting AUD pharmacotherapy can improve treatment outcomes by preventing early relapse, which is often associated with untreated withdrawal symptoms. [177][178][179] Completion of withdrawal management may also be required when patients wish to enter inpatient treatment programs.
Withdrawal management may not be necessary for patients whose goal is reduced drinking. Patients who are assessed to be at low-risk of developing severe complications may be able to start AUD pharmacotherapy immediately (see Continuing Care -Pharmacotherapy). Clinicians should be aware, however, that alcohol withdrawal symptoms can still occur with a sudden or significant reduction in alcohol consumption, and closely monitor these patients during early stages of treatment.
It is important to note that withdrawal management alone is not considered a standalone treatment. As a shortterm intervention, withdrawal management is not intended to resolve any underlying medical, psychological, or social issues related to AUD, and should be considered a bridge to continuing care, treatment, and support that will address these concerns. Referring patients to withdrawal management alone is neither sufficient nor appropriate care.
# Overview of Alcohol Withdrawal
While other neurotransmitter systems are involved, alcohol primarily affects the central nervous system (CNS) by acting as a gamma-aminobutyric acid (GABA) agonist and glutamate antagonist. In normal conditions, the brain maintains a balance between the inhibitory effects of GABA and excitatory effects of glutamate. Alcohol disrupts this balance by increasing the inhibitory effects of GABA and supressing excitatory effects of glutamate, resulting in calm or relaxed feelings, reduced inhibitions, impaired balance and coordination, and slowed reaction speed, cognition, and breathing rate. 180 With chronic alcohol use, the brain adapts and compensates for its effects; GABA-mediated systems become less sensitive to GABA and glutamate-mediated systems become more sensitive to glutamate to restore neurochemical equilibrium. 181 In these conditions, a sudden cessation or a significant reduction of alcohol consumption triggers an acute imbalance between the GABA and glutamate systems, resulting in an overall state of CNS excitation and a lower seizure threshold. 181 This mechanism explains many symptoms of alcohol withdrawal that occur in patients with a history of chronic heavy alcohol use when they abruptly discontinue alcohol intake.
Up to 50% of individuals with long-term alcohol dependence will experience some degree of withdrawal upon cessation of alcohol use. [182][183][184] Symptoms of alcohol withdrawal typically begin 6-24 hours after the last intake of alcohol and reach peak intensity at 24-48 hours, with resolution of symptoms within 5-7 days. 185 Within hours of alcohol use cessation, autonomic hyperactivity can present as tachycardia, pyrexia, tremor, nausea, vomiting, and sweating, which may also be accompanied by psychological distress in the form of anxiety, restlessness, and sleep disturbance or insomnia (see Box 4).
# Box 4 DSM-5 Diagnostic Criteria for Alcohol Withdrawal Syndrome 2
A. Cessation of (or reduction in) alcohol use that has been heavy and prolonged.
B. Two (or more) of the following, developing within several hours to a few days after the cessation of (or reduction in) alcohol use described in Criterion A:
• Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100 bpm).
• Increased hand tremor.
• Insomnia.
• Nausea or vomiting.
• Transient visual, tactile, or auditory hallucinations or illusions.
• Psychomotor agitation.
• Anxiety.
• Generalized tonic-clonic seizures.
C. The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
D. The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance.
Data on the natural history of alcohol withdrawal has mainly been derived from studies of medically-ill, hospitalized patients. These studies have shown that while alcohol withdrawal is typically limited to the symptoms listed above, approximately 7-8% of symptomatic individuals may also experience transient visual, auditory and/or tactile hallucinations. 186 Additionally, approximately 10% of symptomatic patients experience withdrawalrelated generalized tonic-clonic seizures that require medical intervention. 176,187 If left untreated, approximately one-third of individuals experiencing withdrawal seizures are at risk of progression to delirium tremens. 188 Delirium tremens is the most serious manifestation of alcohol withdrawal and is characterized by the onset of severe confusion, disorientation and/or hallucinations accompanied by severe autonomic hyperactivity. 189 Delirium tremens occurs in approximately 3-5% of patients who are hospitalized for the management of alcohol withdrawal. 180,182,190
# Assessing Risk of Severe Complications of Alcohol Withdrawal
Not all individuals with alcohol use disorder will experience severe complications upon reduction or cessation of alcohol use; for example, some reviews suggest that youth and individuals with a shorter lifetime history or severity of AUD may be less likely to experience severe complications. [182][183][184] A widely cited theory known as the "kindling effect" 191 suggests that the severity of withdrawal symptoms experienced by a patient directly correlates to their alcohol use history (e.g., duration of any and heavy alcohol use) and previous experiences of withdrawal (e.g., number of previous attempts at abstinence, symptom severity, history of complications). The kindling theory proposes that repeated episodes of untreated alcohol withdrawal symptoms progressively increases neural excitability and lowers the seizure threshold, leading to successively more severe withdrawal episodes, with increased likelihood of progression to seizures and delirium tremens. 188,192 A systematic method for predicting the risk of severe withdrawal symptoms based on alcohol use history, withdrawal history, and other relevant factors would enable clinicians to stratify withdrawal management pathways and devise tailored strategies, reducing unnecessary acute care admissions and medication use among patients at low risk of severe complications. Risk-stratifying patients can also potentially allow for the use of a non-benzodiazepine or benzodiazepine-sparing approach in patients at low risk for withdrawal complications, avoiding adverse effects commonly observed with benzodiazepine use, such as oversedation, falls, delirium, respiratory depression, and prolonged hospitalization. 193,194 A number of meta-analyses have reported that the following factors are associated with increased risk of severe withdrawal and complications: previous episodes of alcohol withdrawal, seizures, delirium tremens, inpatient alcohol rehabilitation treatment, and/or blackouts; current concomitant use of CNS-depressant agents (e.g., benzodiazepines, barbiturates) and/or other licit or illicit substances; recent intoxication; positive blood alcohol level on admission to care; and evidence of increased autonomic activity, including elevated blood pressure, heart rate, and body temperature. 183,189,195 The Prediction of Alcohol Withdrawal Severity Scale (PAWSS, see Appendix 3) is a validated score-based tool for estimating the risk of severe withdrawal, facilitating the selection of appropriate withdrawal management pathways. 195 The PAWSS incorporates the risk factors listed above into a 10-item cumulative scale with a maximum score of 10, wherein a score of <4 indicates low risk and a score of ≥4 denotes high risk for severe complications of withdrawal. 195 A 12-month prospective study of 403 hospitalized patients showed that the PAWSS has a high predictive value for identification of patients at high-risk of severe complications (positive predictive value [PPV], 93.1; negative predictive value [NPV], 99.5) and good inter-rater reliability (96.3%). 196 The authors concluded that this tool may enable clinicians to accurately identify patients at risk of severe complications and devise an appropriate treatment plan to prevent these symptoms. 196 The accuracy and usefulness of the PAWSS was further demonstrated in a 2018 systematic review of 14 studies (n=71,295) evaluating single and composite measures of severe withdrawal risk. 197 The authors demonstrated that, while no single factor could be used to exclude the risk of severe withdrawal management syndrome, a history of delirium tremens (likelihood ratio [LR], 2.9 [95% CI, 1.7-5.2]) and baseline systolic blood pressure of 140 mmHg or higher (LR, 1.7 [95% CI, 1.3-2.3) were associated with an increased likelihood of developing severe complications of alcohol withdrawal. The review also demonstrated that composite scales that measured multiple signs and symptoms were more useful in predicting an individual's risk than individual signs or symptoms. Of these composite scales, the PAWSS was found to be the most accurate, with a positive LR of 174 [95% CI, 43-696; specificity, 0.93), and a negative LR of 0.07 [95% CI, 0.02-0.26; sensitivity, 0.99). 197 As noted in the 2018 review, 197 the PAWSS has not yet been validated in outpatient care settings and patient populations, or in youth and pregnant individuals. It should also be emphasized that this tool is not suitable for self-assessment; the administering clinician should clearly define the criteria in the PAWSS questionnaire for the patient in order to minimize the risk of a false positive result. As with any other assessment tool, the PAWSS is intended for use in conjunction with best clinical judgment based on a comprehensive assessment of a patient's medical history, current circumstances, needs, and preferences. Some considerations that would prompt referral to inpatient withdrawal management and/or medical care regardless of PAWSS score include acute confusion, gastrointestinal bleeding, electrolyte imbalance, infection, cognitive impairment, old age or physical frailty, chronic and complex pain disorders, pregnancy, and social instability (e.g., unsafe housing, homelessness, intimate partner violence; also see Box 5).
It is emphasized that all patients diagnosed with AUD should be assessed for the risk of developing severe complications of alcohol withdrawal, even if a patient opts not to start treatment, or if withdrawal management is not part of a patient's treatment plan. Severe complications can occur with sudden or significant reductions in alcohol use as well as abstinence. Clinicians should review PAWSS scores with patients and provide education on the risks associated with unsupervised withdrawal.
The PAWSS can only be used to predict the risk of severe complications of withdrawal, and not to assess patients who are currently experiencing withdrawal symptoms. The use of point-of-care withdrawal symptom assessment tools, such as the Clinical Institute Withdrawal Assessment -Alcohol revised (CIWA-Ar) scale and the Short Alcohol Withdrawal Scale (SAWS), in the management of alcohol withdrawal are reviewed in the next section.
# Section Summary and Recommendation
The guideline committee recommends the use of the PAWSS to assess risk of severe complications of alcohol withdrawal and to stratify patients to outpatient (PAWSS<4) and inpatient (PAWSS≥4) withdrawal management care pathways. This recommendation is based on the results of a prospective study that found the PAWSS had an excellent predictive value (PPV=93.1; NPV=99.5) for identification of patients at risk of severe complications, 196 and a 2018 systematic review that found that the PAWSS had the highest sensitivity (93%) and specificity (99%) for identifying patients at risk. 197
# Recommendation 4 Assessing the Risk of Severe Complications of Withdrawal
Clinicians should use the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) to assess the risk of severe alcohol withdrawal complications in all patients with AUD in order to select the most appropriate withdrawal management pathway.
# Quality of Evidence: MODERATE Strength of Recommendation: STRONG
# Remarks
• This tool should be used in conjunction with best clinical judgment based on a comprehensive assessment of a patient's medical history, current circumstances, needs, and preferences.
• The PAWSS is not suitable for self-assessment and should be administered by a clinician.
• The PAWSS has not been validated in pregnant or youth populations.
• Patients may confuse some of the criteria included in the PAWSS questionnaire, specifically seizures and delirium tremens, with common and less severe symptoms of withdrawal. To avoid false positives, the administering clinician should clearly define these criteria prior to obtaining the patient's responses.
# Point-of-care Assessment of Withdrawal Symptom Severity
Periodic measurement of symptoms during the withdrawal process has been shown to facilitate appropriate adjustments in dosing and mitigating the risk of severe symptoms, as high severity scores early in the course of treatment are predictive of severe withdrawal complications, including seizures and delirium. [198][199][200] Several alcohol withdrawal symptom severity assessment scales have been published. Of these, the Clinical Institute Withdrawal Assessment Alcohol revised (CIWA-Ar) and Short Alcohol Withdrawal Scale (SAWS) are the two most widely used and recommended tools for measuring withdrawal symptoms. [200][201][202] 5.3.1 The Clinical Institute Withdrawal Assessment -Alcohol revised (CIWA-Ar)
The CIWA-Ar is considered the gold standard for assessing withdrawal symptom severity in a range of clinical care settings, with demonstrated inter-rater reliability and validity. 203 The CIWA-Ar involves assessment of 10 individual symptoms and signs of alcohol withdrawal including anxiety and agitation; auditory, visual, and tactile disturbances; tremor; sweating; nausea; headache; and clouding of sensorium, which are assigned a numerical score based on objective and subjective measures of severity (see Appendix 3). 203 The CIWA-Ar can be used to determine medication dosing schedules prior to treatment initiation and periodically during withdrawal management (i.e., symptom-triggered schedules). Studies have shown that using the CIWA-Ar in this context minimizes both under-and over-medicating patients. 200,201 Use of the CIWA-Ar may not be appropriate if there are any barriers to communication between provider and patient (i.e., language, verbal capacity, cognitive impairments, or decreased level of consciousness), or if the patient shows signs of instability, disorientation, or delirium. Clinicians should be aware that such circumstances may undermine the validity of scores for subjective CIWA-Ar item symptoms (anxiety, headache, nausea, hallucinations). 204
# Short Alcohol Withdrawal Scale (SAWS)
The Short Alcohol Withdrawal Scale (SAWS) was developed with a focus on minimizing length, observer bias, and communication barriers that can hinder the objective scoring of alcohol withdrawal symptoms. 205,206 The SAWS scoring tool consists of 10 symptoms, with the severity of each symptom assigned a score from nonexistent (0) to severe (3) (see Appendix 3). Patients reporting a combined score of 12 or higher are considered to be candidates for pharmacological withdrawal management. 205 SAWS scoring takes 5-10 minutes and can be completed by the patient or in a structured interview format in inpatient or outpatient settings. 205 Cited advantages of the SAWS instrument are its brevity and ease of interpretation and use by patients and clinicians alike. 205,206 A randomized study involving 122 patients validated the use of the SAWS in outpatient settings and found it easy to understand and relevant to treatment selection and evaluation. 206 Additionally, it is suggested that the completion of the SAWS by patients may help eliminate observation bias and remove practical barriers imposed by frequent scoring among clinical staff. 206 As such, the SAWS may serve as a standalone tool for assessing mild to moderate alcohol withdrawal symptoms or a supplement to clinician-administered tools such as CIWA-Ar. As above, use of the SAWS is limited if there are any barriers to communication or comprehension (e.g., language, low literacy). 206
# Withdrawal Management Strategies
# Outpatient Withdrawal Management (PAWSS <4)
It is estimated that up to 80% of patients with alcohol use disorders can undergo medically supervised withdrawal management in an outpatient care setting (e.g., primary care offices, addiction treatment facilities). 207,208 Outpatient management is generally safe, effective, and more cost-effective than inpatient treatment, 208,209 and may be less disruptive to patients' work and family life. 210 Moreover, reviews report that more than 70% of patients enrolled in outpatient withdrawal management complete treatment, and 50% of these patients remain engaged in ongoing addiction care to meet long-term recovery goals (i.e., a reduction in heavy drinking and related harms, or abstinence). 211,212 Specific patient criteria for outpatient withdrawal management are listed below. Outpatient withdrawal management can be considered for patients who meet all of the following criteria:
• PAWSS score <4
• Absence of contraindications including, but not limited to:
• Severe or uncontrolled comorbid medical conditions (e.g., diabetes, COPD, heart disease, decompensated cirrhosis)
• Acute confusion or cognitive impairment • Acute illness or infection requiring medical intervention • Co-occurring serious psychiatric symptoms or disorders (e.g., suicidal ideation, psychosis)
• Co-occurring severe drug use disorder (excluding tobacco)
• Pregnancy
• Ability to attend daily medical visits for first 3-5 days, and alternating day visits thereafter
• For patients and/or practices in rural or remote areas where daily in-person visits are not feasible, remote follow-up options such as telemedicine, or secure phone or video calls, are acceptable alternatives (but see notes below)
• Ability to take oral medications
• Has a reliable family member or community-based contact who can monitor symptoms during acute withdrawal period (i.e., 3-5 days) and support adherence to medications*
• Any other medical or social condition that, in the treating clinician's best judgment, would present serious risks to patient safety if alcohol withdrawal was managed on an outpatient basis Note: Patients who do not have support from family or community should not be denied treatment. If inpatient treatment is not an option due to scarcity of beds or patient preference, patients with minimal social supports should be accommodated and treated through alternative strategies such as daily clinic visits, home visits, or connection to a local pharmacist. A patient's track record of reliability and adherence to clinical recommendations should be considered as a factor in this decision.
Inpatient withdrawal management in a hospital or specialized facility should be considered for patients who do not meet the criteria specified above, or who have any other contraindications to outpatient management as per the clinical judgment of the treating health care provider. Alternatively, in communities where they are available, medically supervised outpatient withdrawal management programs (e.g., home detox programs involving daily visits from care team, "Daytox" programs) may be considered if feasible and appropriate.
# Absent to Mild Withdrawal Symptoms
While all patients diagnosed with AUD should be offered medication for withdrawal management, patients diagnosed with mild to moderate AUD (as per DSM-5 criteria) may experience negligible withdrawal symptoms on cessation of alcohol use. In this case, some patients may choose supportive therapy alone or initiation of AUD pharmacotherapy (e.g., naltrexone, acamprosate) to support long-term treatment goals (i.e., reduced drinking or abstinence).
There is a lack of consensus and clear guidance regarding outpatient management of patients experiencing mild withdrawal symptoms. Practice guidelines tend to advocate provision of supportive care alone (e.g., supportive environment; minimal interpersonal interactions; adequate nutrition and hydration; encouragement and positive reinforcement; referrals to community resources) until withdrawal symptoms subside. 175,214 This is based on early studies that found supportive care was sufficient for approximately 75% of patients who had no concurrent complex medical conditions. 215,216 In view of these findings, patients with PAWSS <4 who prefer to begin withdrawal without the use of prescription pharmacotherapies should be provided with necessary information and referrals, and monitored frequently. Over-the-counter pain relievers, anti-emetics, and antidiarrheal medications may also be recommended for the management of mild symptoms.
It is emphasized that adequate management of withdrawal symptoms, including pharmacotherapy when appropriate, can increase the likelihood that patients will achieve their treatment goals. Thus, clinicians may also consider writing a prescription for pharmacotherapy that the patient can fill if needed, in order to avoid destabilising delays in managing any significant withdrawal symptoms that emerge. Patients should be advised to contact their health care provider in the event that this occurs. Community pharmacists can also be an important source of support and guidance for patients experiencing unexpected withdrawal symptoms.
# Mild to Moderate Withdrawal Symptoms
Studies have demonstrated that withdrawal management can be provided safely in outpatient settings to most patients with AUD. 207,208,211,212 Patients at low risk of developing severe complications of withdrawal (i.e., PAWSS<4) and who have no other concurrent conditions or complications that would require inpatient management (Box 5) can be offered outpatient withdrawal management. General considerations for outpatient management are listed below (Box 6). The research evidence for several pharmacotherapy options is reviewed in the next section (see Pharmacotherapies for Withdrawal Management).
# Box 6 General Considerations for Outpatient Withdrawal Management
• Schedule withdrawal management in consideration of available coverage and patient circumstances. Starting treatment on a weekend may minimize disruption to a patient's work. If weekend service is unavailable, schedule treatment for Monday or Tuesday to ensure access to service in the following days.
• See the patient daily during the stabilization phase of withdrawal (i.e., 3-5 days), evaluate and adjust the visit schedule thereafter as appropriate. If appropriate, consider remote follow-up options (i.e., phone or video calls and connection to a local pharmacist) for patients residing in remote areas or those with mobility impediments.
• Provide patients with a phone number or alternative contact that they can call in the event of an emergency.
• Where possible, request that a reliable family member or friend is available to provide support, help with treatment schedules, track symptoms and response to medications, and accompany or transport the patient to appointments.
• Provide patients, families and caregivers with educational resources detailing withdrawal symptoms, medications, side effects, and safety issues.
• Advise patients not to drive until their withdrawal symptoms subside.
• Recommend over-the-counter vitamins including thiamine and folate.
• Recommend increased fluid and electrolyte intake, restricted diet consisting of mild foods, and minimal exercise.
• Review risks and benefits of natural remedies, caffeine, or any activity that increases sweating (e.g., hot baths, showers, or saunas), with respect for and understanding of the important role that Indigenous and traditional approaches to healing have for some patients (e.g., sweat lodges).
• Assess vital signs, withdrawal symptoms, hydration, cognition, emotional status, general physical condition, and sleep at each daily visit.
• Provide encouragement and referrals to community resources, support groups, or employee assistance programs.
• Reassess patient's recovery goals regularly.
• Monitor for relapse, and collaboratively explore the cause of relapse and correct if possible; if unable to address the cause, refer for inpatient management.
• BC physicians and nurse practitioners are encouraged to call the Rapid Access to Consultative Expertise (RACE) line (Vancouver area: 604-696-2131; toll-free: 1-877-696-2131; Monday to Friday, 0800-1700) or use the RACE line app (www.raceconnect.ca) to connect with an addiction medicine specialist for advice and guidance.
# Inpatient Withdrawal Management (PAWSS ≥ 4)
Approximately 20% of patients with AUD will require hospitalization or inpatient withdrawal management due to an increased risk of serious complications. Patients located in regions that do not have dedicated inpatient withdrawal management facilities should be admitted to hospital. [217][218][219] Patients, families and care providers in BC can access health information and referrals to withdrawal management services from trained allied health professionals at the following numbers:
If a patient at high risk of severe withdrawal complications is motivated to stop or reduce drinking, but declines the recommended approach of inpatient management, use motivational interviewing techniques (see Motivational Interviewing), delivered over multiple clinical visits if necessary, to explore the factors underlying this decision.
In addition, provide detailed information about acute withdrawal symptoms, and how progression to severe, life-threatening complications can be unpredictable and occur rapidly. Discuss the benefits of continuous medical monitoring and access to immediate care in terms of patient safety, comfort, and recovery planning. If the patient declines the offer of withdrawal management, reiterate the risks of sudden and/or unsupervised withdrawal from alcohol, ensure that they are aware of the need to seek immediate emergency assistance in the event any withdrawal complications are experienced, and consider a referral to an addiction medicine specialist or the most appropriate local addiction services. Outpatient management of patients at high-risk for severe complications is not advised. 175,220
# Section Summary and Recommendation
This guideline recommends outpatient withdrawal management for patients at low risk of developing severe complications of withdrawal. An established body of evidence supports the safety and effectiveness of outpatient withdrawal management for the majority of patients (80%) with AUD. 207,208,221 Outpatient management is generally safe, effective, and more cost-effective than inpatient treatment, 208,209 and may be less disruptive to patients' work and family life. 210 Reviews report that more than 70% of patients enrolled in outpatient withdrawal management complete treatment, and 50% of these patients remain engaged in ongoing addiction care. 211,212 ACCESS CENTRAL • No contraindications such as severe or uncontrolled comorbid medical conditions, serious psychiatric conditions, concurrent severe substance use disorders other than tobacco use, and/or pregnancy.
• Ability to commit to daily medical visits for first 3-5 days, or to participate in an appropriate remote mode of medical follow-up when in-person visits are not feasible.
• Ability to take oral medications.
• Stable accommodation and reliable caregiver for providing support and monitoring symptoms during acute withdrawal period (i.e., 3-5 days).
• Patients who do not meet these criteria should be referred to inpatient treatment.
# Pharmacotherapies for Withdrawal Management
This section reviews the evidence on the efficacy and safety of three categories of medication categories commonly used to manage alcohol withdrawal symptoms: benzodiazepines, anticonvulsants, and α-adrenergic agonists.
Refer to Table 5 for a summary comparison of withdrawal management pharmacotherapies.
# Benzodiazepines
Benzodiazepine medications have the most extensive history in the treatment of alcohol withdrawal, 180,194,207,[222][223][224][225][226] with strong evidence from multiple systematic reviews demonstrating their superior efficacy in the prevention of delirium tremens and seizures compared to placebo and alternative therapies including anticonvulsants (e.g., chlormethiazole, gabapentin, carbamazepine) and antipsychotics (e.g., chlorpromazine). [227][228][229] However, benzodiazepines can present challenges when used for treating alcohol withdrawal in outpatient settings. 175 The mechanism of action of benzodiazepines and their potential for drug-drug interactions can lead to side effects including excess sedation, impaired psychomotor functioning, and cognitive effects, particularly among elderly or frail patients, or those with hepatic dysfunction. 193,194 In addition, if patients either continue or resume alcohol use during benzodiazepine treatment, the combined effect potentiates intoxication, further increasing risk of accidents and injuries, as well as respiratory depression, which can result in overdose, coma and death. [230][231][232][233][234] Potential risks associated with non-medical use and diversion of benzodiazepines should also be considered. 235 To date, no systematic review has conclusively established that any one class of benzodiazepines is superior to another for alcohol withdrawal management, although a 2010 systematic review reported that chlordiazepoxide may be marginally more effective than other benzodiazepines in reducing symptom severity, seizures, and delirium tremens. 229 Therefore, other factors such as provider experience, duration of action (i.e., short-versus long-acting), dosing schedule, patient's health history (e.g., history of hepatic dysfunction), drug coverage and availability, and potential for non-medical use may guide medication selection.
Regardless of benzodiazepine type, the duration of treatment should be short-term and limited to the acute phase of alcohol withdrawal, with a taper schedule determined by the individual's response to treatment (typically 5-7 days). Daily dispensing schedules and compliance packaging (i.e., "blister packs") can be considered to mitigate risks if appropriate. Finally, because the combined use of benzodiazepines and alcohol can cause respiratory depression and death, the importance of abstaining from alcohol use must be emphasized to patients and families or caregivers. Consider enlisting the support of family members and/or caregivers in medication administration, if appropriate and with the patient's consent.
# Anticonvulsants
# Carbamazepine
Carbamazepine has been used in Europe for over 35 years to manage symptoms of alcohol withdrawal, 236 and it has been found safe and effective for the management of alcohol withdrawal in a number of RCTs. 237 Some advantages of carbamazepine are that it is non-sedating, does not interact with alcohol, and has no reported potential for non-medical use or diversion.
To date, five randomized trials conducted in inpatient settings (n=422) have demonstrated that carbamazepine is equivalent [238][239][240][241] or superior 242 to benzodiazepines for the reduction of withdrawal symptom severity. Similar results were demonstrated in an outpatient setting, where 136 participants were randomized to receive a fixed dosage taper over five days of either carbamazepine (800mg on day 1 tapering to 200mg by day 5) or lorazepam (6-8mg on day 1 tapering to 2mg by day 5). 243 The authors reported a significant difference in physician-assessed withdrawal severity over time and at day 7 post-treatment favouring carbamazepine. 243 Furthermore, evaluation of post-treatment drinking behaviour found that participants who received lorazepam were three times more likely to relapse to drinking immediately following treatment than those who received carbamazepine. In all trials conducted to date, there were no reports of safety issues, and carbamazepine was well tolerated with no difference between treatment arms in dropout rates due to side effects. 236 A 2010 systematic review concluded that of all non-benzodiazepine anticonvulsants studied to date, carbamazepine is the only medication that may be more effective than benzodiazepines in reducing the severity of alcohol withdrawal symptoms. 237 Although the potential risk of side effects has likely been a barrier to wider use of carbamazepine in North America, in RCTs, side effects have been shown to be generally mild and temporary. A 2010 systematic review reported that carbamazepine can have side effects in up to 18% of patients; however, the authors also noted that the treatment was generally well tolerated, with fewer than 2% of trial drop-outs due to intolerable side effects. 237 The most commonly reported side effects in carbamazepine RCTs were pruritus (6.9%-18%), dizziness (11.5%), and nausea and vomiting (3.8%-10.3%), while fewer than 3% of participants experienced mental confusion, drowsiness and rash. 237 As some of these side effects can mimic or mask symptoms of alcohol withdrawal, caution should be exercised in distinguishing between withdrawal symptoms and medication side effects prior to dose adjustment. At higher doses (>1200mg/day) and with longer treatment duration (e.g., for seizure disorders), carbamazepine has been associated with rare blood dyscrasias and Stevens Johnson Syndrome, 244 however, these adverse events have not been reported in any RCTs of carbamazepine for alcohol withdrawal. 236 Importantly, pharmacogenetics studies have shown that individuals of Asian ethnicity are at increased risk of severe adverse events due to a higher prevalence of a genetic variant for carbamazepine toxicity (HLA allele B*1502). 245 Prescribing carbamazepine should be avoided in patients of Asian ethnicity unless genetic testing indicates this allelic variant is not present.
# Gabapentin
Gabapentin has a growing evidence base supporting its efficacy and safety for outpatient management of alcohol withdrawal in patients at low risk of complications. To date, results from two RCTs (n=126) indicate that gabapentin (1200mg per day) is as effective as benzodiazepines for the outpatient management of mild alcohol withdrawal symptoms, and may confer additional benefits in terms of greater daytime alertness and sleep quality, and less anxiety and mood disturbances. 246,247 Additional support for gabapentin's efficacy is provided from an open-label trial among 27 inpatients experiencing mild to moderate withdrawal symptoms, which showed that a higher dosage of gabapentin (1200mg BID, tapered by 600mg daily) had effects comparable to those of phenobarbital, with similar outcome scores between the two treatments. 248 In addition, an observational study of 37 inpatients experiencing acute withdrawal showed that two hours after the administration of 800mg of gabapentin, 73% ( 27) patients showed a significant reduction in symptom severity. 249 A more comprehensive review of safety considerations for gabapentin (e.g., non-medical use, diversion, physiological dependence, and overdose risk) can be found in the Pharmacotherapy section.
# Valproic acid
There is limited evidence to support the efficacy of valproic acid for treating alcohol withdrawal and most RCTs conducted to date have been small and underpowered. 250 Only two of six published trials reported a statistically significant difference in favor of valproic acid for the treatment of alcohol withdrawal, and these differences were of marginal clinical significance. 250 Both trials found that valproic acid results in a more rapid and consistent decline in the severity of withdrawal symptoms compared to a benzodiazepine (lorazepam and chlordiazepoxide), 251,252 however, due to small sample sizes, an adequate evaluation of safety (e.g., prevention of severe symptoms, seizures, or delirium tremens) and adverse events could not be performed. 250 The most commonly reported side effect in clinical trials was gastrointestinal upset. 250 Safety advantages of valproic acid are that it does not have a potential for non-medical use or diversion, nor does it potentiate the effects of alcohol or other CNS depressants when taken together. 253
# α-adrenergic Agonists
# Clonidine
Clonidine is a centrally acting alpha-2 adrenergic agonist that can suppress persistent noradrenergic symptoms (e.g., hypertension, tachycardia) associated with alcohol withdrawal. Two RCTs have reported that clonidine (at doses of 0.2-0.6mg per day) is as effective as the benzodiazepine chlordiazepoxide in the management of mild to moderate withdrawal symptoms, with advantages in control of sympathetic symptoms and reductions in patient anxiety. 254,255 Both trials excluded patients with a history of withdrawal-related seizures. 254,255 There have been no reports of safety issues with concomitant administration of clonidine with anticonvulsants, therefore, clonidine can also be considered as an adjunct to carbamazepine, gabapentin, or other anticonvulsants, as it may provide additional benefits in managing withdrawal symptoms via a different mechanism of action than these drugs. 256
# Efficacy
Over 60 RCTs (n>4000) report superior efficacy in the suppression of withdrawal symptoms compared to placebo and other active treatments. 229 Over 20 RCTs (n>2000) report superior efficacy for prevention of seizures compared to placebo and active treatments. [227][228][229] Six RCTs (n=558) of carbamazepine report equal [238][239][240][241] or superior 242,243 efficacy in the reduction of withdrawal symptom severity compared to benzodiazepines.
Insufficient evidence for prevention of seizures or delirium tremens.
# Concurrent Alcohol Use
Potentiates the effects of alcohol; concurrent alcohol use can result in serious safety risks, including over sedation, falls, delirium, respiratory depression (e.g., non-fatal or fatal overdose), and need for prolonged hospitalization.
No safety risk if taken concurrently with alcohol (i.e., in the event of lapse/relapse
# Side Effects
Common side effects are drowsiness, dizziness.
Less common side effects include changes in skin colour, nausea, headache, blurred vision, tremors, hypotension, GI disturbances. Memory loss may also occur.
Side effects may include dizziness, pruritus, ataxia, headache, drowsiness and nausea.
These side effects are often minor and temporary.
# Other Considerations
Potential for non-medical use, diversion, and dependence.
Potential for drug-drug interactions leading to excess sedation, impaired psychomotor and cognitive functioning.
Due to safety concerns, exercise caution when considering this medication for outpatient use. Two RCTs (n=126) reported that gabapentin is as effective as benzodiazepines in suppressing mild to moderate withdrawal symptoms, and may be superior for treating insomnia and anxiety symptoms. 246,247 Insufficient evidence for prevention of seizures or delirium tremens.
Two RCTs (n=50) reported that clonidine was as effective as benzodiazepines in reducing mild to moderate withdrawal symptoms. 254,255 Does not prevent seizure or delirium tremens.
Limited evidence of efficacy. Two open-label trials (n=27) suggest a faster reduction of withdrawal symptoms with valproic acid compared than benzodiazepines. 251,252 Insufficient evidence for prevention of seizures or delirium tremens.
Abstinence is recommended after starting treatment due to potential risk of additive CNS-depressive effects.
Note: Studies suggest concomitant use of alcohol and gabapentin (at therapeutic doses) does not increase sedation or motor impairment. 261 Can have an additive effect on lowering blood pressure if taken with alcohol. Patients and families should receive education on signs and symptoms of hypotension.
No safety risk if taken concurrently with alcohol (i.e., in the event of lapse/relapse).
# Section Summary and Recommendations
Based on available evidence, the guideline committee recommends non-benzodiazepine medications as the preferred approach for the outpatient management of mild to moderate withdrawal symptoms in patients at low risk of severe complications. Carabamazepine [237][238][239][240][241] and gabapentin 237,246,247 have been shown to be safe and effective for the management of mild to moderate withdrawal symptoms in comparison to placebo. The use of clonidine as an alternative or adjunctive option for mild to moderate withdrawal symptoms is also supported by moderate quality evidence. 254,255 There is insufficient evidence that gabapentin, carbamazepine, and clonidine are effective for preventing seizures or delirium tremens, therefore, it is recommended that non-benzodiazepine medications be used only for outpatient management of patients who are at low risk of these complications. The committee's strong recommendation is specific to the use of non-benzodiazepine pharmacotherapies for the outpatient management of mild to moderate alcohol withdrawal in patients at low-risk of severe complications.
There is limited evidence to support the efficacy of valproic acid for the treatment of alcohol withdrawal. 250 Thus, while this medication may still be commonly used for alcohol withdrawal management in some care settings, the committee recommends that it should only be considered when all other pharmacotherapy options are contraindicated.
Benzodiazepines are generally not a preferred option for outpatient withdrawal management due to their well-documented side effects, tendency to potentiate the effects of alcohol if used concurrently, and potential for non-medical use and dependence. 175 Although not preferred, if benzodiazepines are prescribed for outpatient withdrawal management, the following measures should be considered: prescribing a short course prescription (5-7 days) with a fixed-dose schedule, daily dispensing from a pharmacy, and frequent clinical visits to closely monitor side effects, symptoms, and alcohol use, and to make dose adjustments as needed.
# Recommendation 6 Pharmacotherapy for Management of Mild to Moderate Withdrawal
Clinicians should consider non-benzodiazepine medications, such as carbamazepine, gabapentin, or clonidine, for outpatient withdrawal management in patients at low risk of severe complications of alcohol withdrawal.
# Quality of Evidence: MODERATE Strength of Recommendation: STRONG
# Remarks
• Selection of an appropriate medication should be made through shared decision-making by patient and provider in consideration of a patient's goals, needs, and preferences.
• Contraindications, side effects, feasibility (dosing schedules, out-of-pocket costs), and patient history should also be taken into account in selecting a medication.
• Carbamazepine is contraindicated in patients with hepatic disease, bone marrow depression, serious blood disorder, and atrioventricular heart block.
• People of Asian descent are at increased risk of serious cutaneous adverse drug reactions (Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis [TEN], maculopapular rash) due to a higher baseline prevalence of the HLA-B*1502 allele, a marker for carbamazepine toxicity. Carbamazepine should be avoided in this population unless genetic testing is available and has excluded risk. 245 • Gabapentin is contraindicated in patients with hypersensitivity to this medication. Caution is advised for patients with renal impairment. Gabapentin should not be combined with opioids.
• Clonidine is contraindicated in patients with sinus node function impairment, severe bradyarrhythmia, and galactose intolerance. Caution is advised for patients with a history of hypotension.
This guideline recommends inpatient withdrawal management using a benzodiazepine regimen for patients at high risk of developing severe complications of withdrawal. Multiple systematic reviews have reported high quality evidence that benzodiazepines are more effective than placebo and other active treatments for the suppression of severe withdrawal symptoms and prevention of delirium tremens and seizures. [227][228][229] The committee's strong recommendation is specific to the supervised use of benzodiazepines for the management of severe alcohol withdrawal in an inpatient setting, due to their safety profile. 175
# Withdrawal Management in Adolescent Patients
Withdrawal symptoms on cessation of alcohol use are relatively rare among adolescent patients (aged 11-18 years) with AUD. 262 It is estimated that 5 to 10% of adolescents with an AUD will experience withdrawal symptoms of any severity, 262 and only a subset of these individuals will require pharmacological management. 263 Due to the relative rarity of this condition, no empiric data are available to make evidence-based recommendations for pharmacological management of alcohol withdrawal in adolescents. Practice guidelines recommend that in rare cases where pharmacological management is necessary, approaches are generally the same for adolescent as for adult patients. 263 In cases involving adolescents, a consultation with an addiction medicine specialist is strongly recommended prior to initiating monitored withdrawal in an outpatient setting, even if the PAWSS < 4, as this instrument has not been validated for use in youth. All care providers, patients, and families in British Columbia can access information and referrals from the D-Talks (youth detox) provincial contact line (1-866-889-4700).
# Withdrawal Management in Pregnant Patients
There are unique considerations for withdrawal management in pregnant individuals. The potential maternal and fetal risks and benefits of pharmacotherapy must be weighed against the known risks of untreated withdrawal and/or continued alcohol consumption. Adding to this, very few medications have been studied in pregnant individuals, and several options that have been proven safe and effective in non-pregnant adult patients are contraindicated in pregnancy due to the risk of fetal malformations (e.g., carbamazepine).
The limited research on withdrawal management during pregnancy has been focused almost exclusively on benzodiazepine-based pharmacotherapy, and has yielded conflicting results. Early case-control studies suggested that benzodiazepines were associated with increased risk of fetal malformations; however, a more recent meta-analysis including case-control and cohort studies concluded that, overall, the available evidence did not support their teratogenicity. [264][265][266] These results should be considered with caution, as very few studies have been published on the topic, and there have been no randomized or quasi-randomized trials of pharmacological withdrawal management in pregnant individuals with AUD. More research is needed to accurately assess the safety and efficacy of available treatments in this population. 267 Few clinical practice guidelines have made explicit recommendations for withdrawal management in pregnant individuals. The World Health Organization's 2014 Guidelines for Identification and Management of Substance Use and Substance Use Disorders in Pregnancy recommend that pregnant individuals with AUD should be admitted to inpatient withdrawal management facilities or hospital settings that are appropriately equipped to monitor fetal movement and vital signs during treatment. 268 Pharmacotherapy with benzodiazepines is recommended where indicated and appropriate, to be delivered under close observation so that dose can be titrated to severity of withdrawal symptoms (i.e., symptom-triggered protocol). 175,268 In the absence of clear evidence, the risks of untreated maternal alcohol withdrawal symptoms, which include fetal distress, spontaneous abortion, preterm birth, and fetal demise, 266 must be weighed against the risks of pharmacological treatment.
# Committee Consensus Recommendation -Continuity of Care
The guideline committee strongly recommends that patients who complete withdrawal management should be offered a connection to ongoing relapse prevention and recovery management treatment and support. Withdrawal management alone is not adequate treatment for AUD, as it does not address the chronic relapsing nature of the condition. Randomized trials and observational studies have reported that 40% to 85% of individuals with AUD resume drinking following withdrawal management, often within the first few days or weeks. [269][270][271][272][273][274][275] The guideline committee emphasizes that offering withdrawal management as a standalone intervention to patients with AUD is neither sufficient nor appropriate.
# Recommendation 8 Continuing Care Following Withdrawal Management
All patients who complete withdrawal management should be connected with continuing relapse prevention and recovery management care.
# Quality of Evidence: LOW Strength of Recommendation: STRONG
# Remarks
• Withdrawal management is a short-term intervention that does not resolve underlying medical, psychological, or social issues associated to AUD, and should be considered a bridge to continuing care, treatment, and support that will address these concerns.
# Continuing Care -Pharmacotherapy
Pharmacotherapy can play an important role in assisting individuals with AUD to reduce or stop drinking, yet are underutilized in the management of AUD. Primary care providers' lack of education and training are consistently identified as barriers to prescribing AUD pharmacotherapy, 276,277 but research has shown that when these practitioners are provided with evidence-based clinical care guidance and practice tools, they can effectively prescribe these medications in alignment with their patients' goals, leading to clinically meaningful improvements in treatment outcomes. 29,33 All primary care patients with moderate or severe alcohol use disorder can be offered pharmacotherapy for AUD. Additionally, regardless of AUD severity, any patient who has stopped or reduced their drinking but continues to experience strong alcohol cravings or is at risk of relapse may be an appropriate candidate for pharmacotherapy.
# Setting Patient-Centred Treatment Goals
Traditionally, abstinence or cessation of alcohol use has been viewed as the primary goal of AUD treatment. However, it is important to recognize that not all individuals with AUD view abstinence as an acceptable, desirable, or realistic treatment goal, which in turn, can prevent them from seeking treatment for AUD or act as a barrier to continued engagement in care. 278 In recent years, there has been increased recognition that a reduction in drinking is a valid and important treatment goal for some individuals. 83 Studies have shown that individuals with AUD are more likely to achieve self-identified treatment goals -whether that is a reduction in drinking or abstinence -than goals that are set for them. 279,280 As an emerging area of research, relatively few RCTs have been explicitly designed with reduced alcohol consumption as a primary study outcome, and thus, some concerns have been raised about the lack of efficacy data for use of pharmacotherapy in this context. 281 For example, a recent network meta-analysis of 32 RCTs (n=6,036) concluded that there is a lack of high-quality evidence that available pharmacotherapies are effective for reducing alcohol consumption in non-abstinent adults. 282 Additional concerns have been raised about the lack of evidence that a reduction in drinking directly translates into improved health outcomes in patients. 282 In the absence of high-quality RCT data, it is noted that findings from a number of large observational cohort studies do show that reductions in alcohol consumption are associated with reductions in alcohol-attributable morbidity and mortality. 9,51,52,100,113,283 While acknowledging that there are limitations to the evidence base, it is the consensus of this committee that clinicians should adopt a treatment approach that accepts a spectrum of goals from harm reduction to abstinence, and recognizes that a reduction in drinking and alcohol-related harms is a useful and important goal for some patients.
6.2 First-line Pharmacotherapies
# Naltrexone
Naltrexone is a mu-opioid receptor antagonist that has been shown to block euphoria associated with alcohol consumption. 284 It is hypothesized to work by diminishing the rewarding effect of alcohol in the brain following its consumption, as well as reducing cravings for alcohol in some individuals. 284 This blunting effect on neural reward pathways is consistent with research findings that naltrexone is particularly effective in preventing a return to heavy drinking following a temporary lapse to alcohol use. 285 Naltrexone has a well-established evidence base for safety and efficacy in the treatment of AUD. 178 A 2010 metaanalysis of 50 RCTs (n=7,793) reported that participants treated with naltrexone had a 17% lower likelihood of engaging in heavy drinking, and had 4% fewer drinking days per month than those who received placebo. 285 Naltrexone-treated participants also showed a greater reduction in heavy drinking days (-3.25%) and the amount of alcohol consumed (-10.83 grams) compared to the placebo group. 285 Naltrexone is contraindicated in individuals with acute hepatitis and liver failure, and although it no longer carries a "black boxed warning" for hepatoxicity, 286 caution and increased monitoring are advised if prescribed to patients with hepatic impairment. Naltrexone is also contraindicated in patients currently taking or expected to require opioid medications for pain (e.g., long-term opioid treatment) and/or as opioid agonist treatment (i.e., methadone, buprenorphine, slow-release oral morphine, or injectable opioid agonist treatment) for treating opioid use disorder. Commonly reported side effects in placebo-controlled trials of naltrexone include somnolence (29.5% in the naltrexone-treated group vs.17.8% in the placebo group), nausea (25.8% vs.16.3%), vomiting (16.9% vs.10.4%), decreased appetite (17.7% vs.11.8%), abdominal pain (15.9% vs. 7.5%), insomnia (16.4% vs. 13.4%), and dizziness (11.9% vs. 6.2%). 285 Research suggests that predictors of a positive response to naltrexone include high levels of craving and a family history of AUD. 287,288 Two recent studies have also reported that naltrexone may be more effective in individuals who smoke tobacco or use electronic cigarettes, but these results have yet to be validated in large prospective trials. 289,290 As would be expected, treatment adherence is also highly correlated with positive treatment outcomes; therefore, it is recommended that clinicians routinely check-in and provide support with medication adherence when needed, as well as other patient-defined treatment goals, through medical management and regular follow-up visits. 285,291,292 In the majority of clinical trials, naltrexone has been studied as a dose taken once daily. However, several studies have found that when taken "as-needed" (e.g., prior to drinking or when significant cravings are experienced), targeted naltrexone can reduce alcohol consumption in individuals who meet criteria for high-risk drinking, including those diagnosed with mild to severe AUD. 179,[293][294][295] Two RCTs have found that targeted naltrexone reduces the likelihood of heavy drinking 293 and number of drinks consumed per drinking day 294,296 compared to placebo conditions, and one RCT showed that targeted naltrexone was significantly more effective than placebo in maintaining a reduction in drinking following 12-weeks of continuous naltrexone therapy. 179 Reported effect sizes on alcohol-related outcomes were small to moderate, 297 which is consistent with published treatment effects of daily-dosed naltrexone. 178,285 Taken together, these results suggest that targeted naltrexone is an effective approach for reducing alcohol consumption and alcohol-related harms. 297 Targeted dosing regimens may be preferred for patients who experience challenges with adherence or significant side effects with daily-dosed regimens, or patients who are drinking above low-risk limits but do not meet the criteria for an AUD. Prescribing naltrexone "as-needed" may also have advantages in supporting patients to maintain their goals during later stages of AUD treatment, rather than discontinuing pharmacotherapy.
# Acamprosate
Acamprosate's mechanism of action is not well understood, but it is believed to restore the imbalance between glutamate-mediated excitation and GABA-mediated inhibition of neural activity, which is dysregulated by chronic alcohol consumption, and to reduce general neuronal hyperexcitability. 284 Together, these effects are believed to reduce symptoms associated with withdrawal from alcohol, and modify responses to alcohol-related cognitive cues. 284 Acamprosate has an established evidence base for safety and efficacy in the treatment of AUD. [298][299][300][301][302] A 2010 meta-analysis of 24 RCTs (n=6,915) found that acamprosate significantly reduced the likelihood of a return to any drinking by 14% and increased the cumulative duration of abstinence by 11 days compared to placebo. 300 In addition, the review showed that the effects of acamprosate persisted for 3-12 months after treatment discontinuation. 300 The majority of clinical trials of acamprosate have taken place in Europe, where it was used for several decades to treat AUD prior to its approval in North America. This has raised some concerns that research findings may not be generalizable to North American settings, particularly as a large U.S. trial (n=1,383) showed that acamprosate was no more effective than placebo in reducing alcohol consumption. 303 This finding is contrary to most European acamprosate trials. A 2015 meta-analysis (49 RCTs, n=9,435) of acamprosate and naltrexone treatment trials concluded that overall, trial location did not appear to influence abstinence or relapse rates, but that drop-out rates and participant characteristics did differ by location. 304 Participants in European trials were less likely to discontinue treatment early, more likely to have a treatment goal of abstinence, and were better engaged in care than non-European study participants. The review authors speculated that these differences resulted in a lower likelihood of treatment discontinuation for participants in European trials compared to non-European trials, which could account for observed differences in treatment efficacy. 304 No interaction was observed between drop-out and trial location for naltrexone trials. Overall, the review concluded that based on available evidence, acamprosate is effective for the treatment of AUD, but suggested that an individual patient's treatment goal is an important factor to consider when selecting a first-line treatment (see Selecting Between Naltrexone and Acamprosate). 304 Acamprosate is generally well tolerated, and the most common side effects are gastrointestinal disturbances (e.g., diarrhea, nausea, vomiting). In RCTs, diarrhea is the only side effect reported more frequently for acamprosate than placebo. 300 Although this side effect can occur in up to 16% of patients, it usually resolves quickly within a few days. 145 Clinical trials show that the strongest predictors of acamprosate treatment success are completing withdrawal management or being abstinent prior to starting treatment, and having abstinence as a treatment goal. 177,305 Motivation and treatment readiness may be particularly important factors for adherence, as due to its low bioavailability, acamprosate must be administered at a dosage of nearly 2 grams split into three doses per day.
Providing encouragement and informal counselling to support patients with medication adherence is critical at treatment onset and on an ongoing basis. 305 Additional predictors of treatment success with acamprosate that have been identified in the literature include higher baseline anxiety levels, a physiological dependence on alcohol, a lack of family history of AUD, and a later age of AUD onset (i.e., >40 years of age). 306
# Selecting Between Naltrexone and Acamprosate
A 2014 meta-analysis (122 RCTs, n=22,803) of outpatient pharmacotherapy for adults with AUD found that both acamprosate (27 RCTs, n=7,519) and naltrexone (53 RCTs, n=9,140) were associated with a lower likelihood of relapse than placebo. 178 When directly compared with one another (4 RCTs, n=1,141), no significant differences were found between acamprosate and naltrexone in alcohol consumption outcomes. 178 While the overall superiority of one medication over the other has not been established conclusively, there is evidence that naltrexone may be more effective in reducing heavy drinking, while acamprosate may be more effective in supporting abstinence from alcohol. A 2014 systematic review calculated that to prevent one individual from returning to any drinking, the number needed to treat (NNT) was 20 for naltrexone, and 12 for acamprosate. 178 To prevent return to heavy drinking, the NNT for naltrexone was calculated to be 12, whereas acamprosate was not significantly better than placebo. 178 Two independent systematic reviews have reached similar conclusions, finding that acamprosate may be more effective for patients with a goal of abstinence, whereas naltrexone may be beneficial for patients with a goal of reduced drinking or abstinence. 307,308 Thus, a patient's treatment goals are a key consideration when selecting between these medications. Additional information to consider when selecting between these two medications is summarized in Table 6.
# Accessibility and Other Considerations
In British Columbia, both acamprosate and naltrexone are classified as Limited Coverage Drugs in the provincial formulary. To secure PharmaCare coverage for their patients, prescribers must first submit a "Collaborative Prescribing Agreement for Naltrexone and Acamprosate for the Treatment of Alcohol Dependence" to the Pharmaceutical Services Division of the Ministry of Health. Once approved, the Collaborative Prescribing Agreement (CPA) will apply to all patients within a clinician's practice. Once a CPA is in place, naltrexone and acamprosate are eligible for full coverage under the various PharmaCare prescription drug plans, including Plan G, which provides full coverage for psychiatric medications for qualifying individuals with an adjusted net family income of $42,000 or less, plus $3,000 per dependent.
# Efficacy
Established evidence base for safety and efficacy in reducing relapse rates and alcohol consumption compared to placebo (53 RCTs; n=9,140). 178 A 2014 meta-analysis estimated that the NNT to prevent return to any drinking (relapse) was 20 (95%CI, 11 to 500), and the NNT to prevent return to heavy drinking was 12 (95%CI, 8 to 26). 178 Established evidence base for safety and efficacy reducing relapse rates compared to placebo (27 RCTs; n=7,519). 178 A 2014 meta-analysis estimated that the NNT to prevent return to any drinking (relapse) was 12 (95%CI, 8 to 26), but that acamprosate was not associated with an improvement in alcohol consumption. 178
# Concurrent Alcohol Use
Safe to start while patients are using alcohol, but may be more effective and potential side effects minimized if started upon completion of withdrawal management (3-7 days of abstinence from alcohol use). 178,179 Safe to start while patients are using alcohol, but may be more effective if started following completion of withdrawal management. 177
# Safety and Other Considerations
• Liver function tests (LFT) should be assessed at treatment initiation, and again at 1, 3, and 6 months. If LFTs are elevated at baseline, more frequent monitoring is indicated.
• Patients should be advised of the risk of hepatic injury and to stop use of medication if they experience symptoms of acute hepatitis (fatigue, anorexia, nausea, and vomiting).
• No dose adjustment is required for patients with mild renal impairment (creatinine clearance 50-80mL/min).
• Dose reduction is required for patients with moderate renal impairment (creatinine clearance 30-50mL/min).
• No known hepatic toxicities.
* Safety and efficacy of these medications has not been fully established in these patient populations and their use would be at the discretion of the treating clinician. Specialist consultation, careful assessment of benefit and risks, fully informed patient consent, and regular monitoring and assessment is advised in these cases.
# Extended-Release Naltrexone
Note: Extended-release naltrexone is not approved for clinical use in Canada. At the time of this guideline publication, there is also no indication that the manufacturer plans to pursue approval of this medication in Canada.
In the United States, naltrexone is available as an extended-release formulation administered via monthly intramuscular injections, 284 which may promote improved treatment adherence in comparison to daily-dosed oral naltrexone. 311 Several randomized controlled trials have found extended-release naltrexone to be well tolerated and superior to placebo in terms of improved treatment adherence and retention rates, increased abstinence rates, and decreased alcohol cravings. 311,312 Additionally, given the established body of evidence supporting the use of extended-release naltrexone for the treatment of opioid use disorder (OUD), 313 this medication may have advantages for treatment of individuals with co-occurring AUD and OUD. A recent pilot trial that compared extended-release naltrexone to treatmentas-usual in individuals with HIV and co-occurring AUD, OUD, or concurrent AUD/OUD (n=51) found that 88% of participants randomized to extended-release naltrexone were retained in treatment at 16 weeks, compared to 50% of patients in the treatment-as-usual arm (oral naltrexone, gabapentin, acamprosate, disulfiram). 314 The study was not powered to detect differences in treatment-specific outcomes, but the authors noted that alcoholrelated and HIV-specific outcomes (i.e., antiretroviral adherence, HIV viral suppression) improved in both pharmacotherapy groups. 314 At present, extended-release naltrexone is only available through Health Canada's Special Access Programme (SAP). The SAP considers individual requests for access to drugs that are not available or approved in Canada for patients with serious or life-threatening conditions for whom conventional treatments have failed, are unsuitable, or are not accessible. Clinicians can submit applications to the SAP on behalf of their patients, but should be aware that medication costs are not covered by insurance plans when accessed via this route, and that patients incur the full cost out-of-pocket. The injectable formulation of naltrexone is substantially more expensive than the oral option. Providing recommendations on the use of this medication in the treatment of AUD is currently outside the scope of this guideline; however, in future, there may be a need for an expert therapeutic guideline to identify circumstances and patient populations who could benefit from extended-release naltrexone.
# Section Summary and Recommendation
This guideline recommends that all adult patients with moderate or severe alcohol use disorder should be offered pharmacotherapy for AUD. Additionally, regardless of AUD severity, the guideline committee recommends that any patient who has stopped or reduced drinking but is continuing to experience strong alcohol cravings and/or is at risk of relapse may be an appropriate candidate for pharmacotherapy.
Based on moderate-quality evidence, the committee recommends naltrexone and acamprosate as first-line pharmacotherapy options for treatment of AUD. The committee recommends naltrexone for patients with a treatment goal of reduced drinking or abstinence, and acamprosate for patients with a treatment goal of abstinence, based on research evidence supporting each medication's efficacy for achieving these specific outcomes. 178,307,308 Adult patients with moderate to severe alcohol use disorder should be offered naltrexone or acamprosate as a first-line pharmacotherapy to support achievement of patient-identified treatment goals.
A. Naltrexone is recommended for patients who have a treatment goal of either abstinence or a reduction in alcohol consumption.
B. Acamprosate is recommended for patients who have a treatment goal of abstinence.
# Quality of Evidence: MODERATE Strength of Recommendation: STRONG
# Remarks
• Naltrexone is contraindicated in patients who are currently or expected to be taking opioids (prescribed or non-medical use), patients with a known sensitivity to the drug or its constituents, and patients with acute hepatitis or liver failure. Caution is advised in prescribing naltrexone to patients with liver disease, patients who are pregnant, and patients under the age of 18.
• Acamprosate is contraindicated in patients with severe renal impairment (i.e., creatinine clearance ≤30mL/min), patients with a known hypersensitivity to the drug or its constituents, and in patients who are breastfeeding. Caution is advised in prescribing naltrexone to patients with renal disease, patients who are pregnant, patients under the age of 18 and patients over the age of 65.
• Completion of withdrawal management is not a mandatory prerequisite to starting treatment.
# Alternative and Emerging Pharmacotherapies for AUD
Not all individuals with AUD benefit from first-line treatment approaches, despite good adherence and treatment motivation. For example, systematic reviews have reported that 38% to 70% of individuals treated with acamprosate or naltrexone do not benefit or only partially benefit from a trial with one of these medications. 285 As a result, research into alternative pharmacotherapies is ongoing, with the goal of providing a wider range of personalized pharmacotherapy options for individuals seeking treatment for AUD. The research evidence for efficacy and safety of several alternative pharmacotherapies -topiramate, gabapentin, disulfiram, baclofen, and ondasetron -is reviewed below (see Table 7 for summary).
With the exception of disulfiram, which is a Health-Canada approved medication for AUD, use of the medications reviewed below would be considered "off-label". As with any medication that is being prescribed off-label, it is important to conduct a full assessment including carefully reviewing concomitant medications for potential drug-drug interactions, and documenting patient consent in their chart. All five medications are eligible for full coverage through PharmaCare drug benefits Plan C, Plan W and Fair PharmaCare, but only disulfiram is covered by Plan G for the treatment of AUD.
In addition, as comparative safety and efficacy of these alternative therapies has not been fully established in adolescent, pregnant, older adult, or more complex patient populations (e.g., concurrent medical conditions, co-occurring mental health and substance use disorders), prescribing these medications in these cases would be at the clinician's discretion following a careful assessment of risks, benefits, drug-drug interactions and contraindications (particularly for pregnant individuals). British Columbia physicians and nurse practitioners are encouraged to call the RACE line (Vancouver area: 604-696-2131; toll-free: 1-877-696-2131, www.raceconnect.ca) or use the RACE line app to connect with an addiction medicine specialist for advice and guidance on complex cases.
# Topiramate
Topiramate is an anticonvulsant medication that has been investigated off-label for treating AUD. A 2014 metaanalysis of 7 placebo-controlled trials (n=1,125) of topiramate for treating AUD reported significant, moderatesized effects on aggregate measures of abstinence and heavy drinking, and non-significant effects on gammaglutamyl transferase (GGT) levels and craving outcomes, compared to placebo. 315 Topiramate doses ranged from 100-300mg/day and duration of treatment from 12-16 weeks. Of note, three of the trials included in this review enrolled participants who were not abstinent from alcohol at treatment onset, [316][317][318] and outcomes did not appear to systematically differ from trials that required participants to be abstinent at treatment start. [319][320][321][322] In addition, pooled results from three randomized trials directly comparing topiramate to naltrexone suggest that topiramate may be superior to naltrexone for heavy drinking and craving outcomes, and equally effective for abstinencerelated outcomes. 321,323,324 Topiramate is generally well tolerated, but some individuals do experience significant side effects, particularly at higher doses or with more rapid increases in dosage. 316,317,320,322 For this reason, a gradual dose titration over several weeks is strongly recommended (e.g., ~5-8 weeks to full dose). 316,317,320,322 In placebo-controlled trials, adverse effects that were significantly more common with topiramate were paresthesia (50.8% vs.10.6% in the placebo group), dysgeusia (23.0% vs. 4.8%), anorexia (19.7% vs. 6.9%), difficulty with concentration or attention (14.8% vs. 3.2%), nervousness (14.2% vs. 7.5%), dizziness (11.5% vs. 5.3%), and pruritus (10.4% vs. 1.1%). 317 Most clinical trials conducted to date have used a relatively high daily dose of topiramate (up to 300mg per day), however, one randomized trial that compared psychotherapy alone to psychotherapy plus low-dose topiramate (up to 75mg per day) found that participants who received topiramate were more likely to remain continuously abstinent during a 4-month follow-up period than those who did not (33.3% compared to 14.5%). 325 Further research is needed to determine optimal dosing strategies, rates of dose titration, and maintenance dose levels that best balance treatment effectiveness with patient comfort and safety.
# Gabapentin
Emerging evidence for the efficacy of gabapentin in treating AUD is derived primarily from three placebocontrolled clinical trials. One trial randomized 60 participants to receive either gabapentin (600mg/day) or placebo for 7 days, and found that gabapentin was more effective in reducing alcohol craving, the number of drinks per day, and percentage of heavy drinking days, and increasing the number of days abstinent. 326 A second trial randomized 33 participants to receive gabapentin (1200mg/day) or placebo for 7 days, and found that gabapentin was effective in attenuating subjective alcohol craving, and cravings specifically associated with emotionally evocative stimuli, compared to placebo. 327 A third, larger trial (n=150) that compared placebo with gabapentin administered at a dose of either 900mg/day or 1800mg/day for 12 weeks reported abstinence rates of 4.1%, 11.1%, and 17.0% respectively, with an estimated number needed to treat (NNT) of 8 for those participants who received a daily dose of 1800mg. 328 For measures of alcohol consumption, 22.5% of participants in the placebo group, 29.6% of participants in the 900mg/day group, and 44.7% of participants in the 1800mg/day group met criteria for no heavy drinking at 12 weeks, with an estimated NNT of 5 for the 1800mg/day group. 328 There were no differences in adverse events reported for gabapentin at either dose compared to placebo. 328 The authors also noted that gabapentin appeared to have a dose-dependent effect on participants' subjective ratings of mood, insomnia, and craving symptoms. 328 As gabapentin has also been found to be effective for the outpatient management of mild to moderate alcohol withdrawal symptoms, having the option to continue its use beyond the acute withdrawal period as part of a long-term treatment strategy may have advantages. 261 While promising, these initial trials employed relatively small sample sizes and the largest trial reported high drop-out rates (65 dropouts/150 participants, or about ~43%). 328 A 2019 meta-analysis (7 RCTs, n=751) concluded that while gabapentin appears to be more efficacious than placebo for treating AUD, the only outcome measure that clearly favors gabapentin is a reduction in heavy drinking days. 329 As underscored by this meta-analysis, further research is needed to definitively establish the safety and efficacy of gabapentin in comparison to first-line and other alternative treatment options.
While the three trials described above used the immediate-release formulation of gabapentin, a 2019 multi-site RCT (n=346) evaluated the safety and efficacy of an extended-release gabapentin formulation (gabapentin enacarbil) for treating AUD. 330 Participants were randomized to receive either placebo or gabapentin enacarbil (600mg twice per day) for six months. At the conclusion of the trial, the percentage of participants with no heavy drinking days did not differ significantly between treatment and placebo (28.3% vs. 21.5%), and no clinical benefit was found for other drinking measures (percent participants abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. 330 The lack of a demonstrated treatment effect for the extended-release formulation compared to earlier trials of immediate-release gabapentin is not yet fully understood, and more research is needed -in particular, large, well-designed, multi-site trials that directly compare different gabapentin formulations and dosages. 330 At this time, based on these results, extended-release gabapentin is not recommended for the treatment of AUD.
The most common adverse events reported in placebo-controlled clinical trials of (immediate-release) gabapentin are dizziness (19.1% vs. 6.6% in the placebo group), somnolence (14.1% vs. 5.2%), ataxia or gait disorder (14.0% vs. 2.2%), and peripheral edema (6.6% vs. 1.5%). 331 As gabapentin is excreted renally it is safe to use in patients with severe liver disease, but requires conservative dosing in patients with severe renal failure. In patients with chronic kidney disease, glomerular filtration rate (GFR) should be monitored with gabapentin dosage adjusted as needed with any changes in GFR. 332 Due to its side effect profile, caution is advised in prescribing gabapentin to patients at increased risk of confusion, disorientation or falls (e.g., older adults, frail patients, individuals with cognitive impairment).
# Safety Considerations for Gabapentin
Recent reports have raised concerns regarding potential risks of nonmedical use, physiological dependence, and withdrawal syndromes associated with gabapentin. [333][334][335][336][337][338] While large observational cohort studies in the United Kingdom and the United States have shown that the prevalence of non-medical use of gabapentin is low in the general population (~1%) 339 and among individuals prescribed gabapentin (~2%), 340 higher rates (12%-22%) have been documented among opioid-using populations and in facilities where access to alcohol and other drugs is restricted (e.g., inpatient treatment programs, correctional facilities). 338,[340][341][342][343] A 2016 review identified 18 case reports and case series describing non-medical use including non-prescribed (diverted) use and use where not taken as prescribed (e.g., higher and/or more frequent doses, combined with other substances, or taken by inhalation, injection or other routes), as well as physiological dependence and/or withdrawal symptoms on discontinuation of use. 344 Gabapentin dependence was noted only among patients with a history of alcohol, stimulant, or opioid use disorders, and the average daily dose in these cases was approximately 3000mg/day (range 600-8000mg/ day). 344 Withdrawal symptoms, where reported, occurred within 12 hours to 7 days of discontinuation of gabapentin, and included restlessness, disorientation, confusion, agitation, and anxiety, which did not resolve with the administration of benzodiazepines. 344 There have also been a small number of reports of individuals combining high doses of gabapentin with alcohol or other medications (such as quetiapine, buprenorphine/naloxone, methadone, and other prescribed and illicit opioids) to potentiate euphoric effects. [345][346][347][348] The combined use of opioids and gabapentin is of particular concern, due to additive effects on respiratory depression, which can increase risk of fatal overdose. 349 A Canadian study of 5,875 individuals prescribed opioid medications reported that concomitant use of gabapentin increased the risk of fatal overdose by 49% compared to case-controls (matched for age, sex, index year, history of chronic kidney disease, and disease risk index). 350 The study also found evidence that moderate (900-1800mg) and high (≥1800mg) prescribed daily doses of gabapentin increased the adjusted odds of a fatal opioid overdose by 60% compared to individuals with no concomitant gabapentin use. 350 Gabapentin is also increasingly being identified in post-mortem toxicology analyses of individuals who have died from substance-related overdoses. 338 For example, a recent analysis of 4,169 overdose deaths in five U.S. states reported that gabapentin was detected in 22% of all overdose deaths and 26% of opioid-related overdose deaths. 351 It is likely that the risks of non-medical gabapentin use in individuals with AUD remain lower than risks associated with untreated AUD. However, primary care providers do need to be aware of these risks and carefully monitor their patients for any signs of non-medical use, dependence, and diversion, with particular attention to individuals prescribed multiple medications for concurrent medical conditions. If diversion or misuse is a concern, clinicians can consider prescribing gabapentin to be dispensed daily, weekly or biweekly from a pharmacy, or with blisterpackaging to conduct random pill counts. 334
# Disulfiram
As noted above, disulfiram is one of three Health Canada-approved medications for treatment of AUD in adults.
Unlike other AUD pharmacotherapies, disulfiram does not directly influence the neural pathways linked to the rewarding effects of, cravings for, or motivation to drink alcohol. It is an aversive agent that causes an extremely unpleasant physiological reaction if alcohol is consumed (i.e., a "alcohol-disulfiram" reaction). Disulfiram blocks the metabolism of alcohol by inhibiting an alcohol dehydrogenase enzyme, which results in an accumulation of acetaldehyde (the primary metabolite of alcohol) in the body. 284 Acetaldehyde causes a range of side effects that may include sweating, headache, dyspnea, lowered blood pressure, flushing, sympathetic hyperactivity, heart palpitations, nausea, and vomiting. 284 This reaction can occur if alcohol is consumed for up to two weeks after a standard daily dose (125-500mg) of disulfiram is taken. 284 As the alcohol-disulfiram reaction can present as an emergency situation, patients must never be administered disulfiram without full consent and knowledge of its effects. 352 Placebo-controlled trials have not clearly demonstrated that disulfiram is more effective than placebo for the treatment of AUD. A 2014 meta-analysis of two clinical trials (n=492) did not find any significant differences between disulfiram and placebo in preventing a return to any drinking among individuals with AUD. 178 Previous studies have noted that disulfiram adherence rates are low, which contributes to its lack of efficacy. 353 In contrast, a meta-analysis that stratified analyses by blinded (5 RCTs) versus open-label trials (17 trials), concluded that disulfiram can be effective when administered under structured and supervised conditions. 354 For example, an open label clinical trial (n=243) that randomly assigned participants to receive 12 weeks of disulfiram, naltrexone, or acamprosate treatment under supervision found that individuals taking disulfiram showed greater reductions in heavy drinking days, average weekly consumption, and relapse rates compared to naltrexone and acamprosate. 355 However, the relative benefits of disulfiram observed during the trial dissipated in a subsequent unsupervised 52-week treatment period: a setting that may more closely resemble "real-world" conditions. 355 Based on this evidence, disulfiram is not recommended over other available pharmacotherapies for AUD that have been proven effective in preventing relapse and/or reducing alcohol consumption. However, it is recognized that some individuals may be interested in this approach for a variety of reasons. For example, some individuals may wish to take disulfiram as an additional source of support in avoiding alcohol consumption in certain circumstances (e.g., vacations, special occasions) or occupations (e.g., safety sensitive positions). In these cases, the evidence of risks and benefits must be carefully reviewed, and education on adverse effects that may be experienced if alcohol is consumed (including accidental/incidental exposure to non-beverage alcohol) must be provided to patients and families prior to initiating treatment. As clinical trials indicate that disulfiram is most effective when taken under structured and supervised conditions, disulfiram should only be prescribed to patients who are engaged in ongoing addiction care where safety monitoring pathways are in place and adherence can be assessed regularly.
Side effects of disulfiram (in the absence of alcohol) are typically mild, and include fatigue, mild drowsiness, headache, and dermatitis. 284 Although infrequent, hepatotoxicity has been reported in patients with and without prior history of abnormal liver function; baseline and follow-up liver function tests (LFT) should be routinely requested during treatment, and patients and families should be advised to immediately report early signs or symptoms of hepatitis. 352 Contraindications to disulfiram use include severe myocardial disease and/or coronary occlusion, psychosis, or known hypersensitivity to the medication. 284 As the disulfiram-alcohol reaction can present as an emergency, use of disulfiram to reduce drinking rather than sustain abstinence is not appropriate or recommended. Compounded disulfiram (generic formulation) is listed in the BC PharmaCare formulary and eligible for full coverage under the various PharmaCare prescription drug plans, including Plan G, which provides full coverage for psychiatric medications for qualifying individuals with an adjusted net family income of $42,000 or less, plus $3,000 per dependent. [316][317][318][319][320][321][322] Three clinical trials (n=439) have reported that topiramate is as effective or superior to naltrexone for abstinence, heavy drinking and craving outcomes. 323,324 Three RCTs (n=131) of immediate-release gabapentin have reported small to moderate effects on abstinence and heavy drinking outcomes, craving, mood, and insomnia compared to placebo. 326,328,357 One RCT (n=346) of extendedrelease gabapentin found no difference in alcohol consumption or craving compared to placebo. 330 Five RCTs (n=528) found that disulfiram was no more effective than placebo in supporting abstinence or preventing relapse. [358][359][360][361][362] A 2014 meta-analysis of 17 open-label trials (n=2,104) concluded that disulfiram is effective in supporting abstinence if administered under structured and supervised conditions. 354
# Concurrent Alcohol Use
Safe to start while patients are using alcohol; has been studied for the reduction of alcohol consumption in non-abstinent individuals. [316][317][318] Outcomes do not appear to differ for patients who complete withdrawal management prior to starting treatment compared to those who do not. 315 Completion of withdrawal management is not required prior to treatment start.
Safe to start while patients are using alcohol, but outcomes may be improved if patient has been abstinent for ≥ 3 days. 261 Abstinence is recommended after starting treatment (where possible) due to potential risk of combined CNS-related side effects, although studies suggest concomitant use of alcohol and therapeutic doses of gabapentin does not increase sedation or motor impairment. 261 Completion of withdrawal management is not required prior to treatment start. * Note: Safety and efficacy of these medications has not been fully established in these patient populations and their use would be at the discretion of the treating clinician. Specialist consultation, careful assessment of benefit and risks, fully informed patient consent, and regular monitoring and assessment is advised in these cases.
# Baclofen
Baclofen is a GABA receptor agonist that is primarily prescribed as a muscle relaxant, but has also been used for treating AUD. While not commonly prescribed in North America, it is an approved AUD pharmacotherapy in France, and commonly used off-label in Australia and Germany. 363 As baclofen is not metabolized in the liver, it was initially studied as a treatment option for individuals with severe AUD diagnosed with acute hepatitis, liver disease and cirrhosis. 364 Although early trials in this population showed some promise, 365,366 subsequent studies have yielded mixed results. [367][368][369][370] A 2018 Cochrane review (12 RCTs, n=1,128) found no difference between baclofen and placebo for a range of primary (relapse to any drinking, total alcohol consumption) and secondary outcomes (alcohol craving, anxiety). 371 Three other meta-analyses published in 2018 reported similar and mixed findings. The first meta-analysis (13 RCTs, n=1,492) reported that baclofen was superior to placebo for some outcomes (time to relapse, percentage days abstinent), but not for overall abstinence rates. 372 The second meta-analysis (12 RCTs, n=590) reported that baclofen was associated with higher rates of abstinence than placebo but no difference in other outcomes (number of days abstinent, heavy drinking, craving). 373 The third meta-analysis (14 RCTs, n=1,522) found no difference between baclofen and placebo in abstinence rates or alcohol consumption. 374 Inconsistent findings across reviews create uncertainty as to whether baclofen is no more effective than placebo, or if it has marginally harmful or marginally beneficial effects in individuals with AUD. Overall, there is lack of clear evidence regarding the effectiveness of baclofen for the treatment of AUD.
Compared to placebo, baclofen is associated with increased rates of side effects including vertigo, drowsiness, paraesthesia ("pins and needles" sensation), and muscle spasms or rigidity. 371 Safety concerns have also been raised with off-label use of baclofen. 375 For example, a French national registry study (n=165,334) found that baclofen was associated with a dose-dependent increased risk of hospitalization (hazard ratio [HR] = 1.13, 95% CI 1.09 to 1.17) and death (HR =1.31, 95% CI 1.08 to 1.60) compared to other AUD pharmacotherapies approved in France (naltrexone, nalmefene, acamprosate). 376
# Ondansetron
Ondansetron is a selective serotonin (5-HT3) receptor antagonist approved for the treatment of nausea associated with chemotherapy that has also been studied for treating AUD. Based on the findings of several small pilot trials and human laboratory studies, 377 ondansetron appears to be selectively effective in two specific subsets of patients: individuals who developed an AUD at ≤25 years of age (e.g., "early-onset" AUD), 378 a subtype of AUD that is believed to have a genetic or biological basis, 379 and individuals who have a genetic variant of the serotonin transporter (5HTT) gene. 380 These findings have yet to be replicated in a large, multi-site clinical trial. 381 An initial clinical trial (n=71) that did not differentiate participants based on age of onset of AUD or by genotype found no significant difference in alcohol consumption between individuals who received a 6-week trial of ondansetron versus those who received placebo. 382 Side effects most frequently reported in clinical trials of ondansetron for AUD include diarrhea, headache, and fever. Ondansetron prolongs the QT interval in a dose-dependent manner, and should not be prescribed to patients with underlying cardiac conditions, such as congenital long QT syndrome, cardiac hypertrophy, or those taking other medications associated with QT prolongation. 383,384
# Combination Pharmacotherapy
Combination pharmacotherapy is often used in psychiatry for treatment-refractory or -resistant mental health conditions, and there is growing interest in applying similar approaches to AUD. Theoretically, combining AUD pharmacotherapies could address a broader range of symptoms or augment the modest treatment effects that have been observed with AUD monotherapies in research studies and clinical practice.
A 2018 meta-analysis of 16 RCTs evaluating combination pharmacotherapy for the treatment of AUD concluded that no significant benefits were observed for the use of combinations over single medications alone in terms of alcohol-related outcomes, but noted that the current evidence base is limited. 385 Few well-controlled studies have been conducted in this area, and studies that have been published are limited by small sample sizes, low power, imprecise measures of treatment effects, and other methodological flaws. 385 More research is needed to determine the value of combination therapy, which holds the potential to generate important knowledge to advance this field. Select research evidence on safety and efficacy of two promising examples of combination AUD pharmacotherapy is reviewed below.
# Naltrexone and Acamprosate
An RCT that randomized 160 participants to receive placebo, acamprosate, naltrexone, or combined acamprosatenaltrexone therapy for 12 weeks reported relapse rates of 75%, 50%, 35.3%, and 27.5%, respectively. 386 Significance tests showed that combination therapy was superior to acamprosate, but not naltrexone monotherapy, for the prevention of relapse to any drinking and heavy drinking. 386 In contrast, in the Combined Pharmacotherapies and Behavioural Interventions for Alcohol Dependence (COMBINE) trial, in which 1,383 patients were randomized to nine treatment groups, combination therapy was not more effective than naltrexone or acamprosate alone, CBT, or placebo among participants also receiving medical management (e.g., counselling to promote medication adherence, prevent relapse and support recovery). 303 In both trials, combination therapy was well tolerated, with only minor adverse effects (e.g., nausea) observed to occur more frequently in comparison to either medication alone. 303,386 There may be additive benefits in combining these medications; however, at this time, these benefits have not been well established, and clinical indications for use of combination therapy, optimal dosing, contraindications, and patient populations who would benefit from this approach have not been determined.
# Naltrexone and Gabapentin
One RCT has evaluated whether the combination of naltrexone (50mg per day) and gabapentin (up to 1200mg per day) resulted in greater abstinence rates and lower alcohol consumption during the early stages of alcohol cessation than naltrexone alone or placebo. 387 In this trial, 150 individuals were randomly assigned to receive a 16-week course of naltrexone alone, naltrexone with gabapentin added for the first 6 weeks, or double placebo. 387 During the first 6 weeks, the naltrexone-gabapentin group had a longer interval to heavy drinking than the naltrexone monotherapy group (which was comparable to the placebo group). 387 The naltrexone-gabapentin group also had fewer heavy drinking days, and fewer drinks per drinking day than the naltrexone monotherapy and placebo groups. 387 After gabapentin was discontinued, there were no differences between treatment and placebo groups in alcohol-related outcomes. 387 A history of alcohol withdrawal was associated with better treatment outcomes in the naltrexone-gabapentin group. 387 The combination was well tolerated with the most commonly reported side effects being dizziness and daytime sedation. 387 While these results are promising, there is a need for larger, multi-site trials to confirm that the combination of naltrexone and gabapentin is safe and efficacious for the treatment of AUD, and to clarify optimal dosing and duration of combination therapy.
# Pharmacogenetic Approaches to AUD Pharmacotherapy
Recent advances in the field of genetics have led to the identification of several candidate genetic polymorphisms that may predict individual responses to medications for treating AUD. 388 In some cases, initial studies have showed promise, but larger, more robust prospective studies have failed to demonstrate an association between genetic markers and treatment response. For example, several post-hoc analyses of cohort studies found that individuals with a specific polymorphism in the Asn40Asp gene responded more favourably to naltrexone, [389][390][391] but a subsequent large and well-powered trial found no evidence of any gene-treatment interaction effects. 392 Although use of pharmacogenetics is not feasible for treatment-matching at the present time, several pharmacogenetic studies are currently underway, [393][394][395][396][397][398] and hold potential for more targeted "personalized medicine" approaches to AUD treatment in the future.
# Section Summary and Recommendation
This guideline recommends that pharmacotherapy with topiramate and gabapentin be considered on a case-bycase basis for patients who do not benefit from treatment with first-line therapy with naltrexone or acamprosate, have contraindications to their use, or express a preference for an alternative medication. Although the evidence base for topiramate and gabapentin is more limited than that of first-line therapies, research suggests that these medications are safe and effective in reducing alcohol consumption in some patients.
For topiramate, this recommendation is based on moderate quality evidence from several meta-analyses and clinical trials that have demonstrated that topiramate is associated with clinically significant improvements in multiple alcohol-related outcomes, with some evidence that treatment effect sizes are comparable or greater than those observed with naltrexone. 178,315 For gabapentin, there is a limited but promising body of evidence for efficacy, 261 and it has demonstrated advantages in the treatment of symptoms associated with protracted alcohol withdrawal (e.g., insomnia, anxiety). 399 The committee notes that clinicians should be aware of the potential for non-medical use and diversion of this medication and employ risk mitigation strategies if necessary (e.g., blisterpacks, short-course prescriptions, witnessed ingestion at pharmacy).
This recommendation is also in line with other published guidelines. For example, topiramate has been recommended as a first-line treatment (along with disulfiram, acamprosate, and naltrexone) for AUD in the U.S. Department of Veterans Affairs/Department of Defense (VA/DoD) Clinical Practice Guideline for the Management of Substance Use Disorders. 400 Additionally, the American Psychiatric Association's Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder recommends topiramate or gabapentin for treatment of patients with AUD who would prefer these medications or who have not benefited from first-line medications (naltrexone, acamprosate). 401 Due to comparatively weak evidence of efficacy, this committee does not recommend disulfiram over other available pharmacotherapies for AUD. However, it is recognized that some individuals may express a preference for this medication, for example, individuals seeking additional support to avoid alcohol in certain circumstances (e.g., special occasions) or occupations (e.g., safety sensitive positions). As clinical trials indicate that disulfiram is most effective when taken under structured and supervised conditions, disulfiram should only be prescribed to patients who are engaged in ongoing addiction care where adherence can be assessed regularly.
At this time, there is insufficient evidence to recommend use of ondansetron or baclofen for the treatment of AUD in routine practice. Further research is also needed before evidence-based recommendations can be made regarding combination pharmacotherapy. Clinicians are encouraged to consult with an addiction medicine specialist or the RACE line (Vancouver area: 604-696-2131; toll-free: 1-877-696-2131, www.raceconnect.ca) for expert guidance and decision support if considering one of these treatment approaches.
# Recommendation 10 Alternative Pharmacotherapy for Alcohol Use Disorder
Patients with moderate to severe alcohol use disorder who do not benefit from, have contraindications to, or express a preference for an alternate to first-line medications, can be offered topiramate or gabapentin.
# Quality of Evidence: MODERATE Strength of Recommendation: STRONG
# Remarks
• Selection of an appropriate medication should be made through a shared decision-making process between patient and provider after reviewing evidence of benefits and risks, and in the context of the patient's goals, needs and preferences.
• Contraindications, side effects, feasibility (dosing schedules, out-of-pocket costs), and patient history with either medication should also be taken into account.
• As with any medication prescribed off-label, it is important to conduct a full assessment, including careful review of concomitant medications for potential drug-drug interactions, and to clearly document patient consent prior to initiating treatment.
• Gabapentin is contraindicated in patients with a known hypersensitivity to the drug or its constituents. Caution is advised in prescribing gabapentin to patients a) with cognitive or mental impairment, b) taking opioids (prescribed or non-medical use), c) who are pregnant or breastfeeding, d) under the age of 18, and e) over the age of 65.
• Topiramate is contraindicated in patients with a known hypersensitivity to the drug or its constituents and in patients who are pregnant or planning to become pregnant. Caution is advised in prescribing topiramate to patients a) with renal disease or failure, b) with hepatic disease, c) under the age of 18, and d) over the age of 65. Due to dose-dependent risk of significant CNS side effects, dose should be gradually titrated upwards over a period of 4-8 weeks.
# Duration of Treatment
There is a lack of research evidence to guide the optimal duration of AUD pharmacotherapy. Because AUD is a chronic, relapsing condition, and as emphasized in this guideline, an ongoing and individually-tailored approach to clinical management is required. Most clinical practice guidelines recommend that AUD pharmacotherapy be prescribed for at least 6 months, at which point the utility of continuing treatment can be re-assessed in collaboration with the patient. 284,400,401 If deemed clinically necessary, medications can be continued indefinitely unless safety concerns arise. 402
# Pharmacotherapy Options for Youth
Although medications are often used off-label to treat a range of psychiatric conditions in youth, they are infrequently prescribed for substance use disorders, and treatment of youth has traditionally emphasized psychosocial treatment alone. 403 While several psychosocial treatment interventions have been shown to be effective in youth with AUD (see Psychosocial Treatment Interventions in Youth), not all individuals benefit from this approach. Reported rates of relapse following psychosocial treatment alone for substance use in youth are high, ranging from 46% to 79% at 12 months post-intervention. 403 Prospective studies have shown that unrecognized or untreated alcohol use disorder in adolescents often progresses to more severe forms of AUD and alcohol-related harms in adulthood. 404 Additionally, due to ongoing neurological and cognitive development, there is increasing evidence that adolescents and young adults are particularly vulnerable to adverse effects of heavy alcohol consumption on social and behavioural functioning. 164 For these reasons, use of the most effective treatments, including pharmacotherapy, should be considered on a case-bycase basis for treatment of youth with moderate to severe AUD, particularly among those who have not benefited from non-pharmacologic treatment.
Two pilot studies of naltrexone have been conducted among youth. A small study enrolled five adolescents (mean age = 16.8 ± 3.11 years) diagnosed with moderate to severe AUD in a 6-week open label trial, and reported a significant reduction in alcohol consumption (-7.5 drinks/day) during treatment. 405 A crossover RCT enrolled 28 youth (aged [15][16][17][18][19] to receive naltrexone and placebo for 8-10 days each, with a washout period in between treatments. 406 The authors found that naltrexone reduced craving in both laboratory and natural conditions, and was associated with reductions in frequency of any and heavy drinking. 406 In addition, in two open-label randomized trials comparing naltrexone to disulfiram (n=110), adolescent participants (aged 15-18) who received naltrexone reported significantly lower levels of craving compared than those who received disulfiram. 407,408 In all four studies, naltrexone was well tolerated with few side effects, and no serious adverse events were reported. Acamprosate has not been studied in adolescent patient populations.
In the absence of a substantive evidence base, clinical practice guidelines recommend that pharmacotherapies approved for treatment of AUD in adults (naltrexone, acamprosate) can be considered on a case-by-case basis for treatment of moderate to severe alcohol use disorder in adolescents (aged 12-18). 220,284,364,409,410 Although alcohol is the most commonly used substance in youth, which does warrant routine screening, brief intervention, and advice on safer use (see Screening and Brief Intervention), it is emphasized that very few youths seen in primary care will meet the DSM-5 criteria for a moderate to severe alcohol use disorder. Consultation with a pediatric addiction medicine specialist or the RACE line (Vancouver area: 604-696-2131; toll-free: 1-877-696-2131, www. raceconnect.ca) is recommended prior to prescribing AUD pharmacotherapy to youth.
# Pharmacotherapy Options for Pregnant Patients
Due to the lack of evidence of safety and efficacy in pregnancy, it is strongly emphasized that prescribing AUD pharmacotherapy to such individuals should be done in close consultation with a perinatal addiction medicine specialist.
There have been no RCTs or meta-analyses on the safety and efficacy of AUD pharmacotherapies in pregnant individuals. A 2018 case report and literature review suggests individual consideration be given to prescribing gabapentin, naltrexone, or acamprosate to pregnant individuals on a case-by-case basis, based on evidence that these medications appear to be compatible with pregnancy (i.e., FDA Category C o ) and the known maternal and fetal risks of continued alcohol use or relapse in pregnancy. 411 The authors emphasize that the potential risks of medications must be carefully weighed against the known teratogenic risks of alcohol when making treatment decisions. 411 With regards to other AUD pharmacotherapies reviewed in this guideline, topiramate is contraindicated in pregnancy due to its association with cleft palate if used in the first trimester; 412 and use of disulfiram in pregnancy is strongly recommended against, due to the potential risks of a severe disulfiram-alcohol reaction to the foetus. 266 As there is insufficient evidence to support use of baclofen and ondansetron in non-pregnant patients, neither medication would be considered appropriate for use in pregnancy. Motivational interviewing (MI) is a counselling approach that empowers the patient to develop motivation to change, and creates a therapeutic alliance that is predominantly a partnership, rather than an expert/patient dynamic. 145 MI techniques have been adapted for use in primary care settings to support behavioural change and improve self-management for a range of chronic health conditions, including HIV/AIDS, diabetes, cardiovascular disease, and substance use disorders. [413][414][415] MI-based counselling does not require professional specialization and can be delivered by primary care physicians, nurse practitioners, nurses, and other allied health professionals who have completed appropriate training. 416 In practice, clinicians engage patients in semi-directive discussion about health behaviours while adhering to the general principles of MI, which are to: express empathy, support self-efficacy, avoid argumentation, roll with resistance, and develop understanding of discrepancy. 144 The intended outcome is to bring awareness to any discrepancies between current behaviours and future goals. For individuals with AUD, the patient-provider dyad develops practical strategies to reduce alcohol consumption or achieve abstinence over one or multiple sessions, which can range from 15 to 60 minutes in duration, depending on the care delivery setting. 416 Depending on individual patient circumstances, MI can be adapted to be delivered before, during, and/or after an individual has made a decision to reduce or stop drinking alcohol. 416 A 2011 systematic review of MI for the treatment of substance use disorders (59 RCTs, n=13,342 participants), including alcohol alone (29 RCTs) and in combination with other substances (19 RCTs), showed that MI significantly reduced substance use in comparison to no treatment. 416 Further, review results indicated that MI was as effective as other active psychosocial modalities (e.g., cognitive behavioural therapy, contingency management, counselling) in reducing substance use, although overall, authors noted that treatment effects were modest in scale, and outcomes were similar to assessment/feedback alone. 416 The strongest treatment effects were observed immediately post-intervention, with progressively weaker effects observed at each consecutive follow-up, such that no significant effects were observed more than 12 months post intervention. 416 Additional systematic reviews have reported that, while individual patient variables appear to be unrelated to outcome (e.g., age, gender, AUD severity), MI appears to be most effective when delivered in an individual format rather than group settings, and in combination with assessment and feedback. 413 The effectiveness of brief MI for alcohol-related problems has also been confirmed in specific populations, including adolescents, [417][418][419] young adults, [420][421][422] older adults, 423,424 men who have sex with men, 425 and individuals living with HIV/AIDS, 426 concurrent depression and anxiety disorders, 427,428 severe mental illness (e.g., schizophrenia, psychosis), [429][430][431] chronic liver disease, 432 and individuals who have had repeat encounters with the criminal justice system as a result of their alcohol use. 433 MI led by nurses [434][435][436][437] and other allied health professionals 438 appear to be as effective as physicianled MI in supporting behavioural change.
# Contingency Management
Contingency management (CM) is a well-studied approach for improving outcomes of substance use disorder treatment, particularly tobacco and stimulant use disorders. 439 CM uses positive reinforcement to encourage behavioural change; most often, financial incentives or vouchers are provided when an individual achieves specific goals as outlined in their treatment plan. Typically, treatment goals are abstinence-based, and positive or negative consequences are based on objective evidence of recent substance use (i.e., urine drug testing), but behavioural markers can also be used (e.g., adherence to medication, clinic attendance, participation in peer support groups). CM is not a standalone treatment for substance use disorders and is always delivered as part of a more comprehensive treatment plan.
Although a number of RCTs have found that CM is effective in improving treatment outcomes for other substance use disorders, 439,440 its usefulness for AUD has been limited by the technology available to test for and monitor alcohol use. Breath, blood, and urine alcohol tests can only determine whether alcohol has been consumed within the past 4 to 12 hours, 441 and do not provide any information about alcohol use between clinic visits. The ethyl glucuronide (EtG) biomarker can be detected in urine for 2-5 days after alcohol use, 442 but frequent testing is required when used to assess abstinence, and its sensitivity for detecting recent alcohol use is relatively low. For example, a pilot RCT (n=20,193 samples) reported that EtG urine tests were positive for 75% and 50% of cases where individuals reported alcohol use in the past 24 or 48 hours, respectively. 443 While CM has shown benefits in controlled research studies and structured treatment programs, it is important to note that this approach is not widely used in primary care settings. Practical issues, such as lack of infrastructure and resources, time commitment (for patients and providers), lack of knowledge and training, and costs (vouchers, biological testing, staff training and time) have all been identified as barriers to uptake in primary care practice. [444][445][446] More research is needed to determine whether CM is an effective and feasible strategy for the management of AUD in "real-world" clinical care settings.
# Section Summary and Recommendation
This guideline recommends the use of Motivational Interviewing (MI)-based counselling in the primary care management of AUD. With training, primary care physicians, nurse practitioners, nurses, allied health professionals and other support staff can deliver MI-based counselling effectively in the primary care setting, either alone or in combination with AUD pharmacotherapy. 83,145,447 Several meta-analyses in adult patients with substance use disorders have found low to moderate quality evidence that MI results in significant (albeit modest) reductions in alcohol and other substance use in comparison to no treatment, and that MI was as effective as other active psychosocial modalities (e.g., cognitive behavioural therapy) and assessment/feedback in reducing substance use. 416,[448][449][450][451][452][453] Similarly, a 2016 meta-analysis of MI for the prevention of alcohol-related problems in youth reported low to moderate quality evidence that MI was associated with a small but significant reduction in alcohol consumption and problems compared to no intervention, assessment/feedback only, or other psychosocial treatment interventions. 454 There is insufficient evidence to recommend routine use of contingency management (CM) approaches in the primary care management of AUD, and a need for further research to develop practice-friendly variants of CM that would be feasible in primary care settings.
# Specialist-Led Psychosocial Treatment Interventions
Patients and families who would benefit from or express interest in accessing more structured psychosocial treatment as part of their treatment plan should be referred to specialized services in the community. In this scenario, the primary care provider should continue to play an active role in the treatment and recovery process by connecting individuals to care and services, supporting attendance and patient-or program-defined goals, and monitoring response to treatment. The research evidence for several specialist-led psychosocial treatment modalities -cognitive behavioural therapy, family-based therapy, and mindfulness-based interventions -is reviewed below. Access and other key considerations when referring patients to specialist-led psychosocial treatment are also briefly reviewed.
This guideline does not explicitly endorse one form of specialist-led treatment over another, as research has not demonstrated that one particular approach is superior to any others. Therefore, factors such as patient and family preference, local availability, and accessibility (e.g., waitlists, out-of-pocket costs) can guide the referral process. To support informed decision-making, this section provides an overview of more common specialistled psychosocial approaches to assist health care providers and care teams in selecting an option that best fits their needs.
# Cognitive Behavioural Therapy
Cognitive behavioural therapy (CBT) is a structured, goal-directed form of psychotherapy delivered by a trained counsellor or therapist, where patients learn how their thought processes contribute to their behaviour and emotions. 455 Increased cognitive awareness is combined with techniques to help patients develop new and adaptive behaviours that can alter their social environment and, in turn, reinforce change in thoughts and emotions. 455 CBT for the treatment of substance use disorders is usually time-limited, consisting of approximately 10-20 onehour sessions. 455 A meta-analysis of 53 controlled trials of CBT (n= 9,308) for adults with moderate to severe alcohol and other substance use disorders found that across studies, CBT had a small but statistically significant treatment effect in comparison to passive interventions (e.g., education programs) or no treatment. 456 Outcomes assessed varied by study, but grouped treatment effects included duration of abstinence, and relapse to any or heavy substance use. 456 The effect size of CBT remained significant when analyses were restricted to trials targeting hazardous or harmful alcohol use (23 RCTs; n=6133). 456 Similar to MI, treatment effects were strongest immediately following the intervention, and diminished over time. 456
# Family-Based Therapy
The defining feature of family-based therapy (FBT) for substance use disorders is that it treats individuals within the larger context of social systems where substance use may have first developed and is currently sustained. This approach has been particularly well studied in adolescent populations, where social and/or family environments may play a significant role in the development of substance use disorders. 457 Social network and family-based therapies actively engage friends and family members in the treatment process and may encompass a diversity of approaches and techniques, including CBT, interpersonal therapy, communication training, and skills building.
FBT is typically delivered by a trained psychologist or counsellor.
Several systematic reviews and meta-analyses have reported that family-based approaches are efficacious for the treatment of AUD. 458,459 For example, a meta-analysis of 12 randomized trials (n=1,887) of FBT among adults with substance use disorders, including AUD (8 RCTs), showed that FBT was associated with a small but significant effect on treatment outcomes, with participants showing a greater number of days abstinent and fewer number of days of heavy substance use, as well as improvements in validated measures of relationship satisfaction and adjustment in comparison to than those who received individually-oriented treatments (e.g., MI, CBT, 12-step programs). 460 The effect of FBT also appeared to be more durable over time, with lower rates of relapse to substance use and/or heavy substance use at 6 and 12 months follow-up, compared to individualized psychosocial intervention approaches. 460
# Mindfulness-Based Interventions
Mindfulness-based interventions (MBI) are increasingly being used in the treatment of individuals with substance use disorders, including AUD. While MBI described in the literature vary in terms of structure and design, all generally share the same fundamental goals, which are achieved through individual or group practice: (1) the development of a state of awareness characterized by full attention to internal and external experiences as they occur in any given moment, and (2) the adoption of a mindset of acceptance of internal and external experiences without judgement. 461 In the context of substance use disorders, it has been proposed that MBI could help support individuals learn new skills to accept or cope with distressful events, which, in turn, could reduce substance use behaviours that may have previously been used as a means to suppress or avoid unpleasant emotional experiences. 462,463 Structured MBI programs are typically delivered by a trained psychologist or counsellor.
Systematic reviews of MBI for AUD have yielded mixed results. Three systematic reviews have concluded that MBI is associated with significant reductions in substance use, including alcohol use, compared to no intervention, non-specific education programs, and active comparators (e.g., 12-step, CBT), with some studies showing additional benefits in reducing craving and stress. [463][464][465] The number of studies included in these reviews ranged from 24 to 54, and the majority were not randomized trials. [463][464][465] In contrast, a meta-analysis that included only randomized controlled trials (9 RCTs, 7 RCTs for AUD) evaluating a standardized Mindfulness-based Relapse Prevention program 466 found no difference in relapse rates, frequency of substance use, retention in treatment, depression or anxiety scores from medical management alone, participation in a health education program, or other psychosocial treatment interventions (12-step, CBT, counselling). 467 The review did find a significant difference in favour of Mindfulness-based Relapse Prevention programs in terms of reducing withdrawal symptoms, craving, and substance-related harms, but the authors graded this evidence as weak. 467 Overall, the evidence base for MBI is limited due to a relatively small number of randomized trials with small sample sizes, and heterogeneity in the study methodology and outcomes assessed. More rigorous randomized controlled trials are needed before a definitive conclusion can be drawn with regards to the effects of MBI on alcohol-related outcomes.
# Psychosocial Treatment Interventions and Co-occurring Mental Health Disorders
Attention to the assessment, treatment, and monitoring of emotional and mental health is an essential component in caring for patients with AUD, especially given the high prevalence of co-occurring mental health diagnoses in this population (e.g., post-traumatic stress disorder, depression, anxiety). 59,468 Despite a limited number of controlled trials in more complex patient populations, there is some evidence that the inclusion of specialist-led psychosocial treatment interventions can improve outcomes for individuals with co-occurring substance use and mental health disorders, including anxiety and depression, 427,469 post-traumatic stress disorder, 470 and severe mental illness (e.g., schizophrenia, schizoaffective disorder). 471 However, it is noted that the evidence for efficacy in this patient population tends to be of lower quality, and the effect sizes calculated in meta-analyses were generally small to moderate in scale. 472
# Psychosocial Treatment Interventions in Youth
A 2008 meta-analysis (17 RCTs, n=2,307) evaluating various psychosocial treatment interventions for substance use disorders, including AUD, in patients aged 11-19, found that CBT had a significant, small to moderate effect on treatment outcomes, including the prevention of relapse and reduction of substance use. 473 The review authors also noted that group CBT appeared to be more effective than individual CBT among youth. 473 Several meta-analyses of trials in adolescents with substance use disorders, including AUD, have shown that the effects of FBT on engagement and retention in treatment, reduction in alcohol and drug use, sustained abstinence, and improved psychological, social, and family functioning are comparable to those of CBT and superior to those of other psychosocial treatment interventions. [473][474][475][476] As with adult populations, effect sizes tended to diminish over time, however, a limited number of clinical trials that incorporated long-term follow-up have reported that treatment effects remain significant relative to comparator groups at 12 or more months post-intervention. 477
# Psychosocial Treatment Interventions in Pregnant Individuals
There is limited evidence regarding the effectiveness of psychosocial treatment interventions for the treatment of AUD in pregnant individuals. A 2009 Cochrane review of psychological and educational interventions for reducing alcohol use in pregnancy (4 RCTs, n=715) concluded that overall, there is insufficient data on the effectiveness in reducing alcohol consumption or supporting abstinence, with limiting factors including inconsistent results, small sample sizes, high risk of bias, and heterogeneity in intervention types and outcomes assessed across trials. 157 Nonetheless, although the evidence base is sparse, due to the known maternal and fetal risks of alcohol use in pregnancy, most clinical practice guidelines do recommend that pregnant individuals with AUD be offered psychosocial treatment interventions to support abstinence or reduced alcohol consumption. 4,268
# Duration of Treatment
There is a lack of research evidence to guide the optimal duration of psychosocial treatment interventions for AUD. A 2018 meta-regression of 48 studies (n=8,984) of outpatient psychosocial treatment interventions for AUD found that neither planned nor actual attendance in weeks, duration of sessions, or frequency of sessions per week were associated with improved long-term outcomes of individuals with AUD. 478 Additionally, other factors, such as an individual patient's needs, circumstances, and preferences and/or access to and availability of specialists, programs, and services in a particular community, often determine intensity and duration of psychosocial treatment interventions. As such, it is beyond the scope of this guideline to make recommendations on the optimal duration of psychosocial treatment interventions. However, it is emphasized that primary care providers can play a critical role in ensuring patients are supported during transitions in care and after specialist-led psychosocial treatment has concluded.
# Accessibility and Other Considerations
Important considerations when discussing options for referral to specialized psychosocial treatment services are that publicly-funded programs often have waiting lists, and the costs of private counsellors or facilities (i.e., nonpublicly funded programs) are not covered by BC's Medical Services Plan or extended health insurance plans, necessitating out-of-pocket payment. In rural and remote areas, referral to specialized treatment programs may also require patients to travel long distances or leave their communities in order to access care, which may not be feasible or practical for some individuals. Again, it is emphasized that a lack of access to or a patient's decision not to participate in specialized psychosocial treatment should not be a barrier to accessing evidence-based pharmacotherapy and related services in primary and other care settings.
As noted above, a limitation of traditional CBT, FBT, and MBI approaches is that, unlike MI, they cannot be easily integrated or adapted into routine primary care practice, and specialized services may not be readily accessible.
Research is underway to evaluate and refine accessible and practice-friendly variants, including telephone, text message, and web-based CBT and MBI approaches, [479][480][481] and manualized FBT tailored specifically for primary care, 477 but the efficacy and feasibility of implementing such interventions is not yet known.
# Section Summary and Recommendation
This guideline recommends that patients and families who would benefit from or express interest in accessing more structured, specialist-led psychosocial treatment interventions should be provided with information and/or referred to programs in the community. It is emphasized, however, that a lack of access to or a patient's decision not to participate in specialized psychosocial treatment should not be a barrier to accessing evidence-based pharmacotherapy and related services in primary care.
Several reviews have found that cognitive behavioural therapy (CBT) is associated with small to moderate, but significant, reductions in likelihood of relapse and alcohol consumption in both adults 456 and youth. 473 Familybased therapies (FBT) have also been associated with small but significant effects on alcohol and other substance use outcomes, as well as improvements in relationship satisfaction and adjustment in both adults [458][459][460] and youth. [473][474][475][476] There is limited and mixed evidence regarding the efficacy of mindfulness-based interventions, interpersonal therapy, and dialectical behavioural therapy in the treatment of AUD. More research is needed to clarify the role of these therapeutic approaches within the AUD continuum of care in order to make explicit recommendations.
# Recommendation 12 Specialist-led Psychosocial Treatment Interventions for AUD
Adults and youth with mild to severe AUD can be provided with information about and referrals to specialist-led psychosocial treatment interventions in the community.
# Quality of Evidence: MODERATE Strength of Recommendation: STRONG
# Remarks
• The referring clinician should continue to play an active role after connecting individuals to psychosocial treatment interventions by checking in with patients on their experience and overall satisfaction, encouraging regular attendance, and including related patient-or program-defined goals in their treatment plan.
• Referring clinicians should establish regular communication with specialist providers and programs to facilitate continuity of care, transitions in care, and to share relevant information (with the patient's permission, e.g., assessments, progress notes, discharge summaries).
# Combining Pharmacotherapy and Psychosocial Treatment Interventions
Although the majority of AUD pharmacotherapy trials have also included medical management, structured psychosocial treatment interventions, and/or peer support groups as a standard treatment condition, very few studies have been explicitly designed to evaluate whether the combination of pharmacotherapy and psychosocial treatment is more effective than either treatment alone. Similarly, very few trials have assessed whether stepped care strategies, such as varying the intensity of psychosocial treatment or recovery-oriented support can improve pharmacotherapy treatment outcomes, or vice versa.
The COMBINE trial (n=1,383) randomized participants to receive 4 months of treatment with naltrexone, acamprosate, naltrexone in combination with acamprosate, or placebo. 303 Treatment groups were randomized to receive either medical management or a combined psychosocial treatment intervention (including elements of MI, CBT, and 12-step) delivered by a specialist. 303 At the end of the treatment period, there were no differences in alcohol-related outcomes (percent days abstinent, return to heavy drinking) between the combination of naltrexone and psychosocial treatment compared to groups who received naltrexone or psychosocial treatment alone. 303 In contrast, an earlier single-site trial (n=160) by the same study team compared naltrexone or placebo combined with motivational enhancement therapy (MET) or CBT in a 4-block RCT design, and showed that participants who received naltrexone and CBT had lower relapse rates, and a longer duration of time before returning to drinking and between drinking days, than those treated with naltrexone and MET or psychosocial treatment alone. 482 Whereas there is limited empirical evidence to guide recommendations on the optimal combination of pharmacotherapy, psychosocial treatment, and recovery-oriented services, this guideline supports using a stepped and integrated care approach, in which treatment type and intensity are continually adjusted to match the individual patient's needs and circumstances over time. Such a strategy recognizes that many individuals may benefit from the ability to access different psychosocial treatment and recovery support options at different times in their recovery. The stepped approach may include treatment intensification (e.g., adding specialized psychosocial treatment to a pharmacotherapy-based strategy, consideration of structured treatment programs), transitions between different treatment options, and strategies to de-intensify pharmacological or psychosocial treatment at the patient's discretion, where the patient can opt to re-initiate pharmacotherapy or psychosocial treatment at any time if needs and circumstances change.
8 Community-Based Supports and Programs
# Peer Support Groups
Peer-based support groups are widely available, no-cost, community-based meetings that are often recommended as an adjunct to clinical care and management of substance use disorders, or as a source of additional peer-based guidance, mentorship, and support in achieving and sustaining recovery. Peer support groups are often led by volunteers who have personally experienced addiction and are in recovery. While there have been very few controlled trials or systematic reviews of the effects of peer-based recovery support services in improving alcoholrelated outcomes (i.e., relapse rates, alcohol consumption), it is recognized that peer-based support has consistently been identified as an important component of recovery from substance use disorders in the research literature 483,484 and by those with lived experience. 485-488
# Alcoholics Anonymous and 12-Step Programs
A widely recognized example of a peer support group is Alcoholics Anonymous (AA), an international fellowship of support groups comprised of individuals in recovery, which offers emotional support and a structured "12-step" approach to achieving abstinence. A central concept in AA is that substance use disorders are a spiritual disease, and that recovery is a journey involving belief in a higher power, personal exploration, and acceptance.
Although AA and other 12-step programs have been studied for several decades, few trials have been conducted and these are limited methodologically by a paucity of randomized trials, selection bias, and heterogeneity in the intervention, study populations, and outcomes assessed. 489,490 Moreover, most studies have not assessed standard alcohol use outcomes (e.g., abstinence, quantity or frequency of use), limiting the potential to compare effectiveness of 12-step groups to other treatment interventions for AUD, such as pharmacotherapy or psychosocial treatment interventions. 489,490 To circumvent some of these issues, more recent research has focused on the twelve-step facilitation (TSF) approach, 491 rather than the effectiveness of the programs themselves in reducing alcohol consumption and/or preventing relapse. TSF is a manualized, structured counselling approach in which trained health care providers collaboratively review and discuss the core 12-step principles with their patients, and encourage regular attendance at community-based 12-step meetings. 491 TSF was originally designed as an individually-oriented therapy, but has also been studied as a family-based or group intervention, most often as part of a structured treatment program (e.g., inpatient or intensive outpatient treatment programs). 492 The TSF intervention is not widely used in primary care practice. A 2006 meta-analysis (8 RCTs, n=3,417) found that TSF approaches were as effective as other psychosocial treatment interventions (CBT, motivational enhancement therapy), in reducing alcohol use and preventing relapse. 492 Overall, the review concluded that there is a lack of high-quality RCT evidence that AA or other 12-step groups are effective in preventing relapse, or reducing alcohol consumption and alcoholrelated harms. 492 However, while the evidence base is limited, it is recognized that peer support groups, which are widely accessible in both urban and rural settings, can be beneficial to patients and families in navigating life changes and challenges related to treatment and recovery. For example, individuals who do benefit from participation in 12-step groups report that factors such as the group dynamic (e.g., feeling a connection to and a sense of belonging and community with others), 493 improved self-awareness, [494][495][496] an experience of acceptance and empathy from and for others, 497 and developing or strengthening a connection with their spirituality 498,499 were important in starting and maintaining their recovery.
Twelve-step support groups are reported to be most effective amongst those who identify with the core philosophy, and who attend meetings voluntarily on a regular basis. 500 Voluntary attendance is of particular importance, as evidence suggests that coerced or mandated attendance at peer support groups is not effective in reducing alcohol or other substance use or achieving abstinence. [501][502][503] 8.1.2 Self-Management and Recovery Training © (SMART © Recovery)
Self-Management and Recovery Training, or SMART Recovery, is a secular alternative to the 12-step model that has rapidly expanded in recent years. The SMART Recovery program was designed to reflect evidence-based practice elements of MI, CBT, Rational Emotive Behaviour Therapy (REBT), and mindfulness. 504 The "4-point program" of SMART Recovery, which encompasses building motivation, coping with urges, problem solving, and lifestyle balance, provides members with evidence-based tools and peer support to aid in their recovery. 504 A 2017 systematic review of 12 studies of SMART Recovery programs concluded that while positive effects were found, the lack of RCTs, small sample sizes, and heterogeneity in methods and outcomes assessed across studies prevented drawing conclusions about its effectiveness. 505 To date, only one randomized trial has studied the impact of SMART Recovery among individuals with substance use disorders, and it compared in-person SMART meetings to "Overcoming Addictions" (OA), a web-based intervention based on the SMART Recovery program. 506 Individuals with AUD (n=189) were randomized to receive SMART, OA, or a combination of the two. 506 No differences were found between groups, but at the conclusion of the study there was a significant increase in the percentage of days individuals abstained from alcohol use (44% to 72%) and a reduction in the number of drinks per drinking day (8.0 to 4.6 drinks) for all study participants. 506 There is a need for further research, specifically well-designed clinical trials, to better establish the effectiveness of SMART Recovery and other non-12-step peer support groups in preventing relapse and reducing alcohol consumption and related harms.
# Making Informed Referrals to Peer Support Groups
Several studies have found that active referral and encouragement from a clinician or a peer support worker during initial stages of treatment increases the likelihood that patients will attend community-based peer support meetings. [507][508][509][510] For example, an RCT (n=151) that compared active referral from a clinician, active referral from a peer, or information only about local 12-step groups among individuals undergoing inpatient withdrawal management found that active referrals significantly increased attendance rates at meetings during and after withdrawal management (post discharge attendance rates: peer referral 64%, clinician referral 48%, information only 33%), although there were no differences between groups in abstinence rates (44%, 41% and 36%, respectively). 510 Although in this trial peer-based referral had a stronger impact on attendance, the importance of clinicians adopting an active, informed and encouraging role in referring patients to peer support groups and other community-based services should not be underestimated, particularly for patients and families who may have little to no experience in navigating the AUD treatment system. Involving peer support workers or navigators as part of a clinical care team may also be a valuable strategy for facilitating patient access and engagement. 484 If a patient identifies incompatibilities between their personal belief systems and the core philosophies of a peer support group as barriers to their participation, alternative options can be provided where available. For example, some individuals may prefer peer support groups with a secular mandate (e.g., SMART Recovery, LifeRing), or groups designed for specific populations (e.g., 2SLGBTQ+ individuals, youth, Indigenous peoples, individuals with co-occurring mental health issues). Some women may prefer to attend women-only meetings, or groups like the 16-step program. 511 Access to in-person meetings for other (non-12-step) peer support groups may be limited outside of urban centres, although several peer support groups do have online or "virtual" meetings.
# Section Summary and Recommendation
There is a paucity of high-quality RCTs, systematic reviews, or meta-analyses on the effectiveness of peer support groups among individuals with AUD.
However, it is recognized that some individuals and families may benefit from or express an interest in accessing peer-based support, guidance, and mentorship -a core component of many peer-support programs -to navigate the changes brought about by starting AUD treatment and in the pursuit of long-term recovery. 483,484,512 Active referral and encouragement from a clinician or a peer support worker during the initial stages of treatment increases the likelihood that patients will attend community-based peer support meetings. [507][508][509][510] Recommendation 13 Peer-based Support Groups for Individuals with AUD Adults and youth with mild to severe AUD can be provided with information about and referrals to peer-support groups and other recovery-oriented services in the community.
# Quality of Evidence: LOW Strength of Recommendation: STRONG
# Remarks
• Primary care providers should be aware of peer-support groups that are active locally and online, including groups for specific populations (e.g., men, women, 2SLGBTQ+, co-occurring disorders, etc.), age-appropriate options for youth, and services for families.
• The primary care clinician or care team should continue to play an active role after connecting individuals to peer support groups by checking in on their experiences and overall satisfaction, encouraging regular attendance, and including related patient-or program-defined goals in the patient's treatment plan.
# Community-based Treatment and Recovery Programs
There are a number of recovery-oriented programs and services available in BC that can be beneficial to some patients with AUD. As many of these programs offer a comprehensive range of services, several of which have been reviewed in other sections (e.g., pharmacotherapy, psychosocial treatment interventions, peer-based support), this guideline does not make an explicit recommendation on this topic. However, it is recognized that some patients may benefit from or be interested in accessing more structured treatment and support programs.
To support informed decision-making, clinicians should be aware of recovery-oriented programs in their communities, and able to connect patients and families with these resources as required. A brief evidence review of intensive outpatient programs, inpatient treatment, and supportive recovery housing is included below to support the shared decision making process between health care providers and patients.
# Intensive Outpatient Programs
Intensive outpatient programs (IOP) are ambulatory programs for individuals with substance use disorders who do not require 24-hour care, but require more support than standard outpatient care. IOPs can also provide an intermediate level of support for individuals recently discharged from inpatient treatment programs. The structure and services provided by these programs varies depending on the setting (e.g., hospital, inpatient treatment, community-based public and private treatment centres) and staffing model (e.g., medical or non-medical personnel). Programs generally offer several hours of structured programming per day, and core services may include individual, group, or family therapy; connecting clients with social supports; life skills and vocational training; peer-support group meetings; therapeutic recreational activities; and developing coping skills and strategies to prevent relapse.
Three clinical trials that randomized clients to an IOP or inpatient treatment found that cumulative days abstinent, alcohol use, and alcohol-related problem scores did not differ significantly between service settings, suggesting that they are similarly effective. [513][514][515] As above, there were some methodological flaws in these trials, including small sample sizes, non-equivalent groups, single-site studies, selection bias, and lack of appropriate controls.
Intensive outpatient programs may have advantages for some individuals with AUD who would benefit from an intermediate level of support, the ability to develop and practice new skills and strategies while living in the community, and continuity of care for a longer duration. It is noted that standardization of core services offered in IOPs could aid in future comparative effectiveness research, and help improve quality and effectiveness of programming.
# Inpatient Treatment Programs
Inpatient treatment facilities provide a 24-hour, substance-free environment for individuals with alcohol and other substance use disorders. These programs vary in the types of services and treatment models employed, but all typically include core services such as individual and group counselling, life skills training, and peer support groups. Some programs may also include more tailored services, such as vocational training, medical and mental health services, couples/family counselling, and nutritional counselling. Some also offer aftercare services to patients upon program completion, ranging from follow-up counselling, and supportive recovery housing, to intensive outpatient programs.
Evaluating the effectiveness of inpatient treatment in comparison to other treatment modalities has proven to be methodologically challenging. Although a small number of RCTs and other research studies have been conducted, most have not employed a rigorous experimental design and significant methodological limitations have been noted, such as a lack of adequate controls and comparator groups; over-reliance on retrospective, quasi-experimental and pre-post methods; selection bias; limited generalizability due to setting, study population, and inclusion/exclusion criteria; and heterogeneity in treatment types and outcomes assessed. 516 Additionally, due to ethical concerns associated with randomizing patients to a comparator group that might not provide a sufficient level of care for a patient's needs (e.g., no treatment, outpatient care), several trials excluded participants with moderate to severe AUD and comorbid conditions, to ensure that all study participants received treatment that was clinically appropriate. 516 In this context, while several systematic reviews have concluded there is low to moderate quality evidence that inpatient treatment programs are effective for reducing substance use and improving health, mental health, social and criminal justice-related outcomes among program participants, there is insufficient evidence that inpatient treatment programs are more effective than other treatment approaches, including outpatient management. [516][517][518][519][520] Nonetheless, several practice guidelines have identified specific patient populations that may benefit from the more structured treatment environment provided in an inpatient care setting (Box 7).
Box 7 Considerations for Referral to Inpatient Treatment Programs 517,521,522
• Individuals who have not benefited from multiple previous treatment attempts
• Individuals with co-occurring substance use or mental health disorders
• Individuals with concurrent medical conditions
• Individuals in an unstable social environment or circumstances
# • Pregnant individuals
• Indigenous peoples -some inpatient treatment programs offer cultural interventions and tailored programming
# Supportive Recovery Housing
Supportive recovery housing (i.e., stabilization and transitional living residences and assisted living residences) is a direct support service that provides individuals with substance use disorders or co-occurring mental health and substance use disorders with safe, typically substance-free accommodation. Supportive recovery housing is time-limited or transitional, not permanent, housing, and is often offered to individuals who have completed inpatient treatment as part of a stepped approach to returning to the community. Services offered to residents are generally non-medical, and may include a combination of peer coaching or mentoring, group work, and structured activities (e.g., therapeutic recreational activities), with a focus on education and life-skills training to support reintegration with the community.
Very few controlled studies have evaluated the effectiveness of supportive recovery housing for improving substancerelated outcomes. Two RCTs that compared supportive recovery housing to usual aftercare (e.g., individual or group counselling, 12-step) reported that individuals residing in supportive recovery housing had reduced substance use, and improved employment and criminal justice outcomes compared to individuals in the usual aftercare group. 523,524 However, both trials had methodological limitations, including selection bias, non-equivalent groups, small sample sizes, single-site evaluations, and lack of appropriate statistical controls, which limits ability to draw meaningful conclusions from these results. 525 There is a need for more rigorous research in this area, not only to assess comparative effectiveness of this service option, but also to establish quality standards and best practices for supportive recovery housing programs to optimize patient health outcomes.
# Psychosocial Support Services
Providing patients with referrals to community-based support services may be helpful in supporting overall recovery by improving an individual's psychosocial circumstances and other survival needs. Although no systematic reviews have examined the impact of providing supports for various social needs (e.g., housing support, vocational and skills training, social supports, financial assistance) in the context of AUD, studies have demonstrated that providing access to housing and meeting other survival needs can significantly enhance treatment outcomes. 526,527 There is likely a benefit to AUD care being offered in the context of interdisciplinary primary care teams that are equipped to address these needs when possible. Where patients have encountered barriers to engagement in care, intensive case management, [528][529][530] assertive community outreach teams, [530][531][532] and peer-based outreach and support services 483,484 may also be effective strategies to improve retention in treatment.
# Managed Alcohol Programs
Managed alcohol programs (MAP) are a harm reduction strategy used to minimize the personal harm and adverse societal effects of severe AUD, particularly as experienced by individuals who may be homeless or unstably housed. 533,534 Typically, a MAP will dispense small doses of alcohol to clients at regular intervals, as a means of both regulating alcohol intake and reducing unsafe consumption of non-beverage alcohol. 533 In the community, MAPs are often coupled with, and offered within, housing programs to provide a safe and inclusive alternative to abstinence-only housing for individuals with severe AUD. 534 This low-threshold approach enables clients to gain access to other health and social services that may be offered within the program. 533 In acute care settings, MAPs have also been implemented to support patients with severe AUD for whom withdrawal management or short-term abstinence during their hospital stay is not feasible. 535 There are several MAPs currently operating in BC in both acute care and community settings. For a list of MAP services in and across Canada, refer to the Canadian Institute for Substance Use Research's Overview of MAP Sites in Canada.
Several studies of community-based MAPs have reported that the regulation of alcohol consumption through MAPs may reduce harm and improve quality of life amongst participants. [536][537][538] For example, a 2018 observational study compared alcohol consumption of participants (n=175) from six residential MAPs across Canada (Vancouver, Thunder Bay, Toronto, Ottawa, and Hamilton) with a control group matched for age, sex, and ethnicity (n=189). 539 Results showed that participants who had been MAP clients for longer than two months had fewer standard drinks per day (15.1 drinks) than newer MAP participants (20.2) and controls (22.2). 539 Long-term MAP residents were also significantly less likely to report a range of alcohol-related harms (e.g., physical health issues, involvement in illegal activities, social problems) over the past 30 days than newer MAP participants and controls. 539 Several reviews also report greater reductions in alcohol consumption and related harms (e.g., emergency health service utilization, criminal behavior, housing problems, non-beverage alcohol use) and improved engagement in ongoing medical and psychiatric care among MAP clients in comparison to control groups recruited from similar settings that do not offer managed alcohol services (e.g., homeless shelters). 533,535,538,540 A 2018 review of five randomized and non-randomized trials of hospital-based MAPs found this intervention to be superior and/or non-inferior to no treatment and standard withdrawal management protocols (i.e., treatment with benzodiazepines) for preventing or treating alcohol withdrawal symptoms among hospitalized patients with severe AUD. 535 Similar to other structured treatment programs, there are some ethical and practical challenges associated with conducting randomized trials of MAPs, and as a result, there have been no RCTs or meta-analyses comparing the efficacy and safety of MAPs in community settings with other interventions for AUD. The current evidence base is limited, and of available studies, factors such as heterogeneity among outcome measures and reliance on self-reported data have been noted as limitations. 535,541 While making explicit recommendations on the use of MAPs as a harm reduction strategy is outside the scope of this guideline, the committee wishes to acknowledge the growing body of evidence supporting this approach for individuals with severe AUD. This guideline emphasizes the need for further research and specialized guidance to support the implementation of MAPs in community and clinical care settings as a part of a comprehensive strategy to reduce the significant harms experienced by individuals with severe AUD.
# Conclusion
Despite the significant burden of disease, social harms, and economic costs associated with alcohol use in Canada, high-risk drinking and AUD frequently go unrecognized and untreated in the health care system. Recent literature has highlighted the vital role of primary care providers in meeting the health care needs of individuals with AUD. 58 This guideline presents a systematic review of the research and provides evidence-based clinical recommendations for the identification, intervention, management, and continuing care of individuals with high-risk drinking and AUD.
This guideline emphasizes the importance of clinicians providing education to patients about Canada's Low-Risk Alcohol Drinking Guidelines and performing regular screening for drinking in excess of low-risk limits. Research evidence shows that simple validated screening procedures can be incorporated in primary care routines to reliably identify high-risk drinking and AUD, whereas the current reliance on case identification alone often results in missed opportunities for the timely detection of individuals at risk. 32 Identification of high-risk drinking enables clinicians to intervene at a point where the secondary prevention of AUD is possible through brief counselling interventions. 117,118,164 As such, this guideline recommends annual alcohol use screening of all adult and youth patients, followed by brief intervention in patients who exceed low-risk drinking guidelines and are at increased risk of alcohol-related harms.
Patients who screen positive for AUD should be offered a full range of pharmacological and psychosocial treatment interventions within a framework of comprehensive and continuing care. Treatment and support should be individually tailored and adjusted appropriately based on AUD severity, comorbidities, psychosocial circumstances, and evolving personal preferences and needs. As a standard of patient-centered and recovery-oriented care, treatment goal setting (i.e., abstinence or reduced alcohol consumption) and selection of a management pathway should involve shared decision making, with the recognition that a reduction in drinking is a valid and realistic treatment goal for some patients. 83 Up to 50% of individuals with long-term alcohol dependence will experience alcohol withdrawal symptoms upon cessation of drinking. [182][183][184] Research has shown that appropriate clinical management of withdrawal symptoms can prevent the development of a severe alcohol withdrawal syndrome, including seizures and delirium tremens, as well as early relapse. 177,178 To facilitate tailored treatment selection, this guideline recommends using the Prediction of Alcohol Withdrawal Severity Scale (PAWSS), a score-based, clinician-administered tool for assessing the risk of severe withdrawal complications. This recommendation is supported by a recent meta-analysis that found the PAWSS to be the most useful and accurate predictive assessment tool currently available. 195,197 This guideline recommends outpatient withdrawal management for patients who are at low risk of developing severe complications (i.e., PAWSS<4) and have no other comorbid conditions that would be a contraindication to outpatient management. 207,208,210 Further, this guideline recommends that patients at high risk of developing severe withdrawal complications (PAWSS≥4) should be referred to an inpatient facility where alcohol withdrawal can be medically supervised and closely monitored.
The evidence supporting commonly used pharmacotherapies for outpatient withdrawal management (i.e., benzodiazepines, anticonvulsants, and α2-adrenergic agonists) was also reviewed. While acknowledging the robust evidence base supporting the use of benzodiazepines for alcohol withdrawal management, this guideline highlights safety concerns with the use of this class of medications for outpatient management, including side effects, risk of diversion, non-medical use, dependence, adverse drug-drug interactions, as well as the dangers of combining benzodiazepines with alcohol. 175 For these reasons, non-benzodiazepine medications, such as carbamazepine, gabapentin, and clonidine, are recommended for the outpatient management of mild to moderate withdrawal. [237][238][239][240][241] However, benzodiazepines remain the preferred option for the inpatient treatment of severe alcohol withdrawal, because only benzodiazepines have demonstrated efficacy for preventing seizures and delirium tremens. [227][228][229] This guideline strongly recommends that all patients who complete withdrawal management be offered a connection to ongoing AUD care, treatment, and support. Withdrawal management alone does not constitute treatment for AUD as demonstrated by high post-withdrawal relapse rates reported in the literature. [269][270][271][272][273][274][275] This document also reviewed the evidence on the safety and efficacy of a range of pharmacological and psychosocial treatment interventions that can be offered as part of a continuing care strategy in the clinical management of AUD. Although pharmacotherapy has been shown to play an important role in supporting the achievement of treatment goals among patients with moderate to severe AUD, it is under-utilized in primary care practice. As a part of a comprehensive long-term treatment and support plan, pharmacotherapy can help prevent a return to drinking among patients whose goal is abstinence, and reduce heavy drinking episodes and overall alcohol intake for patients who wish to reduce their alcohol consumption. 178 There is a well-established evidence base that supports offering naltrexone or acamprosate as a first-line pharmacotherapy medication to all patients with moderate to severe AUD. 178,285,300 More specifically, and in line with several meta-analyses, 178,307,308 naltrexone is recommended for patients with a treatment goal of abstinence or reduced drinking, and acamprosate is recommended for patients with a treatment goal of abstinence. For patients for whom first-line medications are not appropriate or preferable, this guideline recommends topiramate or gabapentin, which are supported by a growing body of evidence. 261,315,401 This guideline recommends that clinicians provide motivational interviewing (MI)-based counselling to all patients with mild to severe AUD to support the achievement of their treatment and recovery goals. Available meta-analyses report low to moderate quality evidence that MI results in a modest but significant reduction in alcohol and other substance use compared to no treatment. 416 Research has also shown that MI is as effective as other active psychosocial modalities (e.g., cognitive behavioural therapy) in reducing substance use. [413][414][415] Additionally, this guideline recommends that all patients with AUD receive information about specialist-led psychosocial treatment interventions (e.g., cognitive behavioural therapy, family-based therapy), as well as peer-based support groups and other recovery-oriented services in the community. The evidence suggests that specialist-led psychosocial interventions may have a modest but significant impact on likelihood of relapse and return to heavy drinking among adolescent and adult patients. 456,458,459,[473][474][475][476] Although there is a lack of highquality evidence supporting the effectiveness of peer support groups, the committee recognizes the value of peer-based support, guidance, and mentorship to patients and families in navigating changes during the process of recovery, and recommends that clinicians provide all patients and families affected by AUD with information on and referrals to local peer support groups. 483,484,512 While this guideline has presented specific evidence-based recommendations for the optimal screening, diagnosis, treatment, and care of individuals with AUD, the committee recognizes the need for further work to develop an integrated and comprehensive system of addiction care in British Columbia, including a robust continuum of evidence-based care options that are available and accessible to all patients and families across the province. Additionally, the committee recognizes the need to enhance collaboration between different sectors and across the continuum of care to better support patients and families as they navigate the treatment and recovery process. The present document is intended to serve as a foundation for the development of policies, practice tools, and educational resources that will enable primary care clinicians to assume a central role within this emerging provincial system of care.
# Appendices Preface
The following appendices have been provided to support clinical practice and were developed using a different methodology than the main guideline. Here, recommendations have been derived through discussion and consensus of an interdisciplinary working group convened in addition to the guideline committee. The practice guidance herein was informed by review of existing national and international evidence-based clinical practice guidelines issued by recognized addiction medicine organizations and authorities. Where appropriate, Health Canada-approved drug product monographs were consulted to ensure compliance with provincial and national safety regulations and standards for practice. Recommendations adhere to the CPSBC Professional Standards and Guidelines for Safe Prescribing of Drugs with the Potential for Misuse/Diversion (www.cpsbc.ca/files/pdf/ PSG-Safe-Prescribing.pdf).
# Appendix 1 Alcohol Use Screening
Universal alcohol use screening of adult and youth patients has a significant role in health promotion, as the identification of high-risk alcohol use facilitates the prevention of the wide range of alcohol-related conditions as well as AUD. This appendix provides an instructive overview of the screening process in three steps:
Step 1 -Starting the Conversation, Step 2 -Screening for High-Risk Alcohol Use, and Step 3 -Assessment and Diagnosis of an AUD.
Step 1 Starting the Conversation
Introducing the topic of alcohol use to patients in a non-judgmental, conversational, and clear manner can foster a candid conversation and improve the accuracy of self-reported alcohol use. The following strategies are recommended to establish comfort and trust prior to beginning screening questions.
# Use Canada's Low-Risk Alcohol Drinking Guidelines as a Communication Tool
Briefly reviewing Canada's Low-Risk Alcohol Drinking Guidelines can help guide conversations toward alcohol use screening. An example patient handout describing the low-risk drinking guidelines is provided on the next page. Clinicians should clarify what is meant by "alcoholic beverages" and standard drink sizes using the patient handout.
# Sample Script:
" Have you heard about Canada's Low-Risk Alcohol Drinking Guidelines? I talk to all of my patients about these guidelines. They contain important information about safer alcohol use that everyone needs to know. "
# Secure consent and assure the patient of the confidentiality of the conversation
Patients' reluctance to share information about their alcohol use can be a barrier to obtaining accurate screening results and establishing an effective therapeutic relationship for next steps. It is important to:
• Ask the patient's permission before screening,
• Assure the patient of the confidentiality of the information they share, and • Emphasize that you ask all your patients about alcohol use.
# Sample Script:
" I regularly ask my patients about alcohol and other substance use. Would it be alright for us to talk about this now?"
" Now that we've talked about some of the effects of alcohol on our health, would you mind if I ask you some questions about your alcohol use?"
Step 2 Screening for High-Risk Alcohol Use
# Alcohol Use Screening in Adult Patients
This guideline recommends single-question alcohol screening (SASQ) using the low-risk limits for adult men and women set by Canada's Low-Risk Drinking Guidelines, as illustrated below (Figure 1). If it has not already been established, clinicians should first ask if the patient occasionally drinks alcohol as a pre-screening question. "How many times in the past year have you had…
• 4 or more drinks in one day?" (for men)
• 3 or more drinks in one day?" (for women) * If more information would be helpful, or if patient's response to SASQ is inconsistent with clinical signs and symptoms, additional screening tools may be used to confirm screening results:
• CAGE • AUDIT-C • AUDIT
# High-Risk Drinking
Proceed to diagnosis and assessment for AUD using the DSM-5 criteria
High-Risk Drinking
# Single Alcohol Screening Question (SASQ)
" In the past year, how often have you consumed more than 3 drinks (women) or 4 drinks (men) on any one occasion?" Never : Screening is complete.
• Offer encouragement.
• Review the low-risk limits and situations where drinking should be reduced or avoided:
• In older adults (>65 years of age)
• When driving, at work, and caring for children or other dependents • When taking medications or using substances that interact with alcohol • If patient has a health condition that could be exacerbated by alcohol
• For adolescent and pregnant patients, recommend abstinence.
• If patient reports not drinking, ask about their alcohol use history.
• For patients with a personal or family history of AUD who have cut down or stopped drinking, ask about their progress and offer encouragement and support as needed.
• Re-screen annually.
One or More :
Positive result for high-risk drinking.
• Record the patient's average weekly alcohol consumption in standard drinks for follow-up appointments:
• Ask patient: "On average, how many days a week do you drink alcohol?"
• Ask patient: "On a typical drinking day, how many drinks do you have?"
• (Drinking days x number of drinks per drinking day = weekly average).
• If patient responses are vague or inconsistent with clinical symptoms and signs of alcohol use, an additional screening tool can be used to assess high-risk use (e.g., CAGE, AUDIT or AUDIT-C, see Figure 1).
• Proceed to diagnosis and assessment for AUD (Step 3).
Additional validated screening tools can be used at the discretion of the treating clinician to clarify risk if responses to SASQ are unclear or inconsistent with clinical signs and symptoms of alcohol use. When indicated and feasible, working through more comprehensive screening questionnaires together can also provide patients the opportunity to reflect on their drinking and the impact it may have on their life, and for the care provider to provide feedback and answer any questions the patient may have. Several commonly used screening tools-the CAGE questions, the Alcohol Use Disorders Identification Test (AUDIT), and the AUDIT-Consumption (AUDIT-C) are described briefly below, and summarized in Table 10.
# The Cut-down, Annoyed, Guilty, Eye Opener (CAGE) Tool
CAGE is an mnemonic device that stands for "Cut-down, Annoyed, Guilty, and Eye-opener". 542 The CAGE tool is frequently used in primary care due to its brevity, ease of recall, and sensitivity for detection of AUD and related problems. The CAGE tool consists of four yes/no questions as shown in Box 8 below.
Box 8 The CAGE Tool 542 1
Have you ever felt you ought to Cut down on your drinking?
# 2
Have people Annoyed you by criticizing your drinking?
3
Have you ever felt bad or Guilty about your drinking?
# 4
Have you ever had a drink in the morning (Eye-opener) to steady your nerves or get rid of a hangover?
Using a cut-point of 2 or more "yes" responses, the CAGE has an estimated sensitivity of 84% and specificity of 85% for the detection of AUD and alcohol-related harms. 120 Some studies have reported that the CAGE has a lower sensitivity in youth, non-white, female, and older patient populations than in adult white men; [543][544][545][546] however, of available alcohol screening tools, only the CAGE appears to as effective as more complex tools (e.g., the Michigan Alcohol Screening Test or MAST) for identifying AUD in older adults, and due to its relative brevity, may be more practical to administer in routine clinical practice. 547,548 As a standalone screening tool, the CAGE is less sensitive and specific than SASQ and the AUDIT /AUDIT-C for detecting high-risk drinking, however, when used as a follow-up for patients who screen positive to SASQ, the overall sensitivity for detection of an AUD increases to over 90%, and only requires an average of 3-4 questions to be asked per patient. 121 The Alcohol Use Disorders Identification Test (AUDIT/AUDIT-C)
The AUDIT (see Box 9) was developed by the World Health Organization (WHO) to assist in the early identification of hazardous p or harmful q alcohol consumption, and is one of the most widely studied alcohol screening tools. The AUDIT is also frequently used as a reference standard for the evaluation of other alcohol screening tools. The AUDIT consists of 10 questions that assess alcohol consumption, symptoms of AUD, and alcohol-related harms. Each question is assigned a score of 0-4 that corresponds to frequency of occurrence, resulting in a total score ranging from 0 to 40 points. For adult patients, a score of 8 or higher indicates hazardous or harmful use. The condensed AUDIT-Consumption (AUDIT-C, Box 10) tool consists of three questions about alcohol consumption, and uses sex-specific cut-points: for adult male patients, a score of 4 or higher indicates hazardous or harmful drinking, while in adult female patients, a score of 3 or higher indicates hazardous or harmful drinking.
The 10-item AUDIT takes approximately 3 minutes, while the 3-item AUDIT-C requires approximately 1-2 minutes to administer or complete. Using a cut-point of 8, the AUDIT has an estimated sensitivity of 97% and specificity of 78% for the identification of hazardous alcohol use in general primary care populations. 120 The AUDIT-C has a sensitivity of 86% and specificity of 78% for the identification of hazardous alcohol use in general primary care populations using sex-specific cut points (women -3, men -4). 120 The AUDIT and AUDIT-C have been validated in a range of practice settings, including primary care clinics, assessment and emergency rooms, and acute care wards, [549][550][551][552][553][554][555] and across sexes, ethnicities and age groups, including adolescents (aged 11-18 years), young adults (aged 19-25 years), and older adults (aged 65 years and over). 128,[556][557][558][559][560] The AUDIT and AUDIT-C can be less sensitive for the identification of high-risk drinking in women, youth, older adults and ethnic patient populations compared to white adult men. 560
p Hazardous use: A pattern of alcohol use that increases the risk of harmful physical and/or mental health consequences as well as social consequences for the individual. Hazardous use occurs in the absence of addiction or alcohol use disorder. q Harmful use: A pattern of alcohol use associated with health consequences and/or that causes damage to health. Damage may be physical or mental.
Harmful use commonly, but not invariably, has adverse social consequences, but social consequences alone are not sufficient to justify a diagnosis of harmful use. Harmful use occurs in the absence of addiction or alcohol use disorder. (ICD-10 code, previously known as "non-dependent use" in .
Time constraints, lack of experience, and the requirement to calculate scores have been cited by health care providers as barriers to more widespread uptake and use of AUDIT and AUDIT-C in primary care. 122,[124][125][126] As an alternative, self-administered print and electronic versions of these tools are available and can be provided to patients to complete in advance of scheduled clinical appointments or while they are waiting to be seen. Selfadministered versions of the AUDIT and AUDIT-C appear to be as effective as clinician-administered screening for the identification of hazardous or harmful alcohol use. 561 Providers who elect to use the AUDIT or AUDIT-C in their practice should be aware that low-risk limits and standard drink sizes used in these instruments are slightly different than those used in Canada's Low-Risk Alcohol Drinking Guidelines.
# Box 9 The Alcohol Use Disorders Identification Test ( AUDIT ) 562
Read questions as written. Record answers carefully. Begin the AUDIT by saying "Now I am going to ask you some questions about your use of alcoholic beverages during this past year." Explain what is meant by "alcoholic beverages" by using local examples of beer, wine, vodka, etc. Code answers in terms of "standard drinks". Place the correct answer number in the box at the right.
1. How often do you have a drink containing alcohol? Interpretation: In men, a score of 4 or more is considered positive for hazardous drinking. In women, a score of 3 or more is considered positive for hazardous drinking. If score is positive, proceed to diagnosis and assessment for AUD.
Total score: • Provider-administered in <1 min • Designed for use in a busy primary care setting • Less effective for detection of high-risk drinking and AUD than more complex screening tools, can be combined with another tool to reduce likelihood that cases will be missed
• Logical flow from providing general education on Low-Risk Alcohol Drinking Guidelines to using low-risk limits as SASQ
• Well suited for a general primary care population, where most patients will not screen positive AUD 88 67 CAGE AUD 84 85
• Self-or provider-administered in <2 min • More effective for identifying moderate to severe AUD than mild AUD or high-risk drinking
• Not useful as a standalone screening tool, as patients with high-risk drinking could be missed
• Less effective in detecting AUD in young adults, women, people of non-white ethnicity 563
• Can be used as an "ultra-brief" follow-up when patients screen positive to SASQ • Well suited for general primary care population, where most patients will not screen positive AUDIT Hazardous drinking 97 78
• Self-or provider-administered in 3-4 min • Well studied, has been validated in multiple settings and patient populations
• Less sensitive in female patients • Uses different standard drink sizes and daily drink limits than Low-Risk Alcohol Drinking Guidelines r
• Requires provider scoring (or an electronic health record (EHR) system or other tool to compute scores)
Harmful drinking 95 85
# AUDIT-C
Hazardous drinking 86 78
• Self-or provider-administered in 1-2 min • Well studied, has been validated in multiple settings and patient populations
• Uses different criteria and standard drink sizes than Low-Risk Alcohol Drinking Guidelines r
• Requires provider scoring (or an EHR system or other tool to compute scores)
# Alcohol Use Screening in Adolescent Patients
This guideline recommends using the NIAAA screening tool for adolescent patients (aged 11-18 years). Additional validated screening tools can be used at the discretion of the treating clinician to clarify risk if responses to the NIAAA screening questions are unclear or inconsistent with clinical signs and symptoms of alcohol use. A commonly used substance use screening tool for adolescents -the CRAFFT -is described briefly below. Performance characteristics for use of the NIAAA screening tool, the CRAFFT, and the AUDIT in adolescents are also summarized in Table 9.
r AUDIT/AUDIT-C: Standard drink size = 10 g of ethanol, Low-risk limits = no more than 2 drinks per day, no more than 5 days per week; Canada's Low-Risk Alcohol Drinking Guidelines: Standard drink size = 13.45 g of ethanol, Low-risk limits = no more than 2 drinks per day (women) or 3 drinks per day (men), no more than 5 days per week. 9,146 The NIAAA Screening Tool 131 The NIAAA tool is a 2-question modification of SASQ designed to identify adolescents (age 11-18 years) who are at increased risk of alcohol-related problems including AUD. The screening questions are presented below. For adolescents aged 11-14, it is recommended to first ask about alcohol use among friends as a less-threatening introduction to the topic, followed by personal use questions (i.e., question 1 then 2). For patients who are 15-18 years old, the screening questions should be asked in reversed order (i.e., question 2 then 1). Question 1. "Have any of your friends consumed alcohol in the past year?" Question 2. "Have you consumed any alcohol in the past year?"
If a patient reports that they do not consume alcohol :
• Offer encouragement and reinforce healthy choices.
• If the patient's friends drink:
• Ask how the patient views or feels about their friends' drinking.
• Ask about their plans or thoughts about delaying drinking until of legal age.
• Elicit and affirm the patient's reasons for not consuming alcohol.
• Re-screen at next visit.
• If friends do not drink:
• Provide support for the patient's choices social circle and activities.
• Elicit and affirm the patient's reasons for not consuming alcohol.
• Re-screen annually.
If patient reports drinking:
• Ask patient to estimate the number of drinking days they have had in the past year and assess risk based on the following thresholds: • For patients who drink less than the risk threshold, highlight the risks of alcohol use and provide brief intervention to reduce risk (Appendix 2). Follow-up next visit.
Age
• Patients who drink above the risk threshold are considered to be at increased risk of AUD. Proceed to assessment and diagnosis (Step 3).
The Car, Relax, Alone, Forget, Friends, Trouble (CRAFFT) Screening Tool 564 The CRAFFT screening tool (Box 11) is one of the most widely used screening tool in North America for the assessment of alcohol and drug use in adolescents. 131,162,565 A score of 2 or more to the six CRAFFT questions has a sensitivity of 80% and specificity of 86% for detecting any substance use disorder 564,566 and sensitivity of 98% and specificity of 73% for AUD in adolescents. 567
# Box 11 The CRAFFT Instrument
PART A
# During the PAST 12 MONTHS, on how many days did you:
NUmBER of DAyS
# 1
Drink more than a few sips of beer, wine, or any drink containing alcohol? Put "0" if none.
# 2
Use any marijuana (weed, oil, or hash by smoking, vaping, or in food) or "synthetic marijuana" (like "K2," "Spice")? Put "0" if none.
# 3
Use anything else to get high (like other illegal drugs, prescription or over-the-counter medications, and things that you sniff, huff, or vape)? Put "0" if none.
# Interpretation
• If patient answered "0" for all questions above, ask Part B "CAR" CRAffT question only.
• If patient answered more than "0" for any of the questions above, ask all six CRAffT questions below.
# PART B
CRAFFT Questions -Check "NO" or "YES" in columns on right.
No yES
# C
Have you ever ridden in a CAR driven by someone (including yourself) who was "high" or had been using alcohol or drugs?
# T
Have you ever gotten into TROUBLE while you were using alcohol or drugs?
Interpretation Two or more "yES" answers to the CRAffT questions indicate increased risk need for further assessment. • Takes 1-2 minutes to administer and score • Designed for use in busy primary care settings • Age-specific cut-offs improve sensitivity, but can be difficult to recall from memory
• Less sensitive than CRAFFT for detection of AUD AUD 87 84
# CRAFFT
High-risk use 56 92
• Self-or provider-administered in 3-4 min • Screens for alcohol and drug use • Has been validated in diverse patient populations • Less sensitive for detection of high-risk drinking • Has high sensitivity for detection of AUD AUD 98 73
AUDIT High-risk use 33 99
• Self-or provider-administered in 3-4 min • Less sensitive for detection of heavy drinking or AUD among youth compared than adult populations
• Uses different criteria and standard drink sizes than Low-Risk Alcohol Drinking Guidelines
• Requires provider scoring (or an electronic health record (EHR) system or other tool to compute scores)
# Alcohol Use Screening in Pregnancy
It is imperative that education, screening and assessment of alcohol use in pregnancy is delivered in a balanced and non-judgmental manner to prevent unintended negative consequences, such as loss to care. 4,568 Research has shown that stigma and fear of judgment is a significant barrier to accessing and staying engaged in treatment among pregnant individuals who use substances. 4 This guideline recommends use of SASQ combined with supportive dialogue for alcohol use screening in pregnancy as described above. Structured instruments can also be used to clarify alcohol use and risk, if preferred. The AUDIT, AUDIT-C, CAGE, and CRAFFT tools have been validated in pregnant patients, 268,569 and additional screening instruments have been developed for use in pregnancy (e.g., TWEAK, T-ACE, Substance Use Risk Profile-Pregnancy) that are not reviewed in this guideline. [570][571][572] For additional clinical guidance on alcohol use during pregnancy and postpartum, clinicians can refer to the Alcohol Use and Pregnancy Consensus Clinical Guidelines 4 issued by the Society of Obstetricians and Gynaecologists of Canada. The Centre of Excellence for Women's Health also has several guides to support clinicians in engaging with women and their partners on alcohol use available on their website: http://bccewh.bc.ca/2017/ 05/alcohol-and-pregnancy-brief-intervention-guides/.
In partnership with Perinatal Services BC, the BCCSU will be releasing prescriptive guidance for the Clinical Management of High-Risk Drinking and Alcohol Use Disorder in Pregnancy in the Fall of 2019, including recommendations and practice support tools for alcohol use screening, which will be available at the following link: http://www.bccsu.ca/clinical-care-guidance/.
Step 3 Assessment and Diagnosis of an Alcohol Use Disorder
Patients who screen positive for drinking above low-risk limits should undergo further assessment, and if appropriate, a structured interview using the DSM-5 criteria to confirm the diagnosis and severity of AUD (see Table 10 on next page). Confirmation or exclusion of an AUD, and an assessment of AUD severity and the patient's risk of complications, determines subsequent steps in the treatment pathway.
Patients who are drinking above low-risk limits but do not have an AUD should be administered a brief counselling intervention and encouraged to reduce their alcohol consumption (see Appendix 2).
Brief intervention alone is not effective for individuals with an AUD. 143 A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period, indicates presence of an AUD. 2 Sample Clinical Interview Questions 573 In the past year (12 months), have you...
# 1
Alcohol is often taken in larger amounts or over a longer period than was intended Had times when you ended up drinking more, or longer, than you intended?
2
There is a persistent desire or unsuccessful efforts to cut down or control alcohol use More than once wanted to cut down or stop drinking, or tried to, but couldn't?
# 9
Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol Continued to drink even though it was making you feel depressed or anxious, or adding to another health problem? Or, continued drinking after having a memory blackout?
# 10
Tolerance, as defined by either of the following: a) A need for markedly increased amounts of alcohol to achieve intoxication or desired effect b) A markedly diminished effect with continued use of the same amount of alcohol Had to drink much more than you once did to get the effect you want? Or found that your usual number of drinks had much less effect than before?
# 11
Withdrawal, as manifested by either of the following: a) The characteristic withdrawal syndrome for alcohol b) Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms
Found that when the effects of alcohol were wearing off, you had withdrawal symptoms, such as trouble sleeping, shakiness, restlessness, nausea, sweating, a racing heart, or a seizure? Or sensed things that were not there?
Severity: MILD: presence of 2-3 symptoms, MODERATE: presence of 4-5 symptoms, SEVERE: presence of 6 or more symptoms.
Modifiers for the diagnosis include:
• Early remission: After full criteria for AUD were previously met, none of the criteria for AUD have been met (with the exception of craving) for at least 3 months but less than 12 months. • Sustained remission: After full criteria for AUD were previously met, none of the criteria for AUD have been met
(with the exception of craving) during a period of 12 months or longer. • Controlled environment: If the individual is in an environment where access to alcohol is restricted.
# Appendix 2 Brief Intervention for High Risk Drinking
This guideline recommends that clinicians administer a brief intervention (BI) to all adult and youth patients who screen positive for high-risk drinking to support behavioural change to reduce alcohol consumption. BI is a brief or ultra-brief variant of motivational interviewing (MI), an evidence-based psychosocial treatment intervention (see Appendix 5). 144 BIs are typically structured using the FRAMES approach (Table 11). 144,146 Table 11 The FRAMES Model for MI-Based Brief Interventions 144,146
# Feedback
Provide individualized feedback on screening or assessment results. Asking open-ended questions about how the patient feels or thinks about the feedback can aid discussion.
# Responsibility
Using a strengths-based, patient-centred approach, emphasize that responsibility for making the choice to change behaviour ultimately rests with the individual.
# Advice
Seek permission from the patient first before giving advice. Provide clear advice that cutting down or stopping alcohol use will reduce risk of future problems. Many patients are unaware that their current drinking patterns could potentially lead to health or other problems, or make existing problems worse. Increased awareness of their personal risk can provide reasons to consider changing behaviour.
# Menu
Review a "menu" of different options for reducing alcohol use and encourage patient to choose the strategies that they feel best fit their circumstances and needs. Providing choice reinforces a patient's sense of control and responsibility and can strengthen motivation to change. Using a shared-decision making framework, set goals that are realistic and meaningful to the patient.
# Empathic
Use a warm, empathic counseling style, which involves listening, understanding, and reflecting that understanding back to the patient (e.g., "reflective listening"), and is associated with improved BI outcomes.
# Self-Efficacy
Encourage and reinforce the patient's self-efficacy and confidence in their ability to change. Individuals who believe that they can make changes are much more likely to do so than those who feel powerless or helpless to change their behaviour.
# The 5As Model for Brief Alcohol Interventions
The 5As model is widely used in primary care and other clinical settings to support behavioural change, including dietary changes, exercise plans, smoking cessation, and substance use. 48,148 Guidance for adapting the 5As approach as a brief alcohol intervention is provided below. [574][575][576] Ask Screen and document alcohol use for every patient. Identify individuals who are drinking above low-risk limits. (See Appendix 1)
# Advise
Inform patient of screening result and provide advice to reduce or stop drinking Assess Assess patient's willingness to change their drinking behaviour
# Assist
For the patient willing to reduce or stop alcohol use, provide a menu of treatment and support options, and collaboratively set treatment goals and plans
# Arrange
Schedule a follow-up and/or referral
# Ask
The first step of the 5As intervention is asking patients about their alcohol use -screening -which is covered in Appendix 1.
# Advise
Clearly describe the screening result and its implications on the patient's health, and provide direct personalized recommendations. Where possible, relay relevant health risks in reference to patient's concerns, laboratory investigations, and medical findings (e.g., anxiety, insomnia, liver function tests, gastroesophageal reflux disease, blood pressure).
# Sample Script:
" You are drinking more than is medically safe. I think your drinking is putting your health at risk and is not good for you. " " I strongly recommend that you cut down or stop drinking. "
# Assess
Engage patient in a brief conversation to assess their motivation and ability to reduce or discontinue their alcohol use at this time.
# Sample Questions:
" Are you willing to consider making changes in your drinking?" " How do you feel about my recommendation? Do you have any questions?" " What do you think? Would that work for you? Does that make sense?"
# Assist
If patient expresses readiness to change:
• Express your support and offer encouragement.
• Affirm your confidence in patient's motivation and ability to change.
• Collaboratively set goals that are meaningful to the patient. Goals do not have to be limited to reducing or stopping alcohol use.
• Agree on a specific plan and a change date or schedule.
• In line with the patient's goals, provide a menu of options, including pharmacotherapy, psychosocial interventions, recovery-oriented and community-based supports.
• Provide educational material and referrals to social supports and community resources.
• Schedule a follow-up visit.
If patient does not express readiness to change:
• Restate your concern about patient's health.
• Ask about any barriers to change the patient may be experiencing, and invite the patient to consider how these could be navigated.
• Encourage the patient to take time to reflect on the conversation.
• Reaffirm your willingness to support when patient is ready.
• Offer educational material and referrals to relevant health care and community resources.
• Follow-up. Repeat screening and brief intervention regularly. If the answer to either is yES, proceed to next questions.
# PART B: BASED ON PATIENT INTERVIEW -1 point each 1
Have you been recently intoxicated/drunk, within the last 30 days?
# 2
Have you ever undergone alcohol use disorder rehabilitation treatment or treatment for alcoholism? (i.e., in-patient or out-patient treatment programs or AA attendance)
# 3
Have you ever experienced any previous episodes of alcohol withdrawal, regardless of severity?
# 4
Have you ever experienced blackouts?
# 5
Have you ever experienced alcohol withdrawal seizures?
# 6
Have you ever experienced delirium tremens or DTs?
# 7
Have you combined alcohol with other "downers" like benzodiazepines or barbiturates, during the last 90 days?
# 10
Is there any evidence of increased autonomic activity? e.g., heart rate >120 bpm, tremor, agitation, sweating, nausea * Due to the common absence of a BAL the committee has added this modification. Please see next page.
# Interpretation
Maximum score = 10. This instrument is intended as a SCREENING TOOL. The greater the number of positive findings, the higher the risk for the development of alcohol withdrawal syndrome (AWS).
A score of ≥ 4 suggests HIGH RISK for moderate to severe (complicated) AWS; prophylaxis and/or inpatient treatment are indicated.
An online version of the original (unmodified) PAWSS can be found at: https://www.mdcalc.com/predictionalcohol-withdrawal-severity-scale.
# Remarks and Cautions
The PAWSS has not been validated in outpatient care settings, or in youth or pregnant patient populations. While this guideline endorses the usefulness of the PAWSS for risk assessment in all settings and populations, it emphasizes that, when making clinical decisions, this tool should be used in conjunction with best clinical judgment based on a comprehensive assessment of a patient's medical history, current circumstances, needs, and preferences.
# Modifications
# Question 9 -Blood Alcohol Level (BAL)
The vast majority of outpatient care settings will not be equipped to assess BAL at the point-of-care. As an alternative, the committee recommends that the PAWSS administrator ask patients:
Have you consumed any alcohol in the past 24 hours?
Based on rates of alcohol metabolism and elimination in humans, 577 it is very unlikely that a patient who has not consumed alcohol in the past 24 hours would have a BAL greater than 200 mg/dL. While any alcohol consumption in the past 24 hours is a conservative measure of BAL > 200 mg/dL (i.e., this low threshold may over-identify those at risk), it is the consensus of the committee that the benefits of identifying individuals at risk of severe complications outweigh the risk of false negatives for this questionnaire item.
Alternatively, if a portable breath alcohol concentration device (i.e., a "breathalyzer") is available, breath alcohol concentration can be used in place of BAL. Research indicates that breath alcohol concentration is strongly correlated with BAL. 578,579
# Qualifiers
The following questionnaire items should be clearly understood by the PAWSS administrator and defined for the patient to maximize the accuracy of results.
# Question 4 -Blackouts
Blackouts are transient episodes of retrograde amnesia typically without loss of consciousness that accompany various degrees of alcohol intoxication. 195 Blackouts can be an indicator of severe intoxication or long-term alcohol use, as a considerable degree of alcohol tolerance is required to ingest the amount of alcohol that could trigger a subsequent episode of amnesia without loss of consciousness. 195 The PAWSS administrator should clearly distinguish between alcohol-related blackouts and loss of consciousness (i.e., "passing out") as they pose the question to the patient.
# Question 5 -Withdrawal Seizures
Withdrawal seizures are typically generalized and brief tonic-clonic seizures that occur 6-48 hours after reduction or discontinuation of alcohol use. 210 Patients may mistake other experiences, such as tremor, for a seizure; it is important to define what is meant by a withdrawal seizure and differentiate it from other withdrawal symptoms. Patients with AUD are at increased risk of idiopathic epilepsy or seizure for other reasons, 580,581 so the PAWSS administrator should clearly define withdrawal seizures as those that occur within 1-2 days of ceasing or greatly reducing alcohol use.
# Question 6 -Delirium Tremens (DTs)
Delirium tremens is a severe consequence of alcohol withdrawal that requires immediate hospitalization and management; if left untreated, the risk of death is approximately 3-5%. 582 Symptoms include profound disorientation, confusion and agitation, accompanied by severe autonomic hyperactivity. 582 In colloquial language, delirium tremens or "DTs" has come to loosely represent general symptoms of alcohol withdrawal. The PAWSS administrator should clearly distinguish delirium tremens from other withdrawal symptoms to avoid false positive results.
# Notes
• Training is required to administer this tool accurately; a regular audit and feedback process is recommended to ensure intra-and inter-rater variability is within an acceptable range. 583,584 • This tool should be used in conjunction with best clinical judgment when making decisions on appropriate medication protocols, schedules, and dosages.
• Due to the need for a clinical interview, the CIWA-Ar is not appropriate where there is a language barrier or if the patient is cognitively impaired, delirious, or displaying a decreased level of consciousness. 204 Box 14 Short Alcohol Withdrawal Scale (SAWS) 205 Please put a tick in the boxes to show how you have been feeling for all of the following conditions in the last 24 hours.
# Notes
• The SAWS tool is suitable for self-assessment. It may be completed by the patient or a clinician to assess symptoms of mild to moderate alcohol withdrawal.
• The SAWS may be used as a standalone tool or as supplement to CIWA-Ar for patients who require more frequent assessment.
# B. Selecting the Appropriate Care Setting
Patient Criteria for Outpatient Alcohol Withdrawal Management 212,213 • PAWSS score <4 (see Box 12) • Absence of contraindications including, but not limited to:
• Severe or uncontrolled comorbid medical conditions (e.g., diabetes, COPD, heart disease, decompensated cirrhosis)
• Acute confusion or cognitive impairment • Acute illness or infection requiring medical intervention • Co-occurring serious psychiatric symptoms or disorders (e.g., suicidal ideation, psychosis)
• Chronic or complex pain disorders • Co-occurring severe substance use disorders (excluding tobacco)
• Pregnancy
• Ability to attend daily medical visits for first 3-5 days, and alternating day visits thereafter
• For patients and/or practices in rural or remote areas where daily in-person visits are not feasible, remote follow-up options such as telemedicine, or secure phone or video calls, are acceptable alternatives (but see notes below)
• Ability to take oral medications
• Has a reliable family member or community-based contact who can monitor symptoms during acute withdrawal period (i.e., 3-5 days) and support adherence to medications (see notes below)
• Any other medical or social condition that, in the treating clinician's best judgment, would present serious risks to patient safety if alcohol withdrawal was managed on an outpatient basis
# Additional Considerations
• Patients who do not have support from family or community should not be denied treatment; inpatient treatment should be considered as an alternative. If inpatient care is not an option due to patient preference or scarcity of beds, patients with insufficient social supports should be accommodated and treated through alternative strategies such as supplementary follow-up visits and/or connection to local pharmacist.
• In communities where medically-supervised home withdrawal management programs are available, primary care follow-ups can be supplemented by home visits as appropriate.
• Intensive outpatient withdrawal management programs (e.g., "DayTox") may also be an option in some communities.
• A patient's track record of adherence to clinical recommendations should be considered as a factor in this decision.
# C. Prescribing Pharmacotherapy for Outpatient Withdrawal Management
Baseline Assessment and Preparation
• Confirm DSM-5 diagnosis of AUD (see Table 10).
• Conduct physical and mental health assessment to determine appropriate setting and pathway for withdrawal management. See previous page for criteria for outpatient withdrawal management.
• Obtain a complete substance use history including assessment for tobacco and other substance use disorders.
Identify any concurrent use of CNS depressants (e.g., opioids, benzodiazepines, Z-drugs, other sedatives).
• Conduct a nutritional assessment and advise on supplementation. Assess and provide advice to correct fluid imbalances and electrolyte deficiencies. It is recommended that all patients with AUD receive multivitamin supplementation including thiamine (100mg), folic acid (1mg), and vitamin B6 (2mg). 585 • Note: BC PharmaCare does not provide benefit coverage for over-the-counter vitamins or supplements.
• Review patient's record on PharmaNet to assess for potential drug-drug interactions and contraindications with concomitant prescriptions. • Identify and address the risk of impaired driving.
• Note: Section 230 of the Motor Vehicle Act (MVA) requires that physicians and nurse practitioners file a report with RoadSafetyBC if any patient who has a medical condition that makes it dangerous for them to drive continues to do so against medical advice. For more information, please refer to: https://www2.gov. bc.ca/assets/gov/driving-and-transportation/driving/publications/reporting-a-condition-fact-sheet-fordoctors.pdf.
• Patients undergoing withdrawal management should be advised not to drive or operate machinery until treatment is complete and symptoms are resolved.
# Laboratory Investigations
The following tests may be ordered to assess general health, alcohol-related comorbidities, and other conditions that could impact pharmacotherapy selection:
• Complete blood count (CBC), serum electrolytes, glucose, liver function and renal function panels.
• Pregnancy test for patients of childbearing capacity.
• Electrocardiogram (ECG) for patients with cardiac disease or a history of arrhythmia or syncope.
• Chest x-ray for patients with chronic respiratory problems or respiratory symptoms.
Note : Treatment should be initiated immediately whenever possible, and should not be delayed by waiting for laboratory test results unless patient safety would be compromised.
# Pharmacotherapy Options
This appendix lists medications for withdrawal management in order of supporting evidence; it does not stratify treatments in terms of first-and second-line options. Prescribers should select the most appropriate medication for a particular patient based on their medical history, circumstances, and preferences.
Of note, while the efficacy of benzodiazepines for withdrawal management is supported by the largest body of evidence, this guideline recommends non-benzodiazepine pharmacotherapies for outpatient withdrawal management due to their superior safety profile.
To facilitate decision making, this appendix includes profiles of each alcohol withdrawal medication reviewed in this guideline, including sample dosing protocols. With the exception of benzodiazepines, which include Health-Canada approved medications for AUD (chlorazepate, 586 diazepam, 257 and oxazepam 587 ), use of the medications reviewed below would be considered "off-label". As with any medication that is being prescribed off-label, it is important to conduct a full assessment including carefully reviewing concomitant medications for potential drug-drug interactions, and documenting patient consent in their chart. All five medications are eligible for full coverage through PharmaCare drug benefits Plan C, Plan W and Fair PharmaCare. None are covered by Plan G for treatment of alcohol withdrawal.
As comparative safety and efficacy of off-label pharmacotherapies has not been fully established in adolescent, pregnant, older adult, or more complex patient populations (e.g., concurrent medical conditions, co-occurring mental health and substance use disorders), prescribing these medications in these cases would be at the clinician's discretion following a careful assessment of risks, benefits, drug-drug interactions and contraindications (particularly for pregnant individuals). Clinicians are encouraged to call the Rapid Access to Consultative Expertise (RACE) line to speak with an addiction medicine specialist for additional information and case-specific guidance:
Vancouver Area: 604-696-2131 Toll Free: 1-877-696-2131 Hours of operation are Monday to Friday, 0800-1700 www.raceconnect.ca Contraindications, cautions, and side effects have been abstracted from clinical trials and supplemented with data from Health Canada-approved product monographs for specific clinical indications. For medications prescribed off-label, duration and dosages differ from those used for indicated conditions (e.g., seizure disorders, hypertension). Clinicians must be aware of these differences when prescribing off-label medications for alcohol withdrawal. • The most common side effects of benzodiazepines are drowsiness and dizziness.
• Less common side effects include changes in skin colour, nausea, headache, blurred vision, tremors, hypotension, GI disturbances, and memory loss.
# Coverage
Benzodiazepines are eligible for full coverage under Fair PharmaCare, and PharmaCare Plans C and W.
# Concurrent Alcohol Use
Benzodiazepines potentiate the effects of alcohol; concurrent alcohol use can result in serious safety risks including oversedation, falls, delirium, respiratory depression (e.g., non-fatal or fatal overdose), and need for prolonged hospitalization.
# Safety Considerations
• If benzodiazepines are selected for outpatient withdrawal management, consider a fixed dosing schedule to limit risks. Benzodiazepines should be discontinued after withdrawal symptoms have resolved (typically 5-7 days).
• All patients and families should be aware of the risk of dependence and tolerance, and receive education on safe use, the signs of an overdose, and emergency contact information.
• Where appropriate, consider the following strategies to reduce risk: daily dispensing from a pharmacy, involving family members or caregivers to administer medication and monitor patient response, frequent follow-up visits, or daily check-ins by phone.
# Sample Dosing
Protocol 207,212 Example four-day fixed and flexible protocols for diazepam (Valium) • Carbamazepine use has been associated with rare blood dyscrasias and Stevens Johnson Syndrome, which usually develops within the first few months of taking this medication.
SCHEDULE
• Since the onset of potentially serious blood dyscrasias may be rapid, patients should be informed of early toxic signs of a potential hematological problem.
• Patients should be advised to immediately consult their physician if they experience reactions such as fever, sore throat, rash, ulcers in the mouth, easy bruising, or if petechial or purpuric hemorrhage appear.
• Patients of Asian ethnicity are at increased risk of carbamazepine toxicity due to higher prevalence of the HLA-B*1502 allele. Genetic testing to exclude those at high-risk must be performed before prescribing to this patient population. Consultation with a pharmacist is recommended.
Side Effects 237
• The most commonly reported side effects are dizziness, pruritus, ataxia, headache, drowsiness, nausea.
• Side effects are often minor and temporary, but can occur in up to 18% of patients.
# Coverage
Carbamazepine is eligible for full coverage under Fair PharmaCare, and PharmaCare Plans C and W.
# Concurrent Alcohol Use
No safety risk if used concurrently with alcohol.
# Safety
Considerations 237,244,245 • Conduct a critical risk-benefit appraisal when considering carbamazepine in patients with a history of cardiac, hepatic or renal damage, adverse hematological reactions to other drugs, or previously interrupted treatments with carbamazepine. A comprehensive clinical assessment including appropriate laboratory investigations should be conducted prior to treatment initiation.
• A CBC including platelets and possibly reticulocytes and serum iron should be requested to ensure healthy bone marrow function prior to prescribing carbamazepine. If low platelet counts are observed, the patient should be monitored closely.
• Patients should also be aware of symptoms of dermatological or hepatic reactions. In addition to baseline testing, hepatic function in elderly patients and patients with a history of liver disease must be monitored in the course of treatment.
• Prescribers should review carbamazepine's drug-drug interactions with a pharmacist or other source when considering this medication for alcohol withdrawal management.
# Sample Dosing
# Gabapentin
Contraindications 244,258 Hypersensitivity to gabapentin
# Cautions 258
Renal impairment -Gabapentin is eliminated solely by renal excretion. Dosage adjustments are recommended for patients with renal impairment (including elderly patients with declining renal function) and patients undergoing hemodialysis.
# Side Effects 258
The most common side effects are ataxia, slurred speech, and drowsiness.
# Coverage
Gabapentin is eligible for full coverage under Fair PharmaCare, and PharmaCare Plans C and W.
# Concurrent
Alcohol Use 258,261 A higher-than-therapeutic dose and concurrent alcohol or opioid use increases the risk of respiratory depression, profound sedation, syncope, and death. Patients who continue to use alcohol or other CNS depressants should be observed closely for signs and symptoms of CNS depression, and the dose of gabapentin may need to be adjusted accordingly.
Note: Studies suggest concomitant use of alcohol and gabapentin at therapeutic doses does not increase sedation or motor impairment.
# Safety Considerations 258
• Patients with compromised respiratory function, respiratory or neurological disease, renal impairment and the elderly are at higher risk of experiencing severe adverse effects on the CNS including sedation, somnolence, loss of consciousness as well as serious cases of respiratory depression.
• Gabapentin is eliminated primarily by renal excretion; dosage adjustment may be required in elderly patients and patients with renal impairment.
• Prescribers should review gabapentin's drug-drug interactions when considering this medication for alcohol withdrawal management.
# Sample Dosing Protocol 261
Note: This protocol applies to immediate-release (IR) tablets.
• Start with 300 mg TID + additional 300 mg PRN + 600 mg to 1200 mg HS.
• Titrate quickly to 600 mg TID + 600 mg to 1200 mg HS as tolerated.
• If symptoms persist, an additional 300 mg TID PRN + 600 mg to 1200 mg HS PRN can be prescribed. do not exceed daily dose of 3600 mg. • On resolution of acute withdrawal symptoms, taper to 600 mg TID + 600 mg to 900 mg HS.
• Taper to zero over next 3-5 days, decreasing dose by 600 mg daily.
Abbreviations: TID -three times per day, PRN -as needed/when necessary, HS -at bedtime. Clinical Tip: To determine whether any additional gabapentin is needed for treatment of breakthrough withdrawal symptoms, the patient can be instructed to use the Short Alcohol Withdrawal Scale (SAWS) to determine PRN dosing (see Box 14). Regardless of whether the patient is at 300mg or 600mg TID regular, additional doses of gabapentin 300mg TID PRN can be taken if SAWS scores are ≥12 and/or the patient is experiencing craving, insomnia, or irritability.
# Clonidine (adjunct treatment)
Contraindications 244,259 1. Sinus node function impairment 2. Severe bradyarrhythmia 3. Galactose intolerance
# Cautions 259
May cause hypotension in patients with a history of low blood pressure.
# Side Effects 259
The most common side effects include hypotension, dry mouth, dizziness, fatigue, headache, nausea, vomiting, constipation, malaise, sleep disorder, sedation, and erectile dysfunction.
# Coverage
Clonidine is eligible for full coverage under Fair PharmaCare, and PharmaCare Plans C and W.
# Concurrent Alcohol Use 259
Clonidine and alcohol can have additive effects in lowering blood pressure. If consumed together, patients may experience headache, dizziness, light-headedness, fainting, and/or changes in pulse or heart rate.
# Safety
Considerations 256,259
• As a standalone treatment, clonidine should only be used for treating mild-moderate withdrawal symptoms in patients at low risk of severe complications. Clonidine is more often prescribed as an adjunct treatment.
• Safe to use with benzodiazepines or other anticonvulsants (gabapentin, carbamazepine, valproic acid) as an adjunct treatment for alcohol withdrawal.
• Patients and families should receive education on the signs and symptoms of hypotension.
# Sample Dosing
Protocol 254,256 • Starting dose is 0.1 mg to 0.2 mg BID.
• To ensure blood pressure control during sleep, it is recommended that the last dose of the day be taken immediately before retiring.
• Daily dose can be increased in increments of 0.2 mg according to patient response and tolerance.
• Final dosage of clonidine ranges from 0.1mg to 0.6 mg BID.
Abbreviations: BID -two times per day.
# Concurrent Alcohol Use
Safe to start while patients are using alcohol, but may be more effective and side effects minimized if started following completion of withdrawal management. 178,179 Safe to start while patients are using alcohol, but may be more effective if started following completion of withdrawal management. 177,178 Safety and Other Considerations
• Liver function tests (LFT) should be assessed at treatment initiation, and again at 1, 3, and 6 months. If LFTs are elevated at baseline, more frequent monitoring is indicated.
• Patients should be advised of the risk of hepatic injury and to stop use of medication if they experience symptoms of acute hepatitis (fatigue, anorexia, nausea, and vomiting).
• No dose adjustment is required for patients with mild renal impairment (creatinine clearance 50-80 mL/min).
• Dose reduction is required for patients with moderate renal impairment (creatinine clearance 30-50 mL/min). 31
• No known hepatic toxicities. • Side effects are most often CNS-related, and may include psychomotor slowing, difficulty concentrating, speech/language problems, somnolence, fatigue, and mood disturbance (irritability, depression).
• Most are mild to moderate in severity, and occur early in therapy.
• Starting at a low dose with slow titration up to a stable dose over a period of several weeks is recommended to avoid or reduce severity of side effects (see below).
# Coverage
Topiramate is eligible for full coverage under Fair PharmaCare, and PharmaCare Plans C and W.
# Concurrent Alcohol Use
Safe to start while patients are using alcohol; has been studied for indication of reducing alcohol consumption in non-abstinent individuals.
# Safety and Other Considerations
• Due to risk of fetal harm, women of reproductive age should be advised to use an effective contraceptive.
• Safe to prescribe to patients with liver disease.
• Patients should be monitored for signs of hyperammonemia (unexplained vomiting, lethargy, confusion, changes in mental status, hyperthermia) and metabolic acidosis (hyperventilation, fatigue, anorexia, cardiac arrhythmias, stupor).
# Sample Dosing
Protocol 316,317,320,322 Topiramate is generally well tolerated, but some individuals do experience significant side effects, particularly at higher doses or with more rapid increases in dosage. A gradual dose titration over several weeks is strongly recommended (e.g., ~4-8 weeks to full dose). Topiramate does not interact with alcohol and can be initiated while a patient is still drinking.
The recommended initial target dose for topiramate monotherapy in adults is 100mg/day, administered in two divided doses, as needed and tolerated.
Week If doses above 100mg/day are required, the dosage may be increased at weekly intervals in increments of 50mg up to a maximum of 400mg/day. Dose and titration rate should be guided by side effects and clinical outcome. Some patients may benefit from a slower titration schedule or smaller increments in dose. Daily doses above 400mg have not been adequately studied.
• Gabapentin is eliminated primarily by renal excretion; dosage adjustment may be required in elderly patients and patients with renal impairment.
• Prescribers should review gabapentin's drug-drug interactions when considering this medication as treatment for AUD.
• Care should be taken when prescribing to the elderly, those with renal impairment, or those with cognitive impairment. In these populations, close follow-up must be ensured. Do not prescribe to actively delirious patients.
# Sample Dosing
Protocol 261,328 • Start gabapentin at a dose of 100 mg to 300 mg TID.
• If the patient continues to experience anxiety or cravings, TID doses can be increased up to a suggested maximum daily dose of 1800 mg.
• If patient continues to experience insomnia, a higher HS dose may be warranted.
Note: This protocol applies to immediate-release (IR) tablets.
# Side Effects
• In the absence of alcohol, most common side effects are drowsiness, skin eruptions (acne, dermatitis), fatigue, erectile dysfunction, headache, and a metallic or garlic-like aftertaste.
• A less common but serious side effect is hepatic toxicity (cholestatic or fulminant hepatitis, hepatic failure resulting in transplantation or death), which has been reported in patients taking disulfiram with and without prior history of abnormal liver function.
# Coverage
Disulfiram is eligible for full coverage under Fair PharmaCare, and PharmaCare Plans C, G and W.
Note: This medication is no longer commercially sold and must be compounded at a community pharmacy. Prescribers should contact the patient's pharmacy in advance to ensure that it is available or can be accessed.
# Concurrent
Alcohol Use 284,352 Due to severity of disulfiram-alcohol reaction, patients must not consume alcohol while taking disulfiram.
# Safety and Other Considerations
• Clinicians should obtain full informed consent of patient before prescribing disulfiram. Patients and families must receive education on side effects and risks associated with the disulfiramalcohol reaction.
• Disulfiram should never be administered to a patient until they have abstained from using alcohol for at least 12 hours.
• The disulfiram-alcohol reaction can present as an emergency situation. It is recommended that patients carry an identification card on their person listing symptoms of disulfiram-alcohol reaction and their clinician's contact information in the event of emergencies.
• Due to risk of hepatotoxicity, it is recommended to perform baseline and follow-up liver function tests and to monitor CBC and blood chemistries. Patients and families should be advised to immediately report early signs or symptoms of hepatitis.
# Sample Dosing Protocol
• 250 mg per day, administered as a single daily dose in morning or evening.
• Patients experiencing daytime sedation can be instructed to take their dose in the evenings.
If sedation persists, dose can be reduced to 125 mg.
• Patients who can still drink alcohol without experiencing a disulfiram-alcohol reaction despite good adherence (very rare) can be increased to 500 mg daily.
• Do not exceed a daily dose of 500 mg.
# Appendix 5 Motivational Interviewing
It is strongly recommended that providers complete Motivational Interviewing (MI) training to maximize the effectiveness of this intervention. This appendix provides a brief overview of MI principles and guidance on using this intervention with patients who have AUD. MI training programs and continuing education courses are listed in the Resources section.
# Principles of Motivational Interviewing
MI is a conversational person-centered counseling method that seeks to empower patients to examine and address feelings of ambivalence that may impact their motivation to change. This intervention is based on the recognition that when clinicians issue directives or otherwise exert pressure (whether real or perceived) on patients to change their behaviour, this often results in pushback or resistance. By following the overarching principles of MI listed below, 144,592 clinicians can empower patients to define and pursue well-being in their own way.
• Partnership: The MI counsellor s joins the patient as a collaborator, not an authority, to understand the patient's individual obstacles to change and to work together to overcome them.
• Acceptance: In conversation, the MI counsellor consistently acknowledges and affirms the patient's inherent worth, potential, and autonomy. This allows the MI counsellor to approach the patient with "accurate empathy" -an active, non-judgmental interest in the patient perspective, which is the key to collaborative progress towards well-being.
• Compassion: The MI counsellor's ultimate concern is the patient's safety and wellbeing, and understanding what that means from the patient's perspective.
• Evocation: Rather than imposing a set of goals and values on the patient, the MI counsellor evokes from the patient what their goals are and how they prefer to receive help and support.
# Task 1 Active Listening
Active listening strategies can help build a productive partnership with the patient. The strategies of active listening are often referred to by the mnemonic "OARS", which stands for Open questions, Affirmations, Reflective listening, and providing Summaries. 592 Open questions: The goal of asking open questions is to support the patient to say more. The MI counsellor's goal is for the patient to speak for at least half of the total session time. Open questions invite the patient to explore their feelings about, motivations for, and barriers to change. Provide Summaries: Summaries are a specific form reflective listening that punctuate the session and recognize key concerns in the conversation. These are particularly useful in transition points -after the patient has spoken about a particular topic, has recounted a personal experience, or when the session is nearing an end. Summaries can provide a stepping-stone towards change by distilling the productive aspects of the conversation. Like reflections, summaries are concise and strategically constructed to recognize problems, concerns, and desire to change. End summaries with an invitation to correct or complete a thought:
"Did I miss anything? "Is that accurate? Anything you want to add or correct?"
# Task 2 Eliciting Change Talk
Active listening may enable the patient to recognize and voice their own desire and potential for change. 592,593 Through reflective and evocative questions, the MI counsellor can elicit and support productive thinking that reflects statements the patient makes about the need, willingness, or ability to make healthy behavioural changes. 592,593 Methods for Evoking Change Talk 593
• Using the "importance ruler": "How important would you say it is for you to…?
• " On a scale of zero to ten, where zero is not at all important and ten is extremely important, where would you say you are?" This scale can also be used to gauge confidence to change.
# Preparation
• Desire to change: "I want to get better, "; "I wish I were more comfortable around people. "
• Ability to change: "I've been able to stop at times in the past, "; "I can do this. "
• Reasons for change: "I would sleep better, "; "I will feel healthier."
• Need to change: "I can't stand living like this anymore, "; "This is worse than I thought. "
# Active Change
• Commitment: "I am going to get help for this problem, "; • Actions: "I have talked to my boss about needing time off to get help, "; and • Taking steps: "I have started cutting back on my alcohol use to make it easier later to stop. "
# Task 3 Collaborative planning
Once the MI counsellor establishes through OARS that they have understood the patient's concerns and current "state of change" (i.e. through noting signifiers of preparation for change or active change), they may offer feedback and share information based on MI counsellor's experience and expertise as requested by the patient. 592 Offering advice is always preceded by asking the patient's permission, as well as inviting them to give their ideas and thoughts first.
In the course of MI, increased change talk and signs of increased motivation signal an opportunity to bridge towards planning for change. Strategic questions may prompt the patient to ask for advice; unsolicited advice should never be imposed on the patient.
The core principles of active listening (OARS) apply to the all the stages of MI, including planning. The MI counsellor should move at the patient's pace and "roll with resistance". In response to the patient's increased motivation for change, the MI counsellor can pose more specific and goal-oriented open questions, providing reflections and affirmation to acknowledge and mobilize motivation into planned action.
Government to these groups, and excludes those who are not formally recognized by the Government of Canada.
In the section below, it is used to specify that health data being reported is specific to people who are registered under the Indian Act, R.S.C. 1985. The most recent Canadian data show that a greater proportion of Aboriginal Peoples aged 12 and over are abstinent from alcohol (27.4%) than non-Aboriginal Canadians (24.6%). 595 However, the prevalence of heavy drinking, AUD, and alcohol-related harms among Aboriginal Peoples who do drink alcohol is significantly higher than in non-Aboriginal Canadians. 595 For example, 25.1% of First Nations peoples reported heavy drinking v in the past month, compared to 19.6% of non-Aboriginal Canadians. 595 Nationally, the rate of alcohol-related mortality is estimated to be 5.43 times higher in First Nations men and 10.11 times higher in First Nations women compared to non-Aboriginal populations. 65 Similarly, in BC, the age-standardized mortality rate (ASMR) for alcohol-related deaths among registered Status Indians in BC was approximately 5 times higher than the alcoholrelated ASMR for other BC residents from 1993 to 2006. 596 These statistics must be interpreted within a broader social framework that acknowledges the historical and ongoing impacts of colonization, institutionalized racism, direct and intergenerational trauma on the social determinants of health among the Indigenous Peoples of Canada. The health and social inequities faced by Indigenous Peoples have created conditions where some individuals use alcohol and other substances to cope with racism, discrimination, poverty, trauma, violence, or other sources of distress in their daily lives. 69,70 Recent research has highlighted the important role of culturally safe and informed approaches to reduce disparities in substance use care for Indigenous populations. 56,597 This guideline strongly recommends that all health care professionals and staff undertake Indigenous cultural safety and cultural humility training to improve their ability to establish safe, positive partnerships with Indigenous patients and families (see Cultural Safety). A human rights-based approach is also essential due to Canada's history of discriminatory, unethical, and harmful treatment of Indigenous Peoples in the mainstream health care system. 72 In addition to incorporating Indigenous cultural safety and cultural humility in standard medical practice, several principles of providing ethical care to Indigenous Peoples have been identified in the literature: 598 • Respecting the individual and their authority over their own health and healing journey;
• Practising conscious communication, active listening, and paying close attention to how a person responds to questions and conversation, both in their speech and body language, to ensure patient comfort and safety;
v Statistics Canada: heavy drinking is defined as five or more drinks on a single occasion at least once a month.
• Using interpreters if fluency in English or French is a barrier to communication;
• Involving family members in decision-making and as key sources of support, and respecting an individual's definition of family, which can include many extended relations;
• Recognizing that some individuals may prefer alternative methods for communicating and receiving information about their health -the practice of "offering truth" 599 and honouring a patient's decision on the type of information they wish to receive and how they wish to receive it may be helpful in this context;
• Practising non-interference in a patient's decision-making, unless there has been a clear misunderstanding -strong advice or persuasive language from a person in a position of power (i.e., clinician to patient) can be interpreted as coercive; and
• Respecting Indigenous Peoples have the inherent and recognized right to access cultural practices as part of their health care.
Clinicians should inquire about their patients' use of traditional medicines and cultural practices, and accommodate these needs as part of culturally safe approach to wellness and substance use care. The value of using the teachings of Mi'kmaq Elder Albert Marshall's "Two-Eyed Seeing" approach, which respects and integrates the strengths of both Indigenous knowledge and Western medicine, 600 has been increasingly recognized in holistic wellness and substance use care for Indigenous Peoples. 601 A diverse range of substance use programs that combine regionally-tailored cultural interventions (e.g., participating in sociocultural learning -traditional languages, art, story-telling, teachings; sweat lodges, smudging, and ceremonial practices; land-based activities and healing; access to Elders and Knowledge Keepers) with Western medicine have been described in the literature. 601 Although individual cultural interventions vary depending on place and the Indigenous groups who developed and practice them, culturally-based substance use programs that provide a connection to and enhance cultural identity are shown to improve wellness of Indigenous clients. 601 The Society of Obstetricians and Gynaecologists of Canada's (SOGC) Consensus Guideline for Health Professionals Working With First Nations, Inuit, and Métis 602 may be a useful clinical resource. While this guideline does include specific guidance on sexual and reproductive health care for Indigenous Peoples, the majority of recommendations are relevant and applicable to general clinical practice and the Canadian health care system at large. Clinicians who provide care to Indigenous Peoples should be familiar with the First Nations Benefit Program (Plan W) and the Non-Insured Health Benefits program, including eligibility and coverage requirements, and the exceptions and special permissions needed in some cases. w Clinicians should also be aware of regional and provincial resources available to Indigenous patients and families in BC. There are several First Nations substance use treatment centres that offer culturally-based services in BC. Detailed information for each treatment centre, including eligibility requirements, can be found on the FNHA website.
# Sex and Gender
Sex and gender are important social determinants of health and influence the physiological and psychosocial aspects of many health conditions, including substance use disorders. 604 Yet, the influence of sex and gender on alcohol use and related harms is often overlooked. 604 It is well-established that male and female bodies process alcohol differently, and many guidelines take this into account by setting lower alcohol consumption limits for women, including Canada's Low-Risk Alcohol Drinking Guidelines (see Table 3). 605 Female bodies are more vulnerable to the effects of alcohol partly due to their comparatively lower average weight, water content, and levels of enzymes that break down alcohol. 606 Additionally, the higher fat content of the female body results in slower rates of alcohol absorption and metabolism. 606 As a result, with increasing alcohol intake, the risk of developing a range of alcohol-related conditions, including stroke, diabetes, and liver disease, increases more rapidly in females compared to males. [606][607][608] Drinking behaviours and consequences are also influenced by both sex and cultural perceptions of gender. For example, substance use is more prevalent among girls than boys during early adolescence 609 and girls are more likely to use alcohol and other substances to manage negative emotions (e.g., depression). 610,611 In men (including transgender men), traditional perceptions of masculinity have been associated with the motivation to consume alcohol and corresponding alcohol-related problems. 612,613 Another consequence of gendered cultural perceptions is that young adult men are less likely than women to accept or adopt harm reduction strategies, such as limiting number of drinks, switching from alcoholic drinks to non-alcoholic alternatives, or having a designated driver. 614 Research has also revealed correlations between gender and substance use treatment access and outcomes. Intersections between gender inequality, stigma, and poverty can be barriers to accessing health care in young women with alcohol use issues. 615 Health care providers are less likely to refer women than men to outpatient or inpatient alcohol treatment programs, even though research shows there are no gender differences in treatment retention or completion rates. 616 Additionally, when they do seek care, women who use alcohol while pregnant or parenting experience disproportionately higher rates of judgment, stigma, and punitive approaches than men in similar circumstances. 617,618 The impact of sex and gender on alcohol use and related harms, including AUD, underscore the importance of sex/gender-informed and gender-inclusive care. The Centre of Excellence in Women's Health has several resources available through their Trauma Gender Substance Use Project, including a Gender-Informed Approaches to Substance Use Resource List and the New Terrain toolkit 57 to support integration of trauma-informed, genderinformed, and gender-transformative approaches in clinical practice. Clinicians and care teams should also be familiar with and offer patients the option of sex/gender-specific substance use treatment and support services in their communities, if available and as appropriate.
# 2SLGBTQ+ Populations
Lesbian, gay, bisexual, trans, Two-Spirit, queer, and other gender and sexually diverse individuals (2SLGBTQ+) face unique challenges that clinicians should be aware of and address when providing substance use care. Both adults [619][620][621] and youth 622,623 who identify as 2SLGBTQ+ report disproportionately higher rates of high-risk alcohol use and alcohol-related harms compared to individuals who do not identify as 2SLGBTQ+. 2SLGBTQ+ individuals also tend to enter treatment with a relatively higher severity of substance-related problems 617,618 and greater physical and mental health care needs 624,625 than individuals who do not identify as 2SLGBTQ+. Suggested explanations for these disproportionate rates include the stress of being in a minority group, dealing with social prejudice and discrimination, and internalized stigma. 626,627 Additionally, a lack of cultural competence within the health care system is believed to deter 2SLGBTQ+ individuals from accessing or staying engaged with medical care. 626,627 A non-judgmental attitude, active demonstration of awareness of and sensitivity to 2SLGBTQ+ issues, and a reinforcement of confidentiality can help 2SLGBTQ+ individuals feel safe accessing care. 628 Strategies for creating a welcoming care environment may include having information about 2SLGBTQ+ programs and services displayed in waiting rooms and common areas (e.g., pamphlets, posters, resource guides); ensuring clinic forms and other materials use inclusive language; using open-ended questions when asking about gender and sexuality; and establishing contacts and referral partners in the 2SLGBTQ+ community. 628 2SLGBTQ+ individuals may also have experienced discrimination in the health care system and thus require extra sensitivity from health care providers in order to build trust. 628 In British Columbia, youth under 19 years of age do not need parental consent in order to receive medical treatment, including substance use care. Capacity to consent for youth under 19 is determined based on the capacity to fully understand the treatment and possible consequences of treatment. 638 A patient under 19 seeking treatment who is determined able to understand the treatment and give consent should not require parental permission or notification. Informed consent and discussion of rationale for treatment should be documented. For more information on determining capacity to provide consent in those under 19, clinicians may refer to guidance from the Canadian Medical Protective Association 639 and the Royal College of Physicians and Surgeons of Canada. 640 Evidence-based guidance for screening, brief intervention, withdrawal management, and AUD pharmacotherapy in youth patients has been included in this guideline. Additional information, medication factsheets, and other resources for youth patients and their families can be accessed through BC Children's Hospital's Kelty Mental Health Centre: https://keltymentalhealth.ca/healthcare-professionals. Youth and families can also access information on mental health and wellbeing, substance use, youth-oriented social support and services (including online and peer support platforms), and self-management tools on the FoundryBC website: https://foundrybc. ca/get-support/.
# Pregnant Individuals x
Abbreviated evidence-based guidance for screening, brief intervention, withdrawal management, and AUD pharmacotherapy in pregnant patients has been included in this guideline. For additional clinical guidance on the management of alcohol use during pregnancy and postpartum, clinicians can refer to the Alcohol Use and Pregnancy Consensus Clinical Guidelines 4 issued by the Society of Obstetricians and Gynaecologists of Canada.
In partnership with Perinatal Services BC, the BCCSU will be releasing guidance for the Clinical Management of High-Risk Drinking and Alcohol Use Disorder in Pregnancy in the Fall of 2019, which will be available at the following link: http://www.bccsu.ca/clinical-care-guidance/.
There are no universally accepted standards for safe use of alcohol in pregnancy, and most jurisdictions, including Canada, recommend no alcohol use. 4,268 However, according to the most recent Canadian data (the Maternity Experiences Survey), 10.5% of those surveyed reported that they continued drinking alcohol (frequently or infrequently) after realizing they were pregnant. 641 This is likely an underestimation of the true prevalence of alcohol use in pregnancy, as fear of judgment and stigma can lead to significant under-reporting in this population. 4,641 Alcohol is a known teratogen (e.g., a substance that is known to cause congenital malformations or birth defects in the fetus if consumed during pregnancy). Prenatal exposure to alcohol is associated with Fetal Alcohol Spectrum Disorder (FASD), a wide range of conditions that can include growth restriction, developmental delay, neurological abnormalities, and physical health, behavioral, and cognitive issues throughout life, 4,266,268,642 and is believed to affect approximately 1% of the Canadian population. 4 Research suggests there is a dose-dependent relationship between the amount of alcohol consumed during pregnancy and severity of alcohol-related effects in the child, 643 however, the degree and type of impairment varies considerably from one individual to the next, and with timing and pattern of alcohol use. 568 In line with clinical practice guidelines from the Society of Obstetricians and Gynaecologists of Canada, 4 it is recommended that primary care clinicians and care teams advise patients and families that the safest choice is
x While the majority of pregnant individuals identify as women, this term does not reflect the identities and experience of all pregnant people. Gender-neutral language has been used in this section where possible. Respect for individual identities and use of corresponding or chosen pronouns is an important component of patient-centred care.
not to consume alcohol during pregnancy. Education, screening and assessment of alcohol use in pregnancy should be delivered in a balanced and non-judgmental manner to prevent unintended negative consequences, such as loss to care. 4,568 Research has shown that stigma and fear of judgment is a significant barrier to accessing and staying engaged in treatment among pregnant individuals who use substances. 4 The Centre of Excellence for Women's Health has several guides to support clinicians in engaging with women and their partners on alcohol use, pregnancy, and prevention of Fetal Alcohol Spectrum Disorder (FASD), including referral information, on their website: http://bccewh.bc.ca/2017/05/alcohol-and-pregnancy-brief-intervention-guides/.
Trauma-and violence-informed care is essential in the care and management of pregnant individuals with AUD.
Pregnancy can be a period of particular vulnerability for individuals who have experienced trauma. 644,645 Some women may also be at increased risk of intimate partner violence during pregnancy, particularly in the case of unintended pregnancies. [646][647][648] As emphasized above, clinicians should be familiar with the principles of traumainformed practice and as well as the signs of and strategies to address intimate partner violence in their patients. [649][650][651] Older Adults
This guideline defines "older adults" as patients aged 65 or older, although it is understood that some age-related conditions may be present in some adults who are younger than 65, and should be managed similarly.
According to the most recent Canadian data, approximately 7.8% of older adults surveyed met the criteria for heavy drinking y , 11 and 0.6% meet the criteria for an AUD. 110 However, under-reporting substance use may be more common in older adults compared to younger counterparts due to stigma and fear of judgment, as well as cognitive and memory deficits that can impact accuracy of self-report. 652,653 Thus, clinicians should approach screening of older adults with patience and sensitivity, while also being mindful of clinical signs of alcohol-related problems.
Clinicians should be aware that older adults are more vulnerable to the effects and harms of alcohol than younger counterparts. 654 In addition to lowered alcohol tolerance related to reduced activity of gastric and liver enzymes, older adults may also have multiple co-morbidities that can be exacerbated by alcohol use. 654,655 However, despite increased risks of alcohol-related harms, drinking above low-risk limits and AUD among older adults is frequently overlooked and unrecognized in primary care practice. 654 As with the general population, alcohol use screening should be always be included in routine primary care assessments in older adults.
Clinicians should also be aware of potential signs of alcohol-related problems in older adults, including worsening chronic conditions (e.g., hypertension, diabetes, osteoporosis); changes in effectiveness of prescribed medications; increased frequency of injuries (e.g., falls, fractures, burns); onset or worsening of cognitive or psychiatric disorders (e.g., confusion, anxiety, depression, insomnia, memory loss); increased social isolation or distress; and poor nutrition and hygiene. 656 Limited data suggests that AUD treatment outcomes among older adults are similar, and in some cases superior, to those observed in younger patient populations. 657 Due to a higher prevalence of comorbid medical conditions and increased susceptibility to severe complications of alcohol withdrawal, older adults may benefit from a higher intensity, more structured approach to care, such as referrals to inpatient withdrawal management, inpatient treatment programs, or intensive outpatient programs. 655 Additionally, as older patients tend to have a higher prevalence of medical conditions and/or take multiple medications for chronic disease management, impact on comorbid conditions and potential drug-drug interactions should be carefully reviewed when selecting AUD pharmacotherapies.
# Co-occurring Mental Health and Substance Use Disorders
Individuals with co-occurring mental health and substance use disorders, including AUD, typically experience more severe substance-related, psychiatric and physical health symptoms, and face higher risk of psychosocial challenges, including unemployment, poverty, food and housing insecurity, and a lack of social support. 658,659 As is emphasized in this guideline, comprehensive medical management that adequately addresses co-occurring physical and mental health disorders is essential to patient-centred care. Additionally, referrals to psychosocial supports and peer-based services in the community should be routinely offered to address social determinants of health and health inequities experienced by this population.
# Co-occurring Alcohol Use and Mental Health Disorders
The co-occurrence of substance use disorders and mental health disorders is not uncommon. Canadian data is lacking, but in the U.S., a nationally representative sample of adults reported an estimated 12-month prevalence rate of co-occurring substance use and mental health disorders of 43.3%, 660 and that over 50% of individuals with a severe psychiatric illness (e.g., schizophrenia, psychosis) were estimated to have a co-occurring substance use disorder. 471 Among individuals with AUD, the most commonly reported co-occurring mental health disorders were major depression disorder (15.6%), post-traumatic stress disorder (10.8%), specific phobia (10.6%), and generalized anxiety disorder (7.1%). 661 Differential diagnosis and treatment of co-occurring disorders can be challenging due to the significant overlap in the symptoms of mental health and substance use disorders, particularly in the early stages of treatment for substance use disorders. For example, untreated anxiety and depression may lead to the development of AUD if individuals use alcohol over an extended time period to relieve their symptoms. 658,659 Conversely, anxiety and depression can also be symptoms of alcohol withdrawal and AUD. 658,662 Thus, assessment of co-occurring disorders should involve consideration of a patient's history, including family history of substance use and mental health disorders, as well as the sequence and timelines of the development of symptoms in order to accurately identify the pre-existing disorder(s). [658][659][660] Following the diagnosis of AUD, and as part of standard care, individuals should be screened for common co-occurring mental health disorders followed by careful assessment to determine if specific symptoms (e.g., anxiety, depression, insomnia) are independent or alcohol-related diagnoses. 658,663 It is preferable to initiate treatment for AUD before starting pharmacotherapy for depression or anxiety disorders, as antidepressant and anxiolytic medications may be ineffective while a patient is still using alcohol. 658,[664][665][666] Additionally, several medication classes that are commonly prescribed off-label for chronic anxiety and insomnia, including benzodiazepines and benzodiazepine-like medications, should be avoided in patients with AUD due to increased risk of injury or overdose if consumed concurrently with alcohol. [667][668][669][670][671] Mental health symptoms should be regularly reassessed during initial stages of treatment, as research has shown that AUD treatment can lead to a significant reduction in alcohol-related depression and anxiety symptoms after 2-4 weeks. 663,672,673 Persistent mental health symptoms would warrant further investigation and treatment. Clinicians should also be aware of and accommodate any potential cognitive and functional impairments related to diagnosis of a co-occurring mental health disorder. 660 Depending on the complexity and severity of co-occurring physical, psychiatric, and alcohol-related symptoms, patients with co-occurring disorders may benefit from a higher intensity or more structured approach to care, such as referrals to inpatient withdrawal management, inpatient treatment programs, or intensive outpatient programs, or to specialist-led psychosocial treatment interventions in the community. 514,516,518,521,527 The integration of peer-based support and outreach services (staffed by individuals who have lived experience with co-occurring disorders, treatment, and recovery) within primary care clinics or referral to such services in the community may also be beneficial for this population. [674][675][676] Co-occurring Substance Use Disorders
Individuals with AUD and one or more co-occurring substance use disorders report higher levels of alcohol consumption (i.e., number of drinking days per week, amount of alcohol consumed per drinking day), and exceed low-risk drinking guidelines more often than individuals with AUD alone. 677 Reported prevalence rates for co-occurring AUD and other substance use disorders vary in the literature, depending on the source and population studied. Nationally representative U.S. studies have reported that between 15% and 25% individuals with an AUD also met diagnostic criteria for another substance use disorder (tobacco, opioids, cocaine and other illicit drug(s)) in the past year. [677][678][679] Conversely, a study of 2000 treatmentseeking primary care patients found that nearly 75% of those with an AUD also met the criteria for one or more co-occurring substance use disorders. 680 Although prevalence rates do vary, it is clear that individuals with co-occurring substance use disorders represent a significant population requiring AUD care.
All individuals with high-risk drinking or AUD should be screened for co-occurring substance use. For those individuals who screen positive, co-occurring substance use disorders should be treated concurrently, when possible, with the severity of each disorder guiding treatment decisions. If concurrent treatment is not possible, patient safety should be prioritized and treatment should be triaged in order of the substance use disorder that carries the highest risk of immediate harm to that individual. Specific guidance for commonly co-occurring substance use disorders is provided below.
# Alcohol and Tobacco Use Disorder
Tobacco use disorder is the most commonly reported co-occurring substance use disorder in people with AUD. 681 Nationally representative U.S. data indicates that between 44% and 51% of individuals who met criteria for an AUD in the past year were also current smokers. 682,683 Current smoking is associated with increased alcohol consumption, days per month of alcohol consumption, severity of AUD, and severity of alcohol withdrawal symptoms in individuals with AUD. 684,685 Individuals with co-occurring alcohol and tobacco use disorders are also more likely to be heavy smokers, initiate smoking at a younger age, and experience more difficulty quitting smoking than individuals with tobacco use disorder alone. 681,686 In addition, individuals with co-occurring alcohol and tobacco use disorders are more likely to experience negative health consequences, including cognitive impairment and increased risk of cirrhosis, pancreatitis, cardiovascular disease, and some cancers including head and neck cancers. [687][688][689][690] Finally, a number of studies have reported that continued smoking is associated with a greater likelihood of relapse to AUD, while tobacco cessation is associated with improved outcomes for individuals engaged in AUD treatment. 686,[691][692][693] For the reasons cited above, concurrent or successive tobacco cessation treatment should be prioritized in individuals with co-occurring alcohol and tobacco use disorders. 694 Although commonly undertreated in addiction treatment programs, 695,696 research has found that between 44% to 80% of individuals with co-occurring tobacco and other substance use disorders report an interest in tobacco cessation interventions and motivation to quit smoking. 686,697,698 Further, the addition of tobacco cessation interventions does not appear to negatively impact alcohol-or drug-related treatment outcomes in individuals with co-occurring substance use disorders, 694 and, in some cases, has been associated with improvements. A 2016 systematic review found a consistent association between tobacco cessation interventions -both pharmacotherapy and combined counselling and pharmacotherapy -and tobacco abstinence, with no evidence of negative effects on abstinence from alcohol and other drugs. 699 First-line pharmacotherapies for tobacco cessation -bupropion and varenicline -can be safely prescribed in combination with first-line AUD pharmacotherapies. A 2015 review identified combination therapy with varenicline and naltrexone as the most effective option for reducing both alcohol and tobacco use in individuals with co-occurrence of these substance use disorders. 700 Research is also underway to evaluate several combined alcohol and tobacco use disorder interventions in primary care. 701,702 Alcohol and Opioid Use Disorder Concurrent use of opioids and alcohol is associated with an increased risk of respiratory depression, overdose, and death. 703,704 Approximately one-third of individuals prescribed opioid agonist treatment (OAT) for the management of an opioid use disorder (OUD) also meet the criteria for high-risk drinking or an AUD. [705][706][707][708] Although alcohol use is a known risk factor for fatal overdose among individuals prescribed opioids, [709][710][711] and associated with suboptimal adherence to OAT, 712,713 there is limited guidance on effective management strategies for this patient population. 714 One European guideline exists for addressing problem alcohol use among people who use drugs, including individuals with OUD, in primary care settings. 715 For individuals on OAT who meet criteria for high-risk drinking but do not have an AUD, physician or nursedelivered brief intervention has been found to reduce alcohol consumption in RCTs 716,717 and non-randomized studies. [718][719][720] Motivational interviewing may also be effective for reducing high-risk drinking in patients prescribed OAT. 437,721 Though not specific to individuals on OAT, the lack of high-quality research in this area was noted in a 2018 meta-analysis of psychosocial interventions to reduce alcohol consumption among people who use illicit drugs (primarily opioids and stimulants). 722 Due to methodological differences between studies (7 RCTs, n=825), the review authors could only perform a limited number of aggregate analyses, and as a result, no clear recommendations could be made for or against the use of psychosocial interventions for concurrent high-risk use of alcohol and other substances. 722 For patients diagnosed with co-occurring AUD and OUD, AUD pharmacotherapy should be offered with consideration of drug-drug interactions with OAT, as applicable. More specifically, naltrexone is an opioid antagonist and is contraindicated in patients prescribed OAT, thus, acamprosate should be considered as first-line for treating co-occurring AUD in this patient population. 300 Individuals with both AUD and OUD (not taking OAT) may also benefit from extended-release naltrexone, as there is evidence that it is effective for both conditions. 311,314 However, extended-release naltrexone is not an approved drug in Canada, and is currently available only through Health Canada's Special Access Programme. Buprenorphine/naloxone, a partial opioid agonist, may also be a preferred OAT medication in this patient population due to its superior safety profile compared to methadone (e.g., lower risk of respiratory depression and overdose, alone or in combination with alcohol), 723 and preliminary evidence showing that high-dose (32mg/day) buprenorphine reduced both alcohol use and craving compared to low-dose buprenorphine and to methadone in individuals with co-occurring alcohol and opioid use disorders. 724 Although gabapentin has a growing evidence base supporting its use for withdrawal management and relapse prevention for AUD, 261 there are specific concerns for individuals with OUD. This includes the possibility of high doses of gabapentin being used with opioids to potentiate euphoric effects, as well as the additive effects on respiratory suppression, which can increase risk of overdose. 349 If these medications are co-prescribed, clinicians should be aware of these risks and monitor patients appropriately. Topiramate has not been well studied for treatment of AUD in patients with co-occurring OUD, but has been studied for treatment of co-occurring stimulant and opioid use disorders.
# Alcohol and Benzodiazepine Use Disorder
Concurrent use of benzodiazepine receptor agonists (BZRAs; i.e., benzodiazepines and "z-drugs") and alcohol is associated with increased risk of respiratory depression, overdose, and death. 667,668,725 Although Canadian data is lacking, European and U.S. data indicate that 19-41% of individuals seeking or receiving treatment for AUD also report non-medical BZRA use, including DSM-5 sedative, hypnotic, or anxiolytic use disorder (hereafter referred to as "sedative use disorder). [726][727][728][729] There is a lack of evidence-based clinical guidance for the management of co-occurring AUD and sedative use disorder. In the absence of a clear approach, and in context of the known risks and harms of combining BZRAs and alcohol, it is recommended that each substance use disorder be treated individually and concurrently. For sedative use disorder, providing patients with evidence-based information on the benefits and risks of BZRA use, alone and in combination with alcohol, can significantly improve patients' chances of successfully reducing or discontinuing their use. 730 A gradual and stepped dose reduction or taper should be initiated for individuals who have been using BZRAs for more than four weeks (whether prescribed or non-medically) and/or those who meet criteria for a sedative use disorder. 731 In the majority of cases, a BZRA taper can be initiated and monitored safely and effectively in an outpatient primary care setting. 731 Additional guidance on tapering BZRAs in primary care is available from the College of Family Physicians of Canada. 732
# Acknowledgements
# Arrange
Schedule follow-up visits at the end of a screening and brief intervention session. In follow-up visits, document alcohol use and assess if patient has been able to meet and sustain planned goals.
If patient has met planned intervention goal:
• Congratulate, reinforce, and support continued change.
• Coordinate care with referral partners if the patient has accessed additional support. Communicate with external/community agencies on patient's progress.
• Assess and address any co-occurring medical conditions and mental health symptoms (e.g., insomnia, depression, anxiety) noting that these may improve with reduction in alcohol use.
• Set new goals and schedule follow-up appointments.
If patient has been unable to meet planned intervention goal:
• Acknowledge that change is difficult.
• Relate drinking to problems a patient may be experiencing (e.g., health, psychological, social) as appropriate.
• If the following measures are not already being taken, consider:
• Referring patient to external or community-based resources (e.g., peer support groups).
• Recommending the involvement of family (if appropriate).
• Offering pharmacotherapy to patients with AUD.
• Reassessing or adjusting current treatment.
• Continue to assess and address any co-occurring medical conditions and mental health symptoms (e.g., insomnia, depression, anxiety). Note: Pharmacological management of depression and anxiety is less effective while the patient continues to use alcohol.
• Schedule follow up appointments.
# Additional Resources
The Public Health Agency of Canada hosts a video series on brief interventions to support behavioural change, including safer alcohol use, using the 5As and the 5Rs (Relevance, Risks, Rewards, Roadblocks, Repetition) models. Available at: https://www.canada.ca/en/public-health/services/chronic-diseases/videos-on-supporting-behaviour-change.html.
# Concurrent Alcohol Use 260
No significant safety risk if taken concurrently with alcohol.
# Safety Considerations 260
• Due to limited evidence of efficacy, valproic acid should be considered only when all other withdrawal pharmacotherapy options are contraindicated.
• Extreme caution should be exercised when considering valproic acid for pregnant patients or individuals with childbearing capacity due to the risk of dose-dependent teratogenic effects such as spina bifida.
• Conservative dosing is recommended for older adults (≥ 65 years of age.)
• Prescribers should review valproic acid's drug-drug interactions when considering this medication for alcohol withdrawal management.
# Sample Dosing
Protocol 590,591 If CIWA <10 prior to treatment :
• Start at 250 mg TID for 5 days • If withdrawal symptoms persist, titrate to 500 mg TID for days 1-3
• Once stabilized, then 250 mg TID for days 4-5
• Discontinue medication on day 6
If CIWA ≥ 10 prior to treatment :
• Start at 500 mg TID for days 1-3 • Reduce to 250 mg TID for days 4-5
• Discontinue medication on day 6
Note : Published dosing protocols for valproic acid use symptom-triggered schedules based on CIWA-Ar score (see Box 13).
Abbreviations: TID -three times per day.
# Appendix 4 AUD Pharmacotherapy
This guideline recommends naltrexone and acamprosate as first-line pharmacotherapies for AUD. In addition to other individual factors, selection between these medications depend on patient's treatment and recovery goals. Naltrexone is recommended for patients with a goal of abstinence or reduced drinking, and acamprosate is recommended for patients who have a goal of abstinence (see Figure 3). This appendix provides dosing instructions and practical considerations to facilitate treatment selection and administration.
This appendix also offers information to support selection of alternative pharmacotherapies -topiramate, gabapentin, and disulfiram -if first-line medications are contraindicated, not effective or not preferred (see Figure 3). With the exception of disulfiram, which is a Health-Canada approved medication for AUD, use of these alternative medications would be considered "off-label". As with any medication that is being prescribed off-label, it is important to conduct a full assessment including carefully reviewing concomitant medications for potential drug-drug interactions, and documenting patient consent in their chart.
In the event that a baseline assessment has not been performed previously (i.e., if patient is initiating pharmacotherapy while actively drinking and/or without first completing withdrawal management), the Baseline Assessment and Preparation section of Appendix 3 should be followed.
All five medications reviewed in this appendix are eligible for full coverage through PharmaCare drug benefits Plan C, Plan W and Fair PharmaCare. Naltrexone, acamprosate, and disulfiram are also covered by Plan G.
As comparative safety and efficacy of AUD pharmacotherapies has not been fully established in adolescent, pregnant, older adult, or more complex patient populations (e.g., concurrent medical conditions, co-occurring mental health and substance use disorders), prescribing these medications in these cases would be at the clinician's discretion following a careful assessment of risks, benefits, drug-drug interactions and contraindications. Clinicians are encouraged to call the Rapid Access to Consultative Expertise (RACE) line to speak with an addiction medicine specialist for additional information and case-specific guidance:
# Supplement : Working with Specific Patient Populations
The recommendations in this guideline should be considered applicable and relevant to the general adult and youth patient population, however, it is recognized that there are additional considerations when working with specific patient populations. This section provides some background on the prevalence of alcohol-related harms and management strategies for working with the following patient populations: Indigenous peoples, sex/gender, 2SLGBTQ+ populations, pregnant individuals, youth, older adults, and individuals with co-occurring mental health and substance use disorders. This section is not intended to provide prescriptive clinical practice guidance for management of AUD in these patient populations, but rather, to provide an overview of general considerations for establishing positive partnerships and providing patient-centred, safe and effective care. Links to online resources have been provided where available.
The specific populations described herein are not intended to be an exhaustive list of all patients impacted by alcohol, but to highlight cases where individuals and families would benefit from tailored approaches to AUD care. It is also emphasized that these are not discrete categories, and that intersectionality is an important factor to consider in treatment planning and service delivery.
Physicians and nurse practitioners in British Columbia are encouraged to call the Rapid Access to Consultative Expertise (RACE) line to speak with an addiction medicine specialist for additional information and case-specific guidance:
Vancouver Area: 604-696-2131 Toll Free: 1-877-696-2131 Hours of operation are Monday to Friday, 0800-1700 www.raceconnect.ca
# Indigenous Peoples
A Note on Terminology: The source material reviewed in this section uses several different terms to describe the Indigenous Peoples of (what is now known as) Canada, some of which are legal terms directly tied to the Canadian constitution and various acts (e.g., Section 35 of the Constitution Act, 1982; the Indian Act, R.S.C. 1985). Terms used in the original source material have been reproduced here for consistency and accuracy.
In Canada, the term Indigenous Peoples is considered to be inclusive of all the Peoples of Turtle Island t and all their descendants, and includes those that have status u or not, and those who self-identify as Indigenous. It is important to be aware of the diversity that exists between and among Indigenous Peoples in Canada, and to use language that reflects a specific peoples, community, or Nations, where possible and appropriate.
# Youth
This guideline defines adolescents as individuals aged 11-18 years, young adults as individuals aged 19-25 years, and youth as individuals aged 11-25 years (e.g., inclusive of adolescent and young adult age categories). It is noted that youth-oriented service providers in the community may use different definitions; clinicians should confirm that a patient is within the age range served by a particular program before making a referral. Further, research studies also use different definitions and age categories for youth; as such, age ranges and definitions used by study authors are reported in the evidence review.
The lack of tailored, age-appropriate approaches to and options for substance use care have consistently been cited as barriers to engaging youth in treatment. 630,631 Strategies that primary care clinicians and care teams can use to improve retention and engagement in care in youth include: emphasizing confidentiality of services, including family members in care, fostering development of longitudinal therapeutic relationships, offering pharmacotherapy when indicated, providing referrals to youth-oriented psychosocial treatment interventions and supports, and ensuring treatment is provided without a pre-determined end date. 95,264,475,[632][633][634][635] Inclusion of peer support staff or referrals to peer support services in the community may also support a youth-centered approach to care. 636,637
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# TABLE OF CONTENTS
# PURPOSE
The prompt diagnosis of a major pelvic ring injury and rapid and effective control of massive pelvic hemorrhage, as part of a general hemostatic resuscitation effort, is a key clinical priority in the successful management of the blunt trauma patient with a mechanically unstable pelvic ring injuries.
The purpose of this clinical practice guideline (CPG) is to review best evidence and generate expert consensus on recommendations for the management of hemodynamically unstable adult patients (age >16) with pelvic ring injuries in B.C.
# KEY MANAGEMENT QUESTIONS I. RESUSCITATION AND STABILIZATION
- What are key considerations in the initial assessment and management of patients with mechanically unstable pelvic ring injuries?
- When and how should REBOA (Resuscitative Endovascular Balloon Occlusion of the Aorta) be used in the acute management of major pelvic ring injuries?
# II. TEMPORARY PELVIC RING INJURY IMMOBILZATION
- How should the mechanically unstable fractured pelvis be immobilized initially?
- What considerations guide the duration of use of pelvic binders?
- What is the role of emergency department C-clamp application in the initial management of pelvic ring injuries?
# III. HEMORRHAGE CONTROL -ANGIOEMBOLIZATION
- When should angioembolization be used in the acute management of major pelvic ring injuries?
- When should selective versus non-selective angioembolization be used in acute management of blunt pelvic ring injury?
# IV. HEMORRHAGE CONTROL -PELVIC PACKING
- When should peritoneal pelvic packing be employed for major pelvic ring injuries? 9. How and by whom should pre-peritoneal pelvic packing be performed?
- Should pre-peritoneal pelvic packing be performed in a rural/remote or community setting?
# V. OPEN PELVIC RING INJURIES
- How should patients be assessed for the presence of open pelvic ring injury?
- What are the indications for fecal diversion in the management of open pelvic ring injuries?
# VI. DIAGNOSTIC IMAGING
- How should patients presenting with proven or suspected major pelvic ring injuries be diagnostically imaged?
- When and how should patients with pelvic ring fracture undergo evaluation of the urethra and the bladder?
# VII. TRANSFER TO HIGHER LEVEL OF CARE
- What are the indications and timing for higher level of care (HLOC) transfer of a trauma patient with major pelvic trauma to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries?
- What is the preferred process for inter-facility transfer of major pelvic ring injuries?
- Which patients with pelvic ring fractures can be managed in a centre with general orthopedic surgery?
- Which mechanically unstable pelvic ring injuries can be managed in a centre without orthopedic surgery?
- How should the orthopedic surgeon on-call in a community hospital be involved in the early management of the patients with pelvic ring injury?
# VIII. HOSPITAL CARE
- What are the care requirements for acceptable management of the stabilized admitted patient with a major pelvic ring injury?
# IX. DEFINITIVE SURGICAL CARE
- What is the preferred timeframe for definitive surgical fixation of major pelvic ring injury?
- How should bladder rupture (intraperitoneal and extraperitoneal) associated with major pelvic injuries be managed?
# X. TRANSFER TO LOWER LEVEL OF CARE (REPATRIATION)
- What are the indications and timing for repatriation back to a sending facility (or equivalent) of patients with major pelvic ring injury transferred to a regional centre with expertise for advanced orthopedic care?
# XI. REHABILITATION
- What is the preferred rehabilitation strategy for patients treated for major pelvic ring injury?
- When and how should patients who have undergone definitive surgical fixation of major pelvic ring injury be mobilized?
- What are the indications for in-patient rehabilitation of a patient treated for major pelvic ring injury?
# XII. FOLLOW-UP
- What is the recommended follow-up for a discharged patient with unstable pelvic ring injury?
# GUIDELINES REFERENCED
# ALGORITHM SUMMARY OF RECOMMENDATIONS
Recommendations are newly drafted by the Complex Orthopedic SAG, unless indicated otherwise.
# I. RESUSCITATION AND STABILIZATION
A. When there is suspected active bleeding from a pelvic ring injury, apply a pelvic binder in the correct position. This should be applied pre-hospital. B. Patients with suspected pelvic ring injuries with signs of hemodynamic instability should be transported directly to a regional centre with orthopedic expertise in the surgical management of complex pelvic ring injuries. If the patient is received into a hospital with general orthopedic capabilities, then resuscitation should be commenced followed by immediate transfer to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries for definitive treatment of active bleeding when advisable and feasible.
C. All patients require IV Tranexamic Acid as soon as possible and ideally within an hour of injury. In the presence of hemodynamic instability, patients should be urgently resuscitated using blood products according to Massive Transfusion Protocols. D. Patients with suspected pelvic ring injuries from high-energy trauma should have a CT scan with IV contrast of the pelvis on admission. Given the energy required to cause pelvic ring injury, other injuries should be expected and investigations should also include CT of the head and Cspine without contrast and CT of the chest and abdomen with contrast. E. All patients with blunt polytrauma undergoing damage control laparotomy should have imaging of the pelvis before surgery (X-ray or CT). All patients should have a pelvic binder in-situ during surgery and this should not be removed for a post binder pelvic X-ray until the patient is hemodynamically stable. F. Active bleeding from the pelvis in patients who do not respond to resuscitation can be managed by surgical packing of the pelvis or interventional radiology with selective embolization of active arterial bleeding vessels. Any hospital receiving trauma patients must have, based on its resources and facilities, clear protocols in place for managing patients with pelvic ring injury and hemodynamic instability. G. In a patient in extremis, where resuscitation is failing, REBOA can be a first measure to temporarily control hemorrhage in conjunction with pelvic packing as a bridge to definitive care. REBOA should only be attempted in institutions with protocols and expertise in place, and in the context of local discussions and surgeon discretion. This novel technology requires further assessment regarding efficacy and safety in the setting of pelvic ring injury with hemodynamic instability.
# II. TEMPORARY PELVIC RING INJURY IMMOBILZATION
A. To immobilize the mechanically unstable fractured pelvis, apply a pelvic binder in the correct position as initial means of immobilization. This should be applied pre-hospital. G. If angiography is performed, selective angioembolization is preferred in acute management of blunt pelvic ring injury to minimize the risk of soft tissue/organ necrosis following mass embolization.
H. Non-selective angioembolization is not desired in acute management of blunt pelvic ring injury. If selective angioembolization is not possible, preferred options include pre-peritoneal pelvic packing or REBOA in conjunction with packing (if protocols are in place and surgeon has experience in REBOA or packing).
# IV. HEMORRHAGE CONTROL -PELVIC PACKING
A. Active bleeding from the pelvis in patients who do not respond to resuscitation can be managed by surgical packing of the pelvis or interventional radiology with selective embolization of active arterial bleeding vessels. Trauma centres with orthopedic surgery (general or expertise in the surgical management of complex pelvic ring injuries) must have a clear protocol in place for managing hemodynamically unstable patients with pelvic ring injuries.
# VI. DIAGNOSTIC IMAGING
A. Patients with proven or suspected major pelvic fractures should be diagnostically imaged via an initial plain X-ray in the trauma bay. They should then undergo an intravenous contrast enhanced CT scan of the abdomen and pelvis when stable. X-ray views which reflect intraoperative imaging (inlet/outlet and judet views) may be done at the discretion of the surgeon when the patient is stable and surgery is planned.
B. Volume rendered 3D images of the bony pelvis based on CT acquisition data should be conducted at the original site where imaging is conducted prior to surgery, as these images provide additional information for surgical planning.
C. All polytraumatised patients require a post-binder removal X-ray after resuscitation, even in the presence of a negative CT scan because a well-applied pelvic binder can mask a catastrophic pelvic ring injury. D. In the setting of gastrointestinal/genitourinary (GI/GU), general surgery and/or urology consultation is recommended. Refer to Diagnostic Imaging Guidelines for Trauma for recommendations regarding imaging of bladder/urethral injury.
# VII. TRANSFER TO HIGHER LEVEL OF CARE
A. A hemodynamically unstable patient with major pelvic trauma should be transported to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries as early as possible. Trauma/general surgery at the referral centre should be the primary point of contact. E. Patients with fractures which are minimally displaced and not requiring fixation, and nonoperative cases can be managed in a centre with general orthopedic surgery but without orthopedic expertise in the surgical management of complex pelvic ring injuries. Such cases should be assessed by the local orthopedic surgeon in discussion with referral centre.
F. All hemodynamically stable patients with mechanically unstable pelvic ring injuries must be transferred to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries, with the exception of patients who cannot tolerate transfer.
G. A local orthopedic surgeon on-call at the site of initial presentation, who is certified in Orthopedic Surgery by the Royal College of Physicians and Surgeons of Canada, should assess the hemodynamically stable patient in person, inform PTN, and consult an orthopedic surgeon with expertise in the surgical management of complex pelvic ring injuries.
# VIII. HOSPITAL CARE
A. Specialised units must have written local policies for thromboprophylaxis for patients with pelvic ring injuries, which should be followed and documented in the medical records. B. Orthopedic surgeon must clarify weight-bearing orders, including timeline, and the need for follow-up imaging and timeline, as well as indicating any rehabilitation or transfer restrictions.
# IX. DEFINITIVE SURGICAL CARE
A. Definitive fixation should be done within 72 hours of stabilization of the patient's physiological state. B. Any bladder rupture with associated contaminated pelvic ring injury and/or trauma to the urethra should involve urology.
C. In the setting of gastrointestinal/genitourinary (GI/GU) injury, general surgery and/or urology consultation is recommended.
# X. TRANSFER TO LOWER LEVEL OF CARE (REPATRIATION)
A. Agreement for repatriation should clearly state weight-bearing orders (including timeline), the need and timing for follow-up imaging, as well as indicating any rehabilitation or transfer restrictions. The follow-up plan, including documentations must be provided by the higher level of care site. See Recommendation B for KMQ-21.
B. Medically stable patients not requiring complex orthopedic care for their pelvic ring injury should be transferred back to sending facility or a facility close to patients' residence.
# XI. REHABILITATION
A B. Patients with suspected pelvic ring injuries with signs of hemodynamic instability should be transported directly to a regional centre with orthopedic expertise in the surgical management of complex pelvic ring injuries. If the patient is received into a hospital with general orthopedic capabilities, then resuscitation should be commenced followed by immediate transfer to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries for definitive treatment of active bleeding when advisable and feasible.
# Additional Literature Support
Several studies show decrease in mortality with the introduction of a multidisciplinary institutional protocol for the management of pelvic trauma:
- A large retroactive analysis at a single trauma centre in Hong Kong (n=1,682) found significant decrease in adjusted pelvic ring injury mortality after implementation of protocol that includes early use of pelvic binder and rapid/appropriate use of pelvic angiography.
Odds ratio for 3 years prior to protocol vs. first 4 years of protocol implementation: 2.05 (95% CI=1.26, 3.3). In the healthiest patients with unstable pelvic ring injuries, the mortality rate is now similar to that of patients with stable fracture patterns. 7 A registry analysis at the Denver Health Medical Center (n=216) found a significant decrease in mortality (from 31% to 15%, p<0.05) after revising its pelvic trauma pathway to include immediate ED presence of orthopedic surgeon, wrapping the pelvis with a sheet, and using C-clamps or early surgical fixation. 8 A retrospective study at a Level 1 trauma centre in Texas (n=199) found an over 30% decrease in 30-day mortality rate after the implementation of protocols for pelvic angiography and pelvic packing by over 30 %. Implementation of protocol for pelvic embolization alone significantly reduced the 30-day mortality rate by more than 20% (p=0.009). 9 A small analysis of prospectively collected data in Australia (n=31) found decrease in 24-hour packed red blood cells transfusion (from 16 ± 2U to 11 ± 1U, p<0.05) and in mortality (from 35% to 7%, p<0.05) after implementing a multidisciplinary practice protocol that includes prehospital notification of pelvic trauma, pelvic binding, and pelvic angioembolization. 10
# Additional Literature Support
# What is the effectiveness of REBOA in controlling hemorrhage in traumatic pelvic injuries?
The use of REBOA is increasing worldwide over the past 10 years and as long as 15 years in Japan. Currently, the quality of evidence supporting the use of this novel technology is low.
- Effectiveness: A recent prospective study (n=114) by the American Association for the Surgery of Trauma showed hemodynamic improvements of 67.4% of patients with REBOA and 47.8% of patients with REBOA achieved stability (systolic blood pressure consistently >90 mm Hg for >5 minutes) compared to 27.9% who received open aortic occlusion. 11 These differences are not statistically significant and the advantages of REBOA compared to resuscitative thoracotomy remain unconfirmed.
- Complications: Studies to date show rates of complications below 1%, which include distal ischemia or thromboembolic events, intracranial massive hemorrhage, pseudoaneurysm at the access site. 12 While the introducer sheath size has been suggested as a risk factor for complications, it is unclear whether a low-profile device offers significant advantages.
- Mortality: A high mortality rate of 65% has been demonstrated but has been suggested to be attributed to the severity of the injuries rather than failure of REBOA. 12 Advantages: Insertion of an arterial catheter allows for angiography in the OR without having to transfer the patient to an interventional radiology suite. 12 Caveats: The attending surgeon requires skillset and confidence. Trained surgeons have been shown to perform REBOA in 3-15 minutes in simulated settings. 12 WSES notes that REBOA is only a temporary solution, which must be followed by definitive care, noting that most trauma centres reserve REBOA only in patients in critical condition with multiple sites of bleeding. 3 The SAG notes that REBOA is a promising clinical option, pending more high-quality evidence and stronger recommendation by other professional bodies. Pelvic hematoma >500 cm 3 in size has an increased incidence of arterial injury and need for angiography. Although fracture pattern or type does not predict arterial injury or need for angiography, anterior fractures are more highly associated with anterior vascular injuries, whereas posterior fractures are more highly associated with posterior vascular injuries. These statements are points of information rather than recommendations for clinical management, and as such were excluded.
# II. TEMPORARY PELVIC RING INJURY IMMOBILIZATION
# III. HEMORRHAGE CONTROL -ANGIOEMBOLIZATION
However, these statements provide supportive evidence to the SAG's recommendations. H. Non-selective angioembolization is not desired in acute management of blunt pelvic ring injury. If selective angioembolization is not possible, preferred options include pre-peritoneal pelvic packing or REBOA in conjunction with packing (if protocols are in place and surgeon has experience in REBOA or packing).
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
- Pelvic angiography with bilateral embolization seems to be safe with few major complications. Gluteal muscle ischemia/necrosis has been reported in patients with hemodynamic instability and prolonged immobilization or primary trauma to the gluteal region as the possible cause, rather than a direct complication of angioembolization. Sexual function in males does not seem to be impaired after bilateral internal iliac arterial embolization. These statements are points of information that support selective angioembolization as preferred method. New recommendation statements were created to guide clinical management.
# Additional Literature Support
# What is the risk of complications associated with non-selective angioembolization of the pelvis?
Potential complications of non-selective angioembolization are gluteal necrosis, wound complications, claudication, neuropathy, poor fracture healing and impotence. Risk of complications ranges from 3.3 to 66 %. 14 A multicentre retrospective cohort study (n=145) comparing selective and non-selective angioembolization in pelvic trauma patients found an increased rate of overall in-patient complications in the non-selective group, longer hospital and ICU stays, and higher rate of thromboembolic complications (12.1% vs. 0, p=0.010).
# IV. HEMORRHAGE CONTROL -PELVIC PACKING
# Additional Literature Support
# What evidence supports the use of pelvic packing to control pelvic hemorrhage after trauma?
80-90% of bleeding in patients with hemodynamically unstable pelvic ring injuries is attributed to venous bleeding, providing rationale for pelvic packing as acute surgical method of hemorrhage control. 3 Inconclusive findings regarding superiority of pelvic packing to pelvic angioembolization.
Small studies have shown shorter times for pelvic packing than pelvic angioembolization. 15,16 However, these findings are dependent on local institutional protocols.
# KMQ-9.
How and by whom should pre-peritoneal pelvic packing be performed?
# RECOMMENDATIONS
F. Hospitals with expertise should develop local protocols for pelvic packing in unstable pelvic ring injuries.
# KNOWLEDGE SYNTHESIS
# V. OPEN PELVIC RING INJURIES AND ASSOCIATED GASTROINTESTINAL/GENITOURINARY INJURIES
# VI. DIAGNOSTIC IMAGING
KMQ-13. How should patients presenting with proven or suspected major pelvic ring injuries be diagnostically imaged?
# RECOMMENDATIONS
A. Patients with proven or suspected major pelvic fractures should be diagnostically imaged via an initial plain X-ray in the trauma bay. They should then undergo an intravenous contrast enhanced CT scan of the abdomen and pelvis when stable. X-ray views which reflect intraoperative imaging (inlet/outlet and judet views) may be done at the discretion of the surgeon when the patient is stable and surgery is planned.
B. Volume rendered 3D images of the bony pelvis based on CT acquisition data should be conducted at the original site where imaging is conducted prior to surgery, as these images provide additional information for surgical planning.
C. All polytraumatised patients require a post-binder removal X-ray after resuscitation, even in the presence of a negative CT scan because a well-applied pelvic binder can mask a catastrophic pelvic ring injury.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
# X-ray and E-FAST
- The use of Pelvic X-ray and E-FAST in the Emergency Department is recommended in hemodynamic and mechanic unstable patients with pelvic trauma and allows to identify the injuries that require an early pelvic stabilization, an early angiography, and a rapid reductive maneuver, as well as laparotomy. B. Orthopedic surgeon must clarify weight-bearing orders (with timeline) and the need for followup imaging (with timeline), as well as indicating any rehabilitation or transfer restrictions.
# VII. TRANSFER TO HIGHER LEVEL OF CARE
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
- Specialised units should have written local policies for thromboprophylaxis for patients with pelvic fractures, which should be followed and documented in the medical records.
Adopted BOA statement.
Created a new recommendation to reflect the BC trauma system.
# IX. DEFINITIVE SURGICAL CARE
# X. TRANSFER TO LOWER LEVEL OF CARE (REPATRIATION)
KMQ-23. What are the indications and timing for repatriation back to a sending facility (or equivalent) of patients with major pelvic ring injury transferred to a regional centre expertise for advanced orthopedic care?
# RECOMMENDATIONS
A. Agreement for repatriation should clearly state weight-bearing orders (including timeline), the need and timing for follow-up imaging, as well as indicating any rehabilitation or transfer restrictions. The follow-up plan, including documentations must be provided by the higher level of care site. See Recommendation B for KMQ-21.
B. Medically stable patients not requiring complex orthopedic care for their pelvic ring injury should be transferred back to sending facility or a facility close to patients' residence.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
None New recommendations created based on provincial realities and the expert opinion of the SAG.
# KMQ-26.
What are the indications for in-patient rehabilitation of a patient treated for major pelvic ring injury?
# RECOMMENDATIONS
C. All patients with major pelvic trauma should receive in-patient rehabilitation.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
None New recommendation created based on the expert opinion of the SAG.
# External Recommendations SAG's Decision
Ignored BOA statement regarding performance monitoring as out of scope.
|
# TABLE OF CONTENTS
# PURPOSE
The prompt diagnosis of a major pelvic ring injury and rapid and effective control of massive pelvic hemorrhage, as part of a general hemostatic resuscitation effort, is a key clinical priority in the successful management of the blunt trauma patient with a mechanically unstable pelvic ring injuries.
The purpose of this clinical practice guideline (CPG) is to review best evidence and generate expert consensus on recommendations for the management of hemodynamically unstable adult patients (age >16) with pelvic ring injuries in B.C.
# KEY MANAGEMENT QUESTIONS I. RESUSCITATION AND STABILIZATION
1. What are key considerations in the initial assessment and management of patients with mechanically unstable pelvic ring injuries?
2. When and how should REBOA (Resuscitative Endovascular Balloon Occlusion of the Aorta) be used in the acute management of major pelvic ring injuries?
# II. TEMPORARY PELVIC RING INJURY IMMOBILZATION
3. How should the mechanically unstable fractured pelvis be immobilized initially?
4. What considerations guide the duration of use of pelvic binders?
5. What is the role of emergency department C-clamp application in the initial management of pelvic ring injuries?
# III. HEMORRHAGE CONTROL -ANGIOEMBOLIZATION
6. When should angioembolization be used in the acute management of major pelvic ring injuries?
7. When should selective versus non-selective angioembolization be used in acute management of blunt pelvic ring injury?
# IV. HEMORRHAGE CONTROL -PELVIC PACKING
8. When should peritoneal pelvic packing be employed for major pelvic ring injuries? 9. How and by whom should pre-peritoneal pelvic packing be performed?
10. Should pre-peritoneal pelvic packing be performed in a rural/remote or community setting?
# V. OPEN PELVIC RING INJURIES
11. How should patients be assessed for the presence of open pelvic ring injury?
12. What are the indications for fecal diversion in the management of open pelvic ring injuries?
# VI. DIAGNOSTIC IMAGING
13. How should patients presenting with proven or suspected major pelvic ring injuries be diagnostically imaged?
14. When and how should patients with pelvic ring fracture undergo evaluation of the urethra and the bladder?
# VII. TRANSFER TO HIGHER LEVEL OF CARE
15. What are the indications and timing for higher level of care (HLOC) transfer of a trauma patient with major pelvic trauma to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries?
16. What is the preferred process for inter-facility transfer of major pelvic ring injuries?
17. Which patients with pelvic ring fractures can be managed in a centre with general orthopedic surgery?
18. Which mechanically unstable pelvic ring injuries can be managed in a centre without orthopedic surgery?
19. How should the orthopedic surgeon on-call in a community hospital be involved in the early management of the patients with pelvic ring injury?
# VIII. HOSPITAL CARE
20. What are the care requirements for acceptable management of the stabilized admitted patient with a major pelvic ring injury?
# IX. DEFINITIVE SURGICAL CARE
21. What is the preferred timeframe for definitive surgical fixation of major pelvic ring injury?
22. How should bladder rupture (intraperitoneal and extraperitoneal) associated with major pelvic injuries be managed?
# X. TRANSFER TO LOWER LEVEL OF CARE (REPATRIATION)
23. What are the indications and timing for repatriation back to a sending facility (or equivalent) of patients with major pelvic ring injury transferred to a regional centre with expertise for advanced orthopedic care?
# XI. REHABILITATION
24. What is the preferred rehabilitation strategy for patients treated for major pelvic ring injury?
25. When and how should patients who have undergone definitive surgical fixation of major pelvic ring injury be mobilized?
26. What are the indications for in-patient rehabilitation of a patient treated for major pelvic ring injury?
# XII. FOLLOW-UP
27. What is the recommended follow-up for a discharged patient with unstable pelvic ring injury?
# GUIDELINES REFERENCED
# ALGORITHM SUMMARY OF RECOMMENDATIONS
Recommendations are newly drafted by the Complex Orthopedic SAG, unless indicated otherwise.
# I. RESUSCITATION AND STABILIZATION
A. When there is suspected active bleeding from a pelvic ring injury, apply a pelvic binder in the correct position. This should be applied pre-hospital. [Adopted from BOA] B. Patients with suspected pelvic ring injuries with signs of hemodynamic instability should be transported directly to a regional centre with orthopedic expertise in the surgical management of complex pelvic ring injuries. If the patient is received into a hospital with general orthopedic capabilities, then resuscitation should be commenced followed by immediate transfer to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries for definitive treatment of active bleeding when advisable and feasible. [Adopted from BOA with modification]
C. All patients require IV Tranexamic Acid as soon as possible and ideally within an hour of injury. In the presence of hemodynamic instability, patients should be urgently resuscitated using blood products according to Massive Transfusion Protocols. [Adopted from BOA] D. Patients with suspected pelvic ring injuries from high-energy trauma should have a CT scan with IV contrast of the pelvis on admission. Given the energy required to cause pelvic ring injury, other injuries should be expected and investigations should also include CT of the head and Cspine without contrast and CT of the chest and abdomen with contrast. [Adopted from BOA with modification] E. All patients with blunt polytrauma undergoing damage control laparotomy should have imaging of the pelvis before surgery (X-ray or CT). All patients should have a pelvic binder in-situ during surgery and this should not be removed for a post binder pelvic X-ray until the patient is hemodynamically stable. [Adopted from BOA] F. Active bleeding from the pelvis in patients who do not respond to resuscitation can be managed by surgical packing of the pelvis or interventional radiology with selective embolization of active arterial bleeding vessels. Any hospital receiving trauma patients must have, based on its resources and facilities, clear protocols in place for managing patients with pelvic ring injury and hemodynamic instability. [Adopted from BOA with modification] G. In a patient in extremis, where resuscitation is failing, REBOA can be a first measure to temporarily control hemorrhage in conjunction with pelvic packing as a bridge to definitive care. REBOA should only be attempted in institutions with protocols and expertise in place, and in the context of local discussions and surgeon discretion. This novel technology requires further assessment regarding efficacy and safety in the setting of pelvic ring injury with hemodynamic instability.
# II. TEMPORARY PELVIC RING INJURY IMMOBILZATION
A. To immobilize the mechanically unstable fractured pelvis, apply a pelvic binder in the correct position as initial means of immobilization. This should be applied pre-hospital. G. If angiography is performed, selective angioembolization is preferred in acute management of blunt pelvic ring injury to minimize the risk of soft tissue/organ necrosis following mass embolization.
H. Non-selective angioembolization is not desired in acute management of blunt pelvic ring injury. If selective angioembolization is not possible, preferred options include pre-peritoneal pelvic packing or REBOA in conjunction with packing (if protocols are in place and surgeon has experience in REBOA or packing).
# IV. HEMORRHAGE CONTROL -PELVIC PACKING
A. Active bleeding from the pelvis in patients who do not respond to resuscitation can be managed by surgical packing of the pelvis or interventional radiology with selective embolization of active arterial bleeding vessels. Trauma centres with orthopedic surgery (general or expertise in the surgical management of complex pelvic ring injuries) must have a clear protocol in place for managing hemodynamically unstable patients with pelvic ring injuries.
# VI. DIAGNOSTIC IMAGING
A. Patients with proven or suspected major pelvic fractures should be diagnostically imaged via an initial plain X-ray in the trauma bay. They should then undergo an intravenous contrast enhanced CT scan of the abdomen and pelvis when stable. X-ray views which reflect intraoperative imaging (inlet/outlet and judet views) may be done at the discretion of the surgeon when the patient is stable and surgery is planned.
B. Volume rendered 3D images of the bony pelvis based on CT acquisition data should be conducted at the original site where imaging is conducted prior to surgery, as these images provide additional information for surgical planning.
C. All polytraumatised patients require a post-binder removal X-ray after resuscitation, even in the presence of a negative CT scan because a well-applied pelvic binder can mask a catastrophic pelvic ring injury. [Adopted from BOA] D. In the setting of gastrointestinal/genitourinary (GI/GU), general surgery and/or urology consultation is recommended. Refer to Diagnostic Imaging Guidelines for Trauma for recommendations regarding imaging of bladder/urethral injury.
# VII. TRANSFER TO HIGHER LEVEL OF CARE
A. A hemodynamically unstable patient with major pelvic trauma should be transported to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries as early as possible. Trauma/general surgery at the referral centre should be the primary point of contact. E. Patients with fractures which are minimally displaced and not requiring fixation, and nonoperative cases can be managed in a centre with general orthopedic surgery but without orthopedic expertise in the surgical management of complex pelvic ring injuries. Such cases should be assessed by the local orthopedic surgeon in discussion with referral centre.
F. All hemodynamically stable patients with mechanically unstable pelvic ring injuries must be transferred to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries, with the exception of patients who cannot tolerate transfer.
G. A local orthopedic surgeon on-call at the site of initial presentation, who is certified in Orthopedic Surgery by the Royal College of Physicians and Surgeons of Canada, should assess the hemodynamically stable patient in person, inform PTN, and consult an orthopedic surgeon with expertise in the surgical management of complex pelvic ring injuries.
# VIII. HOSPITAL CARE
A. Specialised units must have written local policies for thromboprophylaxis for patients with pelvic ring injuries, which should be followed and documented in the medical records. [Adopted from BOA] B. Orthopedic surgeon must clarify weight-bearing orders, including timeline, and the need for follow-up imaging and timeline, as well as indicating any rehabilitation or transfer restrictions.
# IX. DEFINITIVE SURGICAL CARE
A. Definitive fixation should be done within 72 hours of stabilization of the patient's physiological state. [Adopted from BOA with modification] B. Any bladder rupture with associated contaminated pelvic ring injury and/or trauma to the urethra should involve urology.
C. In the setting of gastrointestinal/genitourinary (GI/GU) injury, general surgery and/or urology consultation is recommended.
# X. TRANSFER TO LOWER LEVEL OF CARE (REPATRIATION)
A. Agreement for repatriation should clearly state weight-bearing orders (including timeline), the need and timing for follow-up imaging, as well as indicating any rehabilitation or transfer restrictions. The follow-up plan, including documentations must be provided by the higher level of care site. See Recommendation B for KMQ-21.
B. Medically stable patients not requiring complex orthopedic care for their pelvic ring injury should be transferred back to sending facility or a facility close to patients' residence.
# XI. REHABILITATION
A B. Patients with suspected pelvic ring injuries with signs of hemodynamic instability should be transported directly to a regional centre with orthopedic expertise in the surgical management of complex pelvic ring injuries. If the patient is received into a hospital with general orthopedic capabilities, then resuscitation should be commenced followed by immediate transfer to a centre with orthopedic expertise in the surgical management of complex pelvic ring injuries for definitive treatment of active bleeding when advisable and feasible.
# Additional Literature Support
Several studies show decrease in mortality with the introduction of a multidisciplinary institutional protocol for the management of pelvic trauma:
A large retroactive analysis at a single trauma centre in Hong Kong (n=1,682) found significant decrease in adjusted pelvic ring injury mortality after implementation of protocol that includes early use of pelvic binder and rapid/appropriate use of pelvic angiography.
Odds ratio for 3 years prior to protocol vs. first 4 years of protocol implementation: 2.05 (95% CI=1.26, 3.3). In the healthiest patients with unstable pelvic ring injuries, the mortality rate is now similar to that of patients with stable fracture patterns. 7 A registry analysis at the Denver Health Medical Center (n=216) found a significant decrease in mortality (from 31% to 15%, p<0.05) after revising its pelvic trauma pathway to include immediate ED presence of orthopedic surgeon, wrapping the pelvis with a sheet, and using C-clamps or early surgical fixation. 8 A retrospective study at a Level 1 trauma centre in Texas (n=199) found an over 30% decrease in 30-day mortality rate after the implementation of protocols for pelvic angiography and pelvic packing by over 30 %. Implementation of protocol for pelvic embolization alone significantly reduced the 30-day mortality rate by more than 20% (p=0.009). 9 A small analysis of prospectively collected data in Australia (n=31) found decrease in 24-hour packed red blood cells transfusion (from 16 ± 2U to 11 ± 1U, p<0.05) and in mortality (from 35% to 7%, p<0.05) after implementing a multidisciplinary practice protocol that includes prehospital notification of pelvic trauma, pelvic binding, and pelvic angioembolization. 10
# Additional Literature Support
# What is the effectiveness of REBOA in controlling hemorrhage in traumatic pelvic injuries?
The use of REBOA is increasing worldwide over the past 10 years and as long as 15 years in Japan. Currently, the quality of evidence supporting the use of this novel technology is low.
Effectiveness: A recent prospective study (n=114) by the American Association for the Surgery of Trauma showed hemodynamic improvements of 67.4% of patients with REBOA and 47.8% of patients with REBOA achieved stability (systolic blood pressure consistently >90 mm Hg for >5 minutes) compared to 27.9% who received open aortic occlusion. 11 These differences are not statistically significant and the advantages of REBOA compared to resuscitative thoracotomy remain unconfirmed.
Complications: Studies to date show rates of complications below 1%, which include distal ischemia or thromboembolic events, intracranial massive hemorrhage, pseudoaneurysm at the access site. 12 While the introducer sheath size has been suggested as a risk factor for complications, it is unclear whether a low-profile device offers significant advantages.
Mortality: A high mortality rate of 65% has been demonstrated but has been suggested to be attributed to the severity of the injuries rather than failure of REBOA. 12 Advantages: Insertion of an arterial catheter allows for angiography in the OR without having to transfer the patient to an interventional radiology suite. 12 Caveats: The attending surgeon requires skillset and confidence. Trained surgeons have been shown to perform REBOA in 3-15 minutes in simulated settings. 12 WSES notes that REBOA is only a temporary solution, which must be followed by definitive care, noting that most trauma centres reserve REBOA only in patients in critical condition with multiple sites of bleeding. 3 The SAG notes that REBOA is a promising clinical option, pending more high-quality evidence and stronger recommendation by other professional bodies. Pelvic hematoma >500 cm 3 in size has an increased incidence of arterial injury and need for angiography. [EAST: Level 3] Although fracture pattern or type does not predict arterial injury or need for angiography, anterior fractures are more highly associated with anterior vascular injuries, whereas posterior fractures are more highly associated with posterior vascular injuries. [EAST: Level 3] These statements are points of information rather than recommendations for clinical management, and as such were excluded.
# II. TEMPORARY PELVIC RING INJURY IMMOBILIZATION
# III. HEMORRHAGE CONTROL -ANGIOEMBOLIZATION
However, these statements provide supportive evidence to the SAG's recommendations. H. Non-selective angioembolization is not desired in acute management of blunt pelvic ring injury. If selective angioembolization is not possible, preferred options include pre-peritoneal pelvic packing or REBOA in conjunction with packing (if protocols are in place and surgeon has experience in REBOA or packing).
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
Pelvic angiography with bilateral embolization seems to be safe with few major complications. Gluteal muscle ischemia/necrosis has been reported in patients with hemodynamic instability and prolonged immobilization or primary trauma to the gluteal region as the possible cause, rather than a direct complication of angioembolization. [EAST: Level 3] Sexual function in males does not seem to be impaired after bilateral internal iliac arterial embolization. [EAST: Level 3] These statements are points of information that support selective angioembolization as preferred method. New recommendation statements were created to guide clinical management.
# Additional Literature Support
# What is the risk of complications associated with non-selective angioembolization of the pelvis?
Potential complications of non-selective angioembolization are gluteal necrosis, wound complications, claudication, neuropathy, poor fracture healing and impotence. Risk of complications ranges from 3.3 to 66 %. 14 A multicentre retrospective cohort study (n=145) comparing selective and non-selective angioembolization in pelvic trauma patients found an increased rate of overall in-patient complications in the non-selective group, longer hospital and ICU stays, and higher rate of thromboembolic complications (12.1% vs. 0, p=0.010).
# IV. HEMORRHAGE CONTROL -PELVIC PACKING
# Additional Literature Support
# What evidence supports the use of pelvic packing to control pelvic hemorrhage after trauma?
80-90% of bleeding in patients with hemodynamically unstable pelvic ring injuries is attributed to venous bleeding, providing rationale for pelvic packing as acute surgical method of hemorrhage control. 3 Inconclusive findings regarding superiority of pelvic packing to pelvic angioembolization.
Small studies have shown shorter times for pelvic packing than pelvic angioembolization. 15,16 However, these findings are dependent on local institutional protocols.
# KMQ-9.
How and by whom should pre-peritoneal pelvic packing be performed?
# RECOMMENDATIONS
F. Hospitals with expertise should develop local protocols for pelvic packing in unstable pelvic ring injuries.
# KNOWLEDGE SYNTHESIS
# V. OPEN PELVIC RING INJURIES AND ASSOCIATED GASTROINTESTINAL/GENITOURINARY INJURIES
# VI. DIAGNOSTIC IMAGING
KMQ-13. How should patients presenting with proven or suspected major pelvic ring injuries be diagnostically imaged?
# RECOMMENDATIONS
A. Patients with proven or suspected major pelvic fractures should be diagnostically imaged via an initial plain X-ray in the trauma bay. They should then undergo an intravenous contrast enhanced CT scan of the abdomen and pelvis when stable. X-ray views which reflect intraoperative imaging (inlet/outlet and judet views) may be done at the discretion of the surgeon when the patient is stable and surgery is planned.
B. Volume rendered 3D images of the bony pelvis based on CT acquisition data should be conducted at the original site where imaging is conducted prior to surgery, as these images provide additional information for surgical planning.
C. All polytraumatised patients require a post-binder removal X-ray after resuscitation, even in the presence of a negative CT scan because a well-applied pelvic binder can mask a catastrophic pelvic ring injury. [Adopted from BOA with modification]
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
# X-ray and E-FAST
The use of Pelvic X-ray and E-FAST in the Emergency Department is recommended in hemodynamic and mechanic unstable patients with pelvic trauma and allows to identify the injuries that require an early pelvic stabilization, an early angiography, and a rapid reductive maneuver, as well as laparotomy. B. Orthopedic surgeon must clarify weight-bearing orders (with timeline) and the need for followup imaging (with timeline), as well as indicating any rehabilitation or transfer restrictions.
# VII. TRANSFER TO HIGHER LEVEL OF CARE
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
Specialised units should have written local policies for thromboprophylaxis for patients with pelvic fractures, which should be followed and documented in the medical records.
[BOA]
Adopted BOA statement.
Created a new recommendation to reflect the BC trauma system.
# IX. DEFINITIVE SURGICAL CARE
# X. TRANSFER TO LOWER LEVEL OF CARE (REPATRIATION)
KMQ-23. What are the indications and timing for repatriation back to a sending facility (or equivalent) of patients with major pelvic ring injury transferred to a regional centre expertise for advanced orthopedic care?
# RECOMMENDATIONS
A. Agreement for repatriation should clearly state weight-bearing orders (including timeline), the need and timing for follow-up imaging, as well as indicating any rehabilitation or transfer restrictions. The follow-up plan, including documentations must be provided by the higher level of care site. See Recommendation B for KMQ-21.
B. Medically stable patients not requiring complex orthopedic care for their pelvic ring injury should be transferred back to sending facility or a facility close to patients' residence.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
None New recommendations created based on provincial realities and the expert opinion of the SAG.
# KMQ-26.
What are the indications for in-patient rehabilitation of a patient treated for major pelvic ring injury?
# RECOMMENDATIONS
C. All patients with major pelvic trauma should receive in-patient rehabilitation.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Decision
None New recommendation created based on the expert opinion of the SAG.
# External Recommendations SAG's Decision
Ignored BOA statement regarding performance monitoring as out of scope.
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None
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None
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40839b8be633809bc780b1ec80539d81221ed70a
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cma
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None
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The affiliations of the members of the Ontario COVID-19 Science Advisory Table can be found at https:// covid19-sciencetable.ca/.#
Once a Public Health Unit or neighborhood approaches 50 new COVID-19 cases per million per day (corresponding to 35 cases per 100,000 per week) and is in sustained exponential growth, we advise weekly voluntary screen testing of unvaccinated and incompletely vaccinated individuals in elementary schools. Public health units in this situation may also decide to deploy rapid antigen testing in other settings, such as workplaces and congregate settings.
If a Public Health Unit's or neighborhood's new daily case rate approaches 250 COVID-19 cases per million per day (corresponding to 175 cases per 100,000 per week), weekly testing is likely not frequent enough to reduce spread effectively. In that case, we advise testing unvaccinated and incompletely vaccinated individuals 2 to 3 times per week. Public health units in this situation may also consider voluntary screen testing of fully vaccinated individuals at the same frequency.
Rapid antigen tests may also present a valuable alternative to individual isolation after exposure in schools. Implementing voluntary "test to stay" protocols, where exposed students remain in school as long as daily tests are negative for SARS-CoV-2, could help prevent the harms of isolation without increasing transmission.
Individuals with positive rapid antigen tests should immediately isolate and undergo confirmatory Polymerase Chain Reaction (PCR) testing. Evaluation of the performance of rapid antigen tests for the diagnosis of the Omicron variant is urgently needed.
Ontario COVID-19 Science Advisory Table Rapid Antigen Tests for Voluntary Screen Testing
# Lay Summary
The Delta Variant and Rapid Antigen Tests
Rapid antigen tests identify SARS-CoV2, the virus that causes COVID-19, in the nose or throat by detecting proteins attached to the surface of the virus (the "antigen"). This approach makes rapid antigen tests different than PCR tests, which determine whether someone is infected with SARS-CoV2 by amplifying the virus' genetic material at a lab. Because rapid tests are more easily accessible for many people than PCR tests, can be deployed in a wide range of settings including homes and schools, and produce immediate results, accurate rapid antigen testing could be a useful tool for detecting COVID-19 early and isolating infected people before they have a chance to spread the virus. Understanding the accuracy of rapid antigen tests against the Delta variant, which currently dominates in Ontario, is a key piece of disease control.
This brief establishes the high accuracy of rapid antigen tests in detecting the Delta variant of SARS-CoV-2, which is currently the dominant variant in Ontario. The Delta variant multiplies rapidly in the human body, and so the viral load of infected individuals peaks sooner with Delta than with earlier variants, often before symptoms appear. That high viral load at an earlier stage of infection makes the Delta variant more contagious than earlier variants; it is also what makes rapid antigen testing more accurate with Delta than with earlier variants.
Using studies on people carrying a range of SARS-CoV-2 viral loads, we (1) confirmed that people with high viral loads are likely to transmit the virus to the people around them, and (2) established that rapid antigen tests can reliably detect those cases. Rapid antigen tests could therefore help interrupt the chain of transmission by identifying infectious cases of COVID-19 quickly, leading to prompt isolation of the infected person.
# Our Advice
Ontario could apply rapid antigen tests in many ways, but this brief focuses on voluntary screen testing: the practice of testing asymptomatic volunteers at regular intervals in settings where there is a moderate risk of transmission, such as schools and workplaces. We considered elementary schools a priority for voluntary screen testing given that students less than 12 years of age are not fully vaccinated in Ontario.
If the COVID-19 case rate in an elementary school's Public Health Unit or neighborhood approaches 50 cases per million per day (corresponding to 35 cases per 100,000 per week), we recommend that unvaccinated and incompletely vaccinated people be tested once per week. If the COVID-19 case rate approaches 250 cases per million per day (175 cases per 100,000 per week), we recommend that unvaccinated people, and possibly also vaccinated people, be tested 2 to 3 times per week.
We also recommend using a "test to stay" approach in schools for individuals who have been exposed to someone with COVID-19 but do not have symptoms (often referred to as "contacts"). With this approach, contacts are offered daily rapid antigen testing as an alternative to self-isolation, and can continue with in-person learning as long as they test negative and remain asymptomatic for a defined risk period after exposure.
# Summary
# Background
Delta is currently the predominant variant of the SARS-CoV-2 virus in Ontario and internationally. It is more than twice as transmissible as the wild type virus that caused the first and second waves in Ontario, and 1.5 times as transmissible as the Alpha variant, which caused the third wave. While this early increase in viral load makes transmission of the Delta variant challenging to control, now that it predominates globally, rapid antigen tests may become more sensitive and more useful because of it.
# Questions
What is the peak viral load after infection with the Delta variant?
What is the relationship between viral load and transmission?
What is the performance of rapid antigen tests according to viral load or cycle threshold?
How do rapid antigen tests perform in people who are likely to be infectious?
How can rapid tests be used optimally to prevent transmission as well as the negative impacts of testing?
# Findings
The Delta variant reliably incites viral loads greater than 100,000 copies/mL (5 log 10 units). A higher viral load is reliably associated with a higher probability of transmission: a ten-fold increase in viral load (e.g., from 100,000 copies/mL to 1 million copies/mL) is, on average, associated with a 4.69-fold and 1.33-fold increase in the odds of a positive viral culture and onward transmission of the virus, respectively.
The ability of rapid antigen tests to detect a SARS-CoV-2 infection depends on the viral load of the sample, but diagnostic accuracy studies typically do not quantify viral load directly, and instead report cycle threshold (Ct) values. In subgroups of patients with Ct values of less than 30, the pooled sensitivity for any rapid antigen test and for the Abbott Panbio test (the most commonly used test in Ontario) was 79.9% and 83.4%, respectively. In subgroups of patients with Ct values of less than 25, sensitivity increased to 95.8% for any rapid antigen test, and to 94.1% for the Abbott Panbio test.
The post-test probability of an infectious case after a positive test at 50 cases per 1 million inhabitants per day (corresponding to 35 cases per 100,000 per week) was 25% in unvaccinated individuals, but only 5% in fully vaccinated individuals, which justifies rapid antigen tests only in unvaccinated individuals. However, at a rate of 200 cases per 1 million inhabitants per day, the post-test probability after a positive test was 57% in unvaccinated individuals and 18% in vaccinated individuals, justifying rapid antigen test use in both groups.
If the effective reproduction number (R t ) is consistently above 1.25, or if R t is around 1 and the rate in a Public Health Unit (or other geographical unit as appropriate) approaches 50 cases per million per day (35 cases per 100,000 per week) and if there is sustained exponential growth, weekly voluntary screen testing of unvaccinated and incompletely vaccinated individuals is recommended in elementary schools. If the rate in a Public Health Unit approaches 250 cases per million per day (175 cases per 100,000 per week), weekly testing is unlikely to sufficiently reduce transmission and testing of unvaccinated and incompletely vaccinated individuals 2 to 3 times per week is required. In this scenario, voluntary screen testing of fully vaccinated individuals at the same frequency should also be considered.
A "test-to-stay" approach with daily rapid testing of school-based contacts appears non-inferior to self-isolation for control of SARS-CoV-2 transmission, with similar rates of symptomatic infections among students and staff with both approaches.
# Interpretation
Rapid antigen tests available in Ontario can reliably detect individuals with a viral load greater than 100,000 copies/mL of SARS-CoV-2, who therefore are likely to be infectious. As the viral load of Delta-infected individuals increases earlier in the disease process, these tests likely perform better in the face of the Delta variant compared to previous strains of SARS-CoV-2.
Individuals with positive rapid antigen tests should immediately isolate and undergo confirmatory PCR testing, which will reduce the potential harm of unnecessary prolonged isolation in rare false positive cases, and will also ensure provincial case and contact tracing.
# Background
Delta is currently the predominant variant of the SARS-CoV-2 virus in Ontario and internationally. 1 It is more than twice as transmissible as the wild type virus that caused the first and second waves in Ontario, and 1.5 times as transmissible as the Alpha variant. 2 The Delta variant also causes more severe illness than the wild type and the Alpha variant. 3 While the Omicron variant appears to spread more quickly than Delta, as of December 7, 2021 Delta remains dominant in Ontario. The effectiveness of rapid antigen testing in detecting Omicron also remains unclear, and needs to be studied urgently. This brief thus does not include any evidence or recommendations regarding rapid antigen testing for the Omicron variant.
The increased transmissibility of the Delta variant compared to previous strains can be partially explained by the viral load trajectory after infection. Figure 1 shows the progression of viral load in individuals infected with the delta variant compared to the wild type virus. Within the first four days after exposure, the viral load of the Delta variant increases considerably faster and peaks sooner than the wild type virus, 4,5 typically producing a viral load of 100,000 copies/mL (5 log 10 units) only one to two days after exposure.
# Figure 1. Representative Trajectories of Viral Loads for the Delta Variant as Compared with the Wild Type
The viral load of the Delta variant increases quickly and reaches its peak earlier than the wild type virus, 4 typically producing a viral load of 100,000 copies/mL (5 log 10 units) one to two days after exposure. After reaching the peak viral load, the trajectories are likely similar between the two variants. Each log 10 unit corresponds to a 10-fold increase in viral load (copies/mL). Graph based on data from Li et al 4 and Kang et al. 5 While this early increase in viral load makes transmission of the Delta variant challenging to control, now that it predominates in Ontario and internationally, rapid antigen tests may become more sensitive and more useful because of it. Consistent with this concept, Bekliz et al recently found that rapid antigen tests are sufficiently sensitive to detect variants of concern, including the Delta variant. 9 Rapid antigen tests might be particularly useful for voluntary screen testing, which entails regular voluntary testing of asymptomatic individuals to find cases in moderate-risk settings such as schools and workplaces (Box 1). This Science Brief will only discuss voluntary screen testing and test to stay strategies, as indicated in the Box below.
# Type of Testing Description
Addressed in this Brief? Rapid Antigen Testing in Asymptomatic Individuals Voluntary screen testing Regular voluntary testing of asymptomatic individuals to find cases in moderate-risk settings such as schools and workplaces.
# Yes
# Test to stay
Daily voluntary testing of asymptomatic contacts of individuals with a positive COVID-19 test in schools instead of requiring isolation.
# Yes
# Test to protect
Regular mandatory testing of asymptomatic individuals to find cases in high-risk settings to protect the vulnerable (e.g., hospitals, long-term care homes, prisons).
# No
# Test to enable (including "test to play")
Regular mandatory testing of asymptomatic individuals to enable participation in activities with a high risk of transmission (e.g., close-contact sports, visits to long-term care homes).
# No
# Test to release
One-time or repeated mandatory testing of asymptomatic contacts or travelers to allow for early release from quarantine.
# No
# Outbreak response testing
One-time or repeated voluntary or mandatory testing of asymptomatic individuals in a facility, such as a workplace or congregate setting, with a COVID-19 outbreak as an alternative to closure.
# No
# Rapid Antigen Testing in Symptomatic Individuals Diagnostic testing
One-time or repeated testing of symptomatic individuals in settings where PCR testing is less accessible, or in individuals with few or atypical symptoms.
# No
# Box 1. Potential Indications for Rapid Antigen Testing and Whether they Are Addressed in this Science Brief
Adapted from Crozier et al. 8 In this Science Brief, we assessed the usefulness of rapid antigen testing through a sequence of questions derived from the following logic. Rapid antigen tests detect proteins attached to the surface of a virus. PCR, the established gold standard for testing, identifies the virus by replicating its genetic material through enough cycles to make it detectable; the fewer cycles that are necessary to make viral material detectable, the more viral material there is. The number of cycles needed to surpass this threshold of detection is called cycle threshold. In this Science Brief, we assessed whether cases with high viral loads/low cycle thresholds are likely to be infectious, and if so, whether rapid antigen tests can reliably detect those cases.
# Questions
What is the peak viral load after infection with the Delta variant?
# What is the relationship between viral load and transmission?
What is the performance of rapid antigen tests according to viral load or cycle threshold?
How do rapid antigen tests perform in people who are likely to be infectious?
How can rapid tests be used optimally to prevent transmission as well as the negative impacts of testing?
# Findings Peak Viral Load after Infection with the Delta Variant
Figure 2 presents the peak viral load observed in 45 individuals infected with the Delta variant who underwent daily testing after exposure. A total of 43 individuals had peak viral loads greater than 100,000 copies/mL (5 log 10 units), and 41 individuals (91.1%) had peak viral loads greater than 1 million copies/mL (6 log 10 units). 10 The Delta variant therefore reliably incites high viral loads greater than 100,000 copies/mL. The peak viral loads were similar between unvaccinated and fully vaccinated individuals, but viral load declined faster in vaccinated individuals after reaching the peak. A total of 43 individuals had peak viral loads greater than 100,000 copies/mL (5 log 10 units), and 41 individuals (91.1%) had peak viral loads greater than 1 million copies/mL (6 log 10 units). Data from Singanayagam et al. 10
# Relationship between Viral Load and Transmission
In the sections above, we established that Delta carries a higher viral load at an earlier stage of infection than other variants. If rapid antigen tests can reliably detect cases with a high viral load, then it is important to know if those are the cases that are likely to be infectious. Here, we determine whether a high viral load is associated with a higher probability of transmission.
Table 1 presents the results of the seven identified studies that estimated the association between viral load and the odds of a positive viral culture for the wild type virus and Alpha variant. A positive viral culture suggests viable virus that can potentially be transmitted to others. Conversely, a negative culture implies low transmission potential, as no viable virus could be grown.
The median odds ratio per log 10 increase in viral load was 4.69, indicating that a tenfold increase in viral load (e.g., from 100,000 copies/mL to 1 million copies/mL) is associated with a 4.69-fold increase in the odds of a positive viral culture, on average. Results were consistent across studies, with the exception of those reported by Korenkov et al, which suggested a considerably stronger relationship between viral load and the odds of a positive culture. 12 Six of the seven identified studies were suitable for inclusion in a meta-analysis of the probability of a positive viral culture by viral load. At a viral load of 10,000 copies/ mL (4 log 10 units), there was little variation between estimates, resulting in a pooled probability of a positive culture of 0.2% (Figure 3). The probability increased alongside viral load, with higher variation between studies at a viral load of 10 million copies/mL (7 log 10 units) or more. At the maximum viral load of 1 billion copies/mL, the pooled probability of a positive culture was 92.5%.
Table 2 presents the results of five identified studies that estimated the association between viral load and the odds of transmission, mainly for the wild type virus and Alpha variant. The association for the Delta variant was consistent. 22 The median odds ratio per log 10 increase in viral load in any setting, or within a non-household setting, was 1.33, indicating that, on average, a ten-fold increase in viral load (e.g., from 100,000 copies/mL to 1 million copies/mL) is associated with a 1.33-fold increase in the odds of transmission. The only study that assessed the association in a household setting specifically found an odds ratio of 1.77 per log 10 increase in viral load. 19 Since there is less variation in the exposure of contacts in household settings, this stronger association is expected.
# Five Studies Estimating the Association Between Observed Viral Load and Odds of Transmission by Virus Strain and Setting
The median odds ratio per log 10 increase in viral load in any setting, or within a non-household setting, was 1.33, indicating that a ten-fold increase in viral load (e.g., from 100,000 copies/mL to 1 million copies/mL) is associated with a 1.33-fold increase in the odds of transmission, on average. The only study that assessed the association in a household setting specifically found an odds ratio of 1.77 per log 10 increase in viral load. 19 Figure 4 shows the estimated relationship between viral load and the probability of positive culture, the probability of transmission in households, and the probability of transmission in any setting, based on the studies included in Tables 1 and 2. The association with viral load was strong in all three cases. Below a viral load of 1 million copies/mL (6 log 10 units), the estimated probability of transmission is higher than the estimated probability of a positive culture, which may be due to the timing of sampling: individuals with viral loads below 1 million copies/mL who caused transmission may not have been sampled at their peak viral load. Regardless, a high viral load appears to be associated with a higher probability of positive viral culture and onward transmission for the wild type virus and the Alpha variant, and this relationship likely also holds true for the Delta variant. At a viral load of 10,000 copies/mL (4 log 10 units), there was little variation between estimates, resulting in a pooled probability of a positive culture of 0.2%. The probability increased alongside viral load, with higher variation between studies at a viral load of 10 million copies/mL (7 log 10 units) or more. At the maximum viral load of 1 billion copies/mL, the pooled probability of a positive culture was 92.5%.
# Figure 4. Estimated Association Between Observed Viral Load and Probability of Positive Culture, Transmission in Households and Transmission in Any Setting
There are strong associations between viral load and the probability of positive culture, the probability of transmission in household settings, and the probability of transmission in any setting. Median estimates of the associations were taken from Tables 1 and 2, the association for household settings is from Marc et al. 19
# Performance of Rapid Antigen Tests According to Viral Load and Cycle Threshold
Having established that Delta is characterized by early, high viral loads and that a higher viral load is associated with a higher probability of cultured virus and transmission, we assessed whether rapid antigen tests are effective at detecting infections in people with early, high viral loads that appear to drive Delta's transmission. Below, we relate the detection of SARS-CoV-2 by rapid antigen tests with minimum cycle threshold (Ct) values found in PCR tests. 23 The Abbott Panbio test is the most commonly used test in Ontario. 24 A higher viral load is associated with a lower PCR Ct value, as less amplification of the viral genetic material in the sample is needed to reach the threshold for detection.
At a viral load of 100,000 copies/mL (corresponding to a Ct value of 25.0 according to a single study by Peto et al) 23 , the estimated sensitivity of the Abbott Panbio test was 84.3%. At a viral load of 1 million copies/mL (corresponding to a Ct value of 21.5), the estimated sensitivity was 94.1%. At 100 million copies/mL, which corresponds to the peak viral load in more than 50% of the 45 people studied in Figure 2, the estimated sensitivity was 99.3%. 6 The manufacturer of the BTNX Rapid Response test reported a specificity of 100%. 25 There are many rapid antigen tests available globally, and their sensitivity can vary widely; 26 however, the tests available in Ontario are all sufficiently sensitive and specific to be useful.
# Relationship between Cycle Threshold (Ct) Values and Viral Load
In the course of establishing that rapid antigen tests are effective in detecting cases with high viral loads, we now assess the variation in the reported relationship between Ct values and actual viral loads. This relationship is established at the level of the laboratory performing the PCR tests during test calibration. Our assessment allows us to define a maximum Ct value, that may be used to identify the subgroup of people with SARS-CoV-2 infections that should be analyzed to estimate the diagnostic performance of rapid antigen tests when detecting infectious cases.
The relationship between Ct value and viral load depends on the type of assay, the RNA primer and the calibration process. Figure 5 shows the estimated range of Ct values at a viral load of 100,000 Copies/mL from 42 identified standard curves. 20,22,23, The median Ct value at this viral load was 25 20,22,23, The median Ct value at this viral load was 25.82 (interquartile range 23.03 to 29.27). Ct, cycle threshold.
Figure 6 shows the cumulative distribution of viral loads at a Ct value of 30 from the same 42 standard curves used to produce Figure 5. At a Ct value of 30, the median viral load was 5,400 copies/mL (interquartile range 500 to 60,000 copies/mL), and an estimated 83% of assays reported viral loads below 100,000 copies/mL at this threshold.
The pooled sensitivity estimates provided by Brümmer et al 6 for the subgroup of patients with Ct values below 30 can therefore be used to produce conservative estimates of the diagnostic performance of rapid antigen tests when detecting infectious cases with viral loads of 100,000 copies/mL or more.
# Ability of Rapid Antigen Tests to Detect or Rule Out Infectious Cases
In the previous sections, we established that rapid antigen tests can detect the high viral loads that characterize an early Delta infection, and that these high viral loads are associated with the likelihood of transmission. We also established that samples with a Ct value of less than 30 can be used to conservatively estimate the ability of rapid antigen tests to detect or rule out with reasonable certainty currently infectious cases. Here, we return to the patient themselves to assess the probability of being an infectious case after a positive or negative rapid antigen test, taking into account case rates in the community or a Public Health Unit, and the individual's vaccination status.
Figure 7 presents the number of COVID-19 cases per 1 million inhabitants per day in Ontario by vaccination status. The case numbers are currently five to six times greater in unvaccinated individuals compared to fully vaccinated individuals, which means that the pre-test probability of SARS-CoV-2 infection is also five to six times greater in the unvaccinated population. The results of a rapid antigen test should therefore always be interpreted taking the individual's vaccination status into consideration. 20,22,23, At a Ct value of 30, the median viral load was 5,400 copies/mL, and an estimated 83% of assays reported viral loads below 100,000 copies/mL at this threshold. Ct, cycle threshold.
The most conservative pooled estimate of the sensitivity of rapid antigen tests for detecting an infectious case reported by Brümmer et al is 79.9% in patients with Ct values less than 30. The most conservative pooled estimate of specificity (reported for the Quidel Sofia test) is 99.1%. 6 We feel that our estimates of sensitivity are conservative, and would account for the lower test sensitivity that occurs when the test is performed by a lay person instead of a professional, such as a laboratory scientist or health worker. 23 These estimates can be used to calculate likelihood ratios for a positive or negative test result, which depend on sensitivity and specificity.
The likelihood ratio for a positive test result specifies how much more likely it is to obtain a positive test result in an infectious case compared to someone who is not infected or unlikely to be infectious. 44 Using the aforementioned sensitivity and specificity, the positive likelihood ratio is 0.799/(1-0.991)=88.8, indicating that the test has the power to confidently rule in an infectious case.
The likelihood ratio for a negative test result indicates how much less likely it is to obtain a negative result in a potentially infectious case compared to someone who is not infected or unlikely to be infectious. 44 Using the aforementioned sensitivity and specificity, the negative likelihood ratio is (1-0.799)/ 0.991=0.20, which is low enough to be clinically relevant and have the power to rule out an infectious case.
Figure 8 presents the relationship between the daily rate of COVID-19 cases in Ontario and the post-test probability of an infectious case after a positive or negative rapid antigen test. The post-test probability is influenced by the pre-test probability, and the test result (positive vs. negative) and by the likelihood ratio of the rapid antigen test being used.
# Figure 7. COVID-19 Cases per 1 Million Inhabitants per Day in Ontario by Vaccination Status
The number of COVID-19 Cases per 1 million inhabitants per day in unvaccinated people is currently 4 to 6 times higher than in fully vaccinated people, which needs to be taken into account when interpreting results of rapid antigen tests.
# Figure adapted from Ontario Dashboard. 1
Unvaccinated people have a higher pre-test probability of disease, and therefore have a higher probability of being an infectious case after both a positive or a negative test compared to vaccinated people. This information is relevant to decisions about rapid antigen test use. For example, the post-test probability of an infectious case after a positive test at 50 cases per 1 million inhabitants per day (corresponding to 740 cases per day in Ontario, or to 35 cases per 100,000 per week) is 25% in unvaccinated individuals, but only 5% in fully vaccinated individuals, which justifies rapid antigen tests only in unvaccinated individuals. However, at a rate of 200 cases per 1 million inhabitants per day (140 cases per 100,000 per week), the post-test probability after a positive test is 57% in unvaccinated individuals and 18% in vaccinated individuals, justifying rapid antigen test use in both groups. Individuals with positive rapid antigen tests should immediately isolate and undergo confirmatory PCR testing. The post-test probability of an infectious case after a negative test is always below 1% when the rate is below 600 cases per 1 million inhabitants per day (420 cases per 100,000 per week).
# Frequency of Voluntary Screen Testing
Having established the value of rapid antigen testing as a screening test, we can now ask when and how Public Health Units should deploy them to control the spread of Delta and possibly other variants.
Figure 9 presents different epidemiological and testing scenarios modelled by Paltiel et al for unvaccinated college students, 45 suggesting that the rate of COVID-19 cases and the effective reproduction number (Rt) in the community dictates testing frequency. Scenario A assumed a rate of 40 COVID-19 cases per million per day in the community and moderate exponential growth with an R t of 1.5. Scenario B assumed 80 cases per million per day in the community, and high exponential growth with an R t of 2.5. Scenario C assumed 200 cases per million per day in the community, and explosive exponential growth with an R t of 3.5. Rapid antigen tests can be used as a tool to reduce transmission when they identify infectious cases of COVID-19 quickly and lead to prompt isolation of the infected person. In scenario A, weekly testing resulted in an 84% reduction of COVID-19 cases, with only small reductions in transmission with further increases in the frequency of testing. However, in scenario B, the increase in frequency from once to twice a week resulted in a further 22% reduction in cases, which could justify more frequent testing.
In scenario C, weekly testing was insufficient to reduce transmission; testing should be performed 2 to 5 times per week.
# Test to Stay Approach
Rapid antigen tests are a potentially useful alternative to isolation following exposure to a SARS-CoV-2-infected individual, particularly in schools. A randomized cluster trial performed in England by Young et al found no difference in rates of SARS-CoV-2 infections in staff and students between schools that offered daily rapid antigen testing to close contacts of cases, and schools that used self-isolation to manage close contacts when COVID-19 case rates were low to moderate. 46 The trial took place over a 10-week period between April and June of 2021, before the Delta variant predominated, and randomly allocated participating schools to two groups. 102 schools with approximately 112,000 students and 12,000 staff offered daily rapid antigen testing to close contacts as an alternative to self-isolation. 99 schools with 103,000 students and 12,000 staff were assigned to the control: mandatory 10day self-isolation after close contact with a case. 42% of the contacts of cases in the intervention group consented to daily testing as an alternative to self-isolation. The study reported 59.1 infections per 100,000 person-weeks at risk in the control group and 61.8 infections per 100,000 person-weeks at risk in the intervention group, for an adjusted incidence rate ratio of 0.96 (95% CI 0.75-1.22). The authors concluded that daily rapid testing of school-based contacts was non-inferior to self-isolation for control of SARS-CoV-2 transmission, with similar rates of symptomatic infections among students and staff with both approaches. Using a "test to stay" approach could therefore allow in-person learning of those who do test negative to continue whenever possible, minimizing the harm of voluntary screen testing and isolation of contacts of detected cases.
# Interpretation
Rapid antigen tests available in Ontario can reliably detect individuals with a viral load greater than 100,000 copies/mL of SARS-CoV-2, who therefore are likely to be infectious (see Figure 1). As the viral load of Delta-infected individuals increases earlier in the disease process, these tests likely perform better in the face of the Delta variant compared to previous strains of SARS-CoV-2.
Rapid antigen tests, when used for voluntary screen testing to identify asymptomatic infectious cases at specific thresholds, can be a useful tool to reduce transmission in schools and other settings. If the rate in a Public Health Unit approaches 50 COVID-19 cases per million per day (corresponding to 35 cases per 100,000 per week), weekly voluntary screen testing of unvaccinated and incompletely vaccinated individuals is recommended in elementary schools, and potentially in other settings.
If the rate in a Public Health Unit approaches 250 COVID-19 cases per million per day (corresponding to 175 cases per 100,000 per week), weekly testing is unlikely to sufficiently reduce transmission and testing of unvaccinated and incompletely vaccinated individuals 2 to 3 times per week is required. In this scenario, voluntary screen testing of fully vaccinated individuals should also be considered.
It is important to note that while rapid tests may help with earlier detection of Delta variant cases, they are not sufficient for controlling spread. Successful implementation of a rapid testing program relies on ensuring that supports are in place for all related activities, including distribution, case and contact tracing and lab-based testing, results management, and education. This brief does not address the additional challenges associated with implementation.
Individuals with positive rapid antigen tests should immediately isolate and undergo confirmatory PCR testing, which will reduce the potential harm of unnecessary prolonged isolation in rare false positive cases, and will also ensure provincial case and contact tracing. The recommended thresholds were derived based on the assumptions outlined in this Science Brief and can serve as a guidance for Public Health Units. Evaluation of the performance of rapid antigen tests for the diagnosis of the Omicron variant is urgently needed. 47
# Methods Used for This Science Brief
We searched PubMed, Google Scholar, the COVID-19 Rapid Evidence Reviews, the Joanna Briggs Institute's COVID-19 Special Collection, LitCovid in PubMed, the Oxford COVID-19 Evidence Service, the World Health Organization's Global Literature on Coronavirus Disease, and other COVID-19 specific resources listed by the Guidelines International Network and the McMaster Health Forum. In addition, we retrieved reports citing relevant articles through Google Scholar and reviewed references from identified articles for additional studies. The search was last updated on November 18, 2021.
The COVID-19 Evidence Synthesis Network performed a research evidence scan for this Science Brief, published in an Evidence Synthesis Briefing Note. 48 The COVID-19 Evidence Synthesis Network is comprised of organizations in Ontario's evidence synthesis and knowledge translation community who collectively provide high-quality, relevant, and timely synthesized research evidence about COVID-19. The Methods for the evidence scan can be found in the methods section of the Briefing Note.
We performed a random-effects meta-analysis of the probability of a positive viral culture by viral load. The relationship between the rate of cases per million inhabitants per day and the post-test probability after a positive or negative rapid antigen test in unvaccinated and vaccinated individuals was estimated based on pre-test probabilities, which were a function of rates of diagnosed cases. We transformed these probabilities into pre-test odds, multiplied the pre-test odds with likelihood ratios to derive post-test odds, and back-transformed these post-test odds into posttest probabilities. To derive pre-test probabilities we assumed that 40% of actual SARS-CoV-2 infections were diagnosed in Ontario; that diagnosed cases would remain active and contributed to community transmission for an average of 6 days, while undiagnosed cases contributed to community transmission for an average of 10 days; and that the average rate of COVID-19 cases would need to be multiplied by a factor of 3.5 to estimate the rate in unvaccinated individuals, and by 0.6 to estimate the rate in vaccinated individuals. These factors corresponded to the mean of observed multiplication factors of 3.5 (standard deviation 0.1) for unvaccinated and 0.6 (standard deviation 0.02) for vaccinated individuals during the previous 30 days.
# Author Contributions
PJ conceived the Science Brief. PJ and PB performed analyses. PJ and SB performed literature searches and wrote the first draft of the Science Brief. PJ and PB extracted data. All authors revised the Science Brief critically for important intellectual content and approved the final version.
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The affiliations of the members of the Ontario COVID-19 Science Advisory Table can be found at https:// covid19-sciencetable.ca/.#
Once a Public Health Unit or neighborhood approaches 50 new COVID-19 cases per million per day (corresponding to 35 cases per 100,000 per week) and is in sustained exponential growth, we advise weekly voluntary screen testing of unvaccinated and incompletely vaccinated individuals in elementary schools. Public health units in this situation may also decide to deploy rapid antigen testing in other settings, such as workplaces and congregate settings.
If a Public Health Unit's or neighborhood's new daily case rate approaches 250 COVID-19 cases per million per day (corresponding to 175 cases per 100,000 per week), weekly testing is likely not frequent enough to reduce spread effectively. In that case, we advise testing unvaccinated and incompletely vaccinated individuals 2 to 3 times per week. Public health units in this situation may also consider voluntary screen testing of fully vaccinated individuals at the same frequency.
Rapid antigen tests may also present a valuable alternative to individual isolation after exposure in schools. Implementing voluntary "test to stay" protocols, where exposed students remain in school as long as daily tests are negative for SARS-CoV-2, could help prevent the harms of isolation without increasing transmission.
Individuals with positive rapid antigen tests should immediately isolate and undergo confirmatory Polymerase Chain Reaction (PCR) testing. Evaluation of the performance of rapid antigen tests for the diagnosis of the Omicron variant is urgently needed.
Ontario COVID-19 Science Advisory Table Rapid Antigen Tests for Voluntary Screen Testing
# Lay Summary
The Delta Variant and Rapid Antigen Tests
Rapid antigen tests identify SARS-CoV2, the virus that causes COVID-19, in the nose or throat by detecting proteins attached to the surface of the virus (the "antigen"). This approach makes rapid antigen tests different than PCR tests, which determine whether someone is infected with SARS-CoV2 by amplifying the virus' genetic material at a lab. Because rapid tests are more easily accessible for many people than PCR tests, can be deployed in a wide range of settings including homes and schools, and produce immediate results, accurate rapid antigen testing could be a useful tool for detecting COVID-19 early and isolating infected people before they have a chance to spread the virus. Understanding the accuracy of rapid antigen tests against the Delta variant, which currently dominates in Ontario, is a key piece of disease control.
This brief establishes the high accuracy of rapid antigen tests in detecting the Delta variant of SARS-CoV-2, which is currently the dominant variant in Ontario. The Delta variant multiplies rapidly in the human body, and so the viral load of infected individuals peaks sooner with Delta than with earlier variants, often before symptoms appear. That high viral load at an earlier stage of infection makes the Delta variant more contagious than earlier variants; it is also what makes rapid antigen testing more accurate with Delta than with earlier variants.
Using studies on people carrying a range of SARS-CoV-2 viral loads, we (1) confirmed that people with high viral loads are likely to transmit the virus to the people around them, and (2) established that rapid antigen tests can reliably detect those cases. Rapid antigen tests could therefore help interrupt the chain of transmission by identifying infectious cases of COVID-19 quickly, leading to prompt isolation of the infected person.
# Our Advice
Ontario could apply rapid antigen tests in many ways, but this brief focuses on voluntary screen testing: the practice of testing asymptomatic volunteers at regular intervals in settings where there is a moderate risk of transmission, such as schools and workplaces. We considered elementary schools a priority for voluntary screen testing given that students less than 12 years of age are not fully vaccinated in Ontario.
If the COVID-19 case rate in an elementary school's Public Health Unit or neighborhood approaches 50 cases per million per day (corresponding to 35 cases per 100,000 per week), we recommend that unvaccinated and incompletely vaccinated people be tested once per week. If the COVID-19 case rate approaches 250 cases per million per day (175 cases per 100,000 per week), we recommend that unvaccinated people, and possibly also vaccinated people, be tested 2 to 3 times per week.
We also recommend using a "test to stay" approach in schools for individuals who have been exposed to someone with COVID-19 but do not have symptoms (often referred to as "contacts"). With this approach, contacts are offered daily rapid antigen testing as an alternative to self-isolation, and can continue with in-person learning as long as they test negative and remain asymptomatic for a defined risk period after exposure.
# Summary
# Background
Delta is currently the predominant variant of the SARS-CoV-2 virus in Ontario and internationally. It is more than twice as transmissible as the wild type virus that caused the first and second waves in Ontario, and 1.5 times as transmissible as the Alpha variant, which caused the third wave. While this early increase in viral load makes transmission of the Delta variant challenging to control, now that it predominates globally, rapid antigen tests may become more sensitive and more useful because of it.
# Questions
What is the peak viral load after infection with the Delta variant?
What is the relationship between viral load and transmission?
What is the performance of rapid antigen tests according to viral load or cycle threshold?
How do rapid antigen tests perform in people who are likely to be infectious?
How can rapid tests be used optimally to prevent transmission as well as the negative impacts of testing?
# Findings
The Delta variant reliably incites viral loads greater than 100,000 copies/mL (5 log 10 units). A higher viral load is reliably associated with a higher probability of transmission: a ten-fold increase in viral load (e.g., from 100,000 copies/mL to 1 million copies/mL) is, on average, associated with a 4.69-fold and 1.33-fold increase in the odds of a positive viral culture and onward transmission of the virus, respectively.
The ability of rapid antigen tests to detect a SARS-CoV-2 infection depends on the viral load of the sample, but diagnostic accuracy studies typically do not quantify viral load directly, and instead report cycle threshold (Ct) values. In subgroups of patients with Ct values of less than 30, the pooled sensitivity for any rapid antigen test and for the Abbott Panbio test (the most commonly used test in Ontario) was 79.9% and 83.4%, respectively. In subgroups of patients with Ct values of less than 25, sensitivity increased to 95.8% for any rapid antigen test, and to 94.1% for the Abbott Panbio test.
The post-test probability of an infectious case after a positive test at 50 cases per 1 million inhabitants per day (corresponding to 35 cases per 100,000 per week) was 25% in unvaccinated individuals, but only 5% in fully vaccinated individuals, which justifies rapid antigen tests only in unvaccinated individuals. However, at a rate of 200 cases per 1 million inhabitants per day, the post-test probability after a positive test was 57% in unvaccinated individuals and 18% in vaccinated individuals, justifying rapid antigen test use in both groups.
If the effective reproduction number (R t ) is consistently above 1.25, or if R t is around 1 and the rate in a Public Health Unit (or other geographical unit as appropriate) approaches 50 cases per million per day (35 cases per 100,000 per week) and if there is sustained exponential growth, weekly voluntary screen testing of unvaccinated and incompletely vaccinated individuals is recommended in elementary schools. If the rate in a Public Health Unit approaches 250 cases per million per day (175 cases per 100,000 per week), weekly testing is unlikely to sufficiently reduce transmission and testing of unvaccinated and incompletely vaccinated individuals 2 to 3 times per week is required. In this scenario, voluntary screen testing of fully vaccinated individuals at the same frequency should also be considered.
A "test-to-stay" approach with daily rapid testing of school-based contacts appears non-inferior to self-isolation for control of SARS-CoV-2 transmission, with similar rates of symptomatic infections among students and staff with both approaches.
# Interpretation
Rapid antigen tests available in Ontario can reliably detect individuals with a viral load greater than 100,000 copies/mL of SARS-CoV-2, who therefore are likely to be infectious. As the viral load of Delta-infected individuals increases earlier in the disease process, these tests likely perform better in the face of the Delta variant compared to previous strains of SARS-CoV-2.
Individuals with positive rapid antigen tests should immediately isolate and undergo confirmatory PCR testing, which will reduce the potential harm of unnecessary prolonged isolation in rare false positive cases, and will also ensure provincial case and contact tracing.
# Background
Delta is currently the predominant variant of the SARS-CoV-2 virus in Ontario and internationally. 1 It is more than twice as transmissible as the wild type virus that caused the first and second waves in Ontario, and 1.5 times as transmissible as the Alpha variant. 2 The Delta variant also causes more severe illness than the wild type and the Alpha variant. 3 While the Omicron variant appears to spread more quickly than Delta, as of December 7, 2021 Delta remains dominant in Ontario. The effectiveness of rapid antigen testing in detecting Omicron also remains unclear, and needs to be studied urgently. This brief thus does not include any evidence or recommendations regarding rapid antigen testing for the Omicron variant.
The increased transmissibility of the Delta variant compared to previous strains can be partially explained by the viral load trajectory after infection. Figure 1 shows the progression of viral load in individuals infected with the delta variant compared to the wild type virus. Within the first four days after exposure, the viral load of the Delta variant increases considerably faster and peaks sooner than the wild type virus, 4,5 typically producing a viral load of 100,000 copies/mL (5 log 10 units) only one to two days after exposure.
# Figure 1. Representative Trajectories of Viral Loads for the Delta Variant as Compared with the Wild Type
The viral load of the Delta variant increases quickly and reaches its peak earlier than the wild type virus, 4 typically producing a viral load of 100,000 copies/mL (5 log 10 units) one to two days after exposure. After reaching the peak viral load, the trajectories are likely similar between the two variants. Each log 10 unit corresponds to a 10-fold increase in viral load (copies/mL). Graph based on data from Li et al 4 and Kang et al. 5 While this early increase in viral load makes transmission of the Delta variant challenging to control, now that it predominates in Ontario and internationally, rapid antigen tests may become more sensitive and more useful because of it. [6][7][8] Consistent with this concept, Bekliz et al recently found that rapid antigen tests are sufficiently sensitive to detect variants of concern, including the Delta variant. 9 Rapid antigen tests might be particularly useful for voluntary screen testing, which entails regular voluntary testing of asymptomatic individuals to find cases in moderate-risk settings such as schools and workplaces (Box 1). This Science Brief will only discuss voluntary screen testing and test to stay strategies, as indicated in the Box below.
# Type of Testing Description
Addressed in this Brief? Rapid Antigen Testing in Asymptomatic Individuals Voluntary screen testing Regular voluntary testing of asymptomatic individuals to find cases in moderate-risk settings such as schools and workplaces.
# Yes
# Test to stay
Daily voluntary testing of asymptomatic contacts of individuals with a positive COVID-19 test in schools instead of requiring isolation.
# Yes
# Test to protect
Regular mandatory testing of asymptomatic individuals to find cases in high-risk settings to protect the vulnerable (e.g., hospitals, long-term care homes, prisons).
# No
# Test to enable (including "test to play")
Regular mandatory testing of asymptomatic individuals to enable participation in activities with a high risk of transmission (e.g., close-contact sports, visits to long-term care homes).
# No
# Test to release
One-time or repeated mandatory testing of asymptomatic contacts or travelers to allow for early release from quarantine.
# No
# Outbreak response testing
One-time or repeated voluntary or mandatory testing of asymptomatic individuals in a facility, such as a workplace or congregate setting, with a COVID-19 outbreak as an alternative to closure.
# No
# Rapid Antigen Testing in Symptomatic Individuals Diagnostic testing
One-time or repeated testing of symptomatic individuals in settings where PCR testing is less accessible, or in individuals with few or atypical symptoms.
# No
# Box 1. Potential Indications for Rapid Antigen Testing and Whether they Are Addressed in this Science Brief
Adapted from Crozier et al. 8 In this Science Brief, we assessed the usefulness of rapid antigen testing through a sequence of questions derived from the following logic. Rapid antigen tests detect proteins attached to the surface of a virus. PCR, the established gold standard for testing, identifies the virus by replicating its genetic material through enough cycles to make it detectable; the fewer cycles that are necessary to make viral material detectable, the more viral material there is. The number of cycles needed to surpass this threshold of detection is called cycle threshold. In this Science Brief, we assessed whether cases with high viral loads/low cycle thresholds are likely to be infectious, and if so, whether rapid antigen tests can reliably detect those cases.
# Questions
What is the peak viral load after infection with the Delta variant?
# What is the relationship between viral load and transmission?
What is the performance of rapid antigen tests according to viral load or cycle threshold?
How do rapid antigen tests perform in people who are likely to be infectious?
How can rapid tests be used optimally to prevent transmission as well as the negative impacts of testing?
# Findings Peak Viral Load after Infection with the Delta Variant
Figure 2 presents the peak viral load observed in 45 individuals infected with the Delta variant who underwent daily testing after exposure. A total of 43 individuals had peak viral loads greater than 100,000 copies/mL (5 log 10 units), and 41 individuals (91.1%) had peak viral loads greater than 1 million copies/mL (6 log 10 units). 10 The Delta variant therefore reliably incites high viral loads greater than 100,000 copies/mL. The peak viral loads were similar between unvaccinated and fully vaccinated individuals, but viral load declined faster in vaccinated individuals after reaching the peak. A total of 43 individuals had peak viral loads greater than 100,000 copies/mL (5 log 10 units), and 41 individuals (91.1%) had peak viral loads greater than 1 million copies/mL (6 log 10 units). Data from Singanayagam et al. 10
# Relationship between Viral Load and Transmission
In the sections above, we established that Delta carries a higher viral load at an earlier stage of infection than other variants. If rapid antigen tests can reliably detect cases with a high viral load, then it is important to know if those are the cases that are likely to be infectious. Here, we determine whether a high viral load is associated with a higher probability of transmission.
Table 1 presents the results of the seven identified studies that estimated the association between viral load and the odds of a positive viral culture for the wild type virus and Alpha variant. [11][12][13][14][15][16][17] A positive viral culture suggests viable virus that can potentially be transmitted to others. Conversely, a negative culture implies low transmission potential, as no viable virus could be grown.
The median odds ratio per log 10 increase in viral load was 4.69, indicating that a tenfold increase in viral load (e.g., from 100,000 copies/mL to 1 million copies/mL) is associated with a 4.69-fold increase in the odds of a positive viral culture, on average. Results were consistent across studies, with the exception of those reported by Korenkov et al, which suggested a considerably stronger relationship between viral load and the odds of a positive culture. 12 Six of the seven identified studies were suitable for inclusion in a meta-analysis of the probability of a positive viral culture by viral load. At a viral load of 10,000 copies/ mL (4 log 10 units), there was little variation between estimates, resulting in a pooled probability of a positive culture of 0.2% (Figure 3). The probability increased alongside viral load, with higher variation between studies at a viral load of 10 million copies/mL (7 log 10 units) or more. At the maximum viral load of 1 billion copies/mL, the pooled probability of a positive culture was 92.5%.
Table 2 presents the results of five identified studies that estimated the association between viral load and the odds of transmission, mainly for the wild type virus and Alpha variant. [18][19][20][21][22] The association for the Delta variant was consistent. 22 The median odds ratio per log 10 increase in viral load in any setting, or within a non-household setting, was 1.33, indicating that, on average, a ten-fold increase in viral load (e.g., from 100,000 copies/mL to 1 million copies/mL) is associated with a 1.33-fold increase in the odds of transmission. The only study that assessed the association in a household setting specifically found an odds ratio of 1.77 per log 10 increase in viral load. 19 Since there is less variation in the exposure of contacts in household settings, this stronger association is expected.
# Five Studies Estimating the Association Between Observed Viral Load and Odds of Transmission by Virus Strain and Setting
The median odds ratio per log 10 increase in viral load in any setting, or within a non-household setting, was 1.33, indicating that a ten-fold increase in viral load (e.g., from 100,000 copies/mL to 1 million copies/mL) is associated with a 1.33-fold increase in the odds of transmission, on average. The only study that assessed the association in a household setting specifically found an odds ratio of 1.77 per log 10 increase in viral load. 19 Figure 4 shows the estimated relationship between viral load and the probability of positive culture, the probability of transmission in households, and the probability of transmission in any setting, based on the studies included in Tables 1 and 2. The association with viral load was strong in all three cases. Below a viral load of 1 million copies/mL (6 log 10 units), the estimated probability of transmission is higher than the estimated probability of a positive culture, which may be due to the timing of sampling: individuals with viral loads below 1 million copies/mL who caused transmission may not have been sampled at their peak viral load. Regardless, a high viral load appears to be associated with a higher probability of positive viral culture and onward transmission for the wild type virus and the Alpha variant, and this relationship likely also holds true for the Delta variant. At a viral load of 10,000 copies/mL (4 log 10 units), there was little variation between estimates, resulting in a pooled probability of a positive culture of 0.2%. The probability increased alongside viral load, with higher variation between studies at a viral load of 10 million copies/mL (7 log 10 units) or more. At the maximum viral load of 1 billion copies/mL, the pooled probability of a positive culture was 92.5%.
# Figure 4. Estimated Association Between Observed Viral Load and Probability of Positive Culture, Transmission in Households and Transmission in Any Setting
There are strong associations between viral load and the probability of positive culture, the probability of transmission in household settings, and the probability of transmission in any setting. Median estimates of the associations were taken from Tables 1 and 2, the association for household settings is from Marc et al. 19
# Performance of Rapid Antigen Tests According to Viral Load and Cycle Threshold
Having established that Delta is characterized by early, high viral loads and that a higher viral load is associated with a higher probability of cultured virus and transmission, we assessed whether rapid antigen tests are effective at detecting infections in people with early, high viral loads that appear to drive Delta's transmission. Below, we relate the detection of SARS-CoV-2 by rapid antigen tests with minimum cycle threshold (Ct) values found in PCR tests. 23 The Abbott Panbio test is the most commonly used test in Ontario. 24 A higher viral load is associated with a lower PCR Ct value, as less amplification of the viral genetic material in the sample is needed to reach the threshold for detection.
At a viral load of 100,000 copies/mL (corresponding to a Ct value of 25.0 according to a single study by Peto et al) 23 , the estimated sensitivity of the Abbott Panbio test was 84.3%. At a viral load of 1 million copies/mL (corresponding to a Ct value of 21.5), the estimated sensitivity was 94.1%. At 100 million copies/mL, which corresponds to the peak viral load in more than 50% of the 45 people studied in Figure 2, the estimated sensitivity was 99.3%. 6 The manufacturer of the BTNX Rapid Response test reported a specificity of 100%. 25 There are many rapid antigen tests available globally, and their sensitivity can vary widely; 26 however, the tests available in Ontario are all sufficiently sensitive and specific to be useful.
# Relationship between Cycle Threshold (Ct) Values and Viral Load
In the course of establishing that rapid antigen tests are effective in detecting cases with high viral loads, we now assess the variation in the reported relationship between Ct values and actual viral loads. This relationship is established at the level of the laboratory performing the PCR tests during test calibration. Our assessment allows us to define a maximum Ct value, that may be used to identify the subgroup of people with SARS-CoV-2 infections that should be analyzed to estimate the diagnostic performance of rapid antigen tests when detecting infectious cases.
The relationship between Ct value and viral load depends on the type of assay, the RNA primer and the calibration process. Figure 5 shows the estimated range of Ct values at a viral load of 100,000 Copies/mL from 42 identified standard curves. [12][13][14]20,22,23,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] The median Ct value at this viral load was 25 [12][13][14]20,22,23,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] The median Ct value at this viral load was 25.82 (interquartile range 23.03 to 29.27). Ct, cycle threshold.
Figure 6 shows the cumulative distribution of viral loads at a Ct value of 30 from the same 42 standard curves used to produce Figure 5. At a Ct value of 30, the median viral load was 5,400 copies/mL (interquartile range 500 to 60,000 copies/mL), and an estimated 83% of assays reported viral loads below 100,000 copies/mL at this threshold.
The pooled sensitivity estimates provided by Brümmer et al 6 for the subgroup of patients with Ct values below 30 can therefore be used to produce conservative estimates of the diagnostic performance of rapid antigen tests when detecting infectious cases with viral loads of 100,000 copies/mL or more.
# Ability of Rapid Antigen Tests to Detect or Rule Out Infectious Cases
In the previous sections, we established that rapid antigen tests can detect the high viral loads that characterize an early Delta infection, and that these high viral loads are associated with the likelihood of transmission. We also established that samples with a Ct value of less than 30 can be used to conservatively estimate the ability of rapid antigen tests to detect or rule out with reasonable certainty currently infectious cases. Here, we return to the patient themselves to assess the probability of being an infectious case after a positive or negative rapid antigen test, taking into account case rates in the community or a Public Health Unit, and the individual's vaccination status.
Figure 7 presents the number of COVID-19 cases per 1 million inhabitants per day in Ontario by vaccination status. The case numbers are currently five to six times greater in unvaccinated individuals compared to fully vaccinated individuals, which means that the pre-test probability of SARS-CoV-2 infection is also five to six times greater in the unvaccinated population. The results of a rapid antigen test should therefore always be interpreted taking the individual's vaccination status into consideration. [12][13][14]20,22,23,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] At a Ct value of 30, the median viral load was 5,400 copies/mL, and an estimated 83% of assays reported viral loads below 100,000 copies/mL at this threshold. Ct, cycle threshold.
The most conservative pooled estimate of the sensitivity of rapid antigen tests for detecting an infectious case reported by Brümmer et al is 79.9% in patients with Ct values less than 30. The most conservative pooled estimate of specificity (reported for the Quidel Sofia test) is 99.1%. 6 We feel that our estimates of sensitivity are conservative, and would account for the lower test sensitivity that occurs when the test is performed by a lay person instead of a professional, such as a laboratory scientist or health worker. 23 These estimates can be used to calculate likelihood ratios for a positive or negative test result, which depend on sensitivity and specificity.
The likelihood ratio for a positive test result specifies how much more likely it is to obtain a positive test result in an infectious case compared to someone who is not infected or unlikely to be infectious. 44 Using the aforementioned sensitivity and specificity, the positive likelihood ratio is 0.799/(1-0.991)=88.8, indicating that the test has the power to confidently rule in an infectious case.
The likelihood ratio for a negative test result indicates how much less likely it is to obtain a negative result in a potentially infectious case compared to someone who is not infected or unlikely to be infectious. 44 Using the aforementioned sensitivity and specificity, the negative likelihood ratio is (1-0.799)/ 0.991=0.20, which is low enough to be clinically relevant and have the power to rule out an infectious case.
Figure 8 presents the relationship between the daily rate of COVID-19 cases in Ontario and the post-test probability of an infectious case after a positive or negative rapid antigen test. The post-test probability is influenced by the pre-test probability, and the test result (positive vs. negative) and by the likelihood ratio of the rapid antigen test being used.
# Figure 7. COVID-19 Cases per 1 Million Inhabitants per Day in Ontario by Vaccination Status
The number of COVID-19 Cases per 1 million inhabitants per day in unvaccinated people is currently 4 to 6 times higher than in fully vaccinated people, which needs to be taken into account when interpreting results of rapid antigen tests.
# Figure adapted from Ontario Dashboard. 1
Unvaccinated people have a higher pre-test probability of disease, and therefore have a higher probability of being an infectious case after both a positive or a negative test compared to vaccinated people. This information is relevant to decisions about rapid antigen test use. For example, the post-test probability of an infectious case after a positive test at 50 cases per 1 million inhabitants per day (corresponding to 740 cases per day in Ontario, or to 35 cases per 100,000 per week) is 25% in unvaccinated individuals, but only 5% in fully vaccinated individuals, which justifies rapid antigen tests only in unvaccinated individuals. However, at a rate of 200 cases per 1 million inhabitants per day (140 cases per 100,000 per week), the post-test probability after a positive test is 57% in unvaccinated individuals and 18% in vaccinated individuals, justifying rapid antigen test use in both groups. Individuals with positive rapid antigen tests should immediately isolate and undergo confirmatory PCR testing. The post-test probability of an infectious case after a negative test is always below 1% when the rate is below 600 cases per 1 million inhabitants per day (420 cases per 100,000 per week).
# Frequency of Voluntary Screen Testing
Having established the value of rapid antigen testing as a screening test, we can now ask when and how Public Health Units should deploy them to control the spread of Delta and possibly other variants.
Figure 9 presents different epidemiological and testing scenarios modelled by Paltiel et al for unvaccinated college students, 45 suggesting that the rate of COVID-19 cases and the effective reproduction number (Rt) in the community dictates testing frequency. Scenario A assumed a rate of 40 COVID-19 cases per million per day in the community and moderate exponential growth with an R t of 1.5. Scenario B assumed 80 cases per million per day in the community, and high exponential growth with an R t of 2.5. Scenario C assumed 200 cases per million per day in the community, and explosive exponential growth with an R t of 3.5. Rapid antigen tests can be used as a tool to reduce transmission when they identify infectious cases of COVID-19 quickly and lead to prompt isolation of the infected person. In scenario A, weekly testing resulted in an 84% reduction of COVID-19 cases, with only small reductions in transmission with further increases in the frequency of testing. However, in scenario B, the increase in frequency from once to twice a week resulted in a further 22% reduction in cases, which could justify more frequent testing.
In scenario C, weekly testing was insufficient to reduce transmission; testing should be performed 2 to 5 times per week.
# Test to Stay Approach
Rapid antigen tests are a potentially useful alternative to isolation following exposure to a SARS-CoV-2-infected individual, particularly in schools. A randomized cluster trial performed in England by Young et al found no difference in rates of SARS-CoV-2 infections in staff and students between schools that offered daily rapid antigen testing to close contacts of cases, and schools that used self-isolation to manage close contacts when COVID-19 case rates were low to moderate. 46 The trial took place over a 10-week period between April and June of 2021, before the Delta variant predominated, and randomly allocated participating schools to two groups. 102 schools with approximately 112,000 students and 12,000 staff offered daily rapid antigen testing to close contacts as an alternative to self-isolation. 99 schools with 103,000 students and 12,000 staff were assigned to the control: mandatory 10day self-isolation after close contact with a case. 42% of the contacts of cases in the intervention group consented to daily testing as an alternative to self-isolation. The study reported 59.1 infections per 100,000 person-weeks at risk in the control group and 61.8 infections per 100,000 person-weeks at risk in the intervention group, for an adjusted incidence rate ratio of 0.96 (95% CI 0.75-1.22). The authors concluded that daily rapid testing of school-based contacts was non-inferior to self-isolation for control of SARS-CoV-2 transmission, with similar rates of symptomatic infections among students and staff with both approaches. Using a "test to stay" approach could therefore allow in-person learning of those who do test negative to continue whenever possible, minimizing the harm of voluntary screen testing and isolation of contacts of detected cases.
# Interpretation
Rapid antigen tests available in Ontario can reliably detect individuals with a viral load greater than 100,000 copies/mL of SARS-CoV-2, who therefore are likely to be infectious (see Figure 1). As the viral load of Delta-infected individuals increases earlier in the disease process, these tests likely perform better in the face of the Delta variant compared to previous strains of SARS-CoV-2.
Rapid antigen tests, when used for voluntary screen testing to identify asymptomatic infectious cases at specific thresholds, can be a useful tool to reduce transmission in schools and other settings. If the rate in a Public Health Unit approaches 50 COVID-19 cases per million per day (corresponding to 35 cases per 100,000 per week), weekly voluntary screen testing of unvaccinated and incompletely vaccinated individuals is recommended in elementary schools, and potentially in other settings.
If the rate in a Public Health Unit approaches 250 COVID-19 cases per million per day (corresponding to 175 cases per 100,000 per week), weekly testing is unlikely to sufficiently reduce transmission and testing of unvaccinated and incompletely vaccinated individuals 2 to 3 times per week is required. In this scenario, voluntary screen testing of fully vaccinated individuals should also be considered.
It is important to note that while rapid tests may help with earlier detection of Delta variant cases, they are not sufficient for controlling spread. Successful implementation of a rapid testing program relies on ensuring that supports are in place for all related activities, including distribution, case and contact tracing and lab-based testing, results management, and education. This brief does not address the additional challenges associated with implementation.
Individuals with positive rapid antigen tests should immediately isolate and undergo confirmatory PCR testing, which will reduce the potential harm of unnecessary prolonged isolation in rare false positive cases, and will also ensure provincial case and contact tracing. The recommended thresholds were derived based on the assumptions outlined in this Science Brief and can serve as a guidance for Public Health Units. Evaluation of the performance of rapid antigen tests for the diagnosis of the Omicron variant is urgently needed. 47
# Methods Used for This Science Brief
We searched PubMed, Google Scholar, the COVID-19 Rapid Evidence Reviews, the Joanna Briggs Institute's COVID-19 Special Collection, LitCovid in PubMed, the Oxford COVID-19 Evidence Service, the World Health Organization's Global Literature on Coronavirus Disease, and other COVID-19 specific resources listed by the Guidelines International Network and the McMaster Health Forum. In addition, we retrieved reports citing relevant articles through Google Scholar and reviewed references from identified articles for additional studies. The search was last updated on November 18, 2021.
The COVID-19 Evidence Synthesis Network performed a research evidence scan for this Science Brief, published in an Evidence Synthesis Briefing Note. 48 The COVID-19 Evidence Synthesis Network is comprised of organizations in Ontario's evidence synthesis and knowledge translation community who collectively provide high-quality, relevant, and timely synthesized research evidence about COVID-19. The Methods for the evidence scan can be found in the methods section of the Briefing Note.
We performed a random-effects meta-analysis of the probability of a positive viral culture by viral load. The relationship between the rate of cases per million inhabitants per day and the post-test probability after a positive or negative rapid antigen test in unvaccinated and vaccinated individuals was estimated based on pre-test probabilities, which were a function of rates of diagnosed cases. We transformed these probabilities into pre-test odds, multiplied the pre-test odds with likelihood ratios to derive post-test odds, and back-transformed these post-test odds into posttest probabilities. To derive pre-test probabilities we assumed that 40% of actual SARS-CoV-2 infections were diagnosed in Ontario; that diagnosed cases would remain active and contributed to community transmission for an average of 6 days, while undiagnosed cases contributed to community transmission for an average of 10 days; and that the average rate of COVID-19 cases would need to be multiplied by a factor of 3.5 to estimate the rate in unvaccinated individuals, and by 0.6 to estimate the rate in vaccinated individuals. These factors corresponded to the mean of observed multiplication factors of 3.5 (standard deviation 0.1) for unvaccinated and 0.6 (standard deviation 0.02) for vaccinated individuals during the previous 30 days.
# Author Contributions
PJ conceived the Science Brief. PJ and PB performed analyses. PJ and SB performed literature searches and wrote the first draft of the Science Brief. PJ and PB extracted data. All authors revised the Science Brief critically for important intellectual content and approved the final version.
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The 2022 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for Acute Stroke Management, 7 th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by an interdisciplinary team of healthcare providers and system planners caring for persons with an acute stroke or transient ischemic attack. These recommendations are a timely opportunity to reassess current processes to ensure efficient access to acute stroke diagnostics, treatments, and management strategies, proven to reduce mortality and morbidity. The topics covered include prehospital care, emergency department care, intravenous thrombolysis and endovascular thrombectomy (EVT), prevention and management of inhospital complications, vascular risk factor reduction, early rehabilitation, and end-of-life care. These recommendations pertain primarily to an acute ischemic vascular event. Notable changes in the 7 th edition include recommendations pertaining the use of tenecteplase, thrombolysis as a bridging therapy prior to mechanical thrombectomy, dual antiplatelet therapy for stroke prevention, 1 the management of symptomatic intracerebral hemorrhage following thrombolysis, acute stroke imaging, care of patients undergoing EVT, medical assistance in dying, and virtual stroke care. An explicit effort was made to address sex and gender differences wherever possible. The theme of the 7 th edition of the CSBPR is building connections to optimize individual outcomes, recognizing that many people who present with acute stroke often also have multiple comorbid conditions, are medically more complex, and require a coordinated interdisciplinary approach for optimal recovery. Additional materials to support timely implementation and quality monitoring of these recommendations are available at www.strokebestpractices.ca.Recommandations canadiennes pour les pratiques optimales de soins de l'AVC : prise en charge de l'AVC en phase aiguë, 7e édition, mise à jour des lignes directrices de pratique 2022. La version mise à jour de 2022 de la section des Recommandations canadiennes# Introduction
Stroke prevention, treatment, and recovery have completely transformed over the past several decades due to research breakthroughs, increased awareness, and improvements to systems of care. Canada continues to be a world leader in driving innovation and change across the stroke continuum of care. In Canada, in 2017, there were 108,707 hospital visits for an acute stroke event, 2 and stroke remains a leading cause of adult disability with over 878,000 people living in Canada with the consequences of stroke. 3 In Canada, stroke systems of care have been growing since the late 1990s when acute thrombolysis became available. Currently, 232 hospitals (35%) are capable of providing acute thrombolysis, and this number now includes 155 hospitals with dedicated stroke teams and 95 acute stroke units. Twenty-five hospitals in Canada provide endovascular thrombectomy (EVT). 4 The global pandemic caused by the COVID-19 virus brought increased risk and worse outcomes for people with stroke and impacted response times by both the public and healthcare providers. The 7 th update of the Canadian Stroke Best Practice Recommendations (CSBPR) for Acute Stroke Management is a timely opportunity to reassess current processes to ensure efficient access to acute stroke diagnostics, treatments, and management strategies, which have proven to reduce mortality and morbidity. The topics covered include those related to prehospital care, emergency department (ED) care, acute treatments with intravenous thrombolysis and EVT, the prevention and management in hospital complications, vascular risk factor reduction strategies, early rehabilitation, and end-of-life care. The theme of the 7 th edition of this CSBPR is building connections to optimize individual outcomes. Following an acute stroke, persons often present with multiple comorbid conditions, some of which may have contributed to their stroke, some that are the consequence of their stroke, and some which are unrelated. In many cases, comorbidities such as hypertension, carotid stenosis, and patent foramen ovale (PFO) may be first detected at the time of stroke. Regardless of the etiology, persons presenting with stroke and multiple comorbidities are more complex and are at risk of worse outcomes. These comorbid conditions must be considered within the treatment and care planning process to ensure effective and person-centered care.
The CSBPRs are intended to provide up-to-date evidence-based guidelines for the prevention and management of stroke and to promote optimal recovery and reintegration for people who have experienced stroke, including patients, families, and caregivers. The goal of disseminating and implementing these recommendations is to optimize evidence-based stroke care across Canada to reduce practice variations in care delivery and to narrow the gap between current knowledge and clinical practice. These recommendations have been developed in collaboration with the Canadian Stroke Consortium, Canada's national organization of stroke physicians. The recommendations are applicable to all healthcare providers, health system leaders and planners, and people living with stroke. The CSBPR Acute Stroke Management 2022, 7 th edition supersedes all recommendations contained in the 2018 CSBPR 6 th edition of Acute Stroke Management. 9
# Guideline Development Methodology
The CSBPR development and update process follows a rigorous framework 10,11 and addresses all criteria defined within the Appraisal of Guidelines for Research and Evaluation II (AGREE II) Instrument components. 12 The methodology for development and updates to the CSBPR has been previously published, 13 and detailed methodology can be found on our Canadian Stroke Best Practices website at www.strokebestpractices.ca. An interdisciplinary group of experts was convened and participated in reviewing, drafting, and revising all recommendation statements. Eight people with lived experience of stroke (seven people with stroke and one caregiver) also actively participated in the review and update process as part of our acute stroke community consultation and review panel. 14 Searches were conducted by experienced personnel to identify peer-reviewed literature that examined each topic area addressed in the current module. Systematic reviews, meta-analyses, randomized controlled trials, and observational studies were included, as available. The literature for this module was current to September 2022. Following a standardized abstraction format, evidence tables were constructed including content from selected studies and provided to the writing group for review. The writing group discussed and debated the strength, importance, clinical relevance, and applicability of the evidence and, through consensus, developed a draft set of proposed recommendations. During this process, additional literature may have been identified and used to develop a final set of proposed recommendations. Evidence levels were assigned based on the quality of available evidence, using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system. Expert opinion was used to formulate recommendations in the absence of evidence. These guidelines have undergone extensive internal and external review, and consensus was achieved for all content. For additional details of the methodology and additional materials to support these recommendations, including rationales, system implications, performance measures, knowledge translation and implementation tools, evidence tables, and an extended summary of the evidence, please visit: www. strokebestpractices.ca. Supplemental online materials are available with this publication to support many of the recommendations included.
# Summary of Changes and Updates in the Acute Stroke Management Stroke, 7 th Edition, 2022
Significant updates and new additions to the CSBPR for Acute Stroke Management, 7 th edition 2022 are based, in part, on the results from several new, important clinical trials. Notable changes in the 7 th edition include recommendations pertaining the use of tenecteplase, thrombolysis as a bridging therapy prior to mechanical thrombectomy, dual antiplatelet therapy (DAPT) for stroke prevention, 1 the management of symptomatic intracerebral hemorrhage (ICH) following thrombolysis, acute stroke imaging (Section 4), pre-and post-op care of patients undergoing EVT (Section 5), medical assistance in dying (MAiD) (Section 11), and virtual stroke care in the ED and inpatient care (Sections 4 and 8).
An explicit effort was made to address sex and gender differences wherever possible. The first four sections of this guideline pertain to all people presenting with signs of acute stroke or TIA. The remaining sections pertain largely to the management of acute ischemic stroke and TIA. Guidelines for the management of patients with ICH were released in 2020, 18 while those for subarachnoid hemorrhage and cerebral venous thrombosis are in development.
Acute Stroke Management Recommendations, 7 th Edition, Update 2022
Note, please refer to online Supplemental Material accompanying these recommendations for additional definitions, information, inclusion criteria, and other implementation content. This manuscript has been translated into French and is also available as an online supplement.
# Section 1: Stroke Awareness, Recognition, and Response
Many members of the general public are unable to recognize the signs and symptoms of a stroke, or they attribute them to a less serious health issue. While 61% of the population in Canada knows at least one sign of stroke, only 33% know at least two and only 10% know all three, based on the FAST (Face, Arms, Speech, Time) mnemonic. 22 The failure to recognize the signs of an acute stroke, either by the persons witnessing one or the person experiencing one, can delay contact with emergency services, which may in turn decrease a patient's opportunity to receive time-sensitive treatments. The number of public health campaigns designed to increase recognition of the signs and symptoms of stroke has increased over the past decade. One of the best recognized programs in the healthcare community is FAST. The results of a systematic review 23 suggest that stroke education using mass media campaigns can increase the likelihood of symptom recognition by 20% and increase the likelihood that persons would call emergency services by 19%. Mass media campaigns have also been shown to be associated with increases in the use of thrombolytic agents following acute stroke. 24 1. Stroke Awareness, Recognition, and Response Recommendations 2022 i. Organized and integrated stroke systems of care should be established and sustained in every health region in Canada to enable rapid emergency stroke management, including a public awareness campaign, public emergency system (such as 9-1-1), and monitoring systems that consider equity, age, sex, and gender diverse populations .
ii. All members of the public and all healthcare providers should be educated that stroke is a medical emergency People experiencing signs of stroke require rapid assessment, diagnosis, and determination of risk for a recurrent stroke. Patients diagnosed to have TIA, or subacute, non-disabling ischemic strokes who are not candidates for hyperacute treatment with intravenous thrombolysis and/or EVT still require timely assessment and management, which can often be provided in an outpatient setting. The goal of outpatient management is to rapidly identify neurovascular risk factors, which may have precipitated the index event, and to initiate treatments to reduce the risk of recurrent events. The increased use and availability of sensitive neuroimaging to identify minor events as well as the increased use of antiplatelet agents, anticoagulants, antihypertensive agents, lipid-lowering agents, and carotid revascularization has been shown to significantly reduce the risk of major stroke after an initial minor event in recent years. In the TIARegistry.Org group study, 78.4% of patients were seen by a stroke specialist within 24 h of the event. 25 Most patients received key urgent investigations before discharge, and appropriate treatments were initiated. For example, 5.0% of patients received a new diagnosis of atrial fibrillation, of which 66.8% received anticoagulant therapy before discharge. Carotid stenosis of ≥50% was found in 15.5% of patients, of which 26.9% underwent carotid revascularization
# Triage and Initial Diagnostic Evaluation of Transient Ischemic Attack and Non-Disabling Stroke Recommendations 2022
# Notes
- Section 2 recommendations pertain to the initial management of patients with a suspected acute transient ischemic attack (TIA) or acute ischemic stroke who are not candidates for acute thrombolysis or endovascular intervention. For patients with suspected acute stroke that warrant hyperacute assessment to determine eligibility for intravenous thrombolysis and endovascular thrombectomy (EVT), refer to the current CSBPR Acute Stroke Management treatment recommendations, Sections 4 and 5.
- Refer to online Supplemental Materials for additional notes about this section. 1. Referral to a healthcare professional with stroke expertise should be considered for patients with a suspected uncommon cause of stroke, including for young patients with stroke (e.g., <45 years of age) 27 family history of young-onset stroke; suspected cerebral vasculitis or other intracranial arteriopathy/ vasculopathy; or suspected hereditary or acquired thrombophilia.
- Patients with symptoms of vertebrobasilar ischemia may present with fluctuating brainstem/cerebellar type symptoms (e.g., diplopia, dysarthria, dysphagia, non-positional vertigo, ataxia; rarely as isolated symptoms) over a longer time course (i.e., >48 hours) and can be mistaken for stroke mimics; however, these patients also require urgent assessment, neurovascular imaging, and management as these types of strokes can have a high morbidity. Consultation with a healthcare professional with stroke expertise is strongly encouraged.
# Setting:
In some regions, urgent/rapid TIA clinics are available that have rapid access to diagnostic services and specialist assessment and management. These clinics may be considered an appropriate referral option for patients with TIA and minor stroke.
before discharge. The 1-year estimate of risk of the primary outcome, a composite of death from cardiovascular causes, nonfatal stroke, and nonfatal acute coronary syndrome, was 6.2% (95% confidence interval 5.5-7.0%). Estimates of stroke at days 2, 7, 30, 90, and 365 were 1.5%, 2.1%, 2.8%, 3.7%, and 5.1%, respectively. These estimates were almost half of those compared with historical cohorts, possibly reflecting faster access to preventive care in the contemporary cohort. The availability of TIA outpatient clinics appears to be increasing. Based on the results of a geospatial analysis, there were 123 secondary prevention clinics in Canada, as of 2016. 26 While over 87% of the population had access to such a clinic within a 1-h drive, only 69.2% has access to a service that operates 5-7 days a week.
# Section 3: Emergency Medical Services
Emergency medical services (EMS) play a critical role in prehospital assessment and management of patients with suspected stroke. Patients arriving to hospital using EMS following a stroke experience fewer delays in receiving appropriate diagnostic tests, and are more likely to receive revascularization treatments, if eligible. In 2020, 69.0% of patients with stroke admitted to hospital in Canada were transported by EMS. 30 The odds of a patient receiving treatment with intravenous thrombolysis were increased by 52% if the patient was transported by EMS and increased by 75% if a system of hospital prenotification was employed. 31 Given the time-sensitive nature of acute stroke treatment, it is imperative that patients who may be candidates for these therapies be transported directly to comprehensive stroke centers as quickly as possible and whenever possible. The 90-day outcomes of patients who received EVT following direct transport have been shown to be better than those who were first transported to a primary stroke center. 32,33 However, in a recent cluster-randomized trial 34 in which paramedics transporting patients with ischemic stroke were randomized to the PASTA pathway (including structured prehospital information collection, prompted prenotification, and structured handover of information) or standard care, there was no significant difference between groups in the proportion of patients
Virtual care-enabled evaluations of patients for secondary stroke prevention should be modeled on the topics defined in the post-stroke checklist and core elements of stroke prevention care. Refer to CSBPR Post Stroke Checklist for additional information at www.strokebestpractices.ca.
Validated approaches to virtual neurological exams should be followed.
- Processes should be in place to book follow-up tests, referrals, and other consultations after a virtual care visit.
- Processes to ensure appropriate documentation and communication to other team members who may be involved in remote care should be in place.
- Patients and their families should be encouraged to acquire home blood pressure monitors where appropriate and education or reliable resources on proper use should be provided. Mechanisms should be in place for follow-up and management of blood pressure for patients using home blood pressure devices, by either primary care providers or a stroke prevention service.
- For timely investigations, the use of prolonged cardiac monitors, if available, that can be sent to patient's homes, self-applied, and returned by mail, should be considered. ii. EMS communications centre: All regions in Canada should implement a dispatch process through their EMS communications centres to rapidly recognize signs or symptoms of stroke (e.g., FAST: Face, Arms, Speech, Time), prioritize response to the scene, and transport the patient to a hospital capable of providing acute services for rapid diagnosis and time-sensitive treatment of stroke (such as neuroimaging, and acute thrombolysis) .
# Emergency Medical
iii. After dispatching the ambulance, it is recommended that EMS communications centre personnel provide pre-arrival instructions to the person reporting the stroke (e.g., unlock door, move pets, determine stroke symptom onset time, determine current medications), in order to expedite, optimize, and improve safety for prehospital care . Note: If the person experiencing the signs of stroke is the one to contact EMS, they may not be able to comply with these requests.
# Paramedic On-Scene Management
Note: The on-scene goal is to recognize and mobilize. It is of the utmost importance to rapidly and safely transport suspected patients with stroke, as onscene management for patients with stroke is limited. After completing a brief screen tool to confirm signs and symptoms of a stroke, using an instrument such as FAST 35 or the Cincinnati Prehospital Stroke Scale, 36 EMS personnel should then conduct a subsequent screen to identify potential patients with large vessel occlusions (LVOs) in the anterior circulation who may be potential candidates for EVT. While several validated scales are currently available, most of which are derived from 3-6 components of the National Institutes of Health Stroke Scale (NIHSS), the sensitivities and specificities of these scales are not ideal 37 and most have not been externally validated in the field.
# Section 4: Emergency Department Evaluation
Standard assessments for patients with suspected acute stroke presenting to the ED include a rapid neurological examination and urgent brain and vascular imaging, followed by monitoring of vital signs, blood work, cardiovascular investigations, blood pressure management, glucose control, dysphagia screening, and seizure assessment. Given that some acute stroke symptoms including fatigue, anxiety, and dizziness may overlap with other cardiovascular and general medical conditions, 38 it is important to identify patients who are experiencing stroke "mimics" and to avoid unnecessary and expensive investigations and inappropriate long-term prevention treatments. Patients presenting with stroke symptoms may ultimately be diagnosed with other conditions such as migraine headache, vertigo, metabolic disturbances, brain tumors, or presyncope/syncope. 39 The NIHSS can be used to quickly screen for stroke-specific symptoms. For all patients arriving to hospital with suspected stroke or TIA, immediate brain and vascular imaging is the highest priority investigation once any life-threatening issues with respiration and circulation have been ruled out or addressed. A non-contrast CT scan is considered to be the imaging standard and the most cost-effective method to be used initially to identify acute ischemic stroke and to rule out intracranial hemorrhage. 40 While MRI with DWIs may be more sensitive in detecting early changes associated with ischemia, especially in patients with small infarcts, this technology may be not immediately available in many centers. 41 In the year 2019/20, there were 288 MRI machines in 378 facilities across Canada, equating to an availability of 10 units per million population. 42 Combined multimodal vascular imaging is ii. At hospital arrival, paramedics should provide the receiving hospital with verbal and written information related to the patient's stroke onset time, last known well time, presenting symptoms, and medications, to facilitate rapid assessment and decision-making . Refer to online Supplemental Materials Box 3A for more information.
# Section 3 Clinical Considerations
- The standard window for intravenous thrombolysis is 4.5 hours and the standard time window for EVT is 6 hours. However, patients may be considered eligible beyond these windows based on clinical factors and neuroimaging findings.
- Direct transport in many regions may take one of two potential pathways based on local or regional considerations:
a. Patients who may be eligible for intravenous thrombolysis may be directed to the closest centre, which may be a primary/advanced stroke centre or comprehensive stroke centre.
b. Patients who are likely candidates for EVT may be directed to (1) an EVT-enabled comprehensive stroke centre OR (2) a primary centre to rapidly receive intravenous thrombolysis and then be considered for transport to an EVT-enabled comprehensive stroke centre.
- On-scene time is an important variable that EMS professionals can control and needs to be monitored closely. Time lost due to inefficient on-scene care cannot be made up during subsequent transport to hospital, regardless of the use of lights and sirens.
- Patients should be transported by the method that allows the shortest transport time. In the event that a ground EMS response may cause significant delay in the patient transport, air transport should be considered where available.
- Pre-notification contact with the receiving emergency department should be initiated as soon as possible; where possible, the paramedics and receiving emergency department physician or stroke team member should communicate while enroute.
- For EVT-eligible patients, processes and or algorithms should be put in place that will easily enable a discussion to arrange for the patient to be transferred to the EVT-enabled comprehensive stroke centre in a timely manner. A three-way conference call among the referring clinician (paramedic or emergency department physician at a primary/advanced stroke centre), the receiving physician at the EVT-enabled centre, and the ambulance service involved in patient transport should support decision-making regarding direct to EVT centre or closer centre for initial imaging and assessment.
# Mobile Stroke Units:
The Canadian Stroke Best Practices writing group is currently unable to make a recommendation about mobile stroke units as published data on their use in the context of Canadian geography and health system organization are lacking. The group encourages further research into mobile stroke units in Canada as high-quality studies from other jurisdictions suggest that the use of these specialized units is associated with a reduced time to thrombolysis, an increased proportion of patients receiving thrombolysis, and better functional outcomes at 90 days.
# Initial Emergency Department Evaluation
i. All patients presenting to an emergency department with suspected acute stroke should be immediately assessed and undergo investigations without delay to establish a diagnosis and determine eligibility for thrombolysis and/or endovascular thrombectomy ( Note: Primary stroke centres should make all efforts to perform combined CT and CTA on patient arrival. The CT and CTA should be done at same time and not in separate visits to the imaging suite. Stroke centres that cannot do CTA should have pre-planned arrangements for rapid transfer of appropriate patients. They should complete non-contrast CT (NCCT) and offer intravenous thrombolysis as appropriate and then rapidly transfer the patient to a comprehensive stroke centre for more advanced imaging and consideration for EVT. (Refer to IV thrombolysis Section 5 for additional information).
ii. Note: If there are signs of hemorrhage on initial CT images there is no need to proceed to CTP imaging as part of initial imaging and CTA should be completed based on the clinical judgement of the treating physician.
Note: In most Canadian centres a CT approach may be more practical and more readily available than an MR approach. Choice of imaging modality should be based on most immediate availability and local resources.
Refer to Section 5 Acute Ischemic Stroke Treatment for information on administration of intravenous thrombolysis and EVT.
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- MRI as a first line for imaging can be challenging to obtain urgently in an emergency department setting. Obtaining an MRI scan should not delay decisionmaking regarding intravenous thrombolysis and EVT eligibility.
- Patients with a known allergy to contrast dye or with existing renal failure should not be excluded from consideration for EVT. 2. Routine checks of acute virtual stroke care equipment (both video-conferencing and imaging systems such as PACS) should be done to ensure the equipment will function properly in an emergency. This may be done as part of routine checks on other emergency equipment such as crash carts. Some systems may have a back-up system or alarms for malfunctioning equipment.
- Where electronic health records are available, health information sharing regulations that comply with provincial and federal privacy legislation should be developed, to allow an individual patient's record to be shared with referring and consulting facilities.
- Efforts should be made to design telestroke technology, so it is easy to use and operate, to facilitate adoption of the technology and decrease the time needed to meet educational requirements.
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extremely important, and in highly selected cases, perfusion scans with CT or MRI has the potential to identify patients with an ischemic penumbra and potentially viable brain tissue who may be appropriate for acute reperfusion therapies. Perfusion scans can be especially useful in selecting patient eligible for endovascular therapy in the 6-to-24-h window whereas in the 0-to-6-h time frame, and most cases can be selected with the use of CT and CTA alone.
# Section 5: Acute Ischemic Stroke Treatment
While the weight of evidence clearly indicates that treatment with intravenous alteplase, administered within 4.5 h of symptom onset, improves functional outcomes and reduces the risks of death or disability, 44,45 there are limited data on the benefit of treatment beyond this window. The most recent trials of thrombolytic therapy in the extended time window include EXTEND 46 and WAKE-UP, 47 in which patients presenting with symptoms beyond 4.5 h or with unknown time of onset were selected for treatment on the basis of advanced imaging. In both trials, patients receiving alteplase were more likely to achieve an excellent outcome (mRS 0-1) at 90 days, relative increase 44% 46 % and 61%, 47 symptomatic ICH and death were higher in the intervention group.
The results from several recent trials indicate that tenecteplase, a newer thrombolytic agent that has pharmacokinetic advantages over alteplase, is non-inferior to alteplase. Among the completed trials to date, the AcT trial 48 was the first to report that tenecteplase at a dose of 0.25 mg/kg (maximum 25 mg) is non-inferior to standard dose alteplase. At 90 days, 36.9% of patients in the tenecteplase group achieved the primary outcome (mRS score of 0-1) versus 34.8% in the alteplase group (unadjusted difference = 2.1%, 95% CI -2.6% to 6.9%; adjusted relative risk = 11, 95% CI 10 to 12), meeting the non-inferiority threshold (the lower bound 95% CI of which was set at greater than -5%). There was no significant difference between groups in terms of mortality at 90 days (15.3% vs. 15.4%), or in the proportion with symptomatic ICH at 24 h (3.4% vs. 3.2%). In contrast to these findings, the NOR-TEST 2 49 trial of alteplase versus tenecteplase 0.4 mg/kg was halted early due to safety concerns, which included an increased risk of intracranial hemorrhage and mortality; however, the dose in the tenecteplase group was higher (0.4 mg/kg) than is currently recommended (0.25 mg/kg). In the EXTEND-IA TNK, 50 where patients with LVO received treatment with both thrombolysis and EVT, a significantly higher number of patients receiving tenecteplase 0.25 mg/kg achieved substantial reperfusion (22% vs. 10%, p = 0.02 for superiority), although the percentage of patients who were functionally independent at 90 days or who had achieved an excellent outcome did not differ between groups. Several clinical trials comparing tenecteplase with alteplase (ATTEST2 NCT0281440) and tenecteplase with placebo, or best medical management (TIMELESS NCT03785678, TWIST NCT0318 1360, and TEMPO-2 NCT02398656) are ongoing.
A 2021 Cochrane review 51 that included the results of 19 trials adds to the growing body of evidence indicating that EVT performed within 6 h of symptom onset is an extremely effective treatment for patients with LVO in the anterior circulation. Treatment with EVT was associated with a significantly higher likelihood of favorable outcome (RR = 1.61, 95% CI 1.42 to 1.82) with a high certainty of evidence, without a significantly increased risk of symptomatic intracranial hemorrhage (RR = 1.46, 95% CI 0.91 to 2.36) compared with usual care, which in many cases included the use of alteplase. For selected patients, the treatment window for EVT may be even longer. A pooled analysis of six randomized controlled trials 52 including patients who received treatment between 6 and 24 h after the onset of symptoms also found significantly better outcomes in patients in the intervention group. There was a significant shift in the ordinal analysis of mRS scores favoring less disability in the thrombectomy group (adjusted OR =254, 95% CI 183-354). The odds of achieving an mRS score of 0-1 or 0-2 at 90 days were both significantly higher in the EVT group (adjusted OR = 241, 95% CI 107-543 and adjusted OR = 388, 95% CI 194-778, respectively). The number needed to treat for one more patient to be independent with EVT was 2.6. Presence of a small to moderate ischemic core on non-contrast CT or MRI, usually consistent with an ASPECTS score of ≥6 for the anterior circulation.
a. Patients presenting with an intracranial artery occlusion and large core, such as those with an ASPECT score <6, may be considered for EVT based on expected risks and benefits, after consultation with a physician with stroke expertise and with the treating neurointerventionalist, along with the patient and/or family and/or substitute decision-makers.
4B.2 For posterior circulation: Imaging Criteria for Consideration of Endovascular Thrombectomy for Patients Arriving Within 6 Hours of Stroke Onset 1. Patients presenting with an intracranial occlusion of the posterior circulation (e.g., the basilar artery) may be considered for EVT based on expected risks and benefits, after consultation with a physician with stroke expertise and with the treating neurointerventionalist, along with the patient and family or substitute decision-maker.
Note: Randomized trials are ongoing, and this recommendation will be reviewed once the results become available.
Refer to online Supplemental Materials for additional information. iii. Alteplase dose: If using alteplase, the dose of 0.9 mg/kg to a maximum of 90 mg total dose should be administered, with 10% (0.09 mg/kg) given as an intravenous bolus over one minute and the remaining 90% Caution: The dosing of alteplase and tenecteplase for stroke is NOT the same as the dose protocols for administration of these medications for myocardial infarction or massive pulmonary embolism. a. The benefits and risks of providing intravenous thrombolysis to a patient who is being treated with the combination of antiplatelet and low-dose DOAC (i.e., COMPASS trial protocol) are unclear. Treatment may be considered in consultation with a stroke expert.
b. Anticoagulation is not a contraindication for EVT, and the decision to treat should be based on individual patient factors and assessment of benefit and risk.
c. Patients who present with stroke who are taking a DOAC may be considered for rapid reversal if otherwise eligible for IV thrombolysis and if a reversal agent is readily available. Consultation with an expert in stroke care in strongly advised for these cases.
- The use of epinephrine in angioedema or refractory hypotension should be reserved for life-threatening emergencies due to increased risk of hypertension post-medication administration.
- There are some situations where clinical trial data to support the use of intravenous thrombolytic therapy is more limited. In these situations, urgent consultation with a stroke expert is recommended along with the clinical judgment of the treating physician and discussion with the patient or substitute decision-makers.
a. For example, this may apply to pediatric patients with stroke (newborn to age 18 years); and pregnant women who experience an acute ischemic stroke. Refer to Canadian Stroke Best Practices Management of Acute Stroke During Pregnancy Consensus Statement for additional information. 53 5. (NEW FOR 2022) Evidence for the use of intravenous thrombolysis and EVT is derived from randomized trials that enrolled patients who were functionally independent at baseline. The use of intravenous thrombolysis and/or EVT in patients who are not functionally independent may be considered, based on careful review of risks and benefits for the patient. The patient's goals of care should be discussed in consultation with a physician with stroke expertise, and/or a neurointerventionalist, and the patient and/or family and/or substitute decision-makers.
# (NEW FOR 2022) Hypertension with symptomatic ICH:
In patients with symptomatic ICH who are hypertensive (>185/110 mm HG), blood pressure should be lowered, however, the specific target and duration of therapy are unknown at this time. Note: When an inpatient has a stroke while in hospital, all other sections of the CSBP modules apply to these patients for assessment, diagnosis, management, and recovery.
# Stroke While Already in Hospital
- "Admitted to hospital" is defined as any person admitted to an emergency department, inpatient unit, or outpatient clinic or rehabilitation service in a hospital setting.
# Endovascular Thrombectomy for Acute Ischemic Stroke
Refer to Section 4.2 and to online Supplemental Materials Boxes 4A, 4B, and 4C for detailed recommendations on neuroimaging-based selection criteria. 2. Device selection should be at the discretion of the interventionalists based on clinical and technical factors during the procedure.
- There should be a process at EVT centres to activate anesthesia without delay when deemed necessary.
- Patients with stroke discovered on awakening or with unknown last known well time should be considered for EVT if eligible based on imaging findings and clinical presentation. Refer to online Supplemental Materials Box 5C for more information.
- For patients undergoing EVT following administration of thrombolysis, there should not be a delay in proceeding to EVT to determine clinical effectiveness of thrombolysis.
- (NEW FOR 2022) When a patient who is eligible for both intravenous thrombolysis and EVT presents DIRECTLY TO AN EVT-CAPABLE HOSPITAL, a decision not to administer intravenous thrombolysis and proceed straight to EVT must balance both the patient-related and operational factors in play at that moment, for that patient. The overarching focus is to improve patient outcomes while safely reducing door-to-needle and door-to-puncture times. The main driver for an excellent outcome remains "time is brain".
Note: Clinical consideration 6 is controversial. It will be updated as additional evidence becomes available. In the meantime, clinicians involved in acute stroke care should focus on improving patient outcomes while safely reducing door-to-needle and door-to-puncture times. The main driver for excellent outcomes remains "time is brain".
# Seizure Management
i. Seizure in the presence of suspected acute stroke is not a contraindication for revascularization and could be treated using appropriate short-acting medications (e.g., lorazepam IV) if the seizures are not self-limited . While these criteria are designed to guide clinical decision-making, the decision to use thrombolysis should be based on the clinical judgment of the treating physician. The relative benefits of thrombolysis versus potential risks or contraindications should be weighed on an individual basis.
# Inclusion Criteria
Patients should be considered eligible for intravenous thrombolysis and/or EVT if they fulfill the following clinical criteria:
- Diagnosed with an acute ischemic stroke.
- The stroke is disabling (i.e., significantly impacting function), usually defined as National Institutes of Health Stroke Scale (NIHSS)>4.
- The risks and benefits of thrombolysis are within the patient's goals of care and take into consideration their functional status prior to stroke.
- Life expectancy of 3 months or more.
- Age ≥18 years. (Refer to pediatric guidelines for treatment <18 years of age).
○ For adolescents, a decision to administer intravenous thrombolysis should be based on clinical judgment; presenting symptoms; patient age; and, if possible, consultation with a pediatric stroke specialist.
- Time from last known well (onset of stroke symptoms) is 4.5 hours refer to Section 5.1 for additional information.
# Absolute Exclusion Criteria
- Any source of active hemorrhage or any condition that could increase the risk of major hemorrhage after intravenous thrombolysis administration.
- Any hemorrhage on brain imaging.
Relative Exclusion Criteria (requiring clinical judgement based upon the specific situation. Consult Stroke Specialist at Comprehensive Stroke Centre if there are any questions or concerns about these criteria)
# Historical
- History of intracranial hemorrhage.
- Stroke or serious head or spinal trauma in the preceding 3 months.
- Major surgery (e.g., cardiac, thoracic, abdominal, or orthopedic) in the preceding 14 days. Risk varies according to the procedure.
- Arterial puncture at a non-compressible site in the previous 7 days.
# Clinical
- Stroke symptoms due to another non-ischemic acute neurological condition such as seizure with post-ictal Todd's paralysis or focal neurological signs due to severe hypo-or hyperglycemia.
- Hypertension refractory to aggressive hyperacute antihypertensive treatment such that target blood pressure <180/105 cannot be both achieved and maintained.
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# Section 6: Acute Antiplatelet Therapy
Early antiplatelet therapy, provided soon after ischemic stroke, is known to improve outcomes. Acetylsalicylic acid (ASA) is the most commonly used agent. Results from two of the largest trials of ASA from several decades ago, the Chinese Acute Stroke Trial (CAST) 54 and the International Stroke Trial (IST) 55 represent the majority of the evidence base. In CAST, there were 5.4 fewer deaths and 4.7 fewer recurrent strokes per 1000 patients treated with daily aspirin of 160 mg after 4 weeks. In the aspirin arm of the factorial IST, patients with a suspected acute ischemic stroke received 300 mg/day of aspirin and a similar number avoided aspirin for 14 days. The risk of recurrent ischemic stroke was significantly lower in the aspirin arm, with a number needed to treat of 91, with no significant difference between groups in the frequency of symptomatic ICH. Short-term DAPT, for up to 21 days following ischemic stroke, with either clopidogrel or ticagrelor is more effective than ASA alone in reducing the risk of recurrent ischemic stroke in selected patients. In the POINT trial, Johnston et al. 56 estimated that for every 1,000 patients treated with 75 mg clopidogrel plus 81 mg aspirin for 90 days, 15 ischemic strokes would be prevented but 5 major hemorrhages would result. The greatest protection from treatment was seen in the first 21 days during which the risk of a major ischemic event was lowered by 35%. Although the antiplatelet regimen in the CHANCE trial 57 was slightly different than in the POINT trial, the results were similar, in that the risk of recurrent ischemic stroke was reduced by 33% in the DAPT group.
# Acute Ischemic Stroke Treatment Recommendations 2022
- Currently prescribed and taking a direct non-vitamin K oral anticoagulant. Refer to Section 5.2 Clinical Considerations for additional information.
# CT or MRI Findings
- CT showing early signs of extensive infarction (e.g., >1/3 of middle cerebral artery territory, or ASPECTS score <6).
# Laboratory
- Blood glucose concentration 22.2 mmol/L.
- Elevated activated partial-thromboplastin time.
- International Normalized Ratio >1.7.
- Platelet count <100,000 per cubic millimetre.
# Box 5C Inclusion Criteria for Endovascular Thrombectomy
Refer to Section 4.2 and Boxes 4B and 4C for detailed recommendations on neuroimaging-based selection criteria.
Patients should be considered eligible for endovascular thrombectomy if they fulfill the following clinical criteria:
- Diagnosed with an acute ischemic stroke.
- The stroke is disabling (i.e., significantly impacting function), usually defined as National Institutes of Health Stroke Scale (NIHSS)>4.
- There is a proven, clinically relevant (symptomatic), intra-or extracranial acute arterial occlusion that is amenable to endovascular intervention.
- The risks and benefits of endovascular thrombectomy are within the patient's goals of care and take into consideration their functional status prior to stroke.
- Age ≥18 years. (Refer to pediatric guidelines for treatment <18 years of age).
a. Currently, there is no evidence for EVT in pediatric populations and the decision to treat should be based on the potential benefits and risks of the therapy, made by a physician with pediatric stroke expertise in consultation with the EVT provider and the patient and/or family or substitute decision-makers.
- Intravenous thrombolysis: If intravenous thrombolysis is given in conjunction with endovascular thrombectomy, refer to Box 5B for additional inclusion criteria. 8. Imaging: Patients must qualify for imaging criteria in early and late windows as described in Boxes 4B and 4C.
- Time to treatment: The decision to proceed with EVT should be shared by the physician with clinical stroke expertise and the neuro-interventionalist, who will use the available imaging information as is indicated.
a. Specifically:
i. Patients should have immediate neurovascular imaging (see above) to determine eligibility. Patients can be considered for imaging within a 24-hour window from stroke symptom onset or last known well. ii. For patients presenting <6 hours from stroke symptom onset or last known well to initiation of treatment (i.e., arterial puncture), all patients who meet eligibility criteria should be treated. iii. For patients presenting between 6 and 24 hours from last known well, selected patients may be treated if they meet clinical and imaging criteria and based on local protocols and available expertise in EVT. Patients who are at a very high risk for TIA or minor ischemic stroke caused by high-grade carotid stenosis who are candidates for urgent carotid endarterectomy or carotid stenting should be reviewed with the surgeon or interventionalist to determine the appropriate timing and selection of antiplatelet agent(s).
- For patients on dual antiplatelet therapy, gastrointestinal protection may be considered for those at higher risk of gastrointestinal bleeding.
- For patients with acute stroke or TIA and non-valvular atrial fibrillation, anticoagulation should be initiated; however, there is a lack of randomized evidence to guide specific timing. According to expert consensus, a general approach to the target timing of initiation of DOAC therapy post-stroke is as follows:
a. For patients with a brief TIA and no visible infarct or hemorrhage on imaging, anticoagulation may be started within the first 24 hours post-TIA.
b. For patients with a minor clinical stroke/small non-hemorrhagic infarct on imaging, anticoagulation may be started 3 days post-stroke.
(Continued)
In the THALES trial, 1 patients with minor acute ischemic stroke treated with 90 mg ticagrelor twice a day þ 75-100 aspirin mg/ day also experienced fewer recurrent strokes and death within 30 days (5.5% vs. 6.6%, HR = 0.83, 95% CI 0.71-0.96, number needed to treat =92), compared with patients treated with aspirin alone. 1 However, these benefits were accompanied by a 3.5 to 4 times increased risk of severe or fatal bleeding and intracranial hemorrhage.
# Section 7: Hemicraniectomy
Due to higher risks of cerebral edema, increased intracranial pressure, and subsequent cerebral herniation, mortality is higher for patients with malignant MCA stroke. For these patients, decompressive hemicraniectomy may be a surgical option. In persons under the age of 60 years, early decompressive hemicraniectomy increases the odds of a reasonable functional outcome (mRS score of 0-3) at 1 year. The data are limited for patients over the age of 60 years. In the DESTINY 2 trial, 61 82 patients with a median age of 70 years were randomized to hemicraniectomy or standard care: a significantly higher proportion of patients in the surgical group were alive and living without severe disability (mRS score of 0-4) at 6 months (38% vs.18%, OR = 2.91, 95% CI 1.06-7.49) compared with patients in the medical management group. However, no patients in either the surgical or medical care groups had overall good outcomes (mRS score of 0-2) at 6 or 12 months and most of the survivors required assistance with most bodily needs. In a recent systematic review, which included the results from seven trials, including DESTINY 2, as well as six trials of patients aged <60 years (DESTINY, 59 DESTINY II, 61 DECIMAL, 60 and HAMLET), 62 the odds of a favorable outcome (mRS 0-3) at 1 year were significantly higher in the surgical group (adjusted OR = 2.95, 95% CI 1.55-5.60) and the odds of death at 1 year were significantly lower (adjusted OR = 0.16; 95% CI 0.10-0.24).
(Continued )
- Acute Antithrombotic Therapy Recommendations 2022 c. For patients with a moderate clinical stroke/moderate-sized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 6 to 7 days post-stroke.
d. For patients with a severe clinical stroke/large-sized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 12 to 14 days post-stroke.
e. Antiplatelet therapy may be used prior to initiating anticoagulation.
Refer to CSBPR Secondary Prevention of Stroke module Sections 6 and 7 for additional information on management of atrial fibrillation and choice of therapeutic agents. 13 4. For patients who experience a stroke while receiving one antiplatelet agent, stroke etiology should be reassessed and addressed, and all other vascular risk factors aggressively managed. Continuing the current antiplatelet agent or switching to a different agent are reasonable options. At the time of writing, evidence is lacking to make more specific recommendations. i. For patients aged 18 -60 years old, hemicraniectomy should be considered as a life-saving measure for patients in the early stages of extensive (malignant) middle cerebral artery (MCA) territory ischemic stroke (defined as infarction size >50% MCA territory on visual inspection, or an ischemic lesion volume >150 cm 3 and concomitant clinical features) if patients or their substitute decision-makers are willing to accept a significant risk of living with a degree of disability that may leave them dependent on others for their activities of daily living. Patients who are admitted to stroke units are more likely to survive, return home, and regain their independence compared to patients who are admitted to non-specialized units. The most recent update of the Stroke Unit Trialists' Collaboration 63 identified 29 randomized and quasi-randomized trials, including 5,902 participants, comparing stroke unit care with alternative, less organized care (e.g., an acute medical ward). Compared to less organized forms of care, stroke unit care was associated with a significant reduction in the odds of death (OR = 0.76, 95% CI 0.66 to 0.88), a poor outcome (OR = 0.77, 95% CI 0.69 to 0.87), and death or dependency (OR = 0.75, 95% CI 0.66 to 0.85) at a median follow-up of 1 year. These results were based on moderate quality evidence. Stroke unit care was superior regardless of age, sex, initial stroke severity, stroke type, trial quality, and duration of follow-up.
In Canada, access to stroke unit care varies by region. A survey conducted in 2013/14 identified 32 stroke units within the province of Ontario, of which 21 were acute stroke units, 10 were integrated stroke units, and 1 which was classified as a rehabilitation stroke unit. 64 The estimated average number of stroke patients served per stroke unit was 604 with large variation across centers. iii. Patients with suspected elevation in intracranial pressure may be managed according to institutional protocols (e.g., administration of hyperosmolar therapy, head of bed elevation) .
Section 7 Clinical Considerations:
- Global disability and quality of life outcomes are similar regardless of whether the hemicraniectomy was for right or left sided MCA infarction. 2. Whereas age alone is not a reason to forego hemicraniectomy, the DESTINY II trail reported that for 0% of patients over 60 years had mild or no disability (mRS of 0 -2), and only 7% could function independently (mRS 0-3) after hemicraniectomy surgery.
# Section 9: Inpatient Prevention and Management of Complications Following Stroke 2022
Medical complications are relatively common following stroke and may negatively impact the recovery process, with the potential to result in poorer outcomes. 65 Estimates of the percentage of patients who experience at least one medical complication during hospitalization vary widely from 25% 66 to 85%. 67 Some of the most commonly cited complications include urinary tract infections, fever, pneumonia, and deep vein thrombosis (DVT). Examples of measures that can be taken to reduce the risks of these complications include pharmacological venous thromboembolism prophylaxis, 68 and the use of thigh-high intermittent pneumatic compression (IPC) devices, 69 to prevent thromboembolism, dysphagia screening to reduce the risk of pneumonia, 70 and the avoidance of the use of indwelling catheters to prevent urinary tract infections. 71 Early mobilization post-stroke can reduce the length of hospitalization and is associated with greater ability to perform activities of daily living at 3 months. 72 Cardiac investigations should also be conducted to identify previously undetected or paroxysmal atrial fibrillation, or other cardiac abnormalities. 73,74 (Continued ) Advance care planning (ACP) is a process of reflection and communication in which individuals reflect on their wishes and values to make decisions regarding their healthcare in consultation with healthcare providers, should they become incapable of participating in decision-making at a later date. 76 While there is evidence supporting ACP in the primary care setting, there are limited data on ACP in acute care in general, and even less following stroke. Green et al. 77 used participant observation and semi-structured interviews to gather information related to the communication process regarding ACP from 14 patients, recruited from an acute stroke unit and 2 rehabilitation units, and 4 HCPs. Four key themes emerged as to why or why not participants engaged in the ACP process. First, there was a perceived lack of urgency by participants, many of whom felt the physician and/or family members would make decisions in accordance with their wishes; second, there was a lack of initiation by HCPs to discuss issues around ACP; third, HCPs expressed hesitation about initiating discussions related to ACP, and uncertainty as the best timing for such discussions. Fourth, there was also a lack of understanding of ACP, especially as compared to advance directives, designation of care, and living wills. Although no stroke-specific studies have been published that examine the effectiveness of ACP, several studies included patients with stroke. Results from a small number of studies suggest that interventions aimed at increasing ACP have been successful in significantly increasing the likelihood that end-of-life wishes are known and respected. 78,79 (Continued ) Palliative care is an approach that aims to reduce suffering and improve the quality of life for people who are living with life-limiting illness through the provision of pain and symptom management, psychological, social, emotional, spiritual, and practical support, and support for caregivers during the illness and after the death of the person they are caring for. 80 Palliative care provides comprehensive care throughout a person's illness trajectory and is not solely limited to end-of-life care. The role of palliative care may be complicated as prognosis in the earliest phase of stroke can be unclear. 81 There is currently no integrated model of palliative care in stroke care addressing the appropriate moment to initiate palliative care discussions 82 or which healthcare provider(s) should raise the topic; however, there is agreement that the approach should be interdisciplinary and patient-and familycentered. The palliative care needs of patients following stroke are typically related to the management of common symptoms such as dyspnea, pain, and xerostomia. 83 While palliative care pathways have been developed to ensure that patients receive the most appropriate care possible in the last days of life, there is an absence of high-quality evidence to suggest that current pathways are effective, highlighting the need for additional research in this area. 84 In terms of specific interventions designed to address many common palliative care issues, a systematic review by Cowey et al. 85 concluded that there was insufficient evidence to recommend the best and most effective approaches to this important and essential component of care. iii. Advance care planning may include identifying a substitute decision-maker (proxy, agent, or power of attorney), and discussing the patient's personal values and preferences to be applied in future if the need arises to make healthcare decisions or provide consent on behalf of the patient Challenges and Future Directions
The 7 th update of the Canadian Stroke Best Practice Recommendations for Acute Stroke Management provides a detailed series of recommendations applicable to the care of all adults in Canada who have sustained an ischemic stroke or TIA. These guidelines have been developed through a rigorous process; efforts must now turn to their rapid implementation, especially of the new recommendations, based on emerging high-quality evidence, so as to increase equitable access to timely acute stroke care for all people in Canada. This edition of the guidelines has incorporated Tenecteplase 0.25 mg/kg as an alternate thrombolytic for acute ischemic stroke based on the landmark Canadian AcT trial. It is expected that the knowledge of the clinical applications of tenecteplase will continue to advance, particularly as it pertains to its use in the setting of patients with intracranial arterial occlusions who may or may not be candidates for thrombectomy.
Thrombectomy with or without thrombolysis is the topic of several recent randomized trials; this issue will likely be settled by the time the next edition of these guidelines is ready for publication. At present, trials that most closely reflect Canadian practice suggest that thrombolysis should NOT be withheld for patients who are also candidates for thrombectomy; all eligible patients should receive thrombolysis, regardless of whether they also may receive thrombectomy. We acknowledge the possibility that further refinement in the understanding of the risks and benefits of combination therapy could alter these recommendations. Specifically, it is anticipated that further experience with tenecteplase may impact this calculus in important ways.
We are also excited about the prospect of further developments in the evidence to support EVT for patients with acute ischemic stroke of the posterior circulation. These patients were excluded from the landmark thrombectomy trials published between 2014 and 2018, and upon which current recommendations are based. With the advent of data from high-quality randomized trials, we expect to be able to provide more specific recommendations about thrombectomy for patients suffering strokes of the posterior circulation in the next edition of these guidelines.
The field of neuroprotection is also likely to advance in the coming years. The ESCAPE NA-1 trial suggested that nerinetide could be an effective neuroprotectant in patients with acute ischemic stroke not receiving thrombolysis, and that hypothesis is currently being tested in the Canadian-led ESCAPE NEXT trial. If that trial should be successful, it will be the first instance in the history of clinical neuroscience that a neuroprotectant agent has been found to be clinically effective in humans. Such a discovery could have significant ramifications for the management of acute ischemic stroke and may also influence the care of patients with ICH, subarachnoid hemorrhage, traumatic brain injury, and cardiac arrest.
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The 2022 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for Acute Stroke Management, 7 th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by an interdisciplinary team of healthcare providers and system planners caring for persons with an acute stroke or transient ischemic attack. These recommendations are a timely opportunity to reassess current processes to ensure efficient access to acute stroke diagnostics, treatments, and management strategies, proven to reduce mortality and morbidity. The topics covered include prehospital care, emergency department care, intravenous thrombolysis and endovascular thrombectomy (EVT), prevention and management of inhospital complications, vascular risk factor reduction, early rehabilitation, and end-of-life care. These recommendations pertain primarily to an acute ischemic vascular event. Notable changes in the 7 th edition include recommendations pertaining the use of tenecteplase, thrombolysis as a bridging therapy prior to mechanical thrombectomy, dual antiplatelet therapy for stroke prevention, 1 the management of symptomatic intracerebral hemorrhage following thrombolysis, acute stroke imaging, care of patients undergoing EVT, medical assistance in dying, and virtual stroke care. An explicit effort was made to address sex and gender differences wherever possible. The theme of the 7 th edition of the CSBPR is building connections to optimize individual outcomes, recognizing that many people who present with acute stroke often also have multiple comorbid conditions, are medically more complex, and require a coordinated interdisciplinary approach for optimal recovery. Additional materials to support timely implementation and quality monitoring of these recommendations are available at www.strokebestpractices.ca.Recommandations canadiennes pour les pratiques optimales de soins de l'AVC : prise en charge de l'AVC en phase aiguë, 7e édition, mise à jour des lignes directrices de pratique 2022. La version mise à jour de 2022 de la section des Recommandations canadiennes# Introduction
Stroke prevention, treatment, and recovery have completely transformed over the past several decades due to research breakthroughs, increased awareness, and improvements to systems of care. Canada continues to be a world leader in driving innovation and change across the stroke continuum of care. In Canada, in 2017, there were 108,707 hospital visits for an acute stroke event, 2 and stroke remains a leading cause of adult disability with over 878,000 people living in Canada with the consequences of stroke. 3 In Canada, stroke systems of care have been growing since the late 1990s when acute thrombolysis became available. Currently, 232 hospitals (35%) are capable of providing acute thrombolysis, and this number now includes 155 hospitals with dedicated stroke teams and 95 acute stroke units. Twenty-five hospitals in Canada provide endovascular thrombectomy (EVT). 4 The global pandemic caused by the COVID-19 virus brought increased risk and worse outcomes for people with stroke and impacted response times by both the public and healthcare providers. [5][6][7][8] The 7 th update of the Canadian Stroke Best Practice Recommendations (CSBPR) for Acute Stroke Management is a timely opportunity to reassess current processes to ensure efficient access to acute stroke diagnostics, treatments, and management strategies, which have proven to reduce mortality and morbidity. The topics covered include those related to prehospital care, emergency department (ED) care, acute treatments with intravenous thrombolysis and EVT, the prevention and management in hospital complications, vascular risk factor reduction strategies, early rehabilitation, and end-of-life care. The theme of the 7 th edition of this CSBPR is building connections to optimize individual outcomes. Following an acute stroke, persons often present with multiple comorbid conditions, some of which may have contributed to their stroke, some that are the consequence of their stroke, and some which are unrelated. In many cases, comorbidities such as hypertension, carotid stenosis, and patent foramen ovale (PFO) may be first detected at the time of stroke. Regardless of the etiology, persons presenting with stroke and multiple comorbidities are more complex and are at risk of worse outcomes. These comorbid conditions must be considered within the treatment and care planning process to ensure effective and person-centered care.
The CSBPRs are intended to provide up-to-date evidence-based guidelines for the prevention and management of stroke and to promote optimal recovery and reintegration for people who have experienced stroke, including patients, families, and caregivers. The goal of disseminating and implementing these recommendations is to optimize evidence-based stroke care across Canada to reduce practice variations in care delivery and to narrow the gap between current knowledge and clinical practice. These recommendations have been developed in collaboration with the Canadian Stroke Consortium, Canada's national organization of stroke physicians. The recommendations are applicable to all healthcare providers, health system leaders and planners, and people living with stroke. The CSBPR Acute Stroke Management 2022, 7 th edition supersedes all recommendations contained in the 2018 CSBPR 6 th edition of Acute Stroke Management. 9
# Guideline Development Methodology
The CSBPR development and update process follows a rigorous framework 10,11 and addresses all criteria defined within the Appraisal of Guidelines for Research and Evaluation II (AGREE II) Instrument components. 12 The methodology for development and updates to the CSBPR has been previously published, 13 and detailed methodology can be found on our Canadian Stroke Best Practices website at www.strokebestpractices.ca. An interdisciplinary group of experts was convened and participated in reviewing, drafting, and revising all recommendation statements. Eight people with lived experience of stroke (seven people with stroke and one caregiver) also actively participated in the review and update process as part of our acute stroke community consultation and review panel. 14 Searches were conducted by experienced personnel to identify peer-reviewed literature that examined each topic area addressed in the current module. Systematic reviews, meta-analyses, randomized controlled trials, and observational studies were included, as available. The literature for this module was current to September 2022. Following a standardized abstraction format, evidence tables were constructed including content from selected studies and provided to the writing group for review. The writing group discussed and debated the strength, importance, clinical relevance, and applicability of the evidence and, through consensus, developed a draft set of proposed recommendations. During this process, additional literature may have been identified and used to develop a final set of proposed recommendations. Evidence levels were assigned based on the quality of available evidence, using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system. [15][16][17] Expert opinion was used to formulate recommendations in the absence of evidence. These guidelines have undergone extensive internal and external review, and consensus was achieved for all content. For additional details of the methodology and additional materials to support these recommendations, including rationales, system implications, performance measures, knowledge translation and implementation tools, evidence tables, and an extended summary of the evidence, please visit: www. strokebestpractices.ca. Supplemental online materials are available with this publication to support many of the recommendations included.
# Summary of Changes and Updates in the Acute Stroke Management Stroke, 7 th Edition, 2022
Significant updates and new additions to the CSBPR for Acute Stroke Management, 7 th edition 2022 are based, in part, on the results from several new, important clinical trials. Notable changes in the 7 th edition include recommendations pertaining the use of tenecteplase, thrombolysis as a bridging therapy prior to mechanical thrombectomy, dual antiplatelet therapy (DAPT) for stroke prevention, 1 the management of symptomatic intracerebral hemorrhage (ICH) following thrombolysis, acute stroke imaging (Section 4), pre-and post-op care of patients undergoing EVT (Section 5), medical assistance in dying (MAiD) (Section 11), and virtual stroke care in the ED and inpatient care (Sections 4 and 8).
An explicit effort was made to address sex and gender differences wherever possible. The first four sections of this guideline pertain to all people presenting with signs of acute stroke or TIA. The remaining sections pertain largely to the management of acute ischemic stroke and TIA. Guidelines for the management of patients with ICH were released in 2020, 18 while those for subarachnoid hemorrhage and cerebral venous thrombosis are in development.
Acute Stroke Management Recommendations, 7 th Edition, Update 2022
Note, please refer to online Supplemental Material accompanying these recommendations for additional definitions, information, inclusion criteria, and other implementation content. This manuscript has been translated into French and is also available as an online supplement.
# Section 1: Stroke Awareness, Recognition, and Response
Many members of the general public are unable to recognize the signs and symptoms of a stroke, or they attribute them to a less serious health issue. [19][20][21] While 61% of the population in Canada knows at least one sign of stroke, only 33% know at least two and only 10% know all three, based on the FAST (Face, Arms, Speech, Time) mnemonic. 22 The failure to recognize the signs of an acute stroke, either by the persons witnessing one or the person experiencing one, can delay contact with emergency services, which may in turn decrease a patient's opportunity to receive time-sensitive treatments. The number of public health campaigns designed to increase recognition of the signs and symptoms of stroke has increased over the past decade. One of the best recognized programs in the healthcare community is FAST. The results of a systematic review 23 suggest that stroke education using mass media campaigns can increase the likelihood of symptom recognition by 20% and increase the likelihood that persons would call emergency services by 19%. Mass media campaigns have also been shown to be associated with increases in the use of thrombolytic agents following acute stroke. 24 1. Stroke Awareness, Recognition, and Response Recommendations 2022 i. Organized and integrated stroke systems of care should be established and sustained in every health region in Canada to enable rapid emergency stroke management, including a public awareness campaign, public emergency system (such as 9-1-1), and monitoring systems that consider equity, age, sex, and gender diverse populations [Strong recommendation; Moderate quality of evidence].
ii. All members of the public and all healthcare providers should be educated that stroke is a medical emergency People experiencing signs of stroke require rapid assessment, diagnosis, and determination of risk for a recurrent stroke. Patients diagnosed to have TIA, or subacute, non-disabling ischemic strokes who are not candidates for hyperacute treatment with intravenous thrombolysis and/or EVT still require timely assessment and management, which can often be provided in an outpatient setting. The goal of outpatient management is to rapidly identify neurovascular risk factors, which may have precipitated the index event, and to initiate treatments to reduce the risk of recurrent events. The increased use and availability of sensitive neuroimaging to identify minor events as well as the increased use of antiplatelet agents, anticoagulants, antihypertensive agents, lipid-lowering agents, and carotid revascularization has been shown to significantly reduce the risk of major stroke after an initial minor event in recent years. In the TIARegistry.Org group study, 78.4% of patients were seen by a stroke specialist within 24 h of the event. 25 Most patients received key urgent investigations before discharge, and appropriate treatments were initiated. For example, 5.0% of patients received a new diagnosis of atrial fibrillation, of which 66.8% received anticoagulant therapy before discharge. Carotid stenosis of ≥50% was found in 15.5% of patients, of which 26.9% underwent carotid revascularization
# Triage and Initial Diagnostic Evaluation of Transient Ischemic Attack and Non-Disabling Stroke Recommendations 2022
# Notes
• Section 2 recommendations pertain to the initial management of patients with a suspected acute transient ischemic attack (TIA) or acute ischemic stroke who are not candidates for acute thrombolysis or endovascular intervention. For patients with suspected acute stroke that warrant hyperacute assessment to determine eligibility for intravenous thrombolysis and endovascular thrombectomy (EVT), refer to the current CSBPR Acute Stroke Management treatment recommendations, Sections 4 and 5.
• Refer to online Supplemental Materials for additional notes about this section. 1. Referral to a healthcare professional with stroke expertise should be considered for patients with a suspected uncommon cause of stroke, including for young patients with stroke (e.g., <45 years of age) 27 family history of young-onset stroke; suspected cerebral vasculitis or other intracranial arteriopathy/ vasculopathy; or suspected hereditary or acquired thrombophilia.
2. Patients with symptoms of vertebrobasilar ischemia may present with fluctuating brainstem/cerebellar type symptoms (e.g., diplopia, dysarthria, dysphagia, non-positional vertigo, ataxia; rarely as isolated symptoms) over a longer time course (i.e., >48 hours) and can be mistaken for stroke mimics; however, these patients also require urgent assessment, neurovascular imaging, and management as these types of strokes can have a high morbidity. Consultation with a healthcare professional with stroke expertise is strongly encouraged.
# Setting:
In some regions, urgent/rapid TIA clinics are available that have rapid access to diagnostic services and specialist assessment and management. These clinics may be considered an appropriate referral option for patients with TIA and minor stroke.
before discharge. The 1-year estimate of risk of the primary outcome, a composite of death from cardiovascular causes, nonfatal stroke, and nonfatal acute coronary syndrome, was 6.2% (95% confidence interval [CI] 5.5-7.0%). Estimates of stroke at days 2, 7, 30, 90, and 365 were 1.5%, 2.1%, 2.8%, 3.7%, and 5.1%, respectively. These estimates were almost half of those compared with historical cohorts, possibly reflecting faster access to preventive care in the contemporary cohort. The availability of TIA outpatient clinics appears to be increasing. Based on the results of a geospatial analysis, there were 123 secondary prevention clinics in Canada, as of 2016. 26 While over 87% of the population had access to such a clinic within a 1-h drive, only 69.2% has access to a service that operates 5-7 days a week.
# Section 3: Emergency Medical Services
Emergency medical services (EMS) play a critical role in prehospital assessment and management of patients with suspected stroke. Patients arriving to hospital using EMS following a stroke experience fewer delays in receiving appropriate diagnostic tests, and are more likely to receive revascularization treatments, if eligible. In 2020, 69.0% of patients with stroke admitted to hospital in Canada were transported by EMS. 30 The odds of a patient receiving treatment with intravenous thrombolysis were increased by 52% if the patient was transported by EMS and increased by 75% if a system of hospital prenotification was employed. 31 Given the time-sensitive nature of acute stroke treatment, it is imperative that patients who may be candidates for these therapies be transported directly to comprehensive stroke centers as quickly as possible and whenever possible. The 90-day outcomes of patients who received EVT following direct transport have been shown to be better than those who were first transported to a primary stroke center. 32,33 However, in a recent cluster-randomized trial 34 in which paramedics transporting patients with ischemic stroke were randomized to the PASTA pathway (including structured prehospital information collection, prompted prenotification, and structured handover of information) or standard care, there was no significant difference between groups in the proportion of patients
# 4.
Virtual care-enabled evaluations of patients for secondary stroke prevention should be modeled on the topics defined in the post-stroke checklist and core elements of stroke prevention care. Refer to CSBPR Post Stroke Checklist for additional information at www.strokebestpractices.ca.
# 5.
Validated approaches to virtual neurological exams should be followed.
6. Processes should be in place to book follow-up tests, referrals, and other consultations after a virtual care visit.
7. Processes to ensure appropriate documentation and communication to other team members who may be involved in remote care should be in place.
8. Patients and their families should be encouraged to acquire home blood pressure monitors where appropriate and education or reliable resources on proper use should be provided. Mechanisms should be in place for follow-up and management of blood pressure for patients using home blood pressure devices, by either primary care providers or a stroke prevention service.
9. For timely investigations, the use of prolonged cardiac monitors, if available, that can be sent to patient's homes, self-applied, and returned by mail, should be considered. ii. EMS communications centre: All regions in Canada should implement a dispatch process through their EMS communications centres to rapidly recognize signs or symptoms of stroke (e.g., FAST: Face, Arms, Speech, Time), prioritize response to the scene, and transport the patient to a hospital capable of providing acute services for rapid diagnosis and time-sensitive treatment of stroke (such as neuroimaging, and acute thrombolysis) [Strong recommendation; Low quality of evidence].
# Emergency Medical
iii. After dispatching the ambulance, it is recommended that EMS communications centre personnel provide pre-arrival instructions to the person reporting the stroke (e.g., unlock door, move pets, determine stroke symptom onset time, determine current medications), in order to expedite, optimize, and improve safety for prehospital care [Conditional recommendation; Low quality of evidence]. Note: If the person experiencing the signs of stroke is the one to contact EMS, they may not be able to comply with these requests.
# Paramedic On-Scene Management
Note: The on-scene goal is to recognize and mobilize. It is of the utmost importance to rapidly and safely transport suspected patients with stroke, as onscene management for patients with stroke is limited. After completing a brief screen tool to confirm signs and symptoms of a stroke, using an instrument such as FAST 35 or the Cincinnati Prehospital Stroke Scale, 36 EMS personnel should then conduct a subsequent screen to identify potential patients with large vessel occlusions (LVOs) in the anterior circulation who may be potential candidates for EVT. While several validated scales are currently available, most of which are derived from 3-6 components of the National Institutes of Health Stroke Scale (NIHSS), the sensitivities and specificities of these scales are not ideal 37 and most have not been externally validated in the field.
# Section 4: Emergency Department Evaluation
Standard assessments for patients with suspected acute stroke presenting to the ED include a rapid neurological examination and urgent brain and vascular imaging, followed by monitoring of vital signs, blood work, cardiovascular investigations, blood pressure management, glucose control, dysphagia screening, and seizure assessment. Given that some acute stroke symptoms including fatigue, anxiety, and dizziness may overlap with other cardiovascular and general medical conditions, 38 it is important to identify patients who are experiencing stroke "mimics" and to avoid unnecessary and expensive investigations and inappropriate long-term prevention treatments. Patients presenting with stroke symptoms may ultimately be diagnosed with other conditions such as migraine headache, vertigo, metabolic disturbances, brain tumors, or presyncope/syncope. 39 The NIHSS can be used to quickly screen for stroke-specific symptoms. For all patients arriving to hospital with suspected stroke or TIA, immediate brain and vascular imaging is the highest priority investigation once any life-threatening issues with respiration and circulation have been ruled out or addressed. A non-contrast CT scan is considered to be the imaging standard and the most cost-effective method to be used initially to identify acute ischemic stroke and to rule out intracranial hemorrhage. 40 While MRI with DWIs may be more sensitive in detecting early changes associated with ischemia, especially in patients with small infarcts, this technology may be not immediately available in many centers. 41 In the year 2019/20, there were 288 MRI machines in 378 facilities across Canada, equating to an availability of 10 units per million population. 42 Combined multimodal vascular imaging is ii. At hospital arrival, paramedics should provide the receiving hospital with verbal and written information related to the patient's stroke onset time, last known well time, presenting symptoms, and medications, to facilitate rapid assessment and decision-making [Strong recommendation; Low quality of evidence]. Refer to online Supplemental Materials Box 3A for more information.
# Section 3 Clinical Considerations
1. The standard window for intravenous thrombolysis is 4.5 hours and the standard time window for EVT is 6 hours. However, patients may be considered eligible beyond these windows based on clinical factors and neuroimaging findings.
2. Direct transport in many regions may take one of two potential pathways based on local or regional considerations:
a. Patients who may be eligible for intravenous thrombolysis may be directed to the closest centre, which may be a primary/advanced stroke centre or comprehensive stroke centre.
b. Patients who are likely candidates for EVT may be directed to (1) an EVT-enabled comprehensive stroke centre OR (2) a primary centre to rapidly receive intravenous thrombolysis and then be considered for transport to an EVT-enabled comprehensive stroke centre.
3. On-scene time is an important variable that EMS professionals can control and needs to be monitored closely. Time lost due to inefficient on-scene care cannot be made up during subsequent transport to hospital, regardless of the use of lights and sirens.
4. Patients should be transported by the method that allows the shortest transport time. In the event that a ground EMS response may cause significant delay in the patient transport, air transport should be considered where available.
5. Pre-notification contact with the receiving emergency department should be initiated as soon as possible; where possible, the paramedics and receiving emergency department physician or stroke team member should communicate while enroute.
6. For EVT-eligible patients, processes and or algorithms should be put in place that will easily enable a discussion to arrange for the patient to be transferred to the EVT-enabled comprehensive stroke centre in a timely manner. A three-way conference call among the referring clinician (paramedic or emergency department physician at a primary/advanced stroke centre), the receiving physician at the EVT-enabled centre, and the ambulance service involved in patient transport should support decision-making regarding direct to EVT centre or closer centre for initial imaging and assessment.
# Mobile Stroke Units:
The Canadian Stroke Best Practices writing group is currently unable to make a recommendation about mobile stroke units as published data on their use in the context of Canadian geography and health system organization are lacking. The group encourages further research into mobile stroke units in Canada as high-quality studies from other jurisdictions suggest that the use of these specialized units is associated with a reduced time to thrombolysis, an increased proportion of patients receiving thrombolysis, and better functional outcomes at 90 days.
# Initial Emergency Department Evaluation
i. All patients presenting to an emergency department with suspected acute stroke should be immediately assessed and undergo investigations without delay to establish a diagnosis and determine eligibility for thrombolysis and/or endovascular thrombectomy ( Note: Primary stroke centres should make all efforts to perform combined CT and CTA on patient arrival. The CT and CTA should be done at same time and not in separate visits to the imaging suite. Stroke centres that cannot do CTA should have pre-planned arrangements for rapid transfer of appropriate patients. They should complete non-contrast CT (NCCT) and offer intravenous thrombolysis as appropriate and then rapidly transfer the patient to a comprehensive stroke centre for more advanced imaging and consideration for EVT. (Refer to IV thrombolysis Section 5 for additional information).
ii. Note: If there are signs of hemorrhage on initial CT images there is no need to proceed to CTP imaging as part of initial imaging and CTA should be completed based on the clinical judgement of the treating physician.
Note: In most Canadian centres a CT approach may be more practical and more readily available than an MR approach. Choice of imaging modality should be based on most immediate availability and local resources.
Refer to Section 5 Acute Ischemic Stroke Treatment for information on administration of intravenous thrombolysis and EVT.
(Continued)
1. MRI as a first line for imaging can be challenging to obtain urgently in an emergency department setting. Obtaining an MRI scan should not delay decisionmaking regarding intravenous thrombolysis and EVT eligibility.
2. Patients with a known allergy to contrast dye or with existing renal failure should not be excluded from consideration for EVT. 2. Routine checks of acute virtual stroke care equipment (both video-conferencing and imaging systems such as PACS) should be done to ensure the equipment will function properly in an emergency. This may be done as part of routine checks on other emergency equipment such as crash carts. Some systems may have a back-up system or alarms for malfunctioning equipment.
3. Where electronic health records are available, health information sharing regulations that comply with provincial and federal privacy legislation should be developed, to allow an individual patient's record to be shared with referring and consulting facilities.
4. Efforts should be made to design telestroke technology, so it is easy to use and operate, to facilitate adoption of the technology and decrease the time needed to meet educational requirements.
(Continued)
extremely important, and in highly selected cases, perfusion scans with CT or MRI has the potential to identify patients with an ischemic penumbra and potentially viable brain tissue who may be appropriate for acute reperfusion therapies. Perfusion scans can be especially useful in selecting patient eligible for endovascular therapy in the 6-to-24-h window whereas in the 0-to-6-h time frame, and most cases can be selected with the use of CT and CTA alone.
# Section 5: Acute Ischemic Stroke Treatment
While the weight of evidence clearly indicates that treatment with intravenous alteplase, administered within 4.5 h of symptom onset, improves functional outcomes and reduces the risks of death or disability, 44,45 there are limited data on the benefit of treatment beyond this window. The most recent trials of thrombolytic therapy in the extended time window include EXTEND 46 and WAKE-UP, 47 in which patients presenting with symptoms beyond 4.5 h or with unknown time of onset were selected for treatment on the basis of advanced imaging. In both trials, patients receiving alteplase were more likely to achieve an excellent outcome (mRS 0-1) at 90 days, relative increase 44% 46 % and 61%, 47 symptomatic ICH and death were higher in the intervention group.
The results from several recent trials indicate that tenecteplase, a newer thrombolytic agent that has pharmacokinetic advantages over alteplase, is non-inferior to alteplase. Among the completed trials to date, the AcT trial 48 was the first to report that tenecteplase at a dose of 0.25 mg/kg (maximum 25 mg) is non-inferior to standard dose alteplase. At 90 days, 36.9% of patients in the tenecteplase group achieved the primary outcome (mRS score of 0-1) versus 34.8% in the alteplase group (unadjusted difference = 2.1%, 95% CI -2.6% to 6.9%; adjusted relative risk [RR] = 1•1, 95% CI 1•0 to 1•2), meeting the non-inferiority threshold (the lower bound 95% CI of which was set at greater than -5%). There was no significant difference between groups in terms of mortality at 90 days (15.3% vs. 15.4%), or in the proportion with symptomatic ICH at 24 h (3.4% vs. 3.2%). In contrast to these findings, the NOR-TEST 2 49 trial of alteplase versus tenecteplase 0.4 mg/kg was halted early due to safety concerns, which included an increased risk of intracranial hemorrhage and mortality; however, the dose in the tenecteplase group was higher (0.4 mg/kg) than is currently recommended (0.25 mg/kg). In the EXTEND-IA TNK, 50 where patients with LVO received treatment with both thrombolysis and EVT, a significantly higher number of patients receiving tenecteplase 0.25 mg/kg achieved substantial reperfusion (22% vs. 10%, p = 0.02 for superiority), although the percentage of patients who were functionally independent at 90 days or who had achieved an excellent outcome did not differ between groups. Several clinical trials comparing tenecteplase with alteplase (ATTEST2 NCT0281440) and tenecteplase with placebo, or best medical management (TIMELESS NCT03785678, TWIST NCT0318 1360, and TEMPO-2 NCT02398656) are ongoing.
A 2021 Cochrane review 51 that included the results of 19 trials adds to the growing body of evidence indicating that EVT performed within 6 h of symptom onset is an extremely effective treatment for patients with LVO in the anterior circulation. Treatment with EVT was associated with a significantly higher likelihood of favorable outcome (RR = 1.61, 95% CI 1.42 to 1.82) with a high certainty of evidence, without a significantly increased risk of symptomatic intracranial hemorrhage (RR = 1.46, 95% CI 0.91 to 2.36) compared with usual care, which in many cases included the use of alteplase. For selected patients, the treatment window for EVT may be even longer. A pooled analysis of six randomized controlled trials 52 including patients who received treatment between 6 and 24 h after the onset of symptoms also found significantly better outcomes in patients in the intervention group. There was a significant shift in the ordinal analysis of mRS scores favoring less disability in the thrombectomy group (adjusted OR =2•54, 95% CI 1•83-3•54). The odds of achieving an mRS score of 0-1 or 0-2 at 90 days were both significantly higher in the EVT group (adjusted OR = 2•41, 95% CI 1•07-5•43 and adjusted OR = 3•88, 95% CI 1•94-7•78, respectively). The number needed to treat for one more patient to be independent with EVT was 2.6. Presence of a small to moderate ischemic core on non-contrast CT or MRI, usually consistent with an ASPECTS score of ≥6 for the anterior circulation.
a. Patients presenting with an intracranial artery occlusion and large core, such as those with an ASPECT score <6, may be considered for EVT based on expected risks and benefits, after consultation with a physician with stroke expertise and with the treating neurointerventionalist, along with the patient and/or family and/or substitute decision-makers.
4B.2 For posterior circulation: Imaging Criteria for Consideration of Endovascular Thrombectomy for Patients Arriving Within 6 Hours of Stroke Onset 1. Patients presenting with an intracranial occlusion of the posterior circulation (e.g., the basilar artery) may be considered for EVT based on expected risks and benefits, after consultation with a physician with stroke expertise and with the treating neurointerventionalist, along with the patient and family or substitute decision-maker.
Note: Randomized trials are ongoing, and this recommendation will be reviewed once the results become available.
Refer to online Supplemental Materials for additional information. iii. Alteplase dose: If using alteplase, the dose of 0.9 mg/kg to a maximum of 90 mg total dose should be administered, with 10% (0.09 mg/kg) given as an intravenous bolus over one minute and the remaining 90% Caution: The dosing of alteplase and tenecteplase for stroke is NOT the same as the dose protocols for administration of these medications for myocardial infarction or massive pulmonary embolism. a. The benefits and risks of providing intravenous thrombolysis to a patient who is being treated with the combination of antiplatelet and low-dose DOAC (i.e., COMPASS trial protocol) are unclear. Treatment may be considered in consultation with a stroke expert.
b. Anticoagulation is not a contraindication for EVT, and the decision to treat should be based on individual patient factors and assessment of benefit and risk.
c. Patients who present with stroke who are taking a DOAC may be considered for rapid reversal if otherwise eligible for IV thrombolysis and if a reversal agent is readily available. Consultation with an expert in stroke care in strongly advised for these cases.
3. The use of epinephrine in angioedema or refractory hypotension should be reserved for life-threatening emergencies due to increased risk of hypertension post-medication administration.
4. There are some situations where clinical trial data to support the use of intravenous thrombolytic therapy is more limited. In these situations, urgent consultation with a stroke expert is recommended along with the clinical judgment of the treating physician and discussion with the patient or substitute decision-makers.
a. For example, this may apply to pediatric patients with stroke (newborn to age 18 years); and pregnant women who experience an acute ischemic stroke. Refer to Canadian Stroke Best Practices Management of Acute Stroke During Pregnancy Consensus Statement for additional information. 53 5. (NEW FOR 2022) Evidence for the use of intravenous thrombolysis and EVT is derived from randomized trials that enrolled patients who were functionally independent at baseline. The use of intravenous thrombolysis and/or EVT in patients who are not functionally independent may be considered, based on careful review of risks and benefits for the patient. The patient's goals of care should be discussed in consultation with a physician with stroke expertise, and/or a neurointerventionalist, and the patient and/or family and/or substitute decision-makers.
# (NEW FOR 2022) Hypertension with symptomatic ICH:
In patients with symptomatic ICH who are hypertensive (>185/110 mm HG), blood pressure should be lowered, however, the specific target and duration of therapy are unknown at this time. Note: When an inpatient has a stroke while in hospital, all other sections of the CSBP modules apply to these patients for assessment, diagnosis, management, and recovery.
# Stroke While Already in Hospital
* "Admitted to hospital" is defined as any person admitted to an emergency department, inpatient unit, or outpatient clinic or rehabilitation service in a hospital setting.
# Endovascular Thrombectomy for Acute Ischemic Stroke
Refer to Section 4.2 and to online Supplemental Materials Boxes 4A, 4B, and 4C for detailed recommendations on neuroimaging-based selection criteria. 2. Device selection should be at the discretion of the interventionalists based on clinical and technical factors during the procedure.
3. There should be a process at EVT centres to activate anesthesia without delay when deemed necessary.
4. Patients with stroke discovered on awakening or with unknown last known well time should be considered for EVT if eligible based on imaging findings and clinical presentation. Refer to online Supplemental Materials Box 5C for more information.
5. For patients undergoing EVT following administration of thrombolysis, there should not be a delay in proceeding to EVT to determine clinical effectiveness of thrombolysis.
6. (NEW FOR 2022) When a patient who is eligible for both intravenous thrombolysis and EVT presents DIRECTLY TO AN EVT-CAPABLE HOSPITAL, a decision not to administer intravenous thrombolysis and proceed straight to EVT must balance both the patient-related and operational factors in play at that moment, for that patient. The overarching focus is to improve patient outcomes while safely reducing door-to-needle and door-to-puncture times. The main driver for an excellent outcome remains "time is brain".
Note: Clinical consideration 6 is controversial. It will be updated as additional evidence becomes available. In the meantime, clinicians involved in acute stroke care should focus on improving patient outcomes while safely reducing door-to-needle and door-to-puncture times. The main driver for excellent outcomes remains "time is brain".
# Seizure Management
i. Seizure in the presence of suspected acute stroke is not a contraindication for revascularization and could be treated using appropriate short-acting medications (e.g., lorazepam IV) if the seizures are not self-limited [Conditional recommendation; Low quality of evidence]. While these criteria are designed to guide clinical decision-making, the decision to use thrombolysis should be based on the clinical judgment of the treating physician. The relative benefits of thrombolysis versus potential risks or contraindications should be weighed on an individual basis.
# Inclusion Criteria
Patients should be considered eligible for intravenous thrombolysis and/or EVT if they fulfill the following clinical criteria:
• Diagnosed with an acute ischemic stroke.
• The stroke is disabling (i.e., significantly impacting function), usually defined as National Institutes of Health Stroke Scale (NIHSS)>4.
• The risks and benefits of thrombolysis are within the patient's goals of care and take into consideration their functional status prior to stroke.
• Life expectancy of 3 months or more.
• Age ≥18 years. (Refer to pediatric guidelines for treatment <18 years of age).
○ For adolescents, a decision to administer intravenous thrombolysis should be based on clinical judgment; presenting symptoms; patient age; and, if possible, consultation with a pediatric stroke specialist.
• Time from last known well (onset of stroke symptoms) is <4.5 hours before thrombolysis administration. *For patients >4.5 hours refer to Section 5.1 for additional information.
# Absolute Exclusion Criteria
• Any source of active hemorrhage or any condition that could increase the risk of major hemorrhage after intravenous thrombolysis administration.
• Any hemorrhage on brain imaging.
Relative Exclusion Criteria (requiring clinical judgement based upon the specific situation. Consult Stroke Specialist at Comprehensive Stroke Centre if there are any questions or concerns about these criteria)
# Historical
• History of intracranial hemorrhage.
• Stroke or serious head or spinal trauma in the preceding 3 months.
• Major surgery (e.g., cardiac, thoracic, abdominal, or orthopedic) in the preceding 14 days. Risk varies according to the procedure.
• Arterial puncture at a non-compressible site in the previous 7 days.
# Clinical
• Stroke symptoms due to another non-ischemic acute neurological condition such as seizure with post-ictal Todd's paralysis or focal neurological signs due to severe hypo-or hyperglycemia.
• Hypertension refractory to aggressive hyperacute antihypertensive treatment such that target blood pressure <180/105 cannot be both achieved and maintained.
(Continued)
# Section 6: Acute Antiplatelet Therapy
Early antiplatelet therapy, provided soon after ischemic stroke, is known to improve outcomes. Acetylsalicylic acid (ASA) is the most commonly used agent. Results from two of the largest trials of ASA from several decades ago, the Chinese Acute Stroke Trial (CAST) 54 and the International Stroke Trial (IST) 55 represent the majority of the evidence base. In CAST, there were 5.4 fewer deaths and 4.7 fewer recurrent strokes per 1000 patients treated with daily aspirin of 160 mg after 4 weeks. In the aspirin arm of the factorial IST, patients with a suspected acute ischemic stroke received 300 mg/day of aspirin and a similar number avoided aspirin for 14 days. The risk of recurrent ischemic stroke was significantly lower in the aspirin arm, with a number needed to treat of 91, with no significant difference between groups in the frequency of symptomatic ICH. Short-term DAPT, for up to 21 days following ischemic stroke, with either clopidogrel or ticagrelor is more effective than ASA alone in reducing the risk of recurrent ischemic stroke in selected patients. In the POINT trial, Johnston et al. 56 estimated that for every 1,000 patients treated with 75 mg clopidogrel plus 81 mg aspirin for 90 days, 15 ischemic strokes would be prevented but 5 major hemorrhages would result. The greatest protection from treatment was seen in the first 21 days during which the risk of a major ischemic event was lowered by 35%. Although the antiplatelet regimen in the CHANCE trial 57 was slightly different than in the POINT trial, the results were similar, in that the risk of recurrent ischemic stroke was reduced by 33% in the DAPT group.
# Acute Ischemic Stroke Treatment Recommendations 2022
• Currently prescribed and taking a direct non-vitamin K oral anticoagulant. Refer to Section 5.2 Clinical Considerations for additional information.
# CT or MRI Findings
• CT showing early signs of extensive infarction (e.g., >1/3 of middle cerebral artery [MCA] territory, or ASPECTS score <6).
# Laboratory
• Blood glucose concentration <2.7 mmol/L or >22.2 mmol/L.
• Elevated activated partial-thromboplastin time.
• International Normalized Ratio >1.7.
• Platelet count <100,000 per cubic millimetre.
# Box 5C Inclusion Criteria for Endovascular Thrombectomy
Refer to Section 4.2 and Boxes 4B and 4C for detailed recommendations on neuroimaging-based selection criteria.
Patients should be considered eligible for endovascular thrombectomy if they fulfill the following clinical criteria:
1. Diagnosed with an acute ischemic stroke.
2. The stroke is disabling (i.e., significantly impacting function), usually defined as National Institutes of Health Stroke Scale (NIHSS)>4.
3. There is a proven, clinically relevant (symptomatic), intra-or extracranial acute arterial occlusion that is amenable to endovascular intervention.
4. The risks and benefits of endovascular thrombectomy are within the patient's goals of care and take into consideration their functional status prior to stroke.
5. Age ≥18 years. (Refer to pediatric guidelines for treatment <18 years of age).
a. Currently, there is no evidence for EVT in pediatric populations and the decision to treat should be based on the potential benefits and risks of the therapy, made by a physician with pediatric stroke expertise in consultation with the EVT provider and the patient and/or family or substitute decision-makers.
6. Intravenous thrombolysis: If intravenous thrombolysis is given in conjunction with endovascular thrombectomy, refer to Box 5B for additional inclusion criteria. 8. Imaging: Patients must qualify for imaging criteria in early and late windows as described in Boxes 4B and 4C.
9. Time to treatment: The decision to proceed with EVT should be shared by the physician with clinical stroke expertise and the neuro-interventionalist, who will use the available imaging information as is indicated.
a. Specifically:
i. Patients should have immediate neurovascular imaging (see above) to determine eligibility. Patients can be considered for imaging within a 24-hour window from stroke symptom onset or last known well. ii. For patients presenting <6 hours from stroke symptom onset or last known well to initiation of treatment (i.e., arterial puncture), all patients who meet eligibility criteria should be treated. iii. For patients presenting between 6 and 24 hours from last known well, selected patients may be treated if they meet clinical and imaging criteria and based on local protocols and available expertise in EVT. Patients who are at a very high risk for TIA or minor ischemic stroke caused by high-grade carotid stenosis who are candidates for urgent carotid endarterectomy or carotid stenting should be reviewed with the surgeon or interventionalist to determine the appropriate timing and selection of antiplatelet agent(s).
2. For patients on dual antiplatelet therapy, gastrointestinal protection may be considered for those at higher risk of gastrointestinal bleeding.
3. For patients with acute stroke or TIA and non-valvular atrial fibrillation, anticoagulation should be initiated; however, there is a lack of randomized evidence to guide specific timing. According to expert consensus, a general approach to the target timing of initiation of DOAC therapy post-stroke is as follows:
a. For patients with a brief TIA and no visible infarct or hemorrhage on imaging, anticoagulation may be started within the first 24 hours post-TIA.
b. For patients with a minor clinical stroke/small non-hemorrhagic infarct on imaging, anticoagulation may be started 3 days post-stroke.
(Continued)
In the THALES trial, 1 patients with minor acute ischemic stroke treated with 90 mg ticagrelor twice a day þ 75-100 aspirin mg/ day also experienced fewer recurrent strokes and death within 30 days (5.5% vs. 6.6%, HR = 0.83, 95% CI 0.71-0.96, number needed to treat =92), compared with patients treated with aspirin alone. 1 However, these benefits were accompanied by a 3.5 to 4 times increased risk of severe or fatal bleeding and intracranial hemorrhage.
# Section 7: Hemicraniectomy
Due to higher risks of cerebral edema, increased intracranial pressure, and subsequent cerebral herniation, mortality is higher for patients with malignant MCA stroke. For these patients, decompressive hemicraniectomy may be a surgical option. In persons under the age of 60 years, early decompressive hemicraniectomy increases the odds of a reasonable functional outcome (mRS score of 0-3) at 1 year. [58][59][60] The data are limited for patients over the age of 60 years. In the DESTINY 2 trial, 61 82 patients with a median age of 70 years were randomized to hemicraniectomy or standard care: a significantly higher proportion of patients in the surgical group were alive and living without severe disability (mRS score of 0-4) at 6 months (38% vs.18%, OR = 2.91, 95% CI 1.06-7.49) compared with patients in the medical management group. However, no patients in either the surgical or medical care groups had overall good outcomes (mRS score of 0-2) at 6 or 12 months and most of the survivors required assistance with most bodily needs. In a recent systematic review, which included the results from seven trials, including DESTINY 2, as well as six trials of patients aged <60 years (DESTINY, 59 DESTINY II, 61 DECIMAL, 60 and HAMLET), 62 the odds of a favorable outcome (mRS 0-3) at 1 year were significantly higher in the surgical group (adjusted OR = 2.95, 95% CI 1.55-5.60) and the odds of death at 1 year were significantly lower (adjusted OR = 0.16; 95% CI 0.10-0.24).
(Continued )
6. Acute Antithrombotic Therapy Recommendations 2022 c. For patients with a moderate clinical stroke/moderate-sized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 6 to 7 days post-stroke.
d. For patients with a severe clinical stroke/large-sized infarct on imaging (without hemorrhage on CT), anticoagulation may be started 12 to 14 days post-stroke.
e. Antiplatelet therapy may be used prior to initiating anticoagulation.
Refer to CSBPR Secondary Prevention of Stroke module Sections 6 and 7 for additional information on management of atrial fibrillation and choice of therapeutic agents. 13 4. For patients who experience a stroke while receiving one antiplatelet agent, stroke etiology should be reassessed and addressed, and all other vascular risk factors aggressively managed. Continuing the current antiplatelet agent or switching to a different agent are reasonable options. At the time of writing, evidence is lacking to make more specific recommendations. i. For patients aged 18 -60 years old, hemicraniectomy should be considered as a life-saving measure for patients in the early stages of extensive (malignant) middle cerebral artery (MCA) territory ischemic stroke (defined as infarction size >50% MCA territory on visual inspection, or an ischemic lesion volume >150 cm 3 and concomitant clinical features) if patients or their substitute decision-makers are willing to accept a significant risk of living with a degree of disability that may leave them dependent on others for their activities of daily living. Patients who are admitted to stroke units are more likely to survive, return home, and regain their independence compared to patients who are admitted to non-specialized units. The most recent update of the Stroke Unit Trialists' Collaboration 63 identified 29 randomized and quasi-randomized trials, including 5,902 participants, comparing stroke unit care with alternative, less organized care (e.g., an acute medical ward). Compared to less organized forms of care, stroke unit care was associated with a significant reduction in the odds of death (OR = 0.76, 95% CI 0.66 to 0.88), a poor outcome (OR = 0.77, 95% CI 0.69 to 0.87), and death or dependency (OR = 0.75, 95% CI 0.66 to 0.85) at a median follow-up of 1 year. These results were based on moderate quality evidence. Stroke unit care was superior regardless of age, sex, initial stroke severity, stroke type, trial quality, and duration of follow-up.
In Canada, access to stroke unit care varies by region. A survey conducted in 2013/14 identified 32 stroke units within the province of Ontario, of which 21 were acute stroke units, 10 were integrated stroke units, and 1 which was classified as a rehabilitation stroke unit. 64 The estimated average number of stroke patients served per stroke unit was 604 with large variation across centers. iii. Patients with suspected elevation in intracranial pressure may be managed according to institutional protocols (e.g., administration of hyperosmolar therapy, head of bed elevation) [Conditional recommendation; Low quality of evidence].
Section 7 Clinical Considerations:
1. Global disability and quality of life outcomes are similar regardless of whether the hemicraniectomy was for right or left sided MCA infarction. 2. Whereas age alone is not a reason to forego hemicraniectomy, the DESTINY II trail reported that for 0% of patients over 60 years had mild or no disability (mRS of 0 -2), and only 7% could function independently (mRS 0-3) after hemicraniectomy surgery.
# Section 9: Inpatient Prevention and Management of Complications Following Stroke 2022
Medical complications are relatively common following stroke and may negatively impact the recovery process, with the potential to result in poorer outcomes. 65 Estimates of the percentage of patients who experience at least one medical complication during hospitalization vary widely from 25% 66 to 85%. 67 Some of the most commonly cited complications include urinary tract infections, fever, pneumonia, and deep vein thrombosis (DVT). Examples of measures that can be taken to reduce the risks of these complications include pharmacological venous thromboembolism prophylaxis, 68 and the use of thigh-high intermittent pneumatic compression (IPC) devices, 69 to prevent thromboembolism, dysphagia screening to reduce the risk of pneumonia, 70 and the avoidance of the use of indwelling catheters to prevent urinary tract infections. 71 Early mobilization post-stroke can reduce the length of hospitalization and is associated with greater ability to perform activities of daily living at 3 months. 72 Cardiac investigations should also be conducted to identify previously undetected or paroxysmal atrial fibrillation, or other cardiac abnormalities. 73,74 (Continued ) Advance care planning (ACP) is a process of reflection and communication in which individuals reflect on their wishes and values to make decisions regarding their healthcare in consultation with healthcare providers, should they become incapable of participating in decision-making at a later date. 76 While there is evidence supporting ACP in the primary care setting, there are limited data on ACP in acute care in general, and even less following stroke. Green et al. 77 used participant observation and semi-structured interviews to gather information related to the communication process regarding ACP from 14 patients, recruited from an acute stroke unit and 2 rehabilitation units, and 4 HCPs. Four key themes emerged as to why or why not participants engaged in the ACP process. First, there was a perceived lack of urgency by participants, many of whom felt the physician and/or family members would make decisions in accordance with their wishes; second, there was a lack of initiation by HCPs to discuss issues around ACP; third, HCPs expressed hesitation about initiating discussions related to ACP, and uncertainty as the best timing for such discussions. Fourth, there was also a lack of understanding of ACP, especially as compared to advance directives, designation of care, and living wills. Although no stroke-specific studies have been published that examine the effectiveness of ACP, several studies included patients with stroke. Results from a small number of studies suggest that interventions aimed at increasing ACP have been successful in significantly increasing the likelihood that end-of-life wishes are known and respected. 78,79 (Continued ) Palliative care is an approach that aims to reduce suffering and improve the quality of life for people who are living with life-limiting illness through the provision of pain and symptom management, psychological, social, emotional, spiritual, and practical support, and support for caregivers during the illness and after the death of the person they are caring for. 80 Palliative care provides comprehensive care throughout a person's illness trajectory and is not solely limited to end-of-life care. The role of palliative care may be complicated as prognosis in the earliest phase of stroke can be unclear. 81 There is currently no integrated model of palliative care in stroke care addressing the appropriate moment to initiate palliative care discussions 82 or which healthcare provider(s) should raise the topic; however, there is agreement that the approach should be interdisciplinary and patient-and familycentered. The palliative care needs of patients following stroke are typically related to the management of common symptoms such as dyspnea, pain, and xerostomia. 83 While palliative care pathways have been developed to ensure that patients receive the most appropriate care possible in the last days of life, there is an absence of high-quality evidence to suggest that current pathways are effective, highlighting the need for additional research in this area. 84 In terms of specific interventions designed to address many common palliative care issues, a systematic review by Cowey et al. 85 concluded that there was insufficient evidence to recommend the best and most effective approaches to this important and essential component of care. iii. Advance care planning may include identifying a substitute decision-maker (proxy, agent, or power of attorney), and discussing the patient's personal values and preferences to be applied in future if the need arises to make healthcare decisions or provide consent on behalf of the patient Challenges and Future Directions
The 7 th update of the Canadian Stroke Best Practice Recommendations for Acute Stroke Management provides a detailed series of recommendations applicable to the care of all adults in Canada who have sustained an ischemic stroke or TIA. These guidelines have been developed through a rigorous process; efforts must now turn to their rapid implementation, especially of the new recommendations, based on emerging high-quality evidence, so as to increase equitable access to timely acute stroke care for all people in Canada. This edition of the guidelines has incorporated Tenecteplase 0.25 mg/kg as an alternate thrombolytic for acute ischemic stroke based on the landmark Canadian AcT trial. It is expected that the knowledge of the clinical applications of tenecteplase will continue to advance, particularly as it pertains to its use in the setting of patients with intracranial arterial occlusions who may or may not be candidates for thrombectomy.
Thrombectomy with or without thrombolysis is the topic of several recent randomized trials; this issue will likely be settled by the time the next edition of these guidelines is ready for publication. At present, trials that most closely reflect Canadian practice suggest that thrombolysis should NOT be withheld for patients who are also candidates for thrombectomy; all eligible patients should receive thrombolysis, regardless of whether they also may receive thrombectomy. We acknowledge the possibility that further refinement in the understanding of the risks and benefits of combination therapy could alter these recommendations. Specifically, it is anticipated that further experience with tenecteplase may impact this calculus in important ways.
We are also excited about the prospect of further developments in the evidence to support EVT for patients with acute ischemic stroke of the posterior circulation. These patients were excluded from the landmark thrombectomy trials published between 2014 and 2018, and upon which current recommendations are based. With the advent of data from high-quality randomized trials, we expect to be able to provide more specific recommendations about thrombectomy for patients suffering strokes of the posterior circulation in the next edition of these guidelines.
The field of neuroprotection is also likely to advance in the coming years. The ESCAPE NA-1 trial suggested that nerinetide could be an effective neuroprotectant in patients with acute ischemic stroke not receiving thrombolysis, and that hypothesis is currently being tested in the Canadian-led ESCAPE NEXT trial. If that trial should be successful, it will be the first instance in the history of clinical neuroscience that a neuroprotectant agent has been found to be clinically effective in humans. Such a discovery could have significant ramifications for the management of acute ischemic stroke and may also influence the care of patients with ICH, subarachnoid hemorrhage, traumatic brain injury, and cardiac arrest.
#
Funding. The development of the CSBPR is funded by Heart & Stroke. No funds for the development of these recommendations come from commercial interests, including pharmaceutical and device companies. Writing group members and external reviewers are volunteers who do not receive any remuneration for their participation. All participants complete a conflict of interest declaration prior to participating. Statement of Authorship. Manraj Heran (First Author) and Michel Shamy (Senior Author) are cochairs of the Acute Stroke Management expert writing group and lead authors contributing to all aspects of the development, data analysis, writing, editing, and final approval of this manuscript; Amy Yu, Aravind Ganesh, Sacha Arsenault, Doug Bickford, Donnita Derbyshire, Shannon Doucett, Esseddeeg Ghrooda, Devin Harris, Nick Kanya-Forstner, Eric Kaplovitch, Zachary Liederman, Shauna Martiniuk, Marie McClelland, Genevieve Milot, Jeffrey Minuk, Erica Otto, Jeffrey Perry, Rob Schlamp, Donatella Tampieri, Brian van Adel, David Volders, Ruth Whelan, and Samuel Yip are all members of the Acute Stroke Management expert writing group and contributed by reviewing, analyzing, and discussing the evidence and collectively finalizing the wording of all included recommendations and contributed to additional supporting content. M. Patrice Lindsay is corresponding author, senior editor of the guidelines and this manuscript, involved in all aspects of scientific literature review, writing group deliberations, external review process, manuscript preparation, and a writer of supplementary documentation. Gord Gubitz, Dar Dowlatshahi, and Michael Hill are senior advisors to this writing group and quality committee and contributed significantly to the methodology and recommendation development and provided review and edits to the overall documents. Eric E. Smith and Anita Mountain are cochairs and senior leaders of the stroke best practices advisory committee and oversee all guideline development and participate in ongoing review and feedback of the content. Norine Foley conducted the evidence searches and completed the evidence tables and evidence summaries supporting this guideline update and contributed to the writing of this manuscript. Rebecca Lund and Chelsy Martin are the Heart and Stroke Foundation stroke best practice project leads and supported the internal and external review process and the final revisions of the guidelines and manuscript and are writers of supplementary documentation.
# Conflicts of
#
The advent of mobile stroke units suggests radical change in the way acute stroke care could be delivered, at least for some people in Canada. While high-quality randomized trials in the USA, Germany, and Australia have suggested that mobile stroke units reduce time to treatment, increase treatment eligibility, and lead to better outcomes, we do not feel able to provide specific recommendations for Canadian practice until real-world research addresses our political, economic, and geographic realities. We hope that further research will help to address the question of how mobile stroke units may contribute to the further optimization of stroke care in Canada.
Lastly, at this time, our knowledge of sex and gender differences in acute stroke is evolving. In addition to pregnancy and hormone therapy, the prevalence of risk factors such as hypertension and atrial fibrillation are higher in women. Stroke symptom severity, presentation, and treatment effectiveness are areas that require further research.
The focus throughout these guidelines and stroke systems development in Canada and globally has been on an integrated system to provide seamless care to the patient with vascular risk factors and multimorbidity. Such an approach requires coordinated systems to be in place in all regions of Canada; a challenge given its vast geographical area with many smaller isolated communities. Quality monitoring and efforts to improve care are ongoing, and these recommendations will be updated within the next several years as new evidence emerges.
Supplementary material. To view supplementary material for this article, please visit https://doi.org/10.1017/cjn.2022.344.
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Humira has been proven to be effective in a number of rheumatic and inflammatory diseases. Unfortunately, adherence to Humira injections is often limited by the associated pain reported by patients 1 . This is particularly challenging for young children. Painful injections impact negatively on the quality of life of children and their families. Studies have shown that 40% of children resist medications that involve injections, and parental fear of pain predicts a decrease in treatment adherence 2 . Citrate-free Humira is available to patients in the United States, Europe and many other countries worldwide. Studies have shown that this formulation causes significantly less pain 3,4 , thereby improving adherence and quality of life. Despite Health Canada approval, and for reasons that are not clear, citratefree Humira is not available in Canada. Thus Canadian children are being denied access to citrate-free Humira, which is better tolerated than the current formulation, despite availability of citrate-free Humira to patients elsewhere. The Canadian Rheumatology Association strongly recommends that access to citrate-free Humira be made available for Canadian children requiring treatment with Humira.
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Humira has been proven to be effective in a number of rheumatic and inflammatory diseases. Unfortunately, adherence to Humira injections is often limited by the associated pain reported by patients 1 . This is particularly challenging for young children. Painful injections impact negatively on the quality of life of children and their families. Studies have shown that 40% of children resist medications that involve injections, and parental fear of pain predicts a decrease in treatment adherence 2 . Citrate-free Humira is available to patients in the United States, Europe and many other countries worldwide. Studies have shown that this formulation causes significantly less pain 3,4 , thereby improving adherence and quality of life. Despite Health Canada approval, and for reasons that are not clear, citratefree Humira is not available in Canada. Thus Canadian children are being denied access to citrate-free Humira, which is better tolerated than the current formulation, despite availability of citrate-free Humira to patients elsewhere. The Canadian Rheumatology Association strongly recommends that access to citrate-free Humira be made available for Canadian children requiring treatment with Humira.
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To describe the clinical pharmacology and therapeutic application of clopidogrel. - To discuss drug dosing, duration of therapy, genetic polymorphisms affecting drug metabolism, and potential drug interactions with proton pump inhibitors.Clopidogrel (Plavix®) is an oral platelet inhibitor that has demonstrated cardiovascular protection as monotherapy or in combination with acetylsalicylic acid (ASA) in patients with acute coronary syndrome (ACS), symptomatic peripheral arterial disease, and cerebrovascular disease.Clopidogrel is categorized as a thienopyridine which irreversibly blocks the P2Y12 adenosine diphosphate (ADP) receptor and thereby inhibits ADP-induced platelet aggregation. Clopidogrel is a prodrug which is metabolized into its active agent by the hepatic cytochrome P450 (CYP450) enzyme system (3A4 and 2C19).# INDICATIONS:
- Clopidogrel monotherapy is a treatment option for secondary prevention of atherothrombotic events (myocardial infarction, stroke, or limb ischemia) in patients with stable atherosclerosis. - Clopidogrel may be used as monotherapy in patients not considered candidates for ASA monotherapy (e.g. those with ASA allergies or at high risk of ASA-related gastrointestinal bleeding). - Clopidogrel in combination with ASA is indicated for the secondary prevention of atherothrombotic events in patients with ACS and who receive PCI. The recommended duration of treatment is typically 12 months. Patients who tolerate 1 year of dual antiplatelet therapy (DAPT) with clopidogrel without a major bleeding event and are not at high risk of bleeding may extend DAPT beyond 1 year. Patients who have clinical or angiographic features that increase the risk of thrombotic cardiovascular (CV) events might benefit from extended DAPT beyond 1 year. a. Risk factors for bleeding include: need for oral anticoagulation in addition to DAPT, age >75, frailty, anemia with a hemoglobin <110 g/L, chronic renal failure, weight <60 kg, hospitalization for bleeding within the past year, previous stroke or intracranial bleeding and regular need for NSAIDS or prednisone. b. Clinical features that increase the risk of thrombotic cardiovascular (CV) events include: diabetes mellitus, chronic kidney disease, prior stent thrombosis, and current tobacco use. c. Angiographic features that increase the risk of CV events include: three or more stents implanted or lesions stented, use of a biodegradable vascular scaffold, long lesion length, complex lesions, left main or proximal left anterior descending artery stenting and multivessel PCI - For patients undergoing elective PCI (PCI for a non-ACS indication like stable ischemic heart disease), DAPT is recommended for 6-12 months. In patients who have additional high risk clinical or angiographic features for thrombotic CV events as outlined above and who are at low risk of bleeding, it is reasonable to extend the duration of DAPT for up to 3 years followed by single agent therapy with ASA or clopidogrel. In patients who are at high risk of bleeding, the duration of DAPT may be shortened to a minimum of 1 month (if a bare-metal stent is used) or 3 months (if a drug eluting stent is used). - Clopidogrel is a treatment option for secondary prevention of recurrent cerebral vascular events in patients who develop an ischemic stroke or transient ischemic attack while receiving ASA therapy.
# DOSING:
- There is a delay of approximately 4 days to peak antiplatelet activity if a loading dose of clopidogrel is not given. Therefore, in selected patients at very high risk for thrombosis, a loading dose of 300 or 600 mg should be considered. - ACS: 300-600 mg loading dose followed by 75 mg daily.
- For all other indications, the dose is 75 mg once daily.
- When switching from ticagrelor to clopidogrel, a loading dose of 300-600 mg should be considered in the early post-ACS period; otherwise, switching directly to 75 mg daily is recommended. - When switching from prasugrel to clopidogrel, clopidogrel should be initiated at 75 mg daily.
# MONITORING:
It is advisable to obtain a baseline complete blood count prior to initiating clopidogrel. Ongoing monitoring of platelet function or coagulation parameters in patients taking clopidogrel is not required.
# ADVERSE EFFECTS:
The most common adverse reaction to clopidogrel is an increased rate of bruising and bleeding. The risk of bleeding is increased when clopidogrel is taken with ASA, and in particular, when clopidogrel is taken with an anticoagulant. Gastrointestinal bleeding has been reported. Skin rash is uncommon but statistically more frequent than with ASA. Blood disorders such as agranulocytosis, granulocytopenia, aplastic anemia, neutropenia, and thrombocytopenia have been reported, but are rare events.
# PERI-PROCEDURAL MANAGEMENT:
Clopidogrel should be discontinued 5-7 days prior to an invasive procedure (if it is safe to hold it). However, caution should be used in discontinuing clopidogrel in patients at high risk of thrombotic events, including those with recently implanted coronary stents, and consultation with a specialist is advised. There is increased risk of stent thrombosis when antiplatelet therapy is discontinued prior to 1 year following stent implantation. In patients who have undergone PCI and who require elective noncardiac surgery, surgery should be delayed for at least 1 month following BMS placement and 3 months following DES placement. If there is a need for semi urgent noncardiac surgery, we suggest delaying surgery for at least 1 month after PCI. For patients who require surgery earlier, one of three approaches is used (consultation with a specialist is advised):
- Continue the DAPT without interruption (especially if recent stent placement).
- Continue ASA and hold clopidogrel 5 days preoperatively.
- Hold the oral antiplatelet therapy 5 days preoperatively, admit the patient and start intravenous eptifibatide.
# SPECIAL CONSIDERATIONS:
Genetic polymorphisms: Variations of CYP450 alleles (especially 2C19) may affect the conversion of the pro-drug clopidogrel to its active metabolite. This may lead to reduced benefit of clopidogrel. Specific testing for these variants is not recommended.
Proton pump inhibitors: Some proton pump inhibitors (PPIs) are strong 2C19 inhibitors that can reduce the effect of clopidogrel on platelet aggregation. This can increase the risk of recurrent cardiovascular events. Pantoprazole is not a strong 2C19 inhibitor and should be used whenever a proton pump inhibitor is required. We recommend selective use of PPIs in patients receiving DAPT at high risk of upper gastrointestinal bleeding.
# Date of Version: 04July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To describe the clinical pharmacology and therapeutic application of clopidogrel. • To discuss drug dosing, duration of therapy, genetic polymorphisms affecting drug metabolism, and potential drug interactions with proton pump inhibitors.Clopidogrel (Plavix®) is an oral platelet inhibitor that has demonstrated cardiovascular protection as monotherapy or in combination with acetylsalicylic acid (ASA) in patients with acute coronary syndrome (ACS), symptomatic peripheral arterial disease, and cerebrovascular disease.Clopidogrel is categorized as a thienopyridine which irreversibly blocks the P2Y12 adenosine diphosphate (ADP) receptor and thereby inhibits ADP-induced platelet aggregation. Clopidogrel is a prodrug which is metabolized into its active agent by the hepatic cytochrome P450 (CYP450) enzyme system (3A4 and 2C19).# INDICATIONS:
• Clopidogrel monotherapy is a treatment option for secondary prevention of atherothrombotic events (myocardial infarction, stroke, or limb ischemia) in patients with stable atherosclerosis. • Clopidogrel may be used as monotherapy in patients not considered candidates for ASA monotherapy (e.g. those with ASA allergies or at high risk of ASA-related gastrointestinal bleeding). • Clopidogrel in combination with ASA is indicated for the secondary prevention of atherothrombotic events in patients with ACS and who receive PCI. The recommended duration of treatment is typically 12 months. Patients who tolerate 1 year of dual antiplatelet therapy (DAPT) with clopidogrel without a major bleeding event and are not at high risk of bleeding may extend DAPT beyond 1 year. Patients who have clinical or angiographic features that increase the risk of thrombotic cardiovascular (CV) events might benefit from extended DAPT beyond 1 year. a. Risk factors for bleeding include: need for oral anticoagulation in addition to DAPT, age >75, frailty, anemia with a hemoglobin <110 g/L, chronic renal failure, weight <60 kg, hospitalization for bleeding within the past year, previous stroke or intracranial bleeding and regular need for NSAIDS or prednisone. b. Clinical features that increase the risk of thrombotic cardiovascular (CV) events include: diabetes mellitus, chronic kidney disease, prior stent thrombosis, and current tobacco use. c. Angiographic features that increase the risk of CV events include: three or more stents implanted or lesions stented, use of a biodegradable vascular scaffold, long lesion length, complex lesions, left main or proximal left anterior descending artery stenting and multivessel PCI • For patients undergoing elective PCI (PCI for a non-ACS indication like stable ischemic heart disease), DAPT is recommended for 6-12 months. In patients who have additional high risk clinical or angiographic features for thrombotic CV events as outlined above and who are at low risk of bleeding, it is reasonable to extend the duration of DAPT for up to 3 years followed by single agent therapy with ASA or clopidogrel. In patients who are at high risk of bleeding, the duration of DAPT may be shortened to a minimum of 1 month (if a bare-metal stent [BMS] is used) or 3 months (if a drug eluting stent [DES] is used). • Clopidogrel is a treatment option for secondary prevention of recurrent cerebral vascular events in patients who develop an ischemic stroke or transient ischemic attack while receiving ASA therapy.
# DOSING:
• There is a delay of approximately 4 days to peak antiplatelet activity if a loading dose of clopidogrel is not given. Therefore, in selected patients at very high risk for thrombosis, a loading dose of 300 or 600 mg should be considered. • ACS: 300-600 mg loading dose followed by 75 mg daily.
• For all other indications, the dose is 75 mg once daily.
• When switching from ticagrelor to clopidogrel, a loading dose of 300-600 mg should be considered in the early post-ACS period; otherwise, switching directly to 75 mg daily is recommended. • When switching from prasugrel to clopidogrel, clopidogrel should be initiated at 75 mg daily.
# MONITORING:
It is advisable to obtain a baseline complete blood count prior to initiating clopidogrel. Ongoing monitoring of platelet function or coagulation parameters in patients taking clopidogrel is not required.
# ADVERSE EFFECTS:
The most common adverse reaction to clopidogrel is an increased rate of bruising and bleeding. The risk of bleeding is increased when clopidogrel is taken with ASA, and in particular, when clopidogrel is taken with an anticoagulant. Gastrointestinal bleeding has been reported. Skin rash is uncommon but statistically more frequent than with ASA. Blood disorders such as agranulocytosis, granulocytopenia, aplastic anemia, neutropenia, and thrombocytopenia have been reported, but are rare events.
# PERI-PROCEDURAL MANAGEMENT:
Clopidogrel should be discontinued 5-7 days prior to an invasive procedure (if it is safe to hold it). However, caution should be used in discontinuing clopidogrel in patients at high risk of thrombotic events, including those with recently implanted coronary stents, and consultation with a specialist is advised. There is increased risk of stent thrombosis when antiplatelet therapy is discontinued prior to 1 year following stent implantation. In patients who have undergone PCI and who require elective noncardiac surgery, surgery should be delayed for at least 1 month following BMS placement and 3 months following DES placement. If there is a need for semi urgent noncardiac surgery, we suggest delaying surgery for at least 1 month after PCI. For patients who require surgery earlier, one of three approaches is used (consultation with a specialist is advised):
1. Continue the DAPT without interruption (especially if recent stent placement).
2. Continue ASA and hold clopidogrel 5 days preoperatively.
3. Hold the oral antiplatelet therapy 5 days preoperatively, admit the patient and start intravenous eptifibatide.
# SPECIAL CONSIDERATIONS:
Genetic polymorphisms: Variations of CYP450 alleles (especially 2C19) may affect the conversion of the pro-drug clopidogrel to its active metabolite. This may lead to reduced benefit of clopidogrel. Specific testing for these variants is not recommended.
Proton pump inhibitors: Some proton pump inhibitors (PPIs) are strong 2C19 inhibitors that can reduce the effect of clopidogrel on platelet aggregation. This can increase the risk of recurrent cardiovascular events. Pantoprazole is not a strong 2C19 inhibitor and should be used whenever a proton pump inhibitor is required. We recommend selective use of PPIs in patients receiving DAPT at high risk of upper gastrointestinal bleeding.
# Date of Version: 04July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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Benzodiazepine receptor agonist (BZRA) use disorder among older adults is a relatively common and challenging clinical condition.The Canadian Coalition for Seniors' Mental Health, with financial support from Health Canada, has produced evidencebased guidelines on the prevention, identification, assessment, and management of this form of substance use disorder.Inappropriate use of BZRAs should be avoided by considering non-pharmacological approaches to the management of late life insomnia, anxiety, and other common indications for the use of BZRA. Older persons should only be prescribed BZRAs after they are fully informed of alternatives, benefits, and risks associated with their use. Clinicians should have a high index of suspicion for the presence of BZRA use disorders. The full version of these guidelines can be accessed at www.ccsmh.caA person-centred, stepped care approach utilizing gradual dose reductions should be used in the management of BZRA use disorder.# INTRODUCTION
Substance use disorders affect millions of Canadians. (1) While in general the prevalence rates for these disorders are lower among older (65 years of age or greater) persons, clinicians should be aware that these conditions can still occur in this segment of the population and be vigilant for them. Sedative use disorder is of particular concern in this age group, as the prescription rate in Canada for these agents is highest among older persons. About one in six are consuming a sedative. (2) The Canadian Coalition for Seniors' Mental Health (CC-SMH), with financial support from the Substance Use and Addictions Program of Health Canada, has created a set of four guidelines on the prevention, assessment, and management of substance use disorders among older adults for alcohol, benzodiazepine receptor agonists (BZRAs), cannabis, and opioids. This article deals with the BZRA use disorder guideline. This is not intended to provide a comprehensive guide on the prescription and/or consumption of BZRAs. Rather, the goal is to provide useful advice for practitioners on preventing the development of BZRA use disorder, identifying it if present, and assessing and treating older persons who have developed this condition. Practitioners may wish to deprescribe BZRAS being taken by an older patient. Deprescribing is defined as a process of withdrawal of an inappropriate medication, supervised by a health-care professional, with the goal of managing polypharmacy and improving outcomes. 3 Reasons for deprescribing, other than a BZRA use disorder, include the BZRAs may no longer be needed, the risk of side effects, or the presence of a contraindication to their continued consumption. Recommendations made in this guideline on patient education about the potential risks of BZRA use and how to safely discontinue these agents would be relevant for these purposes.
# METHODS
The CCSMH BZRA Guideline Development Working Group was created to lead the process. DC and DH were appointed as co-leads of the group. Group membership was based on willingness to commit to the project, and either possessing the required expertise or having a lived experience perspective. Ensuring diversity of members in age, gender, disciplinary background, and geographic distribution across Canada guided the final composition of the Guideline Development Working Group.
Members volunteered to focus on either the prevention or management of BZRA use disorder. Within these broad areas, they assumed leadership roles in assessing and creating recommendations to deal with specific topics. This process was guided by systematic searches of databases to identify relevant literature that was then reviewed by Guideline Development Working Group members. A series of in-person and videoconferences were held to maintain progress, discuss emerging issues, refine recommendations, ensure consistency, and identify gaps. A modified version of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was utilized to first assess (and score) the quality of the available evidence for each recommendation (based on consideration of study design and quality of available studies, applicability to the question being addressed, and confidence in the estimate of the effect), and then to assess its overall strength, which took into account additional factors such as the balance between benefit and harm, patient values and preferences and whether this would be a wise use of the required resources for implementation (see Box 1). (4) A separate category was created for recommendations that were not primarily based on empirical evidence but represented best clinical practice. They were categorized as consensus recommendations. Members of the guideline Working Group voted on all recommendations. For adoption, a recommendation had to achieve consensus approval (75%+ affirmative vote by the members of the Working Group). We were actually able to discuss until we reached 100% member consensus on each recommendation. Details on the methodology used are available at the following / substance-use-addiction/intro/.
# BACKGROUND
BZRA use disorder refers to a problematic pattern of BZRA use leading to clinically significant impairment or distress. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, BZRA use disorder is manifested by at least two of the following eleven criteria occurring within a 12-month period (5) :
- The BZRA is being taken in larger amounts and/or over a longer period of time than intended.
# Strength of Recommendation
- Strong: Indicates high confidence that desirable consequences of the proposed course of action outweigh the undesirable consequences (or vice versa) - Weak: Indicates that there is either a close balance between benefits and downsides (including adverse effects and burden of treatment), uncertainty regarding the magnitude of benefits and downsides, uncertainty or great variability in patients' values and preferences, or that the cost or burden of the proposed intervention may not be justified weeks after discontinuing long-acting ones) occurs, or the person takes a BZRA (or a closely related substance such as alcohol) to relieve or avoid withdrawal symptoms.
The number of criteria present determines the severity of the use disorder (i.e., 2-3 = mild, 4-5 = moderate, 6+ = severe).
There are particular challenges in the assessment of BZRA use disorders in older persons. Alterations in social roles or the circumstances of the older person (e.g., retirement from work, living alone) can mask their presentation. Age-related pharmacokinetic and pharmacodynamics changes might render older persons more sensitive to adverse effects from BZRAs. Finally, the presence of co-morbidities can heighten the risks of adverse consequences such as cognitive impairment and falls, as well as masking the presence of a BZRA use disorder.
BZRAs act as allosteric modulators of gamma-aminobutyric acid (GABA) activity by binding to inotropic benzodiazepine receptors at the GABA A receptor complex. BZRAs increase GABA binding and chloride ion channel opening, facilitating inhibitory activity. Some of these drugs have a benzodiazepine chemical structure (e.g., alprazolam, bromazepam, chlordiazepoxide, cobazam, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam), while others do not and are referred to as non-benzodiazepine receptor agonists, novel benzodiazepine receptor agonists, or z-drugs (e.g., zolpidem, zopiclone). In this article, we use the term BZRAs for both. The recommendations made deal with all BZRAs, as they have similar benefits, side effects, and risks.
These drugs have regulatory approval for the management of anxiety and panic disorders, short-term treatment of insomnia, seizures, alcohol withdrawal, sedation, and spasticity. They are also often used in an off-label manner to treat conditions such as anxious depression or the behavioural and psychological symptoms of dementia, which are also referred to as responsive behaviours. Though rates of use are dropping in Canada, (6) these drugs continue to be frequently prescribed, despite widespread agreement that BZRAs should be avoided whenever possible in older adults. (7.8) An estimated 9-10% of older adults taking BZRAs meet criteria for substance dependency. (9)
# KEY CLINICAL RECOMMENDATIONS
The twenty-three recommendations contained in the guideline are included in Box 2 along with the GRADE score for each recommendation. In this summary, we focus on those felt to be of greatest utility for practitioners; however, all the recommendations are listed in Box 2. These key recommendations, as well as the rationale for them and mention of other supporting recommendations, are reviewed below.
# Recommendation #1
Long-term use of BZRAs (> four weeks) in older adults should be avoided for most indications because of their minimal efficacy and risk of harm. Older adults have increased sensitivity to BZRAs and decreased ability to metabolize some longer-acting agents, such as diazepam. All BZRAs increase the risk of cognitive impairment, delirium, falls, fractures, hospitalizations, and motor vehicle crashes. Alternative management strategies for insomnia, anxiety disorders, and the behavioural and psychological symptoms of dementia (also known as responsive behaviours) are recommended. BRZAs have minimal efficacy for anxiety, insomnia, or responsive behaviours related to dementia. This is coupled with concerns about their associated adverse effects. (10) These drugs commonly appear on lists of medications to avoid in the care of older patients. (7,8) Age-related pharmacokinetic and pharmacodynamics changes predispose older patients to adverse effects such as the ones listed in Recommendation #1.
# Recommendations #2
Appropriate first-line non-pharmacological options for the treatment of insomnia and anxiety disorders include cognitive behavioural therapies (CBTs) provided in various formats. Both the American College of Physicians (11) and European Sleep Research Society (12) recommend CBT as first-line therapy for insomnia, with BZRAs and other sedatives reserved for the short-term therapy of those who fail to benefit. CBT is also effective for anxiety. (13) Available data also do not support the routine use of benzodiazepines for the treatment of the behavioural and psychological symptoms of dementia. (14) Other than as bridging therapy until more appropriate approaches become effective, BZRAs should only be considered for these indications after the patient has failed an adequate trial of either a non-pharmacological intervention or a more effective and/or safer pharmacological option (Recommendation #3). An important consideration is the need to advocate for both access and funding of effective non-pharmacological alternatives for the management of these common conditions (Recommendation #10).
Prior to initiating therapy, an assessment of risk for a BZRA use disorder and other potential adverse effects should be conducted (Recommendation #4). As well the patient should be informed of both the limited benefits and risks associated with BZRA use and alternatives (Recommendation #5). Initiating therapy should be a shared decision, with an up-front discussion of how the BZRA should be used and will be monitored (Recommendation #6).
# Recommendation #7
Older adults who are receiving a BZRA should be: a) educated and provided the opportunity to discuss the on-going risks of taking BZRAs; b) encouraged to only take the BZRA for a short period of time (two to four weeks or less) at the minimally effective dose; c) monitored during the course of their prescription for evidence of treatment response and effectiveness, current and Pharmacist-led educational interventions, consisting of a patient brochure about the risks of BZRAs and alternatives, an evidence-based opinion recommending discontinuing the agent provided to the prescribing physician, and/or one-time counseling of patients, have been shown to decrease BZRA use among community-dwelling older adults. (15)(16)(17)(18) As with all prescribed medications, appropriate follow-up care should be provided. Patients must be monitored for evidence of effectiveness and signs of harm, with drug therapy discontinued if the agent is ineffective or the risks of continued use outweigh the benefits.
# Recommendation #13
Health-care practitioners should be aware of and vigilant for the symptoms and signs of substance use disorder, including BZRA use disorder. Particular attention should be paid to this possibility when assessing common conditions encountered in older adults, such as falls and cognitive impairment.
Older adults should be routinely asked about current and past consumption of substances that might be associated with use disorders, including BZRAs, during periodic health examinations, at care transitions (e.g., admissions to facilities or services), preoperative assessments, or when a BZRA is being considered (Recommendation #12). Case finding for a use disorder in those at risk can be done by asking if they have taken a prescription medication for a non-medical reason, made prior efforts to cut down on consumption, and/or have used more than intended over the last year. (19.20) Practitioners should be aware of the DSM-5 criteria for BZRA use disorder and adept in following up on older patients who require a more in-depth evaluation. This assessment should include inquiring about: indication, dose, and duration of BZRA use; presence of BZRA use disorder criteria; readiness of the patient to change their use of the BZRA; and, presence of medical and psychiatric co-morbidities including any other current or past substance misuse or use disorder (Recommendations #14 and #15).
# Recommendation #16
A person-centred, stepped-care approach to enable the gradual withdrawal and discontinuation of BZRAs should be used. Clinicians and patients should share in: a) planning and applying a gradual dose reduction scheme supported by appropriate education of the patient; b) identifying and optimizing alternatives to manage the underlying health issue(s) that initiated or perpetuated the use of BZRAs; c) developing strategies to minimize acute withdrawal and managing rebound symptoms as needed; and d) establishing a schedule of visits for reviewing progress Recommendation #16: A person-centred, stepped-care approach to enable the gradual withdrawal and discontinuation of BZRAs should be used. Clinicians and patients should share in: a) planning and applying a gradual dose reduction scheme supported by appropriate education of the patient; b) identifying and optimizing alternatives to manage the underlying health issue(s) that initiated or perpetuated the use of BZRAs; c) developing strategies to minimize acute withdrawal and managing rebound symptoms as needed; and d) establishing a schedule of visits for reviewing progress. A stepped care approach to deprescribing BZRAs would start with brief interventions, and then progress to multicomponent approaches, as indicated. (21) The involvement of the patient in developing, implementing, and modifying the treatment plan is vital. Gradual dose reduction (GDR), often developed with a pharmacist, and regular planned follow-up meetings to both supervise the withdrawal of the BZRA and manage underlying health issue(s), should be implemented. For the latter, psychological interventions like CBT can be helpful (Recommendation #21). Abrupt discontinuation of a BZRA taken longer than four weeks should be avoided because of the risk of withdrawal symptoms, substance dependence reinforcement, rebound phenomena, and/or higher likelihood of relapse with resumption of the BZRA (Recommendation #17). The ideal rate of tapering with GDR is uncertain. Initially reducing the dosage by 10-25% every one to two weeks, with slower rates of reduction later on, is a reasonable strategy for many, but the type of BZRA consumed (e.g., alprazolam is considered to have unique properties that increase its misuse properties), (22) dosage used, and duration of therapy will influence this. (23) Management of withdrawal symptoms can be informed by the use of validated tools (Recommendation #18).
Other guidance given when deprescribing a BZRA include: simplifying multiple BZRA regimens to a single agent (Recommendation #19); not routinely switching short half-life BZRAs to long half-life ones (Recommendation #20); and, not routinely using a pharmacologically different drug to mitigate BZRA withdrawal symptoms (Recommendation #22).
# Recommendation #23
Older adults with a BZRA use disorder whose drug use is escalating in spite of medical supervision, who have failed prior efforts to withdraw their BZRA, who are at risk for relapse or harm, and/or who suffer from significant psychopathology should be considered for referral to a specialty addiction or mental health service.
# DISCUSSION
While many older adults with BZRA use disorders can be successfully managed in a primary care setting, there are some who should be referred to a specialty service.
# Ethical Challenges
While clinical practice guidelines inform appropriate care, they do not in isolation define it. Proposing the discontinuance of a BZRA may be met with resistance by an older patient who perceives benefit and no significant harm with on-going use. Although avoiding or discontinuing the long-term use of a BZRA is, in general, the recommended course of action, this is not the case for every patient. Discontinuing a medication is an active intervention and should be a shared decision with the patient and governed by professional standards of care for that jurisdiction. Prescribers uncomfortable in continuing to prescribe a BZRA to an older adult where they believe the risk is greater than any likely benefit do not have a duty to do so, as it is ethically indefensible to provide treatment against sound medical judgment. (24) It is emphasized, though, that discontinuing a BZRA being consumed long-term should never be done abruptly, and patients must not be deserted in times of need.
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Benzodiazepine receptor agonist (BZRA) use disorder among older adults is a relatively common and challenging clinical condition.The Canadian Coalition for Seniors' Mental Health, with financial support from Health Canada, has produced evidencebased guidelines on the prevention, identification, assessment, and management of this form of substance use disorder.Inappropriate use of BZRAs should be avoided by considering non-pharmacological approaches to the management of late life insomnia, anxiety, and other common indications for the use of BZRA. Older persons should only be prescribed BZRAs after they are fully informed of alternatives, benefits, and risks associated with their use. Clinicians should have a high index of suspicion for the presence of BZRA use disorders. The full version of these guidelines can be accessed at www.ccsmh.caA person-centred, stepped care approach utilizing gradual dose reductions should be used in the management of BZRA use disorder.# INTRODUCTION
Substance use disorders affect millions of Canadians. (1) While in general the prevalence rates for these disorders are lower among older (65 years of age or greater) persons, clinicians should be aware that these conditions can still occur in this segment of the population and be vigilant for them. Sedative use disorder is of particular concern in this age group, as the prescription rate in Canada for these agents is highest among older persons. About one in six are consuming a sedative. (2) The Canadian Coalition for Seniors' Mental Health (CC-SMH), with financial support from the Substance Use and Addictions Program of Health Canada, has created a set of four guidelines on the prevention, assessment, and management of substance use disorders among older adults for alcohol, benzodiazepine receptor agonists (BZRAs), cannabis, and opioids. This article deals with the BZRA use disorder guideline. This is not intended to provide a comprehensive guide on the prescription and/or consumption of BZRAs. Rather, the goal is to provide useful advice for practitioners on preventing the development of BZRA use disorder, identifying it if present, and assessing and treating older persons who have developed this condition. Practitioners may wish to deprescribe BZRAS being taken by an older patient. Deprescribing is defined as a process of withdrawal of an inappropriate medication, supervised by a health-care professional, with the goal of managing polypharmacy and improving outcomes. 3 Reasons for deprescribing, other than a BZRA use disorder, include the BZRAs may no longer be needed, the risk of side effects, or the presence of a contraindication to their continued consumption. Recommendations made in this guideline on patient education about the potential risks of BZRA use and how to safely discontinue these agents would be relevant for these purposes.
# METHODS
The CCSMH BZRA Guideline Development Working Group was created to lead the process. DC and DH were appointed as co-leads of the group. Group membership was based on willingness to commit to the project, and either possessing the required expertise or having a lived experience perspective. Ensuring diversity of members in age, gender, disciplinary background, and geographic distribution across Canada guided the final composition of the Guideline Development Working Group.
Members volunteered to focus on either the prevention or management of BZRA use disorder. Within these broad areas, they assumed leadership roles in assessing and creating recommendations to deal with specific topics. This process was guided by systematic searches of databases to identify relevant literature that was then reviewed by Guideline Development Working Group members. A series of in-person and videoconferences were held to maintain progress, discuss emerging issues, refine recommendations, ensure consistency, and identify gaps. A modified version of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was utilized to first assess (and score) the quality of the available evidence for each recommendation (based on consideration of study design and quality of available studies, applicability to the question being addressed, and confidence in the estimate of the effect), and then to assess its overall strength, which took into account additional factors such as the balance between benefit and harm, patient values and preferences and whether this would be a wise use of the required resources for implementation (see Box 1). (4) A separate category was created for recommendations that were not primarily based on empirical evidence but represented best clinical practice. They were categorized as consensus recommendations. Members of the guideline Working Group voted on all recommendations. For adoption, a recommendation had to achieve consensus approval (75%+ affirmative vote by the members of the Working Group). We were actually able to discuss until we reached 100% member consensus on each recommendation. Details on the methodology used are available at the following https://ccsmh.ca/ substance-use-addiction/intro/.
# BACKGROUND
BZRA use disorder refers to a problematic pattern of BZRA use leading to clinically significant impairment or distress. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, BZRA use disorder is manifested by at least two of the following eleven criteria occurring within a 12-month period (5) :
1. The BZRA is being taken in larger amounts and/or over a longer period of time than intended.
# Strength of Recommendation
• Strong: Indicates high confidence that desirable consequences of the proposed course of action outweigh the undesirable consequences (or vice versa) • Weak: Indicates that there is either a close balance between benefits and downsides (including adverse effects and burden of treatment), uncertainty regarding the magnitude of benefits and downsides, uncertainty or great variability in patients' values and preferences, or that the cost or burden of the proposed intervention may not be justified weeks after discontinuing long-acting ones) occurs, or the person takes a BZRA (or a closely related substance such as alcohol) to relieve or avoid withdrawal symptoms.
The number of criteria present determines the severity of the use disorder (i.e., 2-3 = mild, 4-5 = moderate, 6+ = severe).
There are particular challenges in the assessment of BZRA use disorders in older persons. Alterations in social roles or the circumstances of the older person (e.g., retirement from work, living alone) can mask their presentation. Age-related pharmacokinetic and pharmacodynamics changes might render older persons more sensitive to adverse effects from BZRAs. Finally, the presence of co-morbidities can heighten the risks of adverse consequences such as cognitive impairment and falls, as well as masking the presence of a BZRA use disorder.
BZRAs act as allosteric modulators of gamma-aminobutyric acid (GABA) activity by binding to inotropic benzodiazepine receptors at the GABA A receptor complex. BZRAs increase GABA binding and chloride ion channel opening, facilitating inhibitory activity. Some of these drugs have a benzodiazepine chemical structure (e.g., alprazolam, bromazepam, chlordiazepoxide, cobazam, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam), while others do not and are referred to as non-benzodiazepine receptor agonists, novel benzodiazepine receptor agonists, or z-drugs (e.g., zolpidem, zopiclone). In this article, we use the term BZRAs for both. The recommendations made deal with all BZRAs, as they have similar benefits, side effects, and risks.
These drugs have regulatory approval for the management of anxiety and panic disorders, short-term treatment of insomnia, seizures, alcohol withdrawal, sedation, and spasticity. They are also often used in an off-label manner to treat conditions such as anxious depression or the behavioural and psychological symptoms of dementia, which are also referred to as responsive behaviours. Though rates of use are dropping in Canada, (6) these drugs continue to be frequently prescribed, despite widespread agreement that BZRAs should be avoided whenever possible in older adults. (7.8) An estimated 9-10% of older adults taking BZRAs meet criteria for substance dependency. (9)
# KEY CLINICAL RECOMMENDATIONS
The twenty-three recommendations contained in the guideline are included in Box 2 along with the GRADE score for each recommendation. In this summary, we focus on those felt to be of greatest utility for practitioners; however, all the recommendations are listed in Box 2. These key recommendations, as well as the rationale for them and mention of other supporting recommendations, are reviewed below.
# Recommendation #1
Long-term use of BZRAs (> four weeks) in older adults should be avoided for most indications because of their minimal efficacy and risk of harm. Older adults have increased sensitivity to BZRAs and decreased ability to metabolize some longer-acting agents, such as diazepam. All BZRAs increase the risk of cognitive impairment, delirium, falls, fractures, hospitalizations, and motor vehicle crashes. Alternative management strategies for insomnia, anxiety disorders, and the behavioural and psychological symptoms of dementia (also known as responsive behaviours) are recommended. BRZAs have minimal efficacy for anxiety, insomnia, or responsive behaviours related to dementia. This is coupled with concerns about their associated adverse effects. (10) These drugs commonly appear on lists of medications to avoid in the care of older patients. (7,8) Age-related pharmacokinetic and pharmacodynamics changes predispose older patients to adverse effects such as the ones listed in Recommendation #1.
# Recommendations #2
Appropriate first-line non-pharmacological options for the treatment of insomnia and anxiety disorders include cognitive behavioural therapies (CBTs) provided in various formats. Both the American College of Physicians (11) and European Sleep Research Society (12) recommend CBT as first-line therapy for insomnia, with BZRAs and other sedatives reserved for the short-term therapy of those who fail to benefit. CBT is also effective for anxiety. (13) Available data also do not support the routine use of benzodiazepines for the treatment of the behavioural and psychological symptoms of dementia. (14) Other than as bridging therapy until more appropriate approaches become effective, BZRAs should only be considered for these indications after the patient has failed an adequate trial of either a non-pharmacological intervention or a more effective and/or safer pharmacological option (Recommendation #3). An important consideration is the need to advocate for both access and funding of effective non-pharmacological alternatives for the management of these common conditions (Recommendation #10).
Prior to initiating therapy, an assessment of risk for a BZRA use disorder and other potential adverse effects should be conducted (Recommendation #4). As well the patient should be informed of both the limited benefits and risks associated with BZRA use and alternatives (Recommendation #5). Initiating therapy should be a shared decision, with an up-front discussion of how the BZRA should be used and will be monitored (Recommendation #6).
# Recommendation #7
Older adults who are receiving a BZRA should be: a) educated and provided the opportunity to discuss the on-going risks of taking BZRAs; b) encouraged to only take the BZRA for a short period of time (two to four weeks or less) at the minimally effective dose; c) monitored during the course of their prescription for evidence of treatment response and effectiveness, current and Pharmacist-led educational interventions, consisting of a patient brochure about the risks of BZRAs and alternatives, an evidence-based opinion recommending discontinuing the agent provided to the prescribing physician, and/or one-time counseling of patients, have been shown to decrease BZRA use among community-dwelling older adults. (15)(16)(17)(18) As with all prescribed medications, appropriate follow-up care should be provided. Patients must be monitored for evidence of effectiveness and signs of harm, with drug therapy discontinued if the agent is ineffective or the risks of continued use outweigh the benefits.
# Recommendation #13
Health-care practitioners should be aware of and vigilant for the symptoms and signs of substance use disorder, including BZRA use disorder. Particular attention should be paid to this possibility when assessing common conditions encountered in older adults, such as falls and cognitive impairment.
Older adults should be routinely asked about current and past consumption of substances that might be associated with use disorders, including BZRAs, during periodic health examinations, at care transitions (e.g., admissions to facilities or services), preoperative assessments, or when a BZRA is being considered (Recommendation #12). Case finding for a use disorder in those at risk can be done by asking if they have taken a prescription medication for a non-medical reason, made prior efforts to cut down on consumption, and/or have used more than intended over the last year. (19.20) Practitioners should be aware of the DSM-5 criteria for BZRA use disorder and adept in following up on older patients who require a more in-depth evaluation. This assessment should include inquiring about: indication, dose, and duration of BZRA use; presence of BZRA use disorder criteria; readiness of the patient to change their use of the BZRA; and, presence of medical and psychiatric co-morbidities including any other current or past substance misuse or use disorder (Recommendations #14 and #15).
# Recommendation #16
A person-centred, stepped-care approach to enable the gradual withdrawal and discontinuation of BZRAs should be used. Clinicians and patients should share in: a) planning and applying a gradual dose reduction scheme supported by appropriate education of the patient; b) identifying and optimizing alternatives to manage the underlying health issue(s) that initiated or perpetuated the use of BZRAs; c) developing strategies to minimize acute withdrawal and managing rebound symptoms as needed; and d) establishing a schedule of visits for reviewing progress Recommendation #16: A person-centred, stepped-care approach to enable the gradual withdrawal and discontinuation of BZRAs should be used. Clinicians and patients should share in: a) planning and applying a gradual dose reduction scheme supported by appropriate education of the patient; b) identifying and optimizing alternatives to manage the underlying health issue(s) that initiated or perpetuated the use of BZRAs; c) developing strategies to minimize acute withdrawal and managing rebound symptoms as needed; and d) establishing a schedule of visits for reviewing progress. A stepped care approach to deprescribing BZRAs would start with brief interventions, and then progress to multicomponent approaches, as indicated. (21) The involvement of the patient in developing, implementing, and modifying the treatment plan is vital. Gradual dose reduction (GDR), often developed with a pharmacist, and regular planned follow-up meetings to both supervise the withdrawal of the BZRA and manage underlying health issue(s), should be implemented. For the latter, psychological interventions like CBT can be helpful (Recommendation #21). Abrupt discontinuation of a BZRA taken longer than four weeks should be avoided because of the risk of withdrawal symptoms, substance dependence reinforcement, rebound phenomena, and/or higher likelihood of relapse with resumption of the BZRA (Recommendation #17). The ideal rate of tapering with GDR is uncertain. Initially reducing the dosage by 10-25% every one to two weeks, with slower rates of reduction later on, is a reasonable strategy for many, but the type of BZRA consumed (e.g., alprazolam is considered to have unique properties that increase its misuse properties), (22) dosage used, and duration of therapy will influence this. (23) Management of withdrawal symptoms can be informed by the use of validated tools (Recommendation #18).
Other guidance given when deprescribing a BZRA include: simplifying multiple BZRA regimens to a single agent (Recommendation #19); not routinely switching short half-life BZRAs to long half-life ones (Recommendation #20); and, not routinely using a pharmacologically different drug to mitigate BZRA withdrawal symptoms (Recommendation #22).
# Recommendation #23
Older adults with a BZRA use disorder whose drug use is escalating in spite of medical supervision, who have failed prior efforts to withdraw their BZRA, who are at risk for relapse or harm, and/or who suffer from significant psychopathology should be considered for referral to a specialty addiction or mental health service.
# DISCUSSION
While many older adults with BZRA use disorders can be successfully managed in a primary care setting, there are some who should be referred to a specialty service.
# Ethical Challenges
While clinical practice guidelines inform appropriate care, they do not in isolation define it. Proposing the discontinuance of a BZRA may be met with resistance by an older patient who perceives benefit and no significant harm with on-going use. Although avoiding or discontinuing the long-term use of a BZRA is, in general, the recommended course of action, this is not the case for every patient. Discontinuing a medication is an active intervention and should be a shared decision with the patient and governed by professional standards of care for that jurisdiction. Prescribers uncomfortable in continuing to prescribe a BZRA to an older adult where they believe the risk is greater than any likely benefit do not have a duty to do so, as it is ethically indefensible to provide treatment against sound medical judgment. (24) It is emphasized, though, that discontinuing a BZRA being consumed long-term should never be done abruptly, and patients must not be deserted in times of need.
# DISCLAIMER
This publication is intended for information purposes only, and is not intended to be interpreted or used as a standard of medical practice. Best efforts were used to ensure that the information in this publication is accurate; however, the publisher and every person involved in the creation of this publication disclaim any warranty as to the accuracy, completeness or currency of the contents of this publication. This publication is distributed with the understanding that neither the publisher nor any person involved in the creation of this publication is rendering professional advice. Physicians and other readers must determine the appropriate clinical care for each individual patient on the basis of all the clinical data available for the individual case. The publisher and every person involved in the creation of this publication disclaim any liability arising from contract, negligence, or any other cause of action, to any party, for the publication contents or any consequences arising from its use.
or approval of the recommendations. Authors received an honorarium for their work. A rigorous process was undertaken to ensure that members of the working group did not have any significant conflict of interest.
# ACKNOWLEDGEMENTS
Funding for the CCSMH Substance Use Disorder Guidelines was provided by Health Canada, Substance Use and Addictions Program. The CCSMH gratefully acknowledges Health Canada for its ongoing support and continued commitment to the area of seniors' mental health. We would also like to thank Drs. Simon Davies, Barbara Farrell, Meldon Kahan, and Karen Reimers for reviewing the draft guideline document and providing clinical perspective to the CCSMH. We would like to thank the Canadian Centre on Substance Use and Addiction and the Behavioural Supports Ontario Substance Use Collaborative for their contributions throughout the development of the Guidelines, Tonya Mahar (Manager, Library Services, Baycrest) for her assistance with literature searches, and CCSMH staff who provided outstanding support of the project (Claire Checkland, Indira Fernando, Natasha Kachan, and Marc-Andre LeBlanc). The CCSMH is a project of the Canadian Academy of Geriatric Psychiatry. Members of the BZRA Use Disorder Among Older Adults Guideline Development Working Group: David K. Conn (co-lead), David B. Hogan, (co-lead), Lori Amdam, Keri-Leigh Cassidy, Peter Cordell, Christopher Frank, David Gardner, Morris Goldhar, Joanne M-W Ho, Christopher Kitamura, Nancy Vasil.
# CONFLICT OF INTEREST DISCLOSURES
The project was funded by Health Canada (Substance Use and Addictions Program). The funder had no role in the creation
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# INTRODUCTION
The Canadian Association of Emergency Physicians (CAEP) recognizes the role of point-of-care ultrasound (POCUS) as a valuable adjunct to the delivery of excellent emergency care. With this document, the CAEP Emergency Ultrasound Committee (EUC) updates the previous CAEP POCUS position statement 1 and provides an expanded framework and series of recommendations, based on the current evidence, to guide emergency departments (ED) and their POCUS programs in the delivery of high quality patient care. Evaluating and summarizing the evidence for the use of POCUS is challenging because, unlike other diagnostic tests where research is primarily focused on test performance, the value of POCUS is further scrutinized in terms of patient-oriented outcomes and system performance measures, such as time to diagnosis or length of stay. Add to this the operator-dependent nature of POCUS, and, not surprisingly, the application of POCUS literature becomes understandably complex.
The recommendations reflect the authors' synthesis of a combination of test performance metrics, patientoriented outcomes, and system performance measures (when available). To date, there is still a paucity of prospective POCUS research focused on patient-oriented outcomes, but the authors do believe there is sufficient evidence in the current literature to support the recommendations within this document.
# LIST OF RECOMMENDATIONS
The following summary of recommendations is expanded with detailed discussion in the full online version of this position statement.
# Scope of practice
The role of POCUS in the practice of emergency medicine (EM) in Canada continues to evolve. The current evidence supports the integration of several potentially life-saving POCUS applications as core skills of the specialty. This list mirrors that of the CAEP EUC's recommended EM Residency emergency ultrasound curriculum. 2 - Focused assessment with sonography for trauma (FAST includes abdominal and thoracic applications.)
- Identification of abdominal aortic aneurysm (AAA)
- Identification of first trimester intrauterine pregnancy (IUP) - Thoracic ultrasound (including identification of pneumothorax, hemothorax, pleural effusion, and interstitial lung syndrome)
- Focused cardiac ultrasound (including assessment of global cardiac activity, gross left ventricular systolic function, right ventricular size, presence of pericardial effusion, and inferior vena cava calibre)
- Ultrasound-guided vascular access (including peripheral and central vascular access)
This document adopts the evolving approach of collating applications into the following groups: resuscitative, diagnostic, procedural, and therapeutic/monitoring (Table 1; also see Appendix 1). In addition, a clinical, presentationbased approach is recommended where selected applications are combined, to differentiate a diagnosis.
# Training and competency
Training in POCUS should incorporate a significant amount of experience scanning patients in a clinical setting. Such experience may be supplemented by scanning workshops or training sessions that involve volunteers or POCUS simulation. The key features of this learning phase relate to optimizing the physician's skills in generating optimal images, interpreting the images, and incorporating the images into clinical decision-making.
Recommending methods of training and assessing proficiency in POCUS continue to stimulate debate. The CAEP EUC has published, in collaboration with EM training programs, a series of core POCUS objectives for EM residents and recommends that moving forward, completion of residency provides evidence of competency in these applications. 2 For physicians who did not receive POCUS training during residency, the CAEP EUC recommends that the following three components of training be considered essential when appraising a physician's POCUS credentials and determining corresponding privileges:
- Clearly defined introduction to the POCUS skill 2. Traineeship with supervision that may include scanning in both the clinical and non-clinical setting.
This training phase should maximize exposure to both normal and abnormal findings and should include exposure to a representative sample of model/patient body habitus.
# A summative assessment of knowledge (including clinical integration and comprehension assessments) and an image generation assessment that includes an observed practical exam
Training for invasive POCUS applications, for example, transvaginal, transesophageal echocardiography, and procedural POCUS, may require a greater reliance on simulation. Incorporating simulation into the training for these applications has been shown to be effective and beneficial. Increasingly, non-physician healthcare providers are using POCUS to enhance their clinical practice. Encouraging evidence exists for both emergency medical services (EMS)/prehospital applications and applications used by nurses. 16,17 It is recommended that POCUS training of these clinicians should include the three components described previously, albeit via a tailored pathway that reflects context and scope of practice.
A growing number of Canadian medical schools have incorporated POCUS into their undergraduate medical education. 18 There is evidence that this can enhance student knowledge and learning of traditional examination skills and also increase student satisfaction. 19 Emergency physicians are well placed and encouraged to facilitate and provide leadership in these programs. POCUS fellowships are well established in Canada (www.PoCUS.ca), and The Royal College of Physicians and Surgeons of Canada (RCPSC) has recently approved an Area of Focused Competence Diploma. 20 Emerging EM POCUS leaders are encouraged to use these programs.
Physicians are expected to keep current with evidence and advances in POCUS practice throughout their careers and are supported by the Canadian colleges in their continuing professional development (CPD) and lifelong learning goals.
# Emergency POCUS program management
Emergency POCUS program management includes components of program leadership, monitoring and quality assessment recommendations, as well as machine choice and maintenance. Recommendations are provided to assist EDs in developing POCUS leaders and to help those leaders develop expertise and establish robust programs that will enhance patient care.
All EDs with POCUS equipment should have a named physician (POCUS Lead) designated and responsible for development and maintenance of the emergency POCUS program. In smaller and rural hospitals, this role may be assumed by those with other quality improvement responsibilities (see Appendix 5 for Rural EM recommendations). Academic centres and larger EDs should have a POCUS Program Director. Recommended responsibilities for these positions are detailed in the full document and may include administration, education of trainees and staff, quality, and research. EM POCUS leaders are expected to have completed additional POCUS training and, in academic centres, have completed POCUS fellowships or the equivalent. 2 Regional POCUS leadership is recommended, with regional academic centres and their associated geographically located smaller EDs collaborating with respect to program management.
POCUS program quality is not only dependent on robust training and competency, but also documentation standards, image archiving (where applicable), and defined quality management process. Recommendations for these are detailed in the full document. Many larger and academic EDs in Canada are archiving images and clips for every examination performed. This is considered best practice and strongly recommended. A local POCUS quality program is the responsibility of the POCUS Lead (with the appropriate support and resources) and will include ongoing review, support, education, and development.
A POCUS program requires resources, including physician time and administrative support. Departments are expected to balance the competing demands placed on resource allocation in order to support successful program delivery. Many larger academic centres will already have implemented much of these mentioned. Others will have EM quality programs in place that could be expanded to include POCUS quality. Smaller hospitals will have to consider which of the previous recommendations are achievable locally and what support is available regionally, for example, regional archiving, regional POCUS education, and competency development.
An ultrasound machine must be immediately available to an attending emergency physician in the ED at all times. The CAEP EUC recommends that EDs should have a minimum of at least one machine for every distinct clinical area and strongly consider the provision of one ultrasound machine for every attending emergency physician on shift. Recommended ultrasound machine specifications are detailed in the full document.
Programs should have a clear policy for infection control, that includes machine hygiene (including keyboard, controls, screen, and cart) and the transducers. Pediatric emergency POCUS Pediatric emergency medicine (PEM) has embraced the potential of POCUS to improve care for their patients. 27 Recommended core POCUS competencies for PEM physicians include eFAST, Focused Cardiac, Thoracic, IUP, Soft Tissue, and Vascular Access. Although clinical indications and use of POCUS in adults and children overlap greatly, our recommendations consider the important differences existing between the two populations. These are detailed in the full document and include resuscitation, lung, neck, ocular, renal/bladder, skull fracture, abdomen, testes, hip and fractures.
Training and competency assessment for PEM POCUS applications follows the same recommendations as those outlined in the previous section on training and competency.
# Emergency POCUS research
The CAEP EUC would not be able to make these recommendations without the body of evidence provided by quality POCUS research. With a greater focus on outcome-centred research, researchers will need to establish networks to design and run the large-scale multi-centre studies required to answer these important patient outcome questions that remain unanswered. 28
# SUMMARY TABLE
Table 2 shows the recommendation categories and themes. The complete list of recommendations is detailed in the full online document.
# GOING FORWARD
These recommendations are intended to provide both motivation and support while being adopted by Canadian EDs. It is anticipated that the rate and completeness of adoption will vary depending on department size, leadership, and resources. The CAEP EUC will continue to provide leadership and support towards improving EM POCUS standards and will complete and publish an annual survey to measure adoption of the recommendations.
# CONCLUSION
The future of POCUS in EM will be influenced by patient outcomes, research, medical school curricula, and technological advances. Local and national leadership is needed to ensure that future generations of emergency physicians will integrate POCUS seamlessly as part of their everyday practice to the benefit of their patients.
Supplementary material: The supplementary material for this article can be found at
Competing interests: None declared.
|
# INTRODUCTION
The Canadian Association of Emergency Physicians (CAEP) recognizes the role of point-of-care ultrasound (POCUS) as a valuable adjunct to the delivery of excellent emergency care. With this document, the CAEP Emergency Ultrasound Committee (EUC) updates the previous CAEP POCUS position statement 1 and provides an expanded framework and series of recommendations, based on the current evidence, to guide emergency departments (ED) and their POCUS programs in the delivery of high quality patient care. Evaluating and summarizing the evidence for the use of POCUS is challenging because, unlike other diagnostic tests where research is primarily focused on test performance, the value of POCUS is further scrutinized in terms of patient-oriented outcomes and system performance measures, such as time to diagnosis or length of stay. Add to this the operator-dependent nature of POCUS, and, not surprisingly, the application of POCUS literature becomes understandably complex.
The recommendations reflect the authors' synthesis of a combination of test performance metrics, patientoriented outcomes, and system performance measures (when available). To date, there is still a paucity of prospective POCUS research focused on patient-oriented outcomes, but the authors do believe there is sufficient evidence in the current literature to support the recommendations within this document.
# LIST OF RECOMMENDATIONS
The following summary of recommendations is expanded with detailed discussion in the full online version of this position statement.
# Scope of practice
The role of POCUS in the practice of emergency medicine (EM) in Canada continues to evolve. The current evidence supports the integration of several potentially life-saving POCUS applications as core skills of the specialty. This list mirrors that of the CAEP EUC's recommended EM Residency emergency ultrasound curriculum. 2 • Focused assessment with sonography for trauma (FAST includes abdominal and thoracic applications.)
• Identification of abdominal aortic aneurysm (AAA)
• Identification of first trimester intrauterine pregnancy (IUP) • Thoracic ultrasound (including identification of pneumothorax, hemothorax, pleural effusion, and interstitial lung syndrome)
• Focused cardiac ultrasound (including assessment of global cardiac activity, gross left ventricular systolic function, right ventricular size, presence of pericardial effusion, and inferior vena cava calibre)
• Ultrasound-guided vascular access (including peripheral and central vascular access)
This document adopts the evolving approach of collating applications into the following groups: resuscitative, diagnostic, procedural, and therapeutic/monitoring (Table 1; also see Appendix 1). In addition, a clinical, presentationbased approach is recommended where selected applications are combined, to differentiate a diagnosis.
# Training and competency
Training in POCUS should incorporate a significant amount of experience scanning patients in a clinical setting. Such experience may be supplemented by scanning workshops or training sessions that involve volunteers or POCUS simulation. The key features of this learning phase relate to optimizing the physician's skills in generating optimal images, interpreting the images, and incorporating the images into clinical decision-making.
Recommending methods of training and assessing proficiency in POCUS continue to stimulate debate. The CAEP EUC has published, in collaboration with EM training programs, a series of core POCUS objectives for EM residents and recommends that moving forward, completion of residency provides evidence of competency in these applications. 2 For physicians who did not receive POCUS training during residency, the CAEP EUC recommends that the following three components of training be considered essential when appraising a physician's POCUS credentials and determining corresponding privileges:
1. Clearly defined introduction to the POCUS skill 2. Traineeship with supervision that may include scanning in both the clinical and non-clinical setting.
This training phase should maximize exposure to both normal and abnormal findings and should include exposure to a representative sample of model/patient body habitus.
# A summative assessment of knowledge (including clinical integration and comprehension assessments) and an image generation assessment that includes an observed practical exam
Training for invasive POCUS applications, for example, transvaginal, transesophageal echocardiography, and procedural POCUS, may require a greater reliance on simulation. Incorporating simulation into the training for these applications has been shown to be effective and beneficial. [3][4][5] Increasingly, non-physician healthcare providers are using POCUS to enhance their clinical practice. Encouraging evidence exists for both emergency medical services (EMS)/prehospital applications [6][7][8][9][10][11][12][13][14][15] and applications used by nurses. 16,17 It is recommended that POCUS training of these clinicians should include the three components described previously, albeit via a tailored pathway that reflects context and scope of practice.
A growing number of Canadian medical schools have incorporated POCUS into their undergraduate medical education. 18 There is evidence that this can enhance student knowledge and learning of traditional examination skills and also increase student satisfaction. 19 Emergency physicians are well placed and encouraged to facilitate and provide leadership in these programs. POCUS fellowships are well established in Canada (www.PoCUS.ca), and The Royal College of Physicians and Surgeons of Canada (RCPSC) has recently approved an Area of Focused Competence Diploma. 20 Emerging EM POCUS leaders are encouraged to use these programs.
Physicians are expected to keep current with evidence and advances in POCUS practice throughout their careers and are supported by the Canadian colleges in their continuing professional development (CPD) and lifelong learning goals.
# Emergency POCUS program management
Emergency POCUS program management includes components of program leadership, monitoring and quality assessment recommendations, as well as machine choice and maintenance. Recommendations are provided to assist EDs in developing POCUS leaders and to help those leaders develop expertise and establish robust programs that will enhance patient care.
All EDs with POCUS equipment should have a named physician (POCUS Lead) designated and responsible for development and maintenance of the emergency POCUS program. In smaller and rural hospitals, this role may be assumed by those with other quality improvement responsibilities (see Appendix 5 for Rural EM recommendations). Academic centres and larger EDs should have a POCUS Program Director. Recommended responsibilities for these positions are detailed in the full document and may include administration, education of trainees and staff, quality, and research. EM POCUS leaders are expected to have completed additional POCUS training and, in academic centres, have completed POCUS fellowships or the equivalent. 2 Regional POCUS leadership is recommended, with regional academic centres and their associated geographically located smaller EDs collaborating with respect to program management.
POCUS program quality is not only dependent on robust training and competency, but also documentation standards, image archiving (where applicable), and defined quality management process. Recommendations for these are detailed in the full document. Many larger and academic EDs in Canada are archiving images and clips for every examination performed. This is considered best practice and strongly recommended. A local POCUS quality program is the responsibility of the POCUS Lead (with the appropriate support and resources) and will include ongoing review, support, education, and development.
A POCUS program requires resources, including physician time and administrative support. Departments are expected to balance the competing demands placed on resource allocation in order to support successful program delivery. Many larger academic centres will already have implemented much of these mentioned. Others will have EM quality programs in place that could be expanded to include POCUS quality. Smaller hospitals will have to consider which of the previous recommendations are achievable locally and what support is available regionally, for example, regional archiving, regional POCUS education, and competency development.
An ultrasound machine must be immediately available to an attending emergency physician in the ED at all times. The CAEP EUC recommends that EDs should have a minimum of at least one machine for every distinct clinical area and strongly consider the provision of one ultrasound machine for every attending emergency physician on shift. Recommended ultrasound machine specifications are detailed in the full document.
Programs should have a clear policy for infection control, that includes machine hygiene (including keyboard, controls, screen, and cart) and the transducers. [21][22][23][24][25][26] Pediatric emergency POCUS Pediatric emergency medicine (PEM) has embraced the potential of POCUS to improve care for their patients. 27 Recommended core POCUS competencies for PEM physicians include eFAST, Focused Cardiac, Thoracic, IUP, Soft Tissue, and Vascular Access. Although clinical indications and use of POCUS in adults and children overlap greatly, our recommendations consider the important differences existing between the two populations. These are detailed in the full document and include resuscitation, lung, neck, ocular, renal/bladder, skull fracture, abdomen, testes, hip and fractures.
Training and competency assessment for PEM POCUS applications follows the same recommendations as those outlined in the previous section on training and competency.
# Emergency POCUS research
The CAEP EUC would not be able to make these recommendations without the body of evidence provided by quality POCUS research. With a greater focus on outcome-centred research, researchers will need to establish networks to design and run the large-scale multi-centre studies required to answer these important patient outcome questions that remain unanswered. 28
# SUMMARY TABLE
Table 2 shows the recommendation categories and themes. The complete list of recommendations is detailed in the full online document.
# GOING FORWARD
These recommendations are intended to provide both motivation and support while being adopted by Canadian EDs. It is anticipated that the rate and completeness of adoption will vary depending on department size, leadership, and resources. The CAEP EUC will continue to provide leadership and support towards improving EM POCUS standards and will complete and publish an annual survey to measure adoption of the recommendations.
# CONCLUSION
The future of POCUS in EM will be influenced by patient outcomes, research, medical school curricula, and technological advances. Local and national leadership is needed to ensure that future generations of emergency physicians will integrate POCUS seamlessly as part of their everyday practice to the benefit of their patients.
#
Supplementary material: The supplementary material for this article can be found at https://doi.org/10.1017/cem.2019.392
Competing interests: None declared.
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We encourage you to share these guidelines with others and we welcome their use as a reference. Please cite each document (part 1 and part 2) in the guideline in keeping with the citation on the table of contents of each of the two documents. If referencing the full guideline, please cite as:# Initial Management of Pediatric Asthma
In Emergent/Urgent Care Settings
# Purpose
This document outlines recommendations for the initial management of pediatric patients presenting to emergent/urgent care settings across British Columbia (BC) with acute asthma exacerbations. This guideline provides recommended actions based on the use of the Pediatric Respiratory Assessment Measure (PRAM) 1,2 .
# Background
Evidence-based management of pediatric patients experiencing acute asthma symptoms includes repeated doses of Salbutamol and Ipratropium, along with oral corticosteroids within the first sixty minutes of care 3 . Lower rates of hospitalization and the improved use of evidence-based medications are associated with the use of a validated and standardized clinical score. The PRAM is a validated scoring tool used to classify the severity of a pediatric patient's respiratory distress and subsequent response to treatment 1,2,3 . The Translating Emergency Knowledge for Kids (TREKK) Bottom Line Recommendations: Asthma (2017) were used as the foundation for building this guideline 3 .
# Scope
This guideline is for use with Children ages 1 year of age to 17 years of age less 1 day- presenting with wheezing, or respiratory distress, AND Diagnosed to have asthma, or Treated 2 times prior with a bronchodilator for wheezing *While children less than 1 year of age with their first known episode of wheeze should not be routinely treated as a part of the PRAM pathway, treating physicians may choose to include these children on a case by case basis following their assessment.
PRAM scoring is performed in the Emergency Department or Urgent Care Centre by members of the health care team including: Physicians, Nurse Practitioners, Registered Nurses and Respiratory Therapists.
# Equipment
# Treatment
Initiate treatment based on severity as determined by PRAM score (mild and moderate pathways may be nurse initiated in known asthmatics only as specifically outlined in the BCCNP limits and conditions) 4 .
- Communicate findings to MRP for treatment orders and ongoing care direction. Older children may present with a lower PRAM score despite having a low FEV1 (Forced expiratory volume measured during the first second of the forced breath) 5 . Consider supplementing the PRAM score with objective markers of airway obstruction such as peak-flow or spirometry. Particularly in patients with a history of severe exacerbations.
*It is important to note that a substantial proportion of patients are not able to perform spirometry during exacerbations and spirometry is not available at all sites 1 .
# Key Points for MILD Category 1
- It is recommended that salbutamol be delivered with metered dose inhalers (MDIs) and spacers rather than nebulization. For children experiencing MILD respiratory distress, there is no clear evidence supporting the administration of oral corticosteroids.
# Key Points for MODERATE Category 1
- It is recommended that salbutamol be delivered with metered dose inhalers (MDIs) and spacers rather than nebulization. Administration of oral corticosteroids just before or immediately after initiating bronchodilator therapy substantially decreases respiratory distress within 2-6 hours of treatment and substantially decreases hospitalization rates. Oral dexamethasone or prednisone/prednisolone are likely to be comparably effective.
Some studies have reported substantially lower rates of vomiting with dexamethasone. The intravenous form of dexamethasone may be given orally in order to minimize the volume of steroid needed to be taken by pediatric patients. Multiple doses of ipratropium (two to three) added to salbutamol aerosols and oral corticosteroids in the first 60 minutes of treatment yield greater improvement and lower hospital rates. There is no role for ipratropium in ongoing asthma management after the initial 2-3 doses.
# Child Health BC Provincial Asthma Guideline
Initial Management of Pediatric Asthma In Emergent/Urgent Care Settings
# Key Points for SEVERE Category 1
- Patients with severe respiratory distress improve more rapidly when bronchodilators are delivered continuously via aerosol over 60 to 180 minutes as compared to intermittently. Although delivery via MDI/spacers is more efficient than nebulization, it is much more convenient to deliver aerosols continuously via nebulization than via MDI/spacers. Large volume nebulizers allow administration of bronchodilators continuously over 60 minutes or more, and should be used in preference to standard-sized nebulizers. Children with severe respiratory distress who do not respond to repeated or continuous bronchodilators and oral corticosteroids have been shown to have greater subsequent improvement if treated with intravenous magnesium sulfate (in addition to repeated or continuous bronchodilator therapy).
# Discharge
# Patient and Caregiver Teaching
Consider using a Patient Education Checklist to guide discharge teaching.
- Patient Education Checklist (Appendix B)
# Key Points
Ensure patients and their caregivers understand: How to take their medication properly (have patient demonstrate this, not just describe it). Are Prescriptions up to date? Are they using an appropriately sized spacer? The difference between a reliever and controller medication. How to use their written action plan (including when to seek help). How to monitor for symptom control. What triggers their asthma and how to avoid their triggers (if possible).
# Action Plans
Asthma fillable action plans for ages 1-5 and 6-18 are available and can be filled out and provided to families on discharge 6 . See www.bcguidelines.ca for more information, including the full guideline "Asthma in Children -Diagnosis and Management (2015), translated action plans (available in Chinese and Punjabi), and fillable PDF versions of the action plans with drop-down medication menus.
# Medications 6
- It is recommended that metered dose inhaler (MDI) always be used with a spacer device in children and are as effective as nebulizers. Spacers increase the amount of medication delivered to the lungs and decrease side effects from medication. In selecting a medication delivery device it is important to ensure that the patient can demonstrate how to use it properly. Controller medication does not need to be increased with an acute loss of asthma control in children.
# Child Health BC Provincial Asthma Guideline
Initial Management of Pediatric Asthma In Emergent/Urgent Care Settings
Inhaled Corticosteroids (ICS) 6 There is insufficient evidence to recommend one ICS molecule over another with respect to efficacy or safety. Children who present with moderate to severe exacerbation should be started on a moderate dose of ICS. Consider starting a trial of ICS in children who present with a mild exacerbation if they have had recurrent exacerbations.
# Follow Up
- All children presenting to the ED with an acute asthma exacerbation should be followed up by their community physician/health care provider within two weeks to ensure resolution of their exacerbation and discuss how to prevent future exacerbations. For patients with good inhaler technique and adherence to daily controller medication, their baseline therapy should be escalated given the high risk of exacerbation in the year following an Emergency Room visit. Please refer to the CHBC/GPAC Guidelines for further details on the management of chronic asthma:
# Documentation
Document the full assessment, medications given, steps taken to escalate care (if applicable), patient and family teaching and discharge instructions in the patient's chart as per your agency's documentation guidelines.
# Definitions
Asthma: Is a chronic inflammatory disease of the airways that is characterized by bronchial hyper reactivity and variable airway obstruction which results in recurrent episodes of wheezing, breathlessness, chest tightness and/or coughing that can vary over time and in intensity.
# College of Registered Nurses of British Columbia (BCCNP):
Under provincial legislation (Health Professions Act), it is the duty of BCCNP to protect the public through regulation of registered nurses, nurse practitioners, and licensed graduate nurses.
Pediatric Respiratory Assessment Measure (PRAM): Is a 12 point clinical scoring rubric that captures a patient's asthma severity using a combination of scalene muscle contraction, suprasternal retractions, wheezing, and air entry and oxygen saturation.
# Child Health BC Provincial Asthma Guideline
|
We encourage you to share these guidelines with others and we welcome their use as a reference. Please cite each document (part 1 and part 2) in the guideline in keeping with the citation on the table of contents of each of the two documents. If referencing the full guideline, please cite as:# Initial Management of Pediatric Asthma
In Emergent/Urgent Care Settings
# Purpose
This document outlines recommendations for the initial management of pediatric patients presenting to emergent/urgent care settings across British Columbia (BC) with acute asthma exacerbations. This guideline provides recommended actions based on the use of the Pediatric Respiratory Assessment Measure (PRAM) 1,2 .
# Background
Evidence-based management of pediatric patients experiencing acute asthma symptoms includes repeated doses of Salbutamol and Ipratropium, along with oral corticosteroids within the first sixty minutes of care 3 . Lower rates of hospitalization and the improved use of evidence-based medications are associated with the use of a validated and standardized clinical score. The PRAM is a validated scoring tool used to classify the severity of a pediatric patient's respiratory distress and subsequent response to treatment 1,2,3 . The Translating Emergency Knowledge for Kids (TREKK) Bottom Line Recommendations: Asthma (2017) were used as the foundation for building this guideline 3 .
# Scope
This guideline is for use with Children ages 1 year of age to 17 years of age less 1 day* presenting with wheezing, or respiratory distress, AND Diagnosed to have asthma, or Treated 2 times prior with a bronchodilator for wheezing *While children less than 1 year of age with their first known episode of wheeze should not be routinely treated as a part of the PRAM pathway, treating physicians may choose to include these children on a case by case basis following their assessment.
PRAM scoring is performed in the Emergency Department or Urgent Care Centre by members of the health care team including: Physicians, Nurse Practitioners, Registered Nurses and Respiratory Therapists.
# Equipment
# Treatment
Initiate treatment based on severity as determined by PRAM score (mild and moderate pathways may be nurse initiated in known asthmatics only as specifically outlined in the BCCNP limits and conditions) 4 .
Communicate findings to MRP for treatment orders and ongoing care direction. Older children may present with a lower PRAM score despite having a low FEV1 (Forced expiratory volume measured during the first second of the forced breath) 5 . Consider supplementing the PRAM score with objective markers of airway obstruction such as peak-flow or spirometry. Particularly in patients with a history of severe exacerbations.
*It is important to note that a substantial proportion of patients are not able to perform spirometry during exacerbations and spirometry is not available at all sites 1 .
# Key Points for MILD Category 1
It is recommended that salbutamol be delivered with metered dose inhalers (MDIs) and spacers rather than nebulization. For children experiencing MILD respiratory distress, there is no clear evidence supporting the administration of oral corticosteroids.
# Key Points for MODERATE Category 1
It is recommended that salbutamol be delivered with metered dose inhalers (MDIs) and spacers rather than nebulization. Administration of oral corticosteroids just before or immediately after initiating bronchodilator therapy substantially decreases respiratory distress within 2-6 hours of treatment and substantially decreases hospitalization rates. Oral dexamethasone or prednisone/prednisolone are likely to be comparably effective.
Some studies have reported substantially lower rates of vomiting with dexamethasone. The intravenous form of dexamethasone may be given orally in order to minimize the volume of steroid needed to be taken by pediatric patients. Multiple doses of ipratropium (two to three) added to salbutamol aerosols and oral corticosteroids in the first 60 minutes of treatment yield greater improvement and lower hospital rates. There is no role for ipratropium in ongoing asthma management after the initial 2-3 doses.
# Child Health BC Provincial Asthma Guideline
Initial Management of Pediatric Asthma In Emergent/Urgent Care Settings
# Key Points for SEVERE Category 1
Patients with severe respiratory distress improve more rapidly when bronchodilators are delivered continuously via aerosol over 60 to 180 minutes as compared to intermittently. Although delivery via MDI/spacers is more efficient than nebulization, it is much more convenient to deliver aerosols continuously via nebulization than via MDI/spacers. Large volume nebulizers allow administration of bronchodilators continuously over 60 minutes or more, and should be used in preference to standard-sized nebulizers. Children with severe respiratory distress who do not respond to repeated or continuous bronchodilators and oral corticosteroids have been shown to have greater subsequent improvement if treated with intravenous magnesium sulfate (in addition to repeated or continuous bronchodilator therapy).
# Discharge
# Patient and Caregiver Teaching
Consider using a Patient Education Checklist to guide discharge teaching.
Patient Education Checklist (Appendix B)
# Key Points
Ensure patients and their caregivers understand: How to take their medication properly (have patient demonstrate this, not just describe it). Are Prescriptions up to date? Are they using an appropriately sized spacer? The difference between a reliever and controller medication. How to use their written action plan (including when to seek help). How to monitor for symptom control. What triggers their asthma and how to avoid their triggers (if possible).
# Action Plans
Asthma fillable action plans for ages 1-5 and 6-18 are available and can be filled out and provided to families on discharge 6 . See www.bcguidelines.ca for more information, including the full guideline "Asthma in Children -Diagnosis and Management (2015), translated action plans (available in Chinese and Punjabi), and fillable PDF versions of the action plans with drop-down medication menus.
# Medications 6
It is recommended that metered dose inhaler (MDI) always be used with a spacer device in children and are as effective as nebulizers. Spacers increase the amount of medication delivered to the lungs and decrease side effects from medication. In selecting a medication delivery device it is important to ensure that the patient can demonstrate how to use it properly. Controller medication does not need to be increased with an acute loss of asthma control in children.
# Child Health BC Provincial Asthma Guideline
Initial Management of Pediatric Asthma In Emergent/Urgent Care Settings
# 4.4
Inhaled Corticosteroids (ICS) 6 There is insufficient evidence to recommend one ICS molecule over another with respect to efficacy or safety. Children who present with moderate to severe exacerbation should be started on a moderate dose of ICS. Consider starting a trial of ICS in children who present with a mild exacerbation if they have had recurrent exacerbations.
# Follow Up
All children presenting to the ED with an acute asthma exacerbation should be followed up by their community physician/health care provider within two weeks to ensure resolution of their exacerbation and discuss how to prevent future exacerbations. For patients with good inhaler technique and adherence to daily controller medication, their baseline therapy should be escalated given the high risk of exacerbation in the year following an Emergency Room visit. Please refer to the CHBC/GPAC Guidelines for further details on the management of chronic asthma: http://www.bcguidelines.ca
# Documentation
Document the full assessment, medications given, steps taken to escalate care (if applicable), patient and family teaching and discharge instructions in the patient's chart as per your agency's documentation guidelines.
# Definitions
Asthma: Is a chronic inflammatory disease of the airways that is characterized by bronchial hyper reactivity and variable airway obstruction which results in recurrent episodes of wheezing, breathlessness, chest tightness and/or coughing that can vary over time and in intensity.
# College of Registered Nurses of British Columbia (BCCNP):
Under provincial legislation (Health Professions Act), it is the duty of BCCNP to protect the public through regulation of registered nurses, nurse practitioners, and licensed graduate nurses.
Pediatric Respiratory Assessment Measure (PRAM): Is a 12 point clinical scoring rubric that captures a patient's asthma severity using a combination of scalene muscle contraction, suprasternal retractions, wheezing, and air entry and oxygen saturation.
# Child Health BC Provincial Asthma Guideline
# Disclaimer
Child Health BC develops evidence-based clinical support documents that include recommendations for the care of children and youth across British Columbia. These documents are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. These documents are for guidance only and not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of a clinical problem. Healthcare professionals should continue to use their own judgment and take into consideration context, resources and other relevant factors. Neither Provincial Health Services Authority nor Child Health BC assume any responsibility or liability from reliance on or use of the documents.
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# Information for Primary Care Providers
Eligible Albertans between the ages of 50 to 74 who currently smoke cigarettes or quit smoking after smoking for many years are now able to get screened for lung cancer through the Alberta Lung Cancer Screening Program (ALCSP).
# The evidence
Lung cancer screening with low-dose computed tomography (LDCT):
- Has demonstrated an almost 25% reduction in lung cancer deaths in 2 large, randomized trials 1,2 ;
- It is much more likely to catch lung cancers at stages I or II when it is more likely curable, improving health outcomes.
# Process for screening
Talk with your eligible patients about lung cancer screening. A decision-making tool about the risks and benefits of participating in the program will be provided for your patient. 2. Unclear: In this situation, your patient will usually be asked to come back for another screen in 6 months.
- Abnormal: In this situation, your patient will be asked to come back in 3 months or be referred for other tests.
If your patient's results are unclear or abnormal, the program nurse practitioner will call the patient to inform them of the result and answer any questions they may have.
You may also wish to contact your patient to discuss their results.
All result reports and patient correspondence will be shared with you.
Incidental findings: Low-dose CT scans may occasionally detect non-lung cancer-related abnormalities. You will receive a copy of the radiology report and we recommend that you schedule an appointment with your patient to Information for Primary Care Providers discuss these findings. Referring providers will take responsibility for any required assessments and investigations for incidental findings.
# Tobacco cessation supports
Quitting smoking is one of the best things your patient can do to improve their health. All patients referred to the ALCSP who are currently smoking cigarettes will be referred to Enhanced Tobacco Cessation Service to discuss their interest in quitting smoking and their options for support. Patients may be eligible to receive coverage for nicotine replacement therapy or prescription medications to help them quit. Supports may include:
# Collection of race and ethnicity data
Race or ethnicity data is being collected as this information has been shown to impact lung cancer risk independent of other factors. This information will not be used by AHS beyond the ALCSP. The collection of this information may make some individuals uncomfortable.
Healthcare personnel requesting this information should be aware of culturally safe collection methods, and ensure:
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# Information for Primary Care Providers
Eligible Albertans between the ages of 50 to 74 who currently smoke cigarettes or quit smoking after smoking for many years are now able to get screened for lung cancer through the Alberta Lung Cancer Screening Program (ALCSP).
# The evidence
Lung cancer screening with low-dose computed tomography (LDCT):
• Has demonstrated an almost 25% reduction in lung cancer deaths in 2 large, randomized trials 1,2 ;
• It is much more likely to catch lung cancers at stages I or II when it is more likely curable, improving health outcomes.
# Process for screening
Talk with your eligible patients about lung cancer screening. A decision-making tool about the risks and benefits of participating in the program will be provided for your patient. 2. Unclear: In this situation, your patient will usually be asked to come back for another screen in 6 months.
3. Abnormal: In this situation, your patient will be asked to come back in 3 months or be referred for other tests.
If your patient's results are unclear or abnormal, the program nurse practitioner will call the patient to inform them of the result and answer any questions they may have.
You may also wish to contact your patient to discuss their results.
All result reports and patient correspondence will be shared with you.
Incidental findings: Low-dose CT scans may occasionally detect non-lung cancer-related abnormalities. You will receive a copy of the radiology report and we recommend that you schedule an appointment with your patient to Information for Primary Care Providers discuss these findings. Referring providers will take responsibility for any required assessments and investigations for incidental findings.
# Tobacco cessation supports
Quitting smoking is one of the best things your patient can do to improve their health. All patients referred to the ALCSP who are currently smoking cigarettes will be referred to Enhanced Tobacco Cessation Service to discuss their interest in quitting smoking and their options for support. Patients may be eligible to receive coverage for nicotine replacement therapy or prescription medications to help them quit. Supports may include:
•
# Collection of race and ethnicity data
Race or ethnicity data is being collected as this information has been shown to impact lung cancer risk independent of other factors. This information will not be used by AHS beyond the ALCSP. The collection of this information may make some individuals uncomfortable.
Healthcare personnel requesting this information should be aware of culturally safe collection methods, and ensure:
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# Preamble
This guidance has been adapted for Canadian use from the WHO document entitled Clinical management of COVID-19 -Interim guidance -27 May 2020. (Available from: ). This guidance is informed by currently available scientific evidence, expert opinion, and a multidisciplinary panel of health care providers with experience in the clinical management of patients with COVID-19 and other viral infections (including other severe respiratory infections due to coronaviruses such as SARS and MERS) as well as sepsis and acute respiratory distress syndrome (ARDS). The information presented is subject to change as new information becomes available.
This guidance provides clinicians with interim advice on timely, effective, and safe supportive management of adults, children and youth with suspected or confirmed acute COVID-19. It is not meant to replace clinical judgment or specialist consultation, but rather to strengthen the clinical management of these patients. Best practices for triage and optimized supportive care are included.
In the guidelines, these symbols are used to flag interventions: Do -the intervention is beneficial (strong recommendation) OR the intervention is a best practice statement Don't -the intervention is known to be harmful.
Consider -the intervention may be beneficial in selected patients (conditional recommendation) OR be careful when considering this intervention.
# Background
Coronavirus disease 2019 (COVID- 19) is a respiratory tract infection caused by a newly emergent coronavirus that was first recognized in Wuhan, China in December 2019. Genetic sequencing of the virus determined that it is a betacoronavirus closely related to the SARS-CoV-1 virus, named Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2). It has been estimated that up to half of persons infected with SARS-CoV-2 will remain pauci-symptomatic or asymptomatic. While most people that develop COVID-19 present with mild or uncomplicated illness, up to 15% of patients may develop severe disease requiring hospitalization and oxygen support and up to 5% may require admission to an intensive care unit (ICU). In severe cases, COVID-19 can be complicated by respiratory failure, acute respiratory distress syndrome (ARDS), sepsis and septic shock, thromboembolism and multiorgan failure, including acute kidney injury and cardiac injury. Older age and co-morbid disease are risk factors for severe disease and death.
Clinical presentation and symptoms of COVID-19 vary in frequency and severity. Symptoms absent at the onset of illness may develop over time with disease progression. Clinical diagnosis should therefore always be confirmed by laboratory testing, and patients should always be encouraged to seek medical consultation if experiencing new or worsening symptoms. The current estimates of the incubation period range from 1-14 days with median estimates of 5-6 days between infection and the onset of clinical symptoms of the disease. People infected with SARS-CoV-2 may be infectious before symptom onset . The risk of infection from most patients at more than 8 days post symptom onset is likely to be low. There are few data on the clinical presentation of COVID-19 in specific populations, such as children and pregnant women. Relatively few infant COVID-19 cases have been reported and in children with COVID-19, the symptoms are usually less severe than adults. However, although severe forms of COVID-19 are much less frequent than in adults, many countries have reported some pediatric ICU admissions and deaths related to COVID-19. Clinicians should also be aware of very rare complications that have been associated with COVID-19 infection. A severe multisystem inflammatory syndrome in children (MIS-C) has been reported to share features of typical or atypical Kawasaki disease or toxic shock syndrome. Pregnant women might be at increased risk for severe COVID-19 illness; experience with severe viral respiratory illness from other etiologies emphasizes the need for unique appreciation of pregnancy-related critical illness.
# Screening and Triage
The primary objective of the COVID-19 response is to slow and stop transmission, find, isolate and test every suspect case, and provide timely, culturally sensitive and appropriate care of patients with COVID-19. The recommended location of care will depend on the patient's severity of illness, patient and cohabitant safety, and patient ability to return to care in the event of worsening illness.
Screening and Triage -Screen and isolate all patients with suspected COVID-19 at the first point of contact with the health care system (such as the emergency department or outpatient department/clinic). Consider COVID-19 as a possible etiology in patients presenting with acute respiratory illness and place all patients suspected to have COVID-19 under Droplet and Contact Precautions, with the addition of Airborne Precautions if performing any aerosol-generating medical procedures. Triage patients using standardized triage tools and manage initial presentations accordingly. National surveillance case definitions have been developed to standardize public health reporting.
These case definitions, however, are not to be used for clinical purposes. Early recognition of suspected patients allows for timely initiation of appropriate infection prevention and control measures (see Section 3.0). Table 1 below outlines the clinical syndromes most often associated with COVID-19. Detailed guidance on infection prevention and control in acute healthcare settings and in outpatient and ambulatory care settings is available on the Public Health Agency of Canada website. Most people with COVID-19 have uncomplicated or mild illness (approximately 80%). Some will develop severe illness requiring oxygen therapy and up to 5% will develop critical illness requiring ICU treatment. Of those critically ill, many will require mechanical ventilation. For those with mild illness, hospitalization is not required unless there is concern about rapid deterioration or inability to return promptly to hospital. Isolation is necessary to contain virus transmission. All patients cared for outside of the hospital (i.e., at home) should be instructed to follow public health protocols for self-isolation and return to hospital if their symptoms worsen. Early identification of those with severe illness or pneumonia, allows for optimized supportive care treatments and safe, rapid referral and admission to a hospital. Older people and those with comorbidities (e.g. cardiovascular disease, diabetes mellitus, obesity, pre-existing lung conditions) have increased risk of severe disease and mortality. While they may present with mild disease, they have a higher risk of deterioration and should be monitored closely. Goals of care discussions should be a component of care for all patients, especially those who are at risk for, or present with, severe disease. Whether or not patients receive intensive and organsupportive care in severe illness, patients should receive symptom-based care (including dyspnea management) and palliative care should be offered as appropriate. Symptom-based care and palliative care can be provided alongside supportive and curative treatments, and do not compromise survival.
# Table 1 -Clinical Syndromes Associated with COVID-19
# Syndrome
# Details Asymptomatic/ presymptomatic
Patients will be tested for SARS-CoV2 and have positive results without ever having symptoms or prior to the development of symptoms.
# Mild illness
Patients with uncomplicated upper respiratory tract viral infection typically present with some signs or symptoms of COVID-19 but without shortness of breath or dyspnea or abnormal imaging. These patients may have non-specific symptoms such as fever, fatigue, cough (with or without sputum production), anorexia, malaise, muscle pain, sore throat, dyspnea, nasal congestion, conjunctivitis, loss/alteration of smell and taste, or headache. Patients may also present with diarrhea, abdominal pain, nausea and vomiting. Many are afebrile or have lowgrade fever.
The elderly and immunocompromised may present with atypical symptoms. Symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events, e.g., dyspnea, fever, GI symptoms or fatigue, may overlap with COVID-19 symptoms.
# Pneumonia
Adult with pneumonia but no signs of severe pneumonia and no need for supplemental oxygen. Child with non-severe pneumonia who has cough or difficulty breathing plus tachypnea (in breaths per minute): < 2 months: ≥ 60; 2-11 months: ≥ 50; 1-5 years: ≥ 40), and no signs of severe pneumonia.
While the diagnosis of pneumonia can be made on clinical grounds; chest imaging (radiograph, CT scan, ultrasound) may assist in diagnosis and identify or exclude pulmonary complications.
# Severe pneumonia
Adolescent or adult: fever or suspected respiratory infection, plus one of the following: respiratory rate > 30 breaths/min; severe respiratory distress; or SpO2 < 90% on room air (adapted). Child with cough and/or difficulty in breathing, plus at least one of the following: central cyanosis or SpO2 < 90%; severe respiratory distress (e.g. grunting, marked chest indrawing); signs of pneumonia with: inability to breastfeed or drink, lethargy or unconsciousness, or convulsions. Other signs of pneumonia may be present: fast breathing (in breaths/min) < 2 months: ≥ 60; 2-11 months: ≥ 50; 1-5 years: ≥ 40. Chest imaging may identify some pulmonary complications.
# Acute respiratory distress syndrome (ARDS)
Onset: within 1 week of a known clinical insult or new or worsening respiratory symptoms. Chest imaging (radiograph, CT scan, or lung ultrasound): bilateral opacities, not fully explained by volume overload, lobar or lung collapse, or nodules.
# Syndrome
Details Origin of pulmonary infiltrates: respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g. echocardiography) to exclude hydrostatic cause of infiltrates/edema if no risk factor present. Oxygenation impairment in adults: This is a syndrome that has been described in children and adolescents that presents with hyperinflammatory markers with features of Kawasaki syndrome or septic shock. It is temporally related to COVID-19 outbreaks in several jurisdictions. Diagnostic criteria and characterization of this syndrome are evolving. A full discussion of this syndrome is beyond the scope of this document.
# Sepsis
Adults: life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection. Signs of organ dysfunction include b : altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinemia. Children: suspected or proven infection and ≥ 2 age-based systemic inflammatory response syndrome criteria, of which one must be abnormal temperature or white blood cell count for age.
# Septic shock
Adults: persisting hypotension despite volume resuscitation, requiring vasopressors to maintain MAP ≥ 60-65 mmHg and serum lactate level > 2 mmol/L. Children: any hypotension (SBP 2 SD below normal for age) or 2 or 3 of the following: altered mental state; tachycardia or bradycardia (HR 160 bpm in infants and HR 150 bpm in children); prolonged capillary refill (> 2 sec) or weak pulse; tachypnea; mottled or cool skin or petechial or purpuric rash; increased lactate; oliguria; hyperthermia or hypothermia. Children often have tachycardia before rapid onset of hypotension occurs. Footnotes a If altitude is higher than 1000m, then correction factor should be calculated as follows: PaO2/FiO2 x barometric pressure/760. b The SOFA score ranges from 0 to 24 and includes points related to six organ systems: respiratory (hypoxemia defined by low PaO2/FiO2); coagulation (low platelets); liver (high bilirubin); cardiovascular (hypotension); central nervous system (low level of consciousness defined by Glasgow Coma Scale); and renal (low urine output or high creatinine). Sepsis is defined by an increase in the sepsis-related SOFA score of ≥ 2 points. Assume the baseline score is 0 if data are not available. Abbreviations: ARI acute respiratory infection; BP blood pressure; bpm beats per minute; CPAP continuous positive airway pressure; FiO2 fraction of inspired oxygen; MAP mean arterial pressure; NIV non-invasive ventilation; OI oxygenation Index; OSI oxygenation Index using SpO2; PaO2 partial pressure of oxygen; PEEP positive end-expiratory pressure; SBP systolic blood pressure; SD standard deviation; SIRS systemic inflammatory response syndrome; SOFA sequential organ failure assessment; SpO2 oxygen saturation.
# Infection Prevention and Control Measures
Infection prevention and control (IPC) is a critical and integral part of the clinical management of patients suspected or confirmed to have COVID-19.
Detailed national IPC guidance for COVID-19 in acute health care settings is available from the Public Health Agency of Canada (PHAC). See . Some provinces and territories have also issued IPC guidance for their jurisdiction, which complement existing regional and institutional policies. IPC guidance documents are revised and updated as new evidence becomes available therefore refer to the guidance documents directly.
Every effort should be made to allow support persons and essential visitors to visit patients. This is perhaps particularly important for persons with disabilities and older persons, as well as at-risk patients and those nearing the end of life, in order to support the emotional burden and stress of both patients and loved ones. Visitation may be dependent upon sufficient local supply of PPE and the epidemiology of the virus in the local community. Visitors should receive in-time education, training, and monitoring for compliance with IPC measures, including practice with putting on and taking off appropriate PPE. Institutions will need to ensure that there are policies in place for PPE supply procurement and use. Health care settings should refer to the relevant local and jurisdictional public health guidance.
# Collection of Specimens for Laboratory Diagnosis
Testing criteria recommendations change as the situation evolves in regions. All patients who are clinically suspected of infection with COVID-19 should be tested.
Currently, PCR-based molecular testing is predominantly being used in Canada. Since the sensitivity and specificity are linked to the viral load in the specimen, test performance varies during the course of the illness and by specimen type and quality of specimen collection. The virus is detected at high levels in the upper respiratory tract early in infection, and declines with time, usually over a 7 -10 day period, although a prolonged period of shedding has been observed in recovering patients. In patients that develop a lower respiratory tract infection, detection from upper respiratory tract specimens (nasopharyngeal or nose/throat specimens) can be variable. In patients who are intubated, a lower respiratory tract specimen should be obtained, if possible. If there is a high suspicion of COVID-19 even after a negative swab of either type, individuals should be re-tested and have imaging of their lungs.
False negative test results/interpretations can occur when:
The patient was not infected at the time of the initial swab, but became infected from a later exposure.
The patient is infected but is not yet shedding much virus in the upper respiratory tract. Every infection has a "window period" during which time the virus incubating in the patient may be there in quantities that are too low to be detected by any diagnostic test.
The patient is shedding virus but the sample collection was poor. Proper collection technique is essential to ensure that an adequate amount of specimen is collected from the correct anatomical site.
The patient's infection is manifesting outside the upper respiratory tract. In symptomatic people with mild infection, we know that the virus is shed just before or soon after symptom onset and in high numbers in the upper respiratory tract, lasting for at least 5-7 days. However, in patients who have pneumonia, the most sensitive specimen is from the lungs.
While it is very unusual to get a false positive result due to the cross reactivity with another RNA virus, PCR testing can sometimes give non-specific reactions or contamination within the laboratory can occur. Expert interpretation may be required in such cases.
Further guidance on appropriate testing and specimen collection for COVID-19 is available from the Public Health Agency of Canada, the Canadian Public Health Laboratory Network and from provincial/territorial public health laboratories. Collect specimens for COVID-19 testing as recommended by your local or provincial public health laboratory.
Collect blood cultures for bacteria where clinically indicated based on the presenting syndrome, e.g., sepsis or severe pneumonia, ideally before antimicrobial therapy. DO NOT delay antimicrobial therapy to collect blood cultures. Blood cultures should be done in children if clinically indicated.
- In admitted patients with suspected COVID-19, the diagnosis should be first attempted with an upper respiratory specimen, preferably a nasopharyngeal swab. However, a mid-turbinate and/or throat swab can be collected as an alternative if nasopharyngeal swabs are not available. For admitted patients with suspected COVID-19, if the upper respiratory swab is negative and there remains a high degree of clinical suspicion a repeat swab should be collected. In severely ill patients whose upper respiratory tract specimen is negative but a COVID-19 diagnosis is still suspected, a lower respiratory tract specimen consisting of sputum, or closed system suctioned endotracheal aspirate should also be collected when possible (e.g., if the patient is producing sputum or they are already ventilated). Once a patient has a positive laboratory test, further testing for diagnostic purposes is not necessary.
Patients can be infected with more than one virus at the same time. Coinfections with other respiratory viruses in people with COVID-19 have been reported. Therefore, identifying infection with one respiratory virus does not exclude SARS-CoV-2 virus infection, and vice-versa.
# SARS-CoV-2 antibody tests are not recommended for diagnosis of current SARS-
CoV-2 infection, but they may be useful in post-infectious syndromes.
# Management of Mild COVID-19
Patients with mild disease do not require hospitalization, unless there is concern for rapid deterioration or an inability to return promptly to hospital.
# Isolation is necessary to contain virus transmission.
All patients cared for outside hospital should be instructed to follow public health protocols for self-isolation and return to hospital if symptoms worsen. Selfisolation protocols are available from PHAC and provincial/territorial and local public health departments.
# Provide patients with mild COVID-19 information on symptomatic treatment.
Counsel patients with mild COVID-19 and their caregivers about the signs and symptoms of complications that should prompt urgent care. If they develop symptoms like difficulty breathing, pain or pressure in the chest, confusion, drowsiness, or weakness, they should seek follow-up care.
- In children signs and symptoms of clinical deterioration requiring urgent re-evaluation include difficulty breathing/fast or shallow breathing (for infants: grunting, inability to breastfeed), blue lips or face, chest pain or pressure, new confusion, inability to awaken/not interacting when awake, inability to drink or keep down liquids, extreme weakness).
Antibiotics should not be prescribed to patients with suspected or confirmed mild COVID-19 unless there is clinical suspicion of a bacterial infection.
# Management of Moderate COVID-19
Patients with moderate suspected or confirmed COVID-19 (i.e. with clinical signs of pneumonia but no signs of severe pneumonia, including SpO2 ≥ 90% on room air) who are not determined to be at high risk of deterioration may not require hospitalization, but they should be isolated.
- The decision regarding the location of care should be made on a case-by-case basis and will depend on the clinical presentation, requirement for supportive care, potential risk factors for severe disease, and conditions at home, including the presence of vulnerable persons in the household. o For patients at high risk for deterioration, admission to hospital should be considered. o The median time to acute respiratory distress syndrome (ARDS) ranges from 8 to 12 days. o Lymphopenia, neutrophilia, elevated serum alanine aminotransferase and aspartate aminotransferase levels, elevated lactate dehydrogenase, high CRP, and high ferritin levels may be associated with greater illness severity. Antibiotics should not be prescribed to patients with suspected or confirmed moderate COVID-19 unless there is clinical suspicion of a bacterial infection.
# Management of Severe COVID-19 7.1 Oxygen Therapy and Monitoring
Give supplemental oxygen therapy immediately to patients with COVID-19 who have severe acute respiratory infection and respiratory distress, hypoxaemia or shock, and target saturations of 90-96% SpO2 during resuscitation.
- Adults with a worsening clinical presentation (obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma or convulsions) should receive airway management and oxygen therapy.
Initiate oxygen therapy at 5 L/min and titrate flow rates to reach target SpO2 ≥ 94% during resuscitation; or use face mask with reservoir bag (at 10-15 L/min) if the patient is in critical condition. Once the patient is stable, the target is > 90% SpO2 in non-pregnant adults and ≥ 92-95% in pregnant patients.
- In adults, techniques such as positioning, e.g. high supported sitting may help to optimize oxygenation, ease breathlessness and reduce energy expenditure. Prone position for awake, spontaneously breathing patients may also improve oxygenation and the ventilation/perfusion ratio, but evidence is lacking and should be done under clinical trial protocols to assess efficacy and safety. Children with a worsening clinical presentation (obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma or convulsions) should receive airway management and oxygen therapy during resuscitation to target SpO2 ≥ 94%; otherwise, the target SpO2 is ≥ 90%. The use of a nasal cannula is preferred in young children, as it may be better tolerated. All areas where patients with severe acute respiratory infection are cared for should be equipped with pulse oximeters, functioning oxygen systems and disposable, single-patient use, oxygen-delivering interfaces (nasal cannula, face mask and mask with reservoir bag).
# Closely monitor patients with COVID
# Understand the patient's co-morbid conditions and tailor management accordingly.
- Determine which chronic therapies should be continued and which should be stopped temporarily.
- Monitor for drug interactions o Revisit the need for any held medications when clinically appropriate Metered dose inhalers with a spacer are preferred to nebulizers to reduce the potential to generate respiratory aerosols. Antihypertensive drugs should not routinely be stopped in patients with COVID-19, but therapy may need to be adjusted based on general considerations for patients with acute illness, with particular reference to maintaining normal blood pressure and renal function. Patients with psychiatric and neurological manifestations should be assessed for any underlying causes, including the monitoring of oxygenation and fluid status, correcting metabolic or endocrine abnormalities, addressing co-infections, minimizing the use of medications that may cause or worsen delirium, treating withdrawal from substances, understanding and minimizing the effects of any harmful drug-drug interactions and maintaining normal sleep cycles as much as possible.
- To reduce delirium in patients who are receiving invasive ventilation, consideration should be given to minimize continuous or intermittent sedation, targeting specific titration endpoints (light sedation unless contraindicated) or with daily interruption of continuous sedative infusions. In patients experiencing agitation (defined as marked restlessness or excessive motor activity, often accompanied by anxiety), calming communication strategies (to reorient the person) should be attempted. Acute pain due to physical illness or air hunger should be considered as triggers for agitation and need to be addressed immediately. While non-pharmacologic strategies are preferred, in case they are unsuccessful or distress is severe, psychotropic medications may need to be trialed alongside nonpharmacologic interventions.
Use conservative fluid management in patients with severe acute respiratory infection when there is no evidence of shock.
- Patients with severe acute respiratory disease should be treated cautiously with intravenous fluids, because aggressive fluid resuscitation may worsen oxygenation, especially in settings where there is limited availability of mechanical ventilation. This applies to the care of both children and adults.
# Treatment of Co-infections
The prevalence of acute co-infections or secondary infections coinciding with COVID-19 has not been adequately described but appears to be low. Antibiotic overuse increases the risk of emergence and transmission of multidrug-resistant bacteria. Infections with multidrug-resistant bacteria are more difficult to treat and are associated with increased morbidity and mortality.
Give empiric antimicrobials to treat all likely pathogens causing severe acute respiratory infection and sepsis as soon as possible, within 1 hour of initial patient assessment for patients with sepsis.
- Empiric antibiotic treatment should be based on the clinical diagnosis (e.g., community-acquired pneumonia, health care-associated pneumonia or sepsis), local epidemiology and susceptibility data. The Infectious Disease Society of America and the American Thoracic Society have published treatment guidelines for community-acquired pneumonia that can be found at: /#/name_na_str/ASC/0/+/.
Frequently re-evaluate and de-escalate empiric therapy where possible on the basis of microbiology results and clinical judgment.
- Regularly review the possibility of switching of intravenous to oral route of administration If antimicrobials are continued, this should be for the shortest recommended duration (for most indications 5-7 days)
- When there is ongoing local circulation of influenza, empiric therapy with a neuraminidase inhibitor should be considered for the treatment of influenza viruses in patients with or at risk for severe disease.
8.0 Management of Critical COVID-19
# Acute Respiratory Distress Syndrome (ARDS)
Recognize severe hypoxemic respiratory failure when a patient with respiratory distress is failing standard oxygen therapy and prepare to provide advanced oxygen/ventilatory support.
- Patients may continue to have increased work of breathing or hypoxemia even when oxygen is delivered via a face mask with reservoir bag (flow rates of 10-15 L/min, which is typically the minimum flow required to maintain bag inflation; FiO2 0.60-0.95). Hypoxemic respiratory failure in ARDS commonly results from intrapulmonary ventilation-perfusion mismatch or shunt and usually requires mechanical ventilation. Endotracheal intubation should be performed by a trained and experienced provider using airborne precautions.
- Patients with ARDS, especially young children or those who are obese or pregnant, may desaturate quickly during intubation. Pre-oxygenate with 100% FiO2 for 5 minutes, via a face mask with reservoir bag, bagvalve mask. The utilization of video laryngoscopy to increase chance of intubation at first attempt should be considered. Rapid sequence intubation is appropriate after an airway assessment that identifies no signs of difficult intubation, avoiding manual ventilation as a means to avoid aerosol generation, where possible and safe for patient care. Among hospitalized adult patients who have COVID-19 and require supplemental oxygen or mechanical ventilation, clinicians should strongly consider dexamethasone 6 mg IV daily for 10 days (or until off oxygen or discharge if earlier) or equivalent glucocorticoid dose. This guidance is not meant to replace clinical judgment or specialist consultation.
- There are currently no data on the use of dexamethasone in children with severe disease who require supplemental oxygen or mechanical ventilation, hence clinical judgement should be applied if considering its use in this population.
# Recommendations for mechanically ventilated adult and pediatric patients with ARDS
Implement mechanical ventilation using lower tidal volumes (4-8 mL/kg predicted body weight ) and lower inspiratory pressures (plateau pressure < 30 cmH2O).
- Adults -This is a strong recommendation from a clinical guideline for patients with ARDS, and is suggested for patients with sepsis-induced respiratory failure who do not meet ARDS criteria. The initial tidal volume is 6 mL/kg PBW; tidal volume up to 8 mL/kg PBW is allowed if undesirable side-effects occur (e.g. dyssynchrony, pH < 7.15). Permissive hypercapnia is permitted. Ventilator protocols are available. The use of deep sedation may be required to control respiratory drive and achieve tidal volume targets. Children -A lower level of plateau pressure (< 28 cmH2O) is targeted, and a lower pH target is permitted (7.15-7.30). Tidal volumes should be adapted to disease severity: 3-6 mL/kg PBW in the case of poor respiratory system compliance, and 5-8 mL/kg PBW with better preserved compliance. Slightly higher Plateau pressures (30-32 cm H20) can be tolerated in case of poor chest wall compliance.
In adult patients with severe ARDS, prone ventilation for 12-16 hours per day should be considered.
- Application of prone ventilation should be considered for adult patients, preferably for 16 hours per day, and may be considered for paediatric patients with severe ARDS but requires sufficient human resources and expertise to be performed safely. 33,34 Protocols (including videos) are available at: . Pregnant women should not be placed in a prone position but in the supine position with a wedge placed under the right hip to decrease aortocaval obstruction, or placed in lateral decubitus position.
# Use a conservative fluid management strategy for ARDS patients without tissue hypoperfusion.
- This is a strong recommendation for both adults and children; the main effect is to shorten the duration of ventilation . See reference for a sample protocol.
In patients with moderate or severe ARDS, higher PEEP instead of lower PEEP is suggested.
- PEEP titration requires consideration of benefits (reducing atelectrauma and improving alveolar recruitment) vs risks (end-inspiratory overdistension leading to lung injury and higher pulmonary vascular resistance). Tables are available to guide PEEP titration based on the FiO2 required to maintain SpO2. Although high driving pressure (plateau pressure minus PEEP) may more accurately predict increased mortality in ARDS compared with high tidal volume or plateau pressure, data from RCTs of ventilation strategies that target driving pressure are not currently available.
Recruitment manoeuvres (RMs) can be delivered as episodic periods of high continuous positive airway pressure (CPAP) (30-40 cmH2O), progressive incremental increases in PEEP with constant driving pressure, or high driving pressure; considerations of benefits vs risks are similar. PEEP and RMs were both conditionally recommended in a clinical practice guideline. For PEEP, the guideline considered an individual patient data meta-analysis of three RCTs. However, a subsequent RCT of high PEEP and prolonged high-pressure RMs showed harm, suggesting that the protocol in this RCT should be avoided. Monitoring of patients to identify those who respond to the initial application of higher PEEP or a different RM protocol, and stopping these interventions in non-responders are suggested, noting that patients with hypoxic respiratory failure without strong suspicion or evidence of alveolar de-recruitment are less likely to benefit from RMs but may still be at risk of side-effects. In patients with moderate-severe ARDS (PaO2/FiO2 < 150), neuromuscular blockade by continuous infusion should not be routinely used.
- While one trial found that this strategy improved survival in adult patients with severe ARDS (PaO2/FiO2 < 150) without causing significant weakness, results of a recent larger trial found that use of neuromuscular blockage with high PEEP strategy was not associated with a survival benefit when compared with a light sedation strategy without neuromuscular blockade. Continuous neuromuscular blockade may still be considered in patients, both adults and children, with ARDS in certain situations, such as ventilator dyssynchrony despite sedation, such that tidal volume limitation cannot be reliably achieved; refractory hypoxemia; or hypercapnia.
# Avoid disconnecting the patient from the ventilator, which results in loss of PEEP and atelectasis.
# Use in-line catheters for airway suctioning and clamp the endotracheal tube when disconnection is required (e.g., transfer to a transport ventilator).
# Recommendations for adult and pediatric patients with ARDS who are treated with non-invasive or high flow oxygen systems
# High-flow nasal oxygen (HFNO) and non-invasive ventilation (NIV) should be considered.
Patients treated with either HFNO or NIV should be closely monitored for clinical deterioration.
- Adult HFNO systems can deliver 60 L/min of gas flow and FiO2 up to 1.0. Pediatric circuits generally only handle up to 25 L/min, and many children will require an adult circuit to deliver adequate flow. Compared with standard oxygen therapy, HFNO reduces the need for intubation. [
# Recommendations for adult and paediatric patients with ARDS in whom a lung protective ventilation strategy fails
# In settings with access to expertise in extracorporeal membrane oxygenation (ECMO), consider referral of patients who have refractory hypoxemia despite lung protective ventilation.
- An RCT of ECMO for adult patients with ARDS was stopped early and found no statistically significant difference in the primary outcome of 60-day mortality between ECMO and standard medical management (including prone positioning and neuromuscular blockade). However, ECMO was associated with a reduced risk of the composite outcome of mortality and crossover to ECMO, and a post hoc Bayesian analysis of this RCT showed that ECMO is very likely to reduce mortality across a range of prior assumptions. In patients with MERS, ECMO vs conventional treatment was associated with reduced mortality in a cohort study. ECMO should ideally be offered in expert centres with a sufficient case volume to maintain expertise and that can apply the IPC measures required for adult and pediatric COVID-19 patients.
# Recommendations for resuscitation strategies for adult and paediatric patients with septic shock.
In resuscitation for septic shock in adults, give 250-500 mL crystalloid fluid as a rapid bolus in the first 15-30 minutes and reassess for signs of fluid overload after each bolus.
In resuscitation for septic shock in children, give 10-20 mL/kg crystalloid fluid as a rapid bolus in the first 30-60 minutes and reassess for signs of fluid overload after each bolus.
# Fluid resuscitation may lead to volume overload, including respiratory failure, particularly with ARDS.
If there is no response to fluid loading or signs of volume overload appear (e.g. jugular venous distension, crackles on lung auscultation, pulmonary edema on imaging, or hepatomegaly in children), then reduce or discontinue fluid administration. This step is particularly important in patients with hypoxemic respiratory failure.
- Crystalloids include normal saline and Ringer's lactate, with a preference for Ringer's lactate. Determine need for additional fluid boluses (500-1000 mL in adults or 10-20 mL/kg in children) based on clinical response and improvement of perfusion targets. Perfusion targets include MAP (≥ 60-65 mmHg or age-appropriate targets in children), urine output (> 0.5 mL/kg/hr in adults, 1 mL/kg/hr in children), and improvement of skin mottling and extremity perfusion, capillary refill, heart rate, level of consciousness, and lactate. Consider dynamic indices of volume responsiveness to guide volume administration beyond initial resuscitation based on local resources and experience. These indices include passive leg raises, fluid challenges with serial stroke volume measurements, or variations in systolic pressure, pulse pressure, inferior vena cava size, or stroke volume in response to changes in intrathoracic pressure during mechanical ventilation. In pregnant women, compression of the inferior vena cava can cause a decrease in venous return and cardiac preload and may result in hypotension. For this reason, pregnant women should be cared for with a wedge under their right hip and may need to be placed in a lateral decubitus position to off-load the inferior vena cava.
Clinical trials conducted in resource limited settings comparing aggressive versus conservative fluid regimens suggest higher mortality in patients treated with aggressive fluid regimes for other severe infections. Do not use hypotonic crystalloids, starches or gelatins for resuscitation.
- Starches are associated with an increased risk of death and acute kidney injury compared with crystalloids. The effects of gelatins are less clear, but they are more expensive than crystalloids. Hypotonic (vs isotonic) solutions are less effective at increasing intravascular volume. Surviving Sepsis also suggests albumin for resuscitation when patients require substantial amounts of crystalloids, but this conditional recommendation is based on low-quality evidence. In adults, administer vasopressors when shock persists during or after fluid resuscitation. The blood pressure target should be MAP ≥ 60-65 mmHg in adults and improvement of markers of perfusion.
# In children administer vasopressors if signs of fluid overload are apparent or the following persist after two fluid boluses:
- there are signs of shock such as altered mental state; Vasopressors (i.e. norepinephrine, epinephrine, vasopressin, and dopamine) are most safely given through a central venous catheter at a strictly controlled rate, but it is also possible to administer them safely via peripheral vein and intraosseous needle. Monitor blood pressure frequently and titrate the vasopressor to the minimum dose necessary to maintain perfusion and prevent side effects. Norepinephrine is considered first-line in adult patients; epinephrine or vasopressin can be added to achieve the MAP target. Because of the risk of tachyarrhythmia, reserve dopamine for selected patients with low risk of tachyarrhythmia or those with bradycardia. In children, epinephrine is considered first-line treatment, while norepinephrine can be added if shock persists despite optimal dose of epinephrine.
- No RCTs have compared dobutamine with placebo for clinical outcomes See Section 10.0 for remarks on corticosteroids and sepsis. Careful consideration should be given to the numerous, clinically significant side-effects of medications that may be used in the context of COVID-19, as well as drug-drug interactions between medications, both of which may affect COVID-19 symptomatology (including effects on respiratory, cardiac, immune and mental and neurological function). Both pharmacokinetic and pharmacodynamic effects should be considered.
# Prevention of Complications
# TABLE 2 -PREVENTION OF COMPLICATIONS IN CRITICALLY ILL PATIENTS
# Anticipated outcome Interventions
Reduce days of invasive mechanical ventilation Use weaning protocols that include daily assessment for readiness to breathe spontaneously; Minimize continuous or intermittent sedation, targeting specific titration endpoints (sedation score targeted light sedation unless contraindicated) or with daily interruption of continuous sedative infusions; Early mobilization; Implementation of the above as a bundle of care (such as the Awakening and Breathing Coordination, Delirium assessment/management, and Early mobility ) may also reduce delirium. Reduce incidence of ventilator-associated pneumonia Oral intubation is preferable to nasal intubation in adolescents and adults; Keep patient in semi-recumbent position (head of bed elevation at 30-45 o ); Use a closed suctioning system; periodically drain and discard condensate in tubing; Continue regular oral care Use a new ventilator circuit for each patient; once patient is ventilated, change circuit if it is soiled or damaged, but not routinely; Change heat moisture exchanger when it malfunctions, when soiled, or every 5-7 days. Reduce incidence of venous thromboembolism Use pharmacological prophylaxis (low molecular-weight heparin or heparin subcutaneously twice daily) in children, adolescents and adults without contraindications, and based on an assessment of individual risk factors for both thrombosis and bleeding. For those with contraindications, use mechanical prophylaxis (intermittent pneumatic compression devices). Reduce incidence of catheter-related bloodstream infection Use a checklist with completion verified by a real-time observer as a reminder of each step needed for sterile insertion and as a daily reminder to remove catheter if no longer needed.
# Anticipated outcome Interventions
Reduce incidence of pressure ulcers Turn patient every 2 hours.
Reduce incidence of stress ulcers and gastrointestinal bleeding Give early enteral nutrition (within 24-48 hours of admission); Consider administering histamine-2 receptor blockers or proton-pump inhibitors in patients with risk factors for GI bleeding. Risk factors for gastrointestinal bleeding include mechanical ventilation for ≥ 48 hours, coagulopathy, renal replacement therapy, liver disease, multiple comorbidities, and higher organ failure score. Stress ulcer prophylaxis should be reassessed as the patient's condition improves and as enteral feeding is established. Reduce incidence of ICU-related weakness Actively mobilize the patient early in the course of illness when safe to do so. Reduce the development of antimicrobial resistance Utilize de-escalation protocols as soon as patient is clinically stable and there is no evidence of bacterial infection.
Promote appropriate antimicrobial prescribing and use during the COVID-19 pandemic Do not prescribe antibiotics to suspected or confirmed COVID-19 patients with low suspicion of a bacterial infection, to avoid short-term side-effects of antibiotics and negative long-term consequences of increased antimicrobial resistance.
# Special Considerations
# Caring for Pregnant Women with COVID-19
The Society for Obstetrician and Gynecologists Canada (SOGC) has published COVID-19 resources on obstetric and perinatal care to assist obstetricians in Canada. These resources can be found on their website at /. To date, there are limited data on clinical presentation and perinatal outcomes after COVID-19 during pregnancy or the post-partum period. There is no solid evidence that pregnant women present with different signs or symptoms or are at higher risk of severe illness. The literature is mixed regarding whether pregnant women are at higher risk of severe illness, however it appears that the rates are not significantly higher, with reports of 4% or women requiring ICU admission and 3% requiring mechanical ventilation, which are similar to the non-pregnant population.
The section below on COVID-19 and pregnancy builds on existing recommendations and provides additional remarks for the management of pregnant and recently pregnant women.
Pregnant and recently pregnant women with suspected or confirmed COVID-19 should be isolated and treated with the supportive and management therapies previously described for other adults, taking into account the immunologic and physiologic adaptations occurring during and after pregnancy.
- Evidence of increased adverse maternal or neonatal outcomes is uncertain. Some literature has reported higher rates of stillbirth and many reports suggest higher rates of preterm birth but recent (August 5, 2020
-Living Systematic Reviews from the WHO collaborating centre for global women's health COVID-19 in Pregnancy (PregCOV-19LSR)), found a cumulative rate of preterm birth in 14,210 women from 49 cohort studies of 17%. In addition, there are reports of higher rates of fetal distress in labour particularly associated with maternal infection in the third trimester. () . Until more evidence becomes available, pregnant women with COVID-19 need to be observed closely for severe illness.
Pregnant women with a suspected, probable or confirmed COVID-19 infection, including women who may need to spend time in isolation, should have access to woman-centred, respectful skilled care, including obstetric, foetal medicine and neonatal care, as well as mental health and psychosocial support, with readiness to care for maternal and neonatal complications. Prevention of complications as described earlier, also apply to pregnant and recently pregnant women including those with miscarriage, late pregnancy fetal loss and postpartum/post-abortion women. The mode of delivery should be individualized based on obstetric indications. Multidisciplinary consultations from obstetric, perinatal, neonatal, infectious disease and intensive care specialists should be provided as required. Access to reproductive health care including termination of pregnancy should be ensured throughout the pandemic.
# All recently pregnant women with COVID-19 infection or who have recovered from COVID-19 should be provided with counselling on safe infant feeding, including recommendations for breast feeding and appropriate infection prevention measures to prevent COVID-19 transmission (see section 9.2 below).
Pregnant and recently pregnant women who have recovered from COVID-19 should be encouraged to attend enhanced antenatal, postpartum or other obstetrical care as appropriate. Enhanced fetal surveillance is recommended for women with COVID-19 illness.
# Caring for Infants and Mothers with COVID-19 -IPC and Breastfeeding
Relatively few cases have been reported of infants confirmed with COVID-19 infection. At this time there is no clear evidence that vertical transmission occurs. Breast milk samples from the mothers after the first lactation were negative for SARS CoV-2. . Although recommendations for infant feeding varies around the world, Canadian recommendations are found below. Additional guidance on feeding and caring for infants and young children of mothers with COVID-19 is available on the WHO website:
Infants born to mothers with suspected, probable, or confirmed COVID-19 should be fed according to standard infant feeding guidelines, primarily breast feeding while providing necessary infection prevention precautions.
Symptomatic mothers who are breastfeeding should practice respiratory hygiene, including during feeding (for example, use of a mask when near a child if the mother has respiratory symptoms), perform hand hygiene before and after contact with the child, and routinely clean and disinfect surfaces with which the symptomatic mother has been in contact.
In situations when severe illness in a mother due to COVID-19 or other complications prevents her from caring for her infant or prevents her from continuing direct breastfeeding, mothers should be encouraged and supported to express milk, and safely provide breast milk to the infant, while applying appropriate IPC measures.
Mothers and infants should be allowed to remain together and to practice rooming-in if desired, especially during establishment of breastfeeding, whether they or their infants have suspected, probable or confirmed COVID-19.
Parents and caregivers who may need to be separated from their children, and children who may need to be separated from their primary caregivers, should have access to appropriately trained health or nonhealth workers for mental health and psychosocial support.
# Caring for Older Persons with COVID-19
Older age and comorbid conditions such as diabetes and cardiovascular disease have been reported as risk factors for death in persons with COVID-19. Because older persons are at highest risk for severe disease and fatality and are one of the most vulnerable populations, they should be screened for COVID-19 at the first point of access to the health system, be diagnosed promptly if they are suspected to have COVID-19 and treated appropriately. As older patients may present with atypical symptoms, health workers should take this into account during the screening process.
Identify if there is an advance care plan for patients with COVID-19 and ensure the care plan takes into consideration their priorities and preferences. Tailor the care plan to be in line with the patient's expressed wishes (refer to section 9.5 for additional guidance on palliative care) For older persons with probable or suspected COVID-19, in addition to a conventional history the assessment should include an understanding of the person's life, values, priorities and preferences for health management.
# Ensure multidisciplinary collaboration (physicians, nurses, pharmacists and other health professionals) in the decision-making process to address multimorbidity and functional decline.
- Physiological changes with age lead to declines in intrinsic capacity such as malnutrition, cognitive decline, depressive symptoms, and those conditions interact at several levels. Hearing and vision impairments become more prevalent among older adults and may pose a communication barrier, especially when masks prevent lip reading and decrease vocal clarity. Cognitive decline may also need to be considered when communicating with older patients. Older people who experience COVID-19, including those admitted to ICU and/or treated with protracted oxygen therapy and bed rest, are more likely to experience pronounced functional decline and may require coordinated rehabilitation care after acute hospitalization.
# Early detection of inappropriate medication prescriptions is recommended to prevent adverse drug events and drug interactions in those being treated for COVID-19.
- Older patients are at greater risk of polypharmacy which increases the risk of negative health consequences. If medications are prescribed for mental and neurological manifestations of COVID-19 in older adults, this should be done with extreme caution given the increased susceptibility to drug sideeffects and drug interactions with other prescribed medications.
Where appropriate, involve caregivers and family members in decision-making and goal setting throughout the management of older COVID-19 patients.
Symptom-based and palliative care should be provided, as appropriate, even for patients with supportive or curative goals of care.
# Managing Patients with COVID-19 in Remote and Isolated Communities
While primary health care services are available in most remote and isolated communities, there is limited capacity to provide acute care and they may lack appropriate medical equipment, supplies and services (e.g., ventilators, access to specialists) to treat patients with severe illness. In many remote and isolated communities, a nurse-led health care team can provide emergency resuscitation and stabilization, emergency ambulatory care and outpatient non-urgent services. Access to physician services is available remotely via telehealth or teleconference, but much variation exists from community to community regarding the availability and frequency of physicians. Severely ill patients requiring complex emergency medical care are evacuated to a secondary or tertiary hospital or facility.
Treatment considerations for these remote and isolated settings include the following measures: Primary care providers or nursing stations, where available, should plan to provide triage and assessment, primary care treatment and monitoring. Mild disease, including uncomplicated pneumonia, should be managed within the community, with appropriate precautions in place. Alternate arrangements for self-isolation may be needed for persons in crowded living arrangements. Fluid management should be conservative when there is no evidence of shock, because aggressive fluid management may worsen oxygenation in settings without access to mechanical ventilation. Mild cases may progress to lower respiratory tract disease. Possible risk factors for progression to severe illness include older age and underlying chronic medical conditions such as lung disease, cancer, heart failure, cerebrovascular disease, renal disease, liver disease, diabetes, immunocompromising conditions, and pregnancy. Patients should be carefully monitored for signs of impending deterioration so that transfer can be arranged before intubation is required. Clinicians should be aware of the potential for some patients to rapidly deteriorate 1 week after illness Anticipate delays in accessing hospital care (awaiting air-ambulance, weather issues). Therefore, a low threshold should be considered for medevac options, particularly for the elderly, persons with underlying medical conditions or persons with evidence of pneumonia.
# Palliative care and COVID-19
We recommend identifying, in all patients with COVID-19, if they have an advance care plan for COVID-19 (such as desires for intensive care support) and to discuss goals of care in the setting of acute illness. Patient priorities and preferences should be respected and their care plan tailored to allow the provision of the best care irrespective of treatment choice.
Palliative care services should be made accessible at each institution that provides care for persons with COVID-19, and symptomatic treatments (e.g. management of dyspnea) should be provided even for patients with supportive or curative goals of care.
# Immunocompromised patients and COVID-19
Patients living with HIV Infection should be offered standard of care. Case series of patients living with HIV and COVID-19 have not shown a higher COVID-19 infection rate or complication rate in patients with suppressed viral loads and CD4> 200. It is assumed that patients with CD4<200 or not receiving Antiretroviral therapy will be at increased risk of disease due to their immunosuppression. In solid organ transplant patients, the risk of COVID 19 infection from a living donor or deceased donor is unknown at this time and such decisions on transplantation are to be made with expert advice. In Hematopoietic Stem Cell Transplantation (HSCT) patients, it is recommended that all recipients should have a negative COVID 19 PCR test prior to start of conditioning In HSCT patients, if a donor has travelled to a high risk area for COVID 19 transmission or has had contact with a patient confirmed to have COVID-19, the donor must be excluded from donation for at least 28 days.
# Specific and Adjunctive COVID-19 Treatments and Clinical Research
There are many ongoing clinical trials testing various potential medical treatments. Until specific therapies become available, any medication should be given as part of a randomized controlled trial.
Collect standardized clinical data on all hospitalized patients to improve our understanding of the natural history of disease. Among hospitalized adult patients who have COVID-19 and require supplemental oxygen or mechanical ventilation, clinicians should strongly consider dexamethasone 6 mg IV daily for 10 days (or until discharge if earlier) or equivalent glucocorticoid dose.
- The recommendation is based on the data from a preliminary report of the RECOVERY trial comparing the use of 6 mg of dexamethasone given once daily for up to ten days. The primary outcome was 28-day mortality in more than 6,400 patients randomly allocated (1:2) to receive dexamethasone or usual care. While the trial demonstrated benefit of dexamethasone use in patients who required supplemental oxygen or mechanical ventilation, it did not reduce mortality in patients who did not require respiratory support at randomization (17.8% vs. 14%, RR 1.18 ).
- There are currently no data on the use of dexamethasone in children with severe disease who require supplemental oxygen or mechanical ventilation, hence clinical judgement should be applied if considering use.
- If oral, IV and/or inhaled steroids are indicated for non-COVID-19 reasons (e.g., asthma or COPD exacerbation, or stress dosing in someone on chronic steroids or with known adrenal insufficiency), they should not be avoided. ). The benefit of Remdesivir on reducing time to recovery was highest among patients who were not intubated but required supplemental oxygen. In mechanically ventilated patients who received Remdesivir there was no observed decrease in time to recovery. Health Canada has authorized the use of Remdesivir for adults and adolescents aged 12 and over, and clinical trials are presently underway in children.
# Do not use hydroxychloroquine or ritonavir/lopinavir outside of a clinical trial.
- The use of hydroxychloroquine and lopinavir-ritonavir in COVID-19 patients was recently reported in a large randomized, controlled, open-label, adaptive, platform trial (the RECOVERY trial). In the hydroxychloroquine arm of the trial, patients were randomised to receive either hydroxychloroquine (n=1,561) or usual care (n=3,155). There was no significant difference in the primary endpoint of 28-day mortality or beneficial effects on hospital stay duration. In the lopinavir-ritonavir arm of the trial, patients were randomised to receive lopinavir-ritonavir (n=1,596) or usual care (n=3,376). There was no significant difference in the primary endpoint of 28-day mortality, the risk of progression to mechanical ventilation or length of hospital stay. Based on these results, the use of hydroxychloroquine and lopinavir-ritonavir in COVID-19 patients should not be considered outside of a clinical trial setting.
Use of investigational anti-COVID-19 therapeutics should be done under ethically approved, randomized, controlled trials.
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# Preamble
This guidance has been adapted for Canadian use from the WHO document entitled Clinical management of COVID-19 -Interim guidance -27 May 2020. (Available from: https://apps.who.int/iris/handle/10665/332196). This guidance is informed by currently available scientific evidence, expert opinion, and a multidisciplinary panel of health care providers with experience in the clinical management of patients with COVID-19 and other viral infections (including other severe respiratory infections due to coronaviruses such as SARS and MERS) as well as sepsis and acute respiratory distress syndrome (ARDS). [1] [2] The information presented is subject to change as new information becomes available.
This guidance provides clinicians with interim advice on timely, effective, and safe supportive management of adults, children and youth with suspected or confirmed acute COVID-19. It is not meant to replace clinical judgment or specialist consultation, but rather to strengthen the clinical management of these patients. Best practices for triage and optimized supportive care are included.
In the guidelines, these symbols are used to flag interventions: Do -the intervention is beneficial (strong recommendation) OR the intervention is a best practice statement Don't -the intervention is known to be harmful.
Consider -the intervention may be beneficial in selected patients (conditional recommendation) OR be careful when considering this intervention.
# Background
Coronavirus disease 2019 (COVID- 19) is a respiratory tract infection caused by a newly emergent coronavirus that was first recognized in Wuhan, China in December 2019. Genetic sequencing of the virus determined that it is a betacoronavirus closely related to the SARS-CoV-1 virus, named Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2). [3] [4] It has been estimated that up to half of persons infected with SARS-CoV-2 will remain pauci-symptomatic or asymptomatic. While most people that develop COVID-19 present with mild or uncomplicated illness, up to 15% of patients may develop severe disease requiring hospitalization and oxygen support and up to 5% may require admission to an intensive care unit (ICU). [5] [4] [6] [7] [8] In severe cases, COVID-19 can be complicated by respiratory failure, acute respiratory distress syndrome (ARDS), sepsis and septic shock, thromboembolism and multiorgan failure, including acute kidney injury and cardiac injury. [9] Older age and co-morbid disease are risk factors for severe disease and death.
Clinical presentation and symptoms of COVID-19 vary in frequency and severity. Symptoms absent at the onset of illness may develop over time with disease progression. Clinical diagnosis should therefore always be confirmed by laboratory testing, and patients should always be encouraged to seek medical consultation if experiencing new or worsening symptoms. [7] [10] The current estimates of the incubation period range from 1-14 days with median estimates of 5-6 days between infection and the onset of clinical symptoms of the disease. People infected with SARS-CoV-2 may be infectious before symptom onset . [7] The risk of infection from most patients at more than 8 days post symptom onset is likely to be low. [11] [12] There are few data on the clinical presentation of COVID-19 in specific populations, such as children and pregnant women. Relatively few infant COVID-19 cases have been reported and in children with COVID-19, the symptoms are usually less severe than adults. [7] However, although severe forms of COVID-19 are much less frequent than in adults, many countries have reported some pediatric ICU admissions and deaths related to COVID-19. [13] Clinicians should also be aware of very rare complications that have been associated with COVID-19 infection. A severe multisystem inflammatory syndrome in children (MIS-C) has been reported to share features of typical or atypical Kawasaki disease or toxic shock syndrome. [14] [15] [16] [17] [18] [19] [20] [21] [22] Pregnant women might be at increased risk for severe COVID-19 illness; experience with severe viral respiratory illness from other etiologies emphasizes the need for unique appreciation of pregnancy-related critical illness. [23]
# Screening and Triage
The primary objective of the COVID-19 response is to slow and stop transmission, find, isolate and test every suspect case, and provide timely, culturally sensitive and appropriate care of patients with COVID-19. The recommended location of care will depend on the patient's severity of illness, patient and cohabitant safety, and patient ability to return to care in the event of worsening illness.
Screening and Triage -Screen and isolate all patients with suspected COVID-19 at the first point of contact with the health care system (such as the emergency department or outpatient department/clinic). Consider COVID-19 as a possible etiology in patients presenting with acute respiratory illness and place all patients suspected to have COVID-19 under Droplet and Contact Precautions, with the addition of Airborne Precautions if performing any aerosol-generating medical procedures. Triage patients using standardized triage tools and manage initial presentations accordingly. National surveillance case definitions have been developed to standardize public health reporting.
These case definitions, however, are not to be used for clinical purposes. [24] Early recognition of suspected patients allows for timely initiation of appropriate infection prevention and control measures (see Section 3.0). Table 1 below outlines the clinical syndromes most often associated with COVID-19. Detailed guidance on infection prevention and control in acute healthcare settings and in outpatient and ambulatory care settings is available on the Public Health Agency of Canada website. [25] [26] Most people with COVID-19 have uncomplicated or mild illness (approximately 80%). Some will develop severe illness requiring oxygen therapy and up to 5% will develop critical illness requiring ICU treatment. Of those critically ill, many will require mechanical ventilation. [9] [27] [7] [11] [8] For those with mild illness, hospitalization is not required unless there is concern about rapid deterioration or inability to return promptly to hospital. Isolation is necessary to contain virus transmission. All patients cared for outside of the hospital (i.e., at home) should be instructed to follow public health protocols for self-isolation and return to hospital if their symptoms worsen. Early identification of those with severe illness or pneumonia, allows for optimized supportive care treatments and safe, rapid referral and admission to a hospital. Older people and those with comorbidities (e.g. cardiovascular disease, diabetes mellitus, obesity, pre-existing lung conditions) have increased risk of severe disease and mortality. While they may present with mild disease, they have a higher risk of deterioration and should be monitored closely. Goals of care discussions should be a component of care for all patients, especially those who are at risk for, or present with, severe disease. Whether or not patients receive intensive and organsupportive care in severe illness, patients should receive symptom-based care (including dyspnea management) and palliative care should be offered as appropriate. Symptom-based care and palliative care can be provided alongside supportive and curative treatments, and do not compromise survival.
# Table 1 -Clinical Syndromes Associated with COVID-19
# Syndrome
# Details Asymptomatic/ presymptomatic
Patients will be tested for SARS-CoV2 and have positive results without ever having symptoms or prior to the development of symptoms. [10]
# Mild illness
Patients with uncomplicated upper respiratory tract viral infection typically present with some signs or symptoms of COVID-19 but without shortness of breath or dyspnea or abnormal imaging. These patients may have non-specific symptoms such as fever, fatigue, cough (with or without sputum production), anorexia, malaise, muscle pain, sore throat, dyspnea, nasal congestion, conjunctivitis, loss/alteration of smell and taste, or headache. Patients may also present with diarrhea, abdominal pain, nausea and vomiting. [7] [28] [29] [30] Many are afebrile or have lowgrade fever.
The elderly and immunocompromised may present with atypical symptoms. Symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events, e.g., dyspnea, fever, GI symptoms or fatigue, may overlap with COVID-19 symptoms.
# Pneumonia
Adult with pneumonia but no signs of severe pneumonia and no need for supplemental oxygen. Child with non-severe pneumonia who has cough or difficulty breathing plus tachypnea (in breaths per minute): < 2 months: ≥ 60; 2-11 months: ≥ 50; 1-5 years: ≥ 40), and no signs of severe pneumonia.
While the diagnosis of pneumonia can be made on clinical grounds; chest imaging (radiograph, CT scan, ultrasound) may assist in diagnosis and identify or exclude pulmonary complications.
# Severe pneumonia
Adolescent or adult: fever or suspected respiratory infection, plus one of the following: respiratory rate > 30 breaths/min; severe respiratory distress; or SpO2 < 90% on room air (adapted). [31] Child with cough and/or difficulty in breathing, plus at least one of the following: central cyanosis or SpO2 < 90%; severe respiratory distress (e.g. grunting, marked chest indrawing); signs of pneumonia with: inability to breastfeed or drink, lethargy or unconsciousness, or convulsions. [32] Other signs of pneumonia may be present: fast breathing (in breaths/min) < 2 months: ≥ 60; 2-11 months: ≥ 50; 1-5 years: ≥ 40. [33] Chest imaging may identify some pulmonary complications.
# Acute respiratory distress syndrome (ARDS)
Onset: within 1 week of a known clinical insult or new or worsening respiratory symptoms. Chest imaging (radiograph, CT scan, or lung ultrasound): bilateral opacities, not fully explained by volume overload, lobar or lung collapse, or nodules.
# Syndrome
Details [34] [35] [36] Origin of pulmonary infiltrates: respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g. echocardiography) to exclude hydrostatic cause of infiltrates/edema if no risk factor present. Oxygenation impairment in adults: [34] This is a syndrome that has been described in children and adolescents that presents with hyperinflammatory markers with features of Kawasaki syndrome or septic shock. It is temporally related to COVID-19 outbreaks in several jurisdictions. Diagnostic criteria and characterization of this syndrome are evolving. A full discussion of this syndrome is beyond the scope of this document.
# Sepsis [1] [2]
Adults: life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection. Signs of organ dysfunction include b : altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinemia. [37] [1] Children: suspected or proven infection and ≥ 2 age-based systemic inflammatory response syndrome criteria, of which one must be abnormal temperature or white blood cell count for age.
# Septic shock [1] [2]
Adults: persisting hypotension despite volume resuscitation, requiring vasopressors to maintain MAP ≥ 60-65 mmHg and serum lactate level > 2 mmol/L. Children: any hypotension (SBP < 5th centile or > 2 SD below normal for age) or 2 or 3 of the following: altered mental state; tachycardia or bradycardia (HR < 90 bpm or > 160 bpm in infants and HR < 70 bpm or > 150 bpm in children); prolonged capillary refill (> 2 sec) or weak pulse; tachypnea; mottled or cool skin or petechial or purpuric rash; increased lactate; oliguria; hyperthermia or hypothermia. [38] Children often have tachycardia before rapid onset of hypotension occurs. Footnotes a If altitude is higher than 1000m, then correction factor should be calculated as follows: PaO2/FiO2 x barometric pressure/760. b The SOFA score ranges from 0 to 24 and includes points related to six organ systems: respiratory (hypoxemia defined by low PaO2/FiO2); coagulation (low platelets); liver (high bilirubin); cardiovascular (hypotension); central nervous system (low level of consciousness defined by Glasgow Coma Scale); and renal (low urine output or high creatinine). Sepsis is defined by an increase in the sepsis-related SOFA score of ≥ 2 points. Assume the baseline score is 0 if data are not available. [39] Abbreviations: ARI acute respiratory infection; BP blood pressure; bpm beats per minute; CPAP continuous positive airway pressure; FiO2 fraction of inspired oxygen; MAP mean arterial pressure; NIV non-invasive ventilation; OI oxygenation Index; OSI oxygenation Index using SpO2; PaO2 partial pressure of oxygen; PEEP positive end-expiratory pressure; SBP systolic blood pressure; SD standard deviation; SIRS systemic inflammatory response syndrome; SOFA sequential organ failure assessment; SpO2 oxygen saturation.
# Infection Prevention and Control Measures
Infection prevention and control (IPC) is a critical and integral part of the clinical management of patients suspected or confirmed to have COVID-19.
Detailed national IPC guidance for COVID-19 in acute health care settings is available from the Public Health Agency of Canada (PHAC). See https://www.canada.ca/en/public-health/services/diseases/2019-novelcoronavirus-infection/health-professionals/infection-prevention-control-covid-19-second-interimguidance.html. Some provinces and territories have also issued IPC guidance for their jurisdiction, which complement existing regional and institutional policies. IPC guidance documents are revised and updated as new evidence becomes available therefore refer to the guidance documents directly.
Every effort should be made to allow support persons and essential visitors to visit patients. This is perhaps particularly important for persons with disabilities and older persons, as well as at-risk patients and those nearing the end of life, in order to support the emotional burden and stress of both patients and loved ones. Visitation may be dependent upon sufficient local supply of PPE and the epidemiology of the virus in the local community. Visitors should receive in-time education, training, and monitoring for compliance with IPC measures, including practice with putting on and taking off appropriate PPE. Institutions will need to ensure that there are policies in place for PPE supply procurement and use. Health care settings should refer to the relevant local and jurisdictional public health guidance.
# Collection of Specimens for Laboratory Diagnosis
Testing criteria recommendations change as the situation evolves in regions. All patients who are clinically suspected of infection with COVID-19 should be tested.
Currently, PCR-based molecular testing is predominantly being used in Canada. Since the sensitivity and specificity are linked to the viral load in the specimen, test performance varies during the course of the illness and by specimen type and quality of specimen collection. The virus is detected at high levels in the upper respiratory tract early in infection, and declines with time, usually over a 7 -10 day period, although a prolonged period of shedding has been observed in recovering patients. In patients that develop a lower respiratory tract infection, detection from upper respiratory tract specimens (nasopharyngeal or nose/throat specimens) can be variable. In patients who are intubated, a lower respiratory tract specimen should be obtained, if possible. If there is a high suspicion of COVID-19 even after a negative swab of either type, individuals should be re-tested and have imaging of their lungs.
False negative test results/interpretations can occur when:
#
The patient was not infected at the time of the initial swab, but became infected from a later exposure.
#
The patient is infected but is not yet shedding much virus in the upper respiratory tract. Every infection has a "window period" during which time the virus incubating in the patient may be there in quantities that are too low to be detected by any diagnostic test.
#
The patient is shedding virus but the sample collection was poor. Proper collection technique is essential to ensure that an adequate amount of specimen is collected from the correct anatomical site.
#
The patient's infection is manifesting outside the upper respiratory tract. In symptomatic people with mild infection, we know that the virus is shed just before or soon after symptom onset and in high numbers in the upper respiratory tract, lasting for at least 5-7 days. [40] However, in patients who have pneumonia, the most sensitive specimen is from the lungs.
While it is very unusual to get a false positive result due to the cross reactivity with another RNA virus, PCR testing can sometimes give non-specific reactions or contamination within the laboratory can occur. Expert interpretation may be required in such cases.
Further guidance on appropriate testing and specimen collection for COVID-19 is available from the Public Health Agency of Canada, the Canadian Public Health Laboratory Network and from provincial/territorial public health laboratories. [10] [41] Collect specimens for COVID-19 testing as recommended by your local or provincial public health laboratory.
Collect blood cultures for bacteria where clinically indicated based on the presenting syndrome, e.g., sepsis or severe pneumonia, ideally before antimicrobial therapy. DO NOT delay antimicrobial therapy to collect blood cultures. Blood cultures should be done in children if clinically indicated.
In admitted patients with suspected COVID-19, the diagnosis should be first attempted with an upper respiratory specimen, preferably a nasopharyngeal swab. However, a mid-turbinate and/or throat swab can be collected as an alternative if nasopharyngeal swabs are not available. For admitted patients with suspected COVID-19, if the upper respiratory swab is negative and there remains a high degree of clinical suspicion a repeat swab should be collected. In severely ill patients whose upper respiratory tract specimen is negative but a COVID-19 diagnosis is still suspected, a lower respiratory tract specimen consisting of sputum, or closed system suctioned endotracheal aspirate should also be collected when possible (e.g., if the patient is producing sputum or they are already ventilated). Once a patient has a positive laboratory test, further testing for diagnostic purposes is not necessary.
[42] Patients can be infected with more than one virus at the same time. Coinfections with other respiratory viruses in people with COVID-19 have been reported. Therefore, identifying infection with one respiratory virus does not exclude SARS-CoV-2 virus infection, and vice-versa.
# SARS-CoV-2 antibody tests are not recommended for diagnosis of current SARS-
CoV-2 infection, but they may be useful in post-infectious syndromes.
# Management of Mild COVID-19
Patients with mild disease do not require hospitalization, unless there is concern for rapid deterioration or an inability to return promptly to hospital.
# Isolation is necessary to contain virus transmission.
All patients cared for outside hospital should be instructed to follow public health protocols for self-isolation and return to hospital if symptoms worsen. Selfisolation protocols are available from PHAC and provincial/territorial and local public health departments.
# Provide patients with mild COVID-19 information on symptomatic treatment.
Counsel patients with mild COVID-19 and their caregivers about the signs and symptoms of complications that should prompt urgent care. If they develop symptoms like difficulty breathing, pain or pressure in the chest, confusion, drowsiness, or weakness, they should seek follow-up care.
In children signs and symptoms of clinical deterioration requiring urgent re-evaluation include difficulty breathing/fast or shallow breathing (for infants: grunting, inability to breastfeed), blue lips or face, chest pain or pressure, new confusion, inability to awaken/not interacting when awake, inability to drink or keep down liquids, extreme weakness).
Antibiotics should not be prescribed to patients with suspected or confirmed mild COVID-19 unless there is clinical suspicion of a bacterial infection.
# Management of Moderate COVID-19
Patients with moderate suspected or confirmed COVID-19 (i.e. with clinical signs of pneumonia but no signs of severe pneumonia, including SpO2 ≥ 90% on room air) who are not determined to be at high risk of deterioration may not require hospitalization, but they should be isolated.
o The decision regarding the location of care should be made on a case-by-case basis and will depend on the clinical presentation, requirement for supportive care, potential risk factors for severe disease, and conditions at home, including the presence of vulnerable persons in the household. o For patients at high risk for deterioration, admission to hospital should be considered. o The median time to acute respiratory distress syndrome (ARDS) ranges from 8 to 12 days. o Lymphopenia, neutrophilia, elevated serum alanine aminotransferase and aspartate aminotransferase levels, elevated lactate dehydrogenase, high CRP, and high ferritin levels may be associated with greater illness severity. [43] Antibiotics should not be prescribed to patients with suspected or confirmed moderate COVID-19 unless there is clinical suspicion of a bacterial infection.
# Management of Severe COVID-19 7.1 Oxygen Therapy and Monitoring
Give supplemental oxygen therapy immediately to patients with COVID-19 who have severe acute respiratory infection and respiratory distress, hypoxaemia or shock, and target saturations of 90-96% SpO2 during resuscitation.
Adults with a worsening clinical presentation (obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma or convulsions) should receive airway management and oxygen therapy.
Initiate oxygen therapy at 5 L/min and titrate flow rates to reach target SpO2 ≥ 94% during resuscitation; or use face mask with reservoir bag (at 10-15 L/min) if the patient is in critical condition. Once the patient is stable, the target is > 90% SpO2 in non-pregnant adults and ≥ 92-95% in pregnant patients.
In adults, techniques such as positioning, e.g. high supported sitting may help to optimize oxygenation, ease breathlessness and reduce energy expenditure. [44] Prone position for awake, spontaneously breathing patients may also improve oxygenation and the ventilation/perfusion ratio, but evidence is lacking and should be done under clinical trial protocols to assess efficacy and safety. Children with a worsening clinical presentation (obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma or convulsions) should receive airway management and oxygen therapy during resuscitation to target SpO2 ≥ 94%; otherwise, the target SpO2 is ≥ 90%. [45] The use of a nasal cannula is preferred in young children, as it may be better tolerated. All areas where patients with severe acute respiratory infection are cared for should be equipped with pulse oximeters, functioning oxygen systems and disposable, single-patient use, oxygen-delivering interfaces (nasal cannula, face mask and mask with reservoir bag).
# Closely monitor patients with COVID
# Understand the patient's co-morbid conditions and tailor management accordingly.
Determine which chronic therapies should be continued and which should be stopped temporarily.
o Monitor for drug interactions o Revisit the need for any held medications when clinically appropriate Metered dose inhalers with a spacer are preferred to nebulizers to reduce the potential to generate respiratory aerosols. Antihypertensive drugs should not routinely be stopped in patients with COVID-19, but therapy may need to be adjusted based on general considerations for patients with acute illness, with particular reference to maintaining normal blood pressure and renal function. Patients with psychiatric and neurological manifestations should be assessed for any underlying causes, including the monitoring of oxygenation and fluid status, correcting metabolic or endocrine abnormalities, addressing co-infections, minimizing the use of medications that may cause or worsen delirium, treating withdrawal from substances, understanding and minimizing the effects of any harmful drug-drug interactions and maintaining normal sleep cycles as much as possible.
To reduce delirium in patients who are receiving invasive ventilation, consideration should be given to minimize continuous or intermittent sedation, targeting specific titration endpoints (light sedation unless contraindicated) or with daily interruption of continuous sedative infusions. In patients experiencing agitation (defined as marked restlessness or excessive motor activity, often accompanied by anxiety), calming communication strategies (to reorient the person) should be attempted. Acute pain due to physical illness or air hunger should be considered as triggers for agitation and need to be addressed immediately. While non-pharmacologic strategies are preferred, in case they are unsuccessful or distress is severe, psychotropic medications may need to be trialed alongside nonpharmacologic interventions.
Use conservative fluid management in patients with severe acute respiratory infection when there is no evidence of shock.
Patients with severe acute respiratory disease should be treated cautiously with intravenous fluids, because aggressive fluid resuscitation may worsen oxygenation, especially in settings where there is limited availability of mechanical ventilation. [48] This applies to the care of both children and adults.
# Treatment of Co-infections
The prevalence of acute co-infections or secondary infections coinciding with COVID-19 has not been adequately described but appears to be low. [49] Antibiotic overuse increases the risk of emergence and transmission of multidrug-resistant bacteria. Infections with multidrug-resistant bacteria are more difficult to treat and are associated with increased morbidity and mortality.
Give empiric antimicrobials to treat all likely pathogens causing severe acute respiratory infection and sepsis as soon as possible, within 1 hour of initial patient assessment for patients with sepsis.
Empiric antibiotic treatment should be based on the clinical diagnosis (e.g., community-acquired pneumonia, health care-associated pneumonia or sepsis), local epidemiology and susceptibility data. The Infectious Disease Society of America and the American Thoracic Society have published treatment guidelines for community-acquired pneumonia that can be found at: https://www.idsociety.org/practiceguideline/practice-guidelines/#/name_na_str/ASC/0/+/.
Frequently re-evaluate and de-escalate empiric therapy where possible on the basis of microbiology results and clinical judgment.
Regularly review the possibility of switching of intravenous to oral route of administration If antimicrobials are continued, this should be for the shortest recommended duration (for most indications 5-7 days)
When there is ongoing local circulation of influenza, empiric therapy with a neuraminidase inhibitor should be considered for the treatment of influenza viruses in patients with or at risk for severe disease.
[50]
8.0 Management of Critical COVID-19
# Acute Respiratory Distress Syndrome (ARDS)
Recognize severe hypoxemic respiratory failure when a patient with respiratory distress is failing standard oxygen therapy and prepare to provide advanced oxygen/ventilatory support.
Patients may continue to have increased work of breathing or hypoxemia even when oxygen is delivered via a face mask with reservoir bag (flow rates of 10-15 L/min, which is typically the minimum flow required to maintain bag inflation; FiO2 0.60-0.95). Hypoxemic respiratory failure in ARDS commonly results from intrapulmonary ventilation-perfusion mismatch or shunt and usually requires mechanical ventilation. [1] Endotracheal intubation should be performed by a trained and experienced provider using airborne precautions.
Patients with ARDS, especially young children or those who are obese or pregnant, may desaturate quickly during intubation. Pre-oxygenate with 100% FiO2 for 5 minutes, via a face mask with reservoir bag, bagvalve mask. The utilization of video laryngoscopy to increase chance of intubation at first attempt should be considered. Rapid sequence intubation is appropriate after an airway assessment that identifies no signs of difficult intubation, avoiding manual ventilation as a means to avoid aerosol generation, where possible and safe for patient care. [51] [52] [53] Among hospitalized adult patients who have COVID-19 and require supplemental oxygen or mechanical ventilation, clinicians should strongly consider dexamethasone 6 mg IV daily for 10 days (or until off oxygen or discharge if earlier) or equivalent glucocorticoid dose. This guidance is not meant to replace clinical judgment or specialist consultation.
There are currently no data on the use of dexamethasone in children with severe disease who require supplemental oxygen or mechanical ventilation, hence clinical judgement should be applied if considering its use in this population.
# Recommendations for mechanically ventilated adult and pediatric patients with ARDS
Implement mechanical ventilation using lower tidal volumes (4-8 mL/kg predicted body weight [PBW]) and lower inspiratory pressures (plateau pressure < 30 cmH2O).
Adults -This is a strong recommendation from a clinical guideline for patients with ARDS, and is suggested for patients with sepsis-induced respiratory failure who do not meet ARDS criteria. [1] The initial tidal volume is 6 mL/kg PBW; tidal volume up to 8 mL/kg PBW is allowed if undesirable side-effects occur (e.g. dyssynchrony, pH < 7.15). Permissive hypercapnia is permitted. Ventilator protocols are available. [54] The use of deep sedation may be required to control respiratory drive and achieve tidal volume targets. Children -A lower level of plateau pressure (< 28 cmH2O) is targeted, and a lower pH target is permitted (7.15-7.30). Tidal volumes should be adapted to disease severity: 3-6 mL/kg PBW in the case of poor respiratory system compliance, and 5-8 mL/kg PBW with better preserved compliance. [53] Slightly higher Plateau pressures (30-32 cm H20) can be tolerated in case of poor chest wall compliance.
In adult patients with severe ARDS, prone ventilation for 12-16 hours per day should be considered.
Application of prone ventilation should be considered for adult patients, preferably for 16 hours per day, and may be considered for paediatric patients with severe ARDS but requires sufficient human resources and expertise to be performed safely. 33,34 Protocols (including videos) are available at: https://www.nejm.org/doi/full/10.1056/NEJMoa1214103. Pregnant women should not be placed in a prone position but in the supine position with a wedge placed under the right hip to decrease aortocaval obstruction, or placed in lateral decubitus position.
# Use a conservative fluid management strategy for ARDS patients without tissue hypoperfusion.
This is a strong recommendation for both adults and children; the main effect is to shorten the duration of ventilation [1]. See reference [55] for a sample protocol.
In patients with moderate or severe ARDS, higher PEEP instead of lower PEEP is suggested.
PEEP titration requires consideration of benefits (reducing atelectrauma and improving alveolar recruitment) vs risks (end-inspiratory overdistension leading to lung injury and higher pulmonary vascular resistance). Tables are available to guide PEEP titration based on the FiO2 required to maintain SpO2. [54] Although high driving pressure (plateau pressure minus PEEP) may more accurately predict increased mortality in ARDS compared with high tidal volume or plateau pressure, data from RCTs of ventilation strategies that target driving pressure are not currently available.
[56] Recruitment manoeuvres (RMs) can be delivered as episodic periods of high continuous positive airway pressure (CPAP) (30-40 cmH2O), progressive incremental increases in PEEP with constant driving pressure, or high driving pressure; considerations of benefits vs risks are similar. PEEP and RMs were both conditionally recommended in a clinical practice guideline. For PEEP, the guideline considered an individual patient data meta-analysis of three RCTs. [57] However, a subsequent RCT of high PEEP and prolonged high-pressure RMs showed harm, suggesting that the protocol in this RCT should be avoided. [58] Monitoring of patients to identify those who respond to the initial application of higher PEEP or a different RM protocol, and stopping these interventions in non-responders are suggested, noting that patients with hypoxic respiratory failure without strong suspicion or evidence of alveolar de-recruitment are less likely to benefit from RMs but may still be at risk of side-effects. [59] In patients with moderate-severe ARDS (PaO2/FiO2 < 150), neuromuscular blockade by continuous infusion should not be routinely used.
While one trial found that this strategy improved survival in adult patients with severe ARDS (PaO2/FiO2 < 150) without causing significant weakness, results of a recent larger trial found that use of neuromuscular blockage with high PEEP strategy was not associated with a survival benefit when compared with a light sedation strategy without neuromuscular blockade. [60] [61] Continuous neuromuscular blockade may still be considered in patients, both adults and children, with ARDS in certain situations, such as ventilator dyssynchrony despite sedation, such that tidal volume limitation cannot be reliably achieved; refractory hypoxemia; or hypercapnia.
# Avoid disconnecting the patient from the ventilator, which results in loss of PEEP and atelectasis.
# Use in-line catheters for airway suctioning and clamp the endotracheal tube when disconnection is required (e.g., transfer to a transport ventilator).
# Recommendations for adult and pediatric patients with ARDS who are treated with non-invasive or high flow oxygen systems
# High-flow nasal oxygen (HFNO) and non-invasive ventilation (NIV) should be considered.
Patients treated with either HFNO or NIV should be closely monitored for clinical deterioration.
Adult HFNO systems can deliver 60 L/min of gas flow and FiO2 up to 1.0. Pediatric circuits generally only handle up to 25 L/min, and many children will require an adult circuit to deliver adequate flow. Compared with standard oxygen therapy, HFNO reduces the need for intubation. [
# Recommendations for adult and paediatric patients with ARDS in whom a lung protective ventilation strategy fails
# In settings with access to expertise in extracorporeal membrane oxygenation (ECMO), consider referral of patients who have refractory hypoxemia despite lung protective ventilation.
An RCT of ECMO for adult patients with ARDS was stopped early and found no statistically significant difference in the primary outcome of 60-day mortality between ECMO and standard medical management (including prone positioning and neuromuscular blockade). [67] However, ECMO was associated with a reduced risk of the composite outcome of mortality and crossover to ECMO, and a post hoc Bayesian analysis of this RCT showed that ECMO is very likely to reduce mortality across a range of prior assumptions. [67] [68] In patients with MERS, ECMO vs conventional treatment was associated with reduced mortality in a cohort study. [69] ECMO should ideally be offered in expert centres with a sufficient case volume to maintain expertise and that can apply the IPC measures required for adult and pediatric COVID-19 patients.
# Recommendations for resuscitation strategies for adult and paediatric patients with septic shock.
In resuscitation for septic shock in adults, give 250-500 mL crystalloid fluid as a rapid bolus in the first 15-30 minutes and reassess for signs of fluid overload after each bolus.
In resuscitation for septic shock in children, give 10-20 mL/kg crystalloid fluid as a rapid bolus in the first 30-60 minutes and reassess for signs of fluid overload after each bolus.
# Fluid resuscitation may lead to volume overload, including respiratory failure, particularly with ARDS.
If there is no response to fluid loading or signs of volume overload appear (e.g. jugular venous distension, crackles on lung auscultation, pulmonary edema on imaging, or hepatomegaly in children), then reduce or discontinue fluid administration. This step is particularly important in patients with hypoxemic respiratory failure.
Crystalloids include normal saline and Ringer's lactate, with a preference for Ringer's lactate. Determine need for additional fluid boluses (500-1000 mL in adults or 10-20 mL/kg in children) based on clinical response and improvement of perfusion targets. Perfusion targets include MAP (≥ 60-65 mmHg or age-appropriate targets in children), urine output (> 0.5 mL/kg/hr in adults, 1 mL/kg/hr in children), and improvement of skin mottling and extremity perfusion, capillary refill, heart rate, level of consciousness, and lactate. Consider dynamic indices of volume responsiveness to guide volume administration beyond initial resuscitation based on local resources and experience. [1] These indices include passive leg raises, fluid challenges with serial stroke volume measurements, or variations in systolic pressure, pulse pressure, inferior vena cava size, or stroke volume in response to changes in intrathoracic pressure during mechanical ventilation. In pregnant women, compression of the inferior vena cava can cause a decrease in venous return and cardiac preload and may result in hypotension. For this reason, pregnant women should be cared for with a wedge under their right hip and may need to be placed in a lateral decubitus position to off-load the inferior vena cava.
[74] Clinical trials conducted in resource limited settings comparing aggressive versus conservative fluid regimens suggest higher mortality in patients treated with aggressive fluid regimes for other severe infections. [72] [73] Do not use hypotonic crystalloids, starches or gelatins for resuscitation.
Starches are associated with an increased risk of death and acute kidney injury compared with crystalloids. The effects of gelatins are less clear, but they are more expensive than crystalloids. [1] [75] Hypotonic (vs isotonic) solutions are less effective at increasing intravascular volume. Surviving Sepsis also suggests albumin for resuscitation when patients require substantial amounts of crystalloids, but this conditional recommendation is based on low-quality evidence. [1] In adults, administer vasopressors when shock persists during or after fluid resuscitation. The blood pressure target should be MAP ≥ 60-65 mmHg in adults and improvement of markers of perfusion.
# In children administer vasopressors if signs of fluid overload are apparent or the following persist after two fluid boluses:
there are signs of shock such as altered mental state; Vasopressors (i.e. norepinephrine, epinephrine, vasopressin, and dopamine) are most safely given through a central venous catheter at a strictly controlled rate, but it is also possible to administer them safely via peripheral vein and intraosseous needle. [76] Monitor blood pressure frequently and titrate the vasopressor to the minimum dose necessary to maintain perfusion and prevent side effects. Norepinephrine is considered first-line in adult patients; epinephrine or vasopressin can be added to achieve the MAP target. Because of the risk of tachyarrhythmia, reserve dopamine for selected patients with low risk of tachyarrhythmia or those with bradycardia. In children, epinephrine is considered first-line treatment, while norepinephrine can be added if shock persists despite optimal dose of epinephrine.
No RCTs have compared dobutamine with placebo for clinical outcomes See Section 10.0 for remarks on corticosteroids and sepsis. Careful consideration should be given to the numerous, clinically significant side-effects of medications that may be used in the context of COVID-19, as well as drug-drug interactions between medications, both of which may affect COVID-19 symptomatology (including effects on respiratory, cardiac, immune and mental and neurological function). Both pharmacokinetic and pharmacodynamic effects should be considered.
# Prevention of Complications
# TABLE 2 -PREVENTION OF COMPLICATIONS IN CRITICALLY ILL PATIENTS
# Anticipated outcome Interventions
Reduce days of invasive mechanical ventilation Use weaning protocols that include daily assessment for readiness to breathe spontaneously; Minimize continuous or intermittent sedation, targeting specific titration endpoints (sedation score targeted light sedation unless contraindicated) or with daily interruption of continuous sedative infusions; Early mobilization; Implementation of the above as a bundle of care (such as the Awakening and Breathing Coordination, Delirium assessment/management, and Early mobility [ABCDE]) may also reduce delirium. Reduce incidence of ventilator-associated pneumonia Oral intubation is preferable to nasal intubation in adolescents and adults; Keep patient in semi-recumbent position (head of bed elevation at 30-45 o ); Use a closed suctioning system; periodically drain and discard condensate in tubing; Continue regular oral care Use a new ventilator circuit for each patient; once patient is ventilated, change circuit if it is soiled or damaged, but not routinely; Change heat moisture exchanger when it malfunctions, when soiled, or every 5-7 days. Reduce incidence of venous thromboembolism Use pharmacological prophylaxis (low molecular-weight heparin [preferred] or heparin subcutaneously twice daily) in children, adolescents and adults without contraindications, and based on an assessment of individual risk factors for both thrombosis and bleeding. For those with contraindications, use mechanical prophylaxis (intermittent pneumatic compression devices). Reduce incidence of catheter-related bloodstream infection Use a checklist with completion verified by a real-time observer as a reminder of each step needed for sterile insertion and as a daily reminder to remove catheter if no longer needed.
# Anticipated outcome Interventions
Reduce incidence of pressure ulcers Turn patient every 2 hours.
Reduce incidence of stress ulcers and gastrointestinal bleeding Give early enteral nutrition (within 24-48 hours of admission); Consider administering histamine-2 receptor blockers or proton-pump inhibitors in patients with risk factors for GI bleeding. Risk factors for gastrointestinal bleeding include mechanical ventilation for ≥ 48 hours, coagulopathy, renal replacement therapy, liver disease, multiple comorbidities, and higher organ failure score. Stress ulcer prophylaxis should be reassessed as the patient's condition improves and as enteral feeding is established. Reduce incidence of ICU-related weakness Actively mobilize the patient early in the course of illness when safe to do so. Reduce the development of antimicrobial resistance Utilize de-escalation protocols as soon as patient is clinically stable and there is no evidence of bacterial infection.
Promote appropriate antimicrobial prescribing and use during the COVID-19 pandemic Do not prescribe antibiotics to suspected or confirmed COVID-19 patients with low suspicion of a bacterial infection, to avoid short-term side-effects of antibiotics and negative long-term consequences of increased antimicrobial resistance.
# Special Considerations
# Caring for Pregnant Women with COVID-19
The Society for Obstetrician and Gynecologists Canada (SOGC) has published COVID-19 resources on obstetric and perinatal care to assist obstetricians in Canada. These resources can be found on their website at https://sogc.org/. To date, there are limited data on clinical presentation and perinatal outcomes after COVID-19 during pregnancy or the post-partum period. There is no solid evidence that pregnant women present with different signs or symptoms or are at higher risk of severe illness. The literature is mixed regarding whether pregnant women are at higher risk of severe illness, however it appears that the rates are not significantly higher, with reports of 4% or women requiring ICU admission and 3% requiring mechanical ventilation, which are similar to the non-pregnant population.
The section below on COVID-19 and pregnancy builds on existing recommendations and provides additional remarks for the management of pregnant and recently pregnant women.
Pregnant and recently pregnant women with suspected or confirmed COVID-19 should be isolated and treated with the supportive and management therapies previously described for other adults, taking into account the immunologic and physiologic adaptations occurring during and after pregnancy.
Evidence of increased adverse maternal or neonatal outcomes is uncertain. Some literature has reported higher rates of stillbirth and many reports suggest higher rates of preterm birth but recent (August 5, 2020
-Living Systematic Reviews from the WHO collaborating centre for global women's health COVID-19 in Pregnancy (PregCOV-19LSR)), found a cumulative rate of preterm birth in 14,210 women from 49 cohort studies of 17%. In addition, there are reports of higher rates of fetal distress in labour particularly associated with maternal infection in the third trimester. (https://www.birmingham.ac.uk/research/whocollaborating-centre/pregcov/about/baby-outcomes.aspx) [81] [82]. Until more evidence becomes available, pregnant women with COVID-19 need to be observed closely for severe illness.
Pregnant women with a suspected, probable or confirmed COVID-19 infection, including women who may need to spend time in isolation, should have access to woman-centred, respectful skilled care, including obstetric, foetal medicine and neonatal care, as well as mental health and psychosocial support, with readiness to care for maternal and neonatal complications. Prevention of complications as described earlier, also apply to pregnant and recently pregnant women including those with miscarriage, late pregnancy fetal loss and postpartum/post-abortion women. The mode of delivery should be individualized based on obstetric indications. Multidisciplinary consultations from obstetric, perinatal, neonatal, infectious disease and intensive care specialists should be provided as required. Access to reproductive health care including termination of pregnancy should be ensured throughout the pandemic.
# All recently pregnant women with COVID-19 infection or who have recovered from COVID-19 should be provided with counselling on safe infant feeding, including recommendations for breast feeding and appropriate infection prevention measures to prevent COVID-19 transmission (see section 9.2 below).
Pregnant and recently pregnant women who have recovered from COVID-19 should be encouraged to attend enhanced antenatal, postpartum or other obstetrical care as appropriate. Enhanced fetal surveillance is recommended for women with COVID-19 illness.
# Caring for Infants and Mothers with COVID-19 -IPC and Breastfeeding
Relatively few cases have been reported of infants confirmed with COVID-19 infection. At this time there is no clear evidence that vertical transmission occurs. Breast milk samples from the mothers after the first lactation were negative for SARS CoV-2. . [81] [82] Although recommendations for infant feeding varies around the world, Canadian recommendations are found below. Additional guidance on feeding and caring for infants and young children of mothers with COVID-19 is available on the WHO website: https://www.who.int/publications/i/item/clinical-management-of-covid-19
Infants born to mothers with suspected, probable, or confirmed COVID-19 should be fed according to standard infant feeding guidelines, primarily breast feeding while providing necessary infection prevention precautions.
Symptomatic mothers who are breastfeeding should practice respiratory hygiene, including during feeding (for example, use of a mask when near a child if the mother has respiratory symptoms), perform hand hygiene before and after contact with the child, and routinely clean and disinfect surfaces with which the symptomatic mother has been in contact.
In situations when severe illness in a mother due to COVID-19 or other complications prevents her from caring for her infant or prevents her from continuing direct breastfeeding, mothers should be encouraged and supported to express milk, and safely provide breast milk to the infant, while applying appropriate IPC measures.
Mothers and infants should be allowed to remain together and to practice rooming-in if desired, especially during establishment of breastfeeding, whether they or their infants have suspected, probable or confirmed COVID-19.
Parents and caregivers who may need to be separated from their children, and children who may need to be separated from their primary caregivers, should have access to appropriately trained health or nonhealth workers for mental health and psychosocial support.
# Caring for Older Persons with COVID-19
Older age and comorbid conditions such as diabetes and cardiovascular disease have been reported as risk factors for death in persons with COVID-19. [40] Because older persons are at highest risk for severe disease and fatality and are one of the most vulnerable populations, they should be screened for COVID-19 at the first point of access to the health system, be diagnosed promptly if they are suspected to have COVID-19 and treated appropriately. As older patients may present with atypical symptoms, health workers should take this into account during the screening process.
Identify if there is an advance care plan for patients with COVID-19 and ensure the care plan takes into consideration their priorities and preferences. Tailor the care plan to be in line with the patient's expressed wishes (refer to section 9.5 for additional guidance on palliative care) For older persons with probable or suspected COVID-19, in addition to a conventional history the assessment should include an understanding of the person's life, values, priorities and preferences for health management.
# Ensure multidisciplinary collaboration (physicians, nurses, pharmacists and other health professionals) in the decision-making process to address multimorbidity and functional decline.
Physiological changes with age lead to declines in intrinsic capacity such as malnutrition, cognitive decline, depressive symptoms, and those conditions interact at several levels. Hearing and vision impairments become more prevalent among older adults and may pose a communication barrier, especially when masks prevent lip reading and decrease vocal clarity. Cognitive decline may also need to be considered when communicating with older patients. Older people who experience COVID-19, including those admitted to ICU and/or treated with protracted oxygen therapy and bed rest, are more likely to experience pronounced functional decline and may require coordinated rehabilitation care after acute hospitalization.
# Early detection of inappropriate medication prescriptions is recommended to prevent adverse drug events and drug interactions in those being treated for COVID-19.
Older patients are at greater risk of polypharmacy which increases the risk of negative health consequences. If medications are prescribed for mental and neurological manifestations of COVID-19 in older adults, this should be done with extreme caution given the increased susceptibility to drug sideeffects and drug interactions with other prescribed medications.
Where appropriate, involve caregivers and family members in decision-making and goal setting throughout the management of older COVID-19 patients.
Symptom-based and palliative care should be provided, as appropriate, even for patients with supportive or curative goals of care.
# Managing Patients with COVID-19 in Remote and Isolated Communities
While primary health care services are available in most remote and isolated communities, there is limited capacity to provide acute care and they may lack appropriate medical equipment, supplies and services (e.g., ventilators, access to specialists) to treat patients with severe illness. In many remote and isolated communities, a nurse-led health care team can provide emergency resuscitation and stabilization, emergency ambulatory care and outpatient non-urgent services. Access to physician services is available remotely via telehealth or teleconference, but much variation exists from community to community regarding the availability and frequency of physicians. Severely ill patients requiring complex emergency medical care are evacuated to a secondary or tertiary hospital or facility.
Treatment considerations for these remote and isolated settings include the following measures: Primary care providers or nursing stations, where available, should plan to provide triage and assessment, primary care treatment and monitoring. Mild disease, including uncomplicated pneumonia, should be managed within the community, with appropriate precautions in place. Alternate arrangements for self-isolation may be needed for persons in crowded living arrangements. Fluid management should be conservative when there is no evidence of shock, because aggressive fluid management may worsen oxygenation in settings without access to mechanical ventilation. Mild cases may progress to lower respiratory tract disease. Possible risk factors for progression to severe illness include older age and underlying chronic medical conditions such as lung disease, cancer, heart failure, cerebrovascular disease, renal disease, liver disease, diabetes, immunocompromising conditions, and pregnancy. [28] [83] Patients should be carefully monitored for signs of impending deterioration so that transfer can be arranged before intubation is required. Clinicians should be aware of the potential for some patients to rapidly deteriorate 1 week after illness Anticipate delays in accessing hospital care (awaiting air-ambulance, weather issues). Therefore, a low threshold should be considered for medevac options, particularly for the elderly, persons with underlying medical conditions or persons with evidence of pneumonia.
# Palliative care and COVID-19
We recommend identifying, in all patients with COVID-19, if they have an advance care plan for COVID-19 (such as desires for intensive care support) and to discuss goals of care in the setting of acute illness. Patient priorities and preferences should be respected and their care plan tailored to allow the provision of the best care irrespective of treatment choice.
Palliative care services should be made accessible at each institution that provides care for persons with COVID-19, and symptomatic treatments (e.g. management of dyspnea) should be provided even for patients with supportive or curative goals of care.
# Immunocompromised patients and COVID-19
Patients living with HIV Infection should be offered standard of care. Case series of patients living with HIV and COVID-19 have not shown a higher COVID-19 infection rate or complication rate in patients with suppressed viral loads and CD4> 200. It is assumed that patients with CD4<200 or not receiving Antiretroviral therapy will be at increased risk of disease due to their immunosuppression. [84] In solid organ transplant patients, the risk of COVID 19 infection from a living donor or deceased donor is unknown at this time and such decisions on transplantation are to be made with expert advice. In Hematopoietic Stem Cell Transplantation (HSCT) patients, it is recommended that all recipients should have a negative COVID 19 PCR test prior to start of conditioning In HSCT patients, if a donor has travelled to a high risk area for COVID 19 transmission or has had contact with a patient confirmed to have COVID-19, the donor must be excluded from donation for at least 28 days.
# Specific and Adjunctive COVID-19 Treatments and Clinical Research
There are many ongoing clinical trials testing various potential medical treatments. Until specific therapies become available, any medication should be given as part of a randomized controlled trial.
Collect standardized clinical data on all hospitalized patients to improve our understanding of the natural history of disease. Among hospitalized adult patients who have COVID-19 and require supplemental oxygen or mechanical ventilation, clinicians should strongly consider dexamethasone 6 mg IV daily for 10 days (or until discharge if earlier) or equivalent glucocorticoid dose.
The recommendation is based on the data from a preliminary report of the RECOVERY trial comparing the use of 6 mg of dexamethasone given once daily for up to ten days. The primary outcome was 28-day mortality in more than 6,400 patients randomly allocated (1:2) to receive dexamethasone or usual care. [85] While the trial demonstrated benefit of dexamethasone use in patients who required supplemental oxygen or mechanical ventilation, it did not reduce mortality in patients who did not require respiratory support at randomization (17.8% vs. 14%, RR 1.18 [95% CI 0.91 to 1.55]).
There are currently no data on the use of dexamethasone in children with severe disease who require supplemental oxygen or mechanical ventilation, hence clinical judgement should be applied if considering use.
If oral, IV and/or inhaled steroids are indicated for non-COVID-19 reasons (e.g., asthma or COPD exacerbation, or stress dosing in someone on chronic steroids or with known adrenal insufficiency), they should not be avoided. ). [94] The benefit of Remdesivir on reducing time to recovery was highest among patients who were not intubated but required supplemental oxygen. In mechanically ventilated patients who received Remdesivir there was no observed decrease in time to recovery. [95] Health Canada has authorized the use of Remdesivir for adults and adolescents aged 12 and over, and clinical trials are presently underway in children.
# Do not use hydroxychloroquine or ritonavir/lopinavir outside of a clinical trial.
The use of hydroxychloroquine and lopinavir-ritonavir in COVID-19 patients was recently reported in a large randomized, controlled, open-label, adaptive, platform trial (the RECOVERY trial). In the hydroxychloroquine arm of the trial, patients were randomised to receive either hydroxychloroquine (n=1,561) or usual care (n=3,155). [96] There was no significant difference in the primary endpoint of 28-day mortality or beneficial effects on hospital stay duration. In the lopinavir-ritonavir arm of the trial, patients were randomised to receive lopinavir-ritonavir (n=1,596) or usual care (n=3,376). [97] There was no significant difference in the primary endpoint of 28-day mortality, the risk of progression to mechanical ventilation or length of hospital stay. Based on these results, the use of hydroxychloroquine and lopinavir-ritonavir in COVID-19 patients should not be considered outside of a clinical trial setting.
Use of investigational anti-COVID-19 therapeutics should be done under ethically approved, randomized, controlled trials.
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# Background
Urinary bladder cancer is the fourth most common cancer among men and accounts for 8% of all new male cancer cases. Urinary bladder cancer is less common among women (ranked 11th) and accounts for less than 3% of all new female cancer cases. Statistics Canada estimates that in 2022 there will be approximately 13,300 new cases of bladder cancer and 2,500 deaths associated with bladder cancer in Canada. 1 Smoking is estimated to account for between 34% and 50% of all bladder cancers. 2,3 There are several histological types of bladder cancer. Urothelial carcinoma (also known as transitional cell carcinoma, henceforth referred to as urothelial) is the most common subtype, accounting for more than 90% of all cases in North America. Other histologic variants include squamous differentiation, glandular differentiation, nested pattern, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid and lymphoma-like, sarcomatoid/carcinosarcoma, giant cell, trophoblastic differentiation, clear cell, lipid cell, and undifferentiated. 4 Other important histologic variants include adenocarcinoma (urachal and non-urachal) and small cell carcinoma. Less commonly, urothelial cancers can arise in other parts of the urinary tract including the renal pelvis, ureter and urethra.
Staging of bladder cancer is currently based on the eighth edition (2017) of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. 5 One of the major updates from the seventh edition (2010) is that lymph node involvement limited to the true pelvis and/or common iliac lymph nodes (N1-N3) in combination with a T1-T4a primary tumour now constitutes stage III disease (previously stage IV). A detailed description of the staging system can be found in the Appendix.
The objective of this guideline is to provide physicians with the latest, evidence-based management strategies for locally advanced/metastatic bladder cancer in Alberta. Guidelines for non-muscleinvasive bladder cancer, muscle-invasive bladder cancer, and upper tract urothelial cancer are available separately.
# Target Population
The target population for this guideline is adult patients (18 years of age or older) with a diagnosis of locally advanced/metastatic bladder cancer (i.e. T4bNxM0, TxN2-3M0, TxNxM1).
# Recommendations
# Management of Locally Advanced Disease (Stages T4bNxM0, TxN2-3M0)
Indications include pre-operatively identified direct pelvic/abdominal wall invasion (cT4b), multiple regional lymph node metastases in the true pelvis (cN2), or lymph node metastases to common iliac lymph nodes (cN3). For post-operatively identified pT4b or pN1-3 disease, please see Muscle-Invasive Bladder Cancer AHS Guidelines for recommendations re: adjuvant therapy. - Carboplatin-gemcitabine (21-day cycle): carboplatin AUC5 day 1, gemcitabine 1000 mg/m 2 days 1 and 8 D. For patients who have a favourable response to first-line chemotherapy, consideration of consolidative definitive loco-regional treatment (i.e. cystectomy with pelvic lymphadenectomy or bladder-preserving trimodality therapy) should be considered in the multidisciplinary setting. E. Patients who do not have a favourable response to first-line chemotherapy and/or are not candidates for local definitive consolidative therapy should be managed as per recommendations for metastatic disease (see below). F. Patients who are ineligible for aggressive multi-agent chemotherapy may be treated with single modality therapy, i.e. single-agent chemotherapy or radiotherapy for palliation and/or survival prolongation.
# Palliative local therapies
A. Palliative local therapies (i.e. TURBT, cystectomy, radiation) may be considered for patients experiencing intolerable pain/voiding symptoms or recurrent/refractory hematuria.
# Follow-up A.
In patients with favourable response to first-line chemotherapy who undergo subsequent consolidative curative-intent locoregional therapy (i.e. surgical resection versus bladder-preserving trimodality therapy), follow up should be performed as outlined in the Muscle-Invasive Bladder Cancer AHS Guidelines. B. In patients who do not undergo curative intent locoregional therapy, follow up should be performed as outlined for Metastatic Bladder Cancer (see below).
# Management of Metastatic Disease (TxNxM1)
Indications include the development of recurrent/metastatic disease post radical therapy or presentation with de novo metastatic disease. E. CBC and diff, electrolytes, creatinine, calcium, magnesium, liver panel within 2 weeks of starting chemotherapy. All patients starting systemic chemotherapy should be considered for HBV screening. i. Carboplatin-gemcitabine (21-day cycle): carboplatin AUC5 day 1, gemcitabine 1000 mg/m 2 days 1 and 8 H. For patients who are ineligible for any of the above systemic treatment options, alternative regimens that may be considered include: gemcitabine-paclitaxel, single-agent gemcitabine, single-agent paclitaxel. I. For patients who are chemotherapy-ineligible, best supportive care is recommended.
# First-line
# Maintenance therapy:
A. For patients who do not progress (ie: have stable disease, a partial response, or complete response) after 4-6 cycles of platinum-based 1 st line chemotherapy, maintenance immunotherapy with avelumab is recommended. Standard dosing is provided below:
i. Avelumab (14-day cycle): The recommended dose is 10 mg/kg body weight administered IV over 60 minutes every 2 weeks. ii. Avelumab is to be started 4-10 weeks after the last dose of chemotherapy.
iii. Avelumab is continued until disease progression or unacceptable toxicity.
# Second-line therapy:
A. In eligible patients, pembrolizumab should be considered for patients who progress on or after 1 st line platinum-based chemotherapy, or in those who have recurred/progressed within 12 months of receiving platinum-based chemotherapy in the (neo)adjuvant setting. 6 Standard dosing of pembrolizumab is as follows: i. Pembrolizumab (21-day cycle): 2mg/kg up to maximum of 200 mg IV day 1 B. Retreatment with platinum-based regimens can be considered if initial progression-free interval to platinum was > 12 months. C. Pembrolizumab is NOT indicated for patients who have progressed on avelumab maintenance therapy. D. For patients who received immunotherapy alone in the first-line setting as part of a clinical trial, platinum-based chemotherapy is recommended as per first-line therapy above if the patient is eligible and has not previously received platinum-based treatment. If prior platinum-based therapy has been received (with <12 month treatment-free interval) and/or the patient is ineligible, secondline options are as per third-line therapy and beyond (see below).
# Third-line therapy:
A. Enfortumab Vedotin is a nectin-4 directed antibody microtubule inhibitor drug conjugate. It is recommended for eligible patients who have progressed after platinum-based 1 st line chemotherapy and immunotherapy (maintenance or 2 nd line). Standard dosing is provided below: i. Enfortumab vedotin (28-day cycle): 1.25mg/kg IV day 1, day 8, day 15 ii. Enfortumab vedotin is continued until disease progression or unacceptable toxicity iii. Enfortumab vedotin is pending Health Canada approval and provincial funding. At time of writing, it is currently available via special access program. This agent has novel toxicities which require monitoring and evaluation. Please refer to the product monograph. Product monograph link here. B. Erdafitinib is a treatment option in patients with selected FGFR mutations and fusions. The phase II BLC 2001 study enrolled patients with advanced urothelial carcinoma with prespecified FGFR alterations demonstrating a ORR of 40%. Patients had all been previously treated with platinum-based chemotherapy and some with immunotherapy. Erdafitinib is currently Health Canada approved and is available via a patient access program, pending provincial approval and funding i. This agent has novel toxicities which require monitoring and evaluation. For dosing and toxicity information, please refer to the product monograph. Product monograph link here.
ii. Currently there is no level I evidence to guide sequencing of therapies after 1 st -line chemotherapy in patients with FGFR mutations and fusions.
# Fourth-line therapy and beyond:
A. Taxane-based chemotherapy can be considered post-progression on platinum-based chemotherapy and immunotherapy and enfortumab vedotin. Commonly used agents are singleagent paclitaxel or docetaxel.
# Palliative local therapies
A. Palliative local therapies (i.e. TURBT, cystectomy, radiation) may be considered for patients experiencing intolerable pain/voiding symptoms or recurrent/refractory hematuria. B. RT or surgery should be considered in patients with symptomatic sites of bony metastases and/or with impending fracture/complication.
# Follow-up
A. Post-chemotherapy: clinical evaluation and imaging (e.g. CT chest, abdomen, pelvis) to evaluate tumour response and then as indicated (q3months is a reasonable interval for most patients). B. Consider early palliative care referral as indicated.
# Special situations
A. Non-urothelial histology i. All pathology reported to have variant histology should be reviewed by an expert GU pathologist.
ii. All patients with pure non-urothelial histology should be discussed in a multidisciplinary setting.
iii. Generally, platinum-based chemotherapy as recommended for metastatic urothelial carcinomas are felt to less effective for pure non-urothelial histologies. However, there are no high-quality data to recommend alternate systemic therapy options for this population. iv. For urachal or non-urachal bladder adenocarcinoma, it is reasonable to consider systemic therapy options similar to those used in the management of metastatic colorectal cancer (e.g. FOLFOX). 7,8 Cisplatin-5FU is another reasonable option. v. For metastatic squamous cell carcinoma of the bladder, standard urothelial cisplatin-based regimens are appropriate. It is also reasonable to consider 5-FU or taxane-based chemotherapy. vi. For metastatic small cell carcinoma of the bladder, first-line treatment should consist of platinum-etoposide combination chemotherapy in all eligible patients. Guidelines for management of metastatic small cell carcinoma of the lung should be followed.
# Discussion
# Management of Locally Advanced Disease (T4b and/or N2-3, M0)
In patients with locally advanced disease (T4b and/or N2-3, M0), recommended first-line therapy is systemic platinum-based chemotherapy for those that are eligible. Subsequent disease management depends on the response to primary systemic chemotherapy.
A retrospective study of 659 patients with node-positive urothelial bladder cancer assessed the effectiveness of induction chemotherapy for downstaging. 6 Amongst patients with cN2-3 disease, the rate of pathologic complete downstaging was 27% in those receiving induction treatment. Patients who exhibit substantial downstaging should be considered for consolidation definitive loco-regional therapy. 3-year OS rates for patients receiving induction chemotherapy followed by radical cystectomy have been reported to be 43% in patients with cN2-3 disease, with 3-year OS rates >80% in those achieving pathologic complete downstaging prior to surgery.
Patients who do not have a favourable response to first-line chemotherapy and/or are not candidates for loco-regional definitive consolidative therapy should be managed as per recommendations for metastatic disease (see below).
# Management of Recurrent or Metastatic Disease (Tx, Nx, M1)
Recurrent or metastatic disease should be treated primarily with systemic chemotherapy. A cisplatinbased regimen is the preferred initial therapy for patients with metastatic urothelial cancer for patients who are eligible. Eligible patients are defined as those who do not have one of the following criteria: CrCl <60 ml/min, PS ≥ 2, NYHA ≥ 3 heart failure, ≥ Grade 2 peripheral neuropathy, ≥ Grade 2 hearing loss. 7 All patients with impaired renal function with a potential reversible cause (e.g. obstructive uropathy due to tumour), should be considered for treatment measures to improve renal function prior to initiation of platinum-based therapy.
Recommended cisplatin-based first-line therapies include cisplatin-gemcitabine and dose-dense MVAC. A randomized, phase III RCT compared cisplatin-gemcitabine to conventionally dosed MVAC in 405 patients and demonstrated no significant differences in response rate (49% vs 46%) or overall survival (HR 1.04, p=0.75). However, cisplatin-gemcitabine was better tolerated with lower rates of side effects including neutropenia, febrile neutropenia, and mucositis. 8 Dose-dense MVAC was also shown to have similar efficacy as conventionally dosed MVAC, with a reduction in toxicity (N=263). 9 Given the data from these 2 landmark trials, conventionally dosed MVAC is no longer recommended.
In general, triplet combination chemotherapy with paclitaxel, gemcitabine and cisplatin is not recommended due to an increase in toxicity with no significant differences in PFS or OS. 10 For patients who are not candidates for cisplatin, carboplatin may be substituted in the recurrent/metastatic setting. For platinum-ineligible patients, first-line immunotherapy with pembrolizumab is Health Canada approved. This is based on the KEYNOTE-052 single-arm phase II study that demonstrated a response rate of 29% (7% CR, 22% PR) with pembrolizumab as first-line therapy in platinumineligible patients. 15 Patients may be able to access pembrolizumab for this indication through patient support programs.
Maintenance avelumab is recommended for patients who have stable disease or a response to 1 stline platinum based chemotherapy. In a randomized phase III trial (JAVELIN Bladder 100), 16 Erdafitinib is currently under investigation in the phase III setting (NCT03390504), however, phase II data has shown great promise in locally advanced and uresectable or metastatic urothelial carcinoma patients with prespecified FGFR alterations. In the trial all patients had disease progression after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy (prior immunotherapy was allowed). A total of n=99 patients were evaluated in an open-label, phase 2 design. The rate of confirmed response to erdafitinib therapy was 40% (3% complete response, 37% partial response). Among n=22 patients who underwent previous immunotherapy, the confirmed response rate was 59%. The median duration for progression-free survival was 5.5 months, and the median duration for overall survival was 13.8 months. Grade 3 or higher adverse events were managed mainly by dose adjustments, and 13% of patients discontinued treatment because of adverse event. 18 Enfortumab Vedotin was evaluated in a phase III clinical trial (EV-301) 19 of 608 patients with locally advanced unresectable or metastatic urothelial carcinoma (including those with squamous differentiation or mixed cell types) previously treated with platinum-based chemotherapy and PD-1/PD-L1 inhibitor. Patients were randomly assigned to either enfortumab vedotin or investigator's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). At median follow-up of approximately 11 months, compared with chemotherapy, enfortumab vedotin improved OS (median 13 versus 9 months, HR 0.70, 95% CI 0.56-0.89), PFS (median 6 versus 4 months, HR 0.62, 95% CI 0.51-0.75) and overall response rates (41 versus 18 percent).Grade ≥3 toxicity rates for any adverse event were similar between the two treatment arms (51 versus 50 percent). Grade ≥3 toxicities specifically associated with enfortumab vedotin included rash (15 percent), peripheral neuropathy (5 percent), and hyperglycemia (4 percent). Ocular toxicities, pneumonitis (eg, interstitial lung disease), and severe cutaneous adverse reactions, including cases of Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have also been reported with this agent. This is currently pending Health Canada review and is currently available via special access program.
# Appendix A: Cancer Staging
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including surgical oncologists, radiation oncologists, medical oncologists, urologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
AHS, Alberta Health Services; AJCC, American Joint Committee on Cancer; CCA, Cancer Care Alberta; MVAC, Methotrexate, vinblastine sulfate, doxorubicin hydrochloride; TURBT, Transurethral resection of a bladder tumor.
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# Background
Urinary bladder cancer is the fourth most common cancer among men and accounts for 8% of all new male cancer cases. Urinary bladder cancer is less common among women (ranked 11th) and accounts for less than 3% of all new female cancer cases. Statistics Canada estimates that in 2022 there will be approximately 13,300 new cases of bladder cancer and 2,500 deaths associated with bladder cancer in Canada. 1 Smoking is estimated to account for between 34% and 50% of all bladder cancers. 2,3 There are several histological types of bladder cancer. Urothelial carcinoma (also known as transitional cell carcinoma, henceforth referred to as urothelial) is the most common subtype, accounting for more than 90% of all cases in North America. Other histologic variants include squamous differentiation, glandular differentiation, nested pattern, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid and lymphoma-like, sarcomatoid/carcinosarcoma, giant cell, trophoblastic differentiation, clear cell, lipid cell, and undifferentiated. 4 Other important histologic variants include adenocarcinoma (urachal and non-urachal) and small cell carcinoma. Less commonly, urothelial cancers can arise in other parts of the urinary tract including the renal pelvis, ureter and urethra.
Staging of bladder cancer is currently based on the eighth edition (2017) of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. 5 One of the major updates from the seventh edition (2010) is that lymph node involvement limited to the true pelvis and/or common iliac lymph nodes (N1-N3) in combination with a T1-T4a primary tumour now constitutes stage III disease (previously stage IV). A detailed description of the staging system can be found in the Appendix.
The objective of this guideline is to provide physicians with the latest, evidence-based management strategies for locally advanced/metastatic bladder cancer in Alberta. Guidelines for non-muscleinvasive bladder cancer, muscle-invasive bladder cancer, and upper tract urothelial cancer are available separately.
# Target Population
The target population for this guideline is adult patients (18 years of age or older) with a diagnosis of locally advanced/metastatic bladder cancer (i.e. T4bNxM0, TxN2-3M0, TxNxM1).
# Recommendations
# Management of Locally Advanced Disease (Stages T4bNxM0, TxN2-3M0)
Indications include pre-operatively identified direct pelvic/abdominal wall invasion (cT4b), multiple regional lymph node metastases in the true pelvis (cN2), or lymph node metastases to common iliac lymph nodes (cN3). For post-operatively identified pT4b or pN1-3 disease, please see Muscle-Invasive Bladder Cancer AHS Guidelines for recommendations re: adjuvant therapy. • Carboplatin-gemcitabine (21-day cycle): carboplatin AUC5 day 1, gemcitabine 1000 mg/m 2 days 1 and 8 D. For patients who have a favourable response to first-line chemotherapy, consideration of consolidative definitive loco-regional treatment (i.e. cystectomy with pelvic lymphadenectomy or bladder-preserving trimodality therapy) should be considered in the multidisciplinary setting. E. Patients who do not have a favourable response to first-line chemotherapy and/or are not candidates for local definitive consolidative therapy should be managed as per recommendations for metastatic disease (see below). F. Patients who are ineligible for aggressive multi-agent chemotherapy may be treated with single modality therapy, i.e. single-agent chemotherapy or radiotherapy for palliation and/or survival prolongation.
# Palliative local therapies
A. Palliative local therapies (i.e. TURBT, cystectomy, radiation) may be considered for patients experiencing intolerable pain/voiding symptoms or recurrent/refractory hematuria.
# Follow-up A.
In patients with favourable response to first-line chemotherapy who undergo subsequent consolidative curative-intent locoregional therapy (i.e. surgical resection versus bladder-preserving trimodality therapy), follow up should be performed as outlined in the Muscle-Invasive Bladder Cancer AHS Guidelines. B. In patients who do not undergo curative intent locoregional therapy, follow up should be performed as outlined for Metastatic Bladder Cancer (see below).
# Management of Metastatic Disease (TxNxM1)
Indications include the development of recurrent/metastatic disease post radical therapy or presentation with de novo metastatic disease. E. CBC and diff, electrolytes, creatinine, calcium, magnesium, liver panel within 2 weeks of starting chemotherapy. All patients starting systemic chemotherapy should be considered for HBV screening. i. Carboplatin-gemcitabine (21-day cycle): carboplatin AUC5 day 1, gemcitabine 1000 mg/m 2 days 1 and 8 H. For patients who are ineligible for any of the above systemic treatment options, alternative regimens that may be considered include: gemcitabine-paclitaxel, single-agent gemcitabine, single-agent paclitaxel. I. For patients who are chemotherapy-ineligible, best supportive care is recommended.
# First-line
# Maintenance therapy:
A. For patients who do not progress (ie: have stable disease, a partial response, or complete response) after 4-6 cycles of platinum-based 1 st line chemotherapy, maintenance immunotherapy with avelumab is recommended. Standard dosing is provided below:
i. Avelumab (14-day cycle): The recommended dose is 10 mg/kg body weight administered IV over 60 minutes every 2 weeks. ii. Avelumab is to be started 4-10 weeks after the last dose of chemotherapy.
iii. Avelumab is continued until disease progression or unacceptable toxicity.
# Second-line therapy:
A. In eligible patients, pembrolizumab should be considered for patients who progress on or after 1 st line platinum-based chemotherapy, or in those who have recurred/progressed within 12 months of receiving platinum-based chemotherapy in the (neo)adjuvant setting. 6 Standard dosing of pembrolizumab is as follows: i. Pembrolizumab (21-day cycle): 2mg/kg up to maximum of 200 mg IV day 1 B. Retreatment with platinum-based regimens can be considered if initial progression-free interval to platinum was > 12 months. C. Pembrolizumab is NOT indicated for patients who have progressed on avelumab maintenance therapy. D. For patients who received immunotherapy alone in the first-line setting as part of a clinical trial, platinum-based chemotherapy is recommended as per first-line therapy above if the patient is eligible and has not previously received platinum-based treatment. If prior platinum-based therapy has been received (with <12 month treatment-free interval) and/or the patient is ineligible, secondline options are as per third-line therapy and beyond (see below).
# Third-line therapy:
A. Enfortumab Vedotin is a nectin-4 directed antibody microtubule inhibitor drug conjugate. It is recommended for eligible patients who have progressed after platinum-based 1 st line chemotherapy and immunotherapy (maintenance or 2 nd line). Standard dosing is provided below: i. Enfortumab vedotin (28-day cycle): 1.25mg/kg IV day 1, day 8, day 15 ii. Enfortumab vedotin is continued until disease progression or unacceptable toxicity iii. Enfortumab vedotin is pending Health Canada approval and provincial funding. At time of writing, it is currently available via special access program. This agent has novel toxicities which require monitoring and evaluation. Please refer to the product monograph. Product monograph link here. B. Erdafitinib is a treatment option in patients with selected FGFR mutations and fusions. The phase II BLC 2001 study enrolled patients with advanced urothelial carcinoma with prespecified FGFR alterations demonstrating a ORR of 40%. Patients had all been previously treated with platinum-based chemotherapy and some with immunotherapy. Erdafitinib is currently Health Canada approved and is available via a patient access program, pending provincial approval and funding i. This agent has novel toxicities which require monitoring and evaluation. For dosing and toxicity information, please refer to the product monograph. Product monograph link here.
ii. Currently there is no level I evidence to guide sequencing of therapies after 1 st -line chemotherapy in patients with FGFR mutations and fusions.
# Fourth-line therapy and beyond:
A. Taxane-based chemotherapy can be considered post-progression on platinum-based chemotherapy and immunotherapy and enfortumab vedotin. Commonly used agents are singleagent paclitaxel or docetaxel.
# Palliative local therapies
A. Palliative local therapies (i.e. TURBT, cystectomy, radiation) may be considered for patients experiencing intolerable pain/voiding symptoms or recurrent/refractory hematuria. B. RT or surgery should be considered in patients with symptomatic sites of bony metastases and/or with impending fracture/complication.
# Follow-up
A. Post-chemotherapy: clinical evaluation and imaging (e.g. CT chest, abdomen, pelvis) to evaluate tumour response and then as indicated (q3months is a reasonable interval for most patients). B. Consider early palliative care referral as indicated.
# Special situations
A. Non-urothelial histology i. All pathology reported to have variant histology should be reviewed by an expert GU pathologist.
ii. All patients with pure non-urothelial histology should be discussed in a multidisciplinary setting.
iii. Generally, platinum-based chemotherapy as recommended for metastatic urothelial carcinomas are felt to less effective for pure non-urothelial histologies. However, there are no high-quality data to recommend alternate systemic therapy options for this population. iv. For urachal or non-urachal bladder adenocarcinoma, it is reasonable to consider systemic therapy options similar to those used in the management of metastatic colorectal cancer (e.g. FOLFOX). 7,8 Cisplatin-5FU is another reasonable option. v. For metastatic squamous cell carcinoma of the bladder, standard urothelial cisplatin-based regimens are appropriate. It is also reasonable to consider 5-FU or taxane-based chemotherapy. vi. For metastatic small cell carcinoma of the bladder, first-line treatment should consist of platinum-etoposide combination chemotherapy in all eligible patients. Guidelines for management of metastatic small cell carcinoma of the lung should be followed.
# Discussion
# Management of Locally Advanced Disease (T4b and/or N2-3, M0)
In patients with locally advanced disease (T4b and/or N2-3, M0), recommended first-line therapy is systemic platinum-based chemotherapy for those that are eligible. Subsequent disease management depends on the response to primary systemic chemotherapy.
A retrospective study of 659 patients with node-positive urothelial bladder cancer assessed the effectiveness of induction chemotherapy for downstaging. 6 Amongst patients with cN2-3 disease, the rate of pathologic complete downstaging was 27% in those receiving induction treatment. Patients who exhibit substantial downstaging should be considered for consolidation definitive loco-regional therapy. 3-year OS rates for patients receiving induction chemotherapy followed by radical cystectomy have been reported to be 43% in patients with cN2-3 disease, with 3-year OS rates >80% in those achieving pathologic complete downstaging prior to surgery.
Patients who do not have a favourable response to first-line chemotherapy and/or are not candidates for loco-regional definitive consolidative therapy should be managed as per recommendations for metastatic disease (see below).
# Management of Recurrent or Metastatic Disease (Tx, Nx, M1)
Recurrent or metastatic disease should be treated primarily with systemic chemotherapy. A cisplatinbased regimen is the preferred initial therapy for patients with metastatic urothelial cancer for patients who are eligible. Eligible patients are defined as those who do not have one of the following criteria: CrCl <60 ml/min, PS ≥ 2, NYHA ≥ 3 heart failure, ≥ Grade 2 peripheral neuropathy, ≥ Grade 2 hearing loss. 7 All patients with impaired renal function with a potential reversible cause (e.g. obstructive uropathy due to tumour), should be considered for treatment measures to improve renal function prior to initiation of platinum-based therapy.
Recommended cisplatin-based first-line therapies include cisplatin-gemcitabine and dose-dense MVAC. A randomized, phase III RCT compared cisplatin-gemcitabine to conventionally dosed MVAC in 405 patients and demonstrated no significant differences in response rate (49% vs 46%) or overall survival (HR 1.04, p=0.75). However, cisplatin-gemcitabine was better tolerated with lower rates of side effects including neutropenia, febrile neutropenia, and mucositis. 8 Dose-dense MVAC was also shown to have similar efficacy as conventionally dosed MVAC, with a reduction in toxicity (N=263). 9 Given the data from these 2 landmark trials, conventionally dosed MVAC is no longer recommended.
In general, triplet combination chemotherapy with paclitaxel, gemcitabine and cisplatin is not recommended due to an increase in toxicity with no significant differences in PFS or OS. 10 For patients who are not candidates for cisplatin, carboplatin may be substituted in the recurrent/metastatic setting. [11][12][13][14] For platinum-ineligible patients, first-line immunotherapy with pembrolizumab is Health Canada approved. This is based on the KEYNOTE-052 single-arm phase II study that demonstrated a response rate of 29% (7% CR, 22% PR) with pembrolizumab as first-line therapy in platinumineligible patients. 15 Patients may be able to access pembrolizumab for this indication through patient support programs.
Maintenance avelumab is recommended for patients who have stable disease or a response to 1 stline platinum based chemotherapy. In a randomized phase III trial (JAVELIN Bladder 100), 16 Erdafitinib is currently under investigation in the phase III setting (NCT03390504), however, phase II data has shown great promise in locally advanced and uresectable or metastatic urothelial carcinoma patients with prespecified FGFR alterations. In the trial all patients had disease progression after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy (prior immunotherapy was allowed). A total of n=99 patients were evaluated in an open-label, phase 2 design. The rate of confirmed response to erdafitinib therapy was 40% (3% complete response, 37% partial response). Among n=22 patients who underwent previous immunotherapy, the confirmed response rate was 59%. The median duration for progression-free survival was 5.5 months, and the median duration for overall survival was 13.8 months. Grade 3 or higher adverse events were managed mainly by dose adjustments, and 13% of patients discontinued treatment because of adverse event. 18 Enfortumab Vedotin was evaluated in a phase III clinical trial (EV-301) 19 of 608 patients with locally advanced unresectable or metastatic urothelial carcinoma (including those with squamous differentiation or mixed cell types) previously treated with platinum-based chemotherapy and PD-1/PD-L1 inhibitor. Patients were randomly assigned to either enfortumab vedotin or investigator's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). At median follow-up of approximately 11 months, compared with chemotherapy, enfortumab vedotin improved OS (median 13 versus 9 months, HR 0.70, 95% CI 0.56-0.89), PFS (median 6 versus 4 months, HR 0.62, 95% CI 0.51-0.75) and overall response rates (41 versus 18 percent).Grade ≥3 toxicity rates for any adverse event were similar between the two treatment arms (51 versus 50 percent). Grade ≥3 toxicities specifically associated with enfortumab vedotin included rash (15 percent), peripheral neuropathy (5 percent), and hyperglycemia (4 percent). Ocular toxicities, pneumonitis (eg, interstitial lung disease), and severe cutaneous adverse reactions, including cases of Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have also been reported with this agent. This is currently pending Health Canada review and is currently available via special access program.
# Appendix A: Cancer Staging
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including surgical oncologists, radiation oncologists, medical oncologists, urologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
AHS, Alberta Health Services; AJCC, American Joint Committee on Cancer; CCA, Cancer Care Alberta; MVAC, Methotrexate, vinblastine sulfate, doxorubicin hydrochloride; TURBT, Transurethral resection of a bladder tumor.
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial GU Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2023) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/.
The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of Cancer Care Alberta's evidence-based clinical practice guidelines and supporting materials comes from the Cancer Care Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
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# Preamble
The College of Physicians and Surgeons of BC (the College) has received inquiries from registrants regarding the prescribing and administration of ketamine for the treatment of mental health conditions and chronic pain.
# College's position
Intravenous administration of ketamine is only acceptable in hospital settings or in accredited non-hospital medical and surgical facilities. For further information on intravenous ketamine in accredited facilities, registrants should contact the Non-Hospital Medical Surgical Facility Accreditation Program at nhmsfap@cpsbc.ca.
For all other routes of administration (IM, oral, sublingual, intranasal, transdermal), caution is advised due to the potential safety risks associated with ketamine, particularly for off-label use. Registrants are reminded not to prescribe or use a treatment that departs from prevailing medical practice, unless they are able to demonstrate that the potential benefits of the treatment outweigh the risks.
Registrants should note that certain products like intranasal esketamine (Spravato) have manufacturer-specific guidelines for use.
Pursuant to the Canadian product monograph, SPRAVATO® is only available through a controlled distribution program called the Janssen Journey™ Program. The goal of the Janssen Journey™ Program is to mitigate the risks of adverse outcomes related to sedation, dissociation, blood pressure changes, and the risk of misuse and abuse.
- SPRAVATO® can only be prescribed by a registrant who is experienced and proficient in the management of major depressive disorder and enrolled in the Janssen Journey™ Program.
- Only pharmacists enrolled in the Janssen Journey™ Program can dispense SPRAVATO®.
- Physicians who prescribe SPRAVATO® and pharmacists who dispense SPRAVATO® must complete training on the risks of the product and agree to adhere to the requirements of the Janssen Journey™ Program.
- Prior to being prescribed SPRAVATO®, patients must be enrolled in the Janssen Journey™ Program.
- Prescribers must ensure that the patients are informed of and understand the conditions of use and risks of treatment with SPRAVATO®.
- SPRAVATO® can only be dispensed to sites of care where patients self-administer the product under the direct supervision of a health-care professional and are monitored by a health-care professional post administration. ketamine have a high risk of dissociation and sedation post administration that requires monitoring. Furthermore, the use of ketamine carries a risk of misuse or diversion, and attention to these risks is an additional expectation of the College.
As with any therapeutic intervention, informed consent is paramount. It is expected that patients be fully informed of the risks, benefits (and unknown nature of the risks and benefits) of any off-label treatments. Particular attention should be paid to informed consent in the offlabel use of ketamine, and the details of such discussions should be available in the patient's medical record.
Registrants are expected to only prescribe and administer a drug if - they have the knowledge, skill, and judgement to do so safely and effectively,
- they have appropriate training and competence, and Registrants must be aware of and comply with the College's relevant practice standards including Charging for Uninsured Services, Complementary and Alternative Therapies, Conflict of Interest, and Sale and Dispensing of Drugs.
Registrants are encouraged to contact the CMPA for advice before proceeding with therapies that are not considered conventional treatment options.
In other jurisdictions, ketamine is scheduled as a controlled drug requiring a duplicate prescription form (Saskatchewan, Alberta). This prospect is being studied in BC as well.
The College acknowledges the assistance of the College of Physicians and Surgeons of Saskatchewan and the College of Physicians and Surgeons of Alberta whose guidance to their registrants has been used in forming this interim guidance.
Note: This interim guidance will remain effective until a practice standard has been drafted and circulated for feedback through the College's usual consultation process. Once developed, the practice standard will be presented to the Board for endorsement and published on the College website.
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# Preamble
The College of Physicians and Surgeons of BC (the College) has received inquiries from registrants regarding the prescribing and administration of ketamine for the treatment of mental health conditions and chronic pain.
# College's position
Intravenous administration of ketamine is only acceptable in hospital settings or in accredited non-hospital medical and surgical facilities. For further information on intravenous ketamine in accredited facilities, registrants should contact the Non-Hospital Medical Surgical Facility Accreditation Program at nhmsfap@cpsbc.ca.
For all other routes of administration (IM, oral, sublingual, intranasal, transdermal), caution is advised due to the potential safety risks associated with ketamine, particularly for off-label use. Registrants are reminded not to prescribe or use a treatment that departs from prevailing medical practice, unless they are able to demonstrate that the potential benefits of the treatment outweigh the risks.
Registrants should note that certain products like intranasal esketamine (Spravato) have manufacturer-specific guidelines for use.
Pursuant to the Canadian product monograph, SPRAVATO® is only available through a controlled distribution program called the Janssen Journey™ Program. The goal of the Janssen Journey™ Program is to mitigate the risks of adverse outcomes related to sedation, dissociation, blood pressure changes, and the risk of misuse and abuse.
• SPRAVATO® can only be prescribed by a registrant who is experienced and proficient in the management of major depressive disorder and enrolled in the Janssen Journey™ Program.
• Only pharmacists enrolled in the Janssen Journey™ Program can dispense SPRAVATO®.
• Physicians who prescribe SPRAVATO® and pharmacists who dispense SPRAVATO® must complete training on the risks of the product and agree to adhere to the requirements of the Janssen Journey™ Program.
• Prior to being prescribed SPRAVATO®, patients must be enrolled in the Janssen Journey™ Program.
• Prescribers must ensure that the patients are informed of and understand the conditions of use and risks of treatment with SPRAVATO®.
• SPRAVATO® can only be dispensed to sites of care where patients self-administer the product under the direct supervision of a health-care professional and are monitored by a health-care professional post administration. ketamine have a high risk of dissociation and sedation post administration that requires monitoring. Furthermore, the use of ketamine carries a risk of misuse or diversion, and attention to these risks is an additional expectation of the College.
As with any therapeutic intervention, informed consent is paramount. It is expected that patients be fully informed of the risks, benefits (and unknown nature of the risks and benefits) of any off-label treatments. Particular attention should be paid to informed consent in the offlabel use of ketamine, and the details of such discussions should be available in the patient's medical record.
Registrants are expected to only prescribe and administer a drug if • they have the knowledge, skill, and judgement to do so safely and effectively,
• they have appropriate training and competence, and Registrants must be aware of and comply with the College's relevant practice standards including Charging for Uninsured Services, Complementary and Alternative Therapies, Conflict of Interest, and Sale and Dispensing of Drugs.
Registrants are encouraged to contact the CMPA for advice before proceeding with therapies that are not considered conventional treatment options.
In other jurisdictions, ketamine is scheduled as a controlled drug requiring a duplicate prescription form (Saskatchewan, Alberta). This prospect is being studied in BC as well.
The College acknowledges the assistance of the College of Physicians and Surgeons of Saskatchewan and the College of Physicians and Surgeons of Alberta whose guidance to their registrants has been used in forming this interim guidance.
Note: This interim guidance will remain effective until a practice standard has been drafted and circulated for feedback through the College's usual consultation process. Once developed, the practice standard will be presented to the Board for endorsement and published on the College website.
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These recommendations are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. They should be used as an adjunct to sound clinical decision making. TARGET POPULATION Asymptomatic adult population EXCLUSIONS Individuals with signs or symptoms suggesting colorectal cancer (CRC) RECOMMENDATIONS RISK ASSESSMENT Assess risk for colorectal cancer (CRC) to determine when to start screening, the appropriate screening test and frequency An assessment of risk for CRC should occur earlier than age 50 Assess for indictors of increased risk including family and/or personal history of colorectal cancer, colonic adenomas or inflammatory bowel disease, and high risk CRC conditions, i.e., Lynch syndrome, familial adenoma polyposis (FAP) AVERAGE RISK POPULATION FECAL IMMUNOCHEMICAL TEST (FIT) 50 TO 74 YEARS OF AGE Screening is recommended with the Fecal Immunochemical Test (FIT) Screen with FIT every 1 to 2 years If the FIT result is positive, promptly refer for a colonoscopy. Referrals should be sent to a local CRC screening program (see Appendix A) or endoscopist, depending on available resources Wait 10 years after a normal colonoscopy to start or re-start screening with FIT. If the quality of the colonoscopy was uncertain, start or re-start screening with FIT five years after the colonoscopyFIT is the recommended screening test for average risk population, aged 50 to 74 years. Screen with FIT every 1 to 2 years.# WHEN NOT TO USE FIT
X DO NOT use as a diagnostic test for CRC in SYMPTOMATIC patients (e.g., reported bloody stools or recent change in bowel habit)
X DO NOT use to determine or exclude a cause for anemia X DO NOT use when an average risk patient has had a high quality colonoscopy within the past 10 years X DO NOT use as a CRC screening test when the patient has an acute gastrointestinal (GI) condition and/or where bleeding is occurring or highly likely:
# OTHER SCREENING TESTS
The FIT is the recommended method of screening for the average risk population. Appendix B summarizes the evidence for other CRC screening tests, e.g., colonoscopy, flexible sigmoidoscopy, CT colonography, and others. Expertise and availability varies across the province.
# INCREASED RISK POPULATIONS FAMILY HISTORY
Family history of colorectal cancer and/or high risk colonic adenomas are warning signs of increased risk (see Risk Assessment section for definition of high risk adenomas). Use clinical judgment.
One first degree relative > 60 years at diagnosis of colorectal cancer and/or high risk adenomas Screen with FIT every 1 to 2 years starting at age 40
# BACKGROUND RISK
CRC is the second most common cause of cancer death for males and the third most common cause of cancer death for females. 1 The probability of developing CRC increases with age and varies with sex. In Alberta, approximately one in 13 men and one in 16 women will develop invasive CRC within their lifetime. 2 Males have a greater chance of dying from CRC than females, i.e., 1 /32 males and 1/36 females will die of invasive CRC. 2 According to Alberta statistics, CRC mortality rates decreased over the period 1990 to 2010, for both males and females. 2 Declining rates may be attributed to screening's effect on early detection and management. CRC can be prevented by the detection and removal of precancerous polyps.
# AGE
The incidence of CRC increases with age. Rates are low until about age 40, with the incidence increasing in older age groups. 2 In Alberta, the probability of developing cancer at ages 30-40 years is one in 1,613 for males and one in 1,365 for females. 2 For those 50-60 years of age, the rate is one in 450 for males and one in 410 for females. 2 According to the United States Preventive Services Task Force, more than 80% of diagnosed cases of CRC occur in those older than 55 years. 3 (See Table 1). For the majority of those with CRC, age is the only risk factor.
# Age Group (Years) Males Females
Lifetime Risk (all ages) 1 in 13 1 in 16 0-20 Less than 1 in 10,000 Less than 1 in 10,000
# FAMILY HISTORY
Next to age, family history is the most common risk factor for CRC. 4 Risk of CRC increases as the number of affected relatives increases and the younger the age of the relative at diagnosis. For
Colorectal Cancer Screening | November 2013 (Revised 2020)
Clinical Practice Guideline Page 5 of 14 Background example, having multiple family members with CRC prior to age 60 carries a higher risk than one family member with CRC at an advanced age. According to one meta-analysis, a population lifetime risk for a 50 year old was 1.8% but increased to 3.4% with at least one affected relative and 6.9% with two or more affected relatives. 6
# LYNCH SYNDROME
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), accounts for 1% to 3% of all colorectal cancers. 8,9 It carries a lifetime risk for CRC estimated at 50-80%, and is higher for men than for women. Besides being associated with CRC, Lynch syndrome carries a 40-60% lifetime risk of endometrial cancer. 10 To a lesser degree (<19%), other cancers associated with Lynch syndrome include: gastric (11-19%), ovarian (9-12%), hepatobiliary (2-7%), upper urinary tract (4-5%), pancreatic (3-4%), small bowel (1-4%), and CNS -glioblastoma (1-3%). 10
# FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
FAP accounts for up to 1% of all CRC. 11 Almost all individuals with FAP will develop CRC if they are not identified and treated at an early stage. 11
# INFLAMMATORY BOWEL DISEASE (IBD)
IBD is associated with increased risk for CRC. For ulcerative colitis, the probability of developing CRC after 10 years of diagnosis is estimated at 2%, reaching 8% after 20 years and 18% after 30 years. 12
# DIABETES MELLITUS
A recent meta-analysis found that diabetes is associated with an increased risk of colon cancer (relative risk 1.38 for both men and women) and rectal cancer (relative risk 1.20 for men). 13 The association remained when the authors controlled for smoking and obesity, or for smoking, obesity and physical exercise.
# OBESITY
Body mass index (BMI) and waist circumference (WC) are positively associated with risk for CRC. In one meta-analysis the relative risks for the obese versus normal category of BMI were 1.334 and the relative risk for the highest versus lowest category of waist circumference were 1.455. 14 There was less heterogeneity among studies of waist circumference.
# LIFESTYLE
Physical activity: There is consistent evidence supporting an inverse relationship between physical activity and risk of CRC. The overall relative risk for those who are physically active is 0.76 with the relative risk at 0.76 for men and 0.79 for women. 15 The impact of physical activity in reducing CRC risk is supported by biological mechanisms, including: "decreased inflammation, reduced intestinal transit time, decreased insulin-like growth factor levels, reduced hyperinsulinemia and modulated immune function. Alcohol consumption: There is a strong link between alcohol consumption and CRC evident for those who drink two or more alcoholic beverages a day. A higher relative risk is observed when comparing moderate drinkers (two to three drinks a day) to heavy drinkers (four or more drinks a day), and there may be a stronger risk for men. 16 Smoking: Smoking is strongly associated with increased risk for colorectal cancer and mortality, including a significant dose-response relationship. 17 Diet: There is evidence that higher intake of processed and red meat are positively associated with CRC. 18
# RECOMMENDATIONS RISK ASSESSMENT
To determine the appropriate approach to CRC screening, it is important to assess an individual's risk considering age, family history, personal history and presence of high-risk conditions. These factors will determine when screening should be initiated, and the appropriate tests and frequency. Individuals considered at increased risk include:
- Family history of CRC or high risk colonic adenomas in a first degree relative or two or more affected relatives.
- A high risk colonic adenoma is defined as having one or more of the following:
# AVERAGE RISK POPULATION
The average risk population includes individuals ages 50 to 74 years with no signs or symptoms suggesting CRC, and the absence of family history, personal history or other high risk CRC conditions as described in the section on Increased Risk Population.
# Colorectal Cancer Screening | November 2013 (Revised 2020)
Clinical Practice Guideline Page 7 of 14 Background
Screening test: The Fecal Immunochemical Test (FIT) is the recommended method for screening those at average risk. This stool-based test relies on the detection of blood from adenomas or carcinomas. 3 The FIT uses an antibody against human globin -the protein part of hemoglobin. 19 In comparison to the guaiac fecal occult blood test (gFOBT), the FIT has higher sensitivity, specificity and test adherences rates. 19 A systematic review of randomized control trials (RCTs) comparing diagnostic accuracy of the gFOBT versus FIT, found better performance by the FIT, with positivity rates and sensitivities both higher than gFOBT. 19 One RCT reported the FIT to be twice as likely to find colorectal cancers and five times more likely to find advanced polyps. 20 The FIT does not have dietary restrictions and thus is not subject to false negative results in the presence of Vitamin C supplements. 20 RCTs have studied the likelihood of completing screening with FIT as compared to the gFOBT 20,21 and colonoscopy. 21 In both cases, compliance with the FIT is superior, i.e., 24.6% for colonoscopy versus 34.2% for FIT; 21 and 12% more favorable participation rate for FIT vs. gFOBT. 20 There are no RCTs available evaluating the outcomes of FIT screening to mortality from CRC. A 2007 Cochrane review 22 pooling RCT results of the gFOBT found that a CRC screening program with biennial gFOBT can lead to a 16% reduction in CRC mortality after 12 to 18 years of periodic screening and a 25% CRC mortality reduction for those attending at least one round of gFOBT screening. Given the increased test performance and adherence rates for FIT compared to the gFOBT, the effect of screening with the FIT is anticipated to produce even better outcomes.
Other guidelines support FIT over gFOBT because FIT has both superior test characteristics and adherence rates for the detection of CRC. Screening interval: One and two year screening intervals are recommended in other CRC screening guidelines and are primarily based on modelling studies. 2,20,22 There is, however, strong evidence to support that the effectiveness of screening, for all screening modalities, will decrease substantially if adherence to the screening regimen declines. 3,26 This committee recommends a 1-2 year interval since it allows family physicians some flexibility to realistically meet this standard.
Screening following a normal colonoscopy: For individuals with a normal colonoscopy result, wait 10 years to start or re-start screening with FIT. This recommendation is based on the recommendations from other guidelines 24,27 and observational and case control studies suggesting that patients with colonoscopy have reduced CRC incidence or mortality for duration of effect of 10 years or more. 27 This recommendation is valid for high quality colonoscopy only. The quality of the colonoscopy depends on its completeness (reaching and inspecting the cecum), the quality of bowel preparation, and the degree of attention paid to mucosal details during the examination.
Positive FIT results: All individuals with a positive FIT result should be referred promptly for a colonoscopy. A repeat FIT test, just to be certain, is not recommended. One cancer is detected for every 20 positive FITs. 21 affected relatives increases and the younger the age of the relative at diagnosis. The evidence for a precise cut-off age is not strong so clinical judgment is called for.
# INCREASED RISK POPULATION
A first degree relative or two or more affected relatives with CRC or adenomatous polyps are warning signs of increased risk. Studies are increasingly showing that first degree relatives of individuals diagnosed with CRC had a risk of CRC at age 40 that was similar to the risk of CRC in average risk individuals at the age of 50. 6
Individuals with a first degree relative ≤ 60 years at diagnosis or two or more affected relatives should be referred for consideration of colonoscopy at age 40 or 10 years before the youngest index case, whichever comes first. Colonoscopy is the recommended screening modality as it affords opportunity for therapeutic intervention and biopsy. 4 Family history of a first degree relative > 60 years at diagnosis makes very little contribution to risk. A recent RCT illustrates FIT used for CRC screening (annual FIT for 3 years) detected all CRCs and was equivalent to colonoscopy for detecting advanced neoplasia in first-degree relatives of patients with CRC. 28 Therefore screening with FIT starting at age 40 is recommended.
In certain cases, an individuals anxiety and "need to know" may influence a referral.
Personal history: For individuals with a personal history of CRC, colonic adenomatous polyps or inflammatory bowel disease, regular surveillance colonoscopy is required. The recommended surveillance interval will depend on the number, type and size of colonic adenomas. Postpolypectomy surveillance recommendations are best made by the program or endoscopist that performed the colonoscopy, upon review of the pathology report. Provincial Post Polypectomy Surveillance guidelines are available at: Not all polyps require surveillance. For example, no follow up is required for small, single, hyperplastic polyps found in the distal colon. A personal history of ulcerative colitis or Crohn's colitis also necessitates an on-going relationship with a specialist for surveillance.
High risk conditions for CRC: It is important to identify individuals with high risk conditions for developing CRC, and ensure they have an established relationship with an endoscopist or surveillance program. These conditions include: Lynch syndrome (HNPCC) and Familial Adenomatous Polyposis (FAP). Consider Lynch syndrome in those with a personal or family history of multiple cancers, some of which include colorectal, endometrial, gastric, ovarian, hepatobiliary, upper urinary tract, pancreatic, small bowel and CNS -glioblastoma. 9 Consider FAP in those presenting with multiple colon polyps at young age.
# CRC SCREENING 75 YEARS OF AGE AND OLDER
# CRC SCREENING ON ASYMPTOMATIC PATIENTS WITH A LIFE EXPECTANCY OF LESS THAN 10 YEARS AND NO FAMILY OR PERSONAL HISTORY OF COLORECTAL NEOPLASIA
CRC screening and surveillance testing may not be appropriate for individuals over 74 years old when risk is greater than benefit. The risk from the colonoscopy procedure increases for patients of older ages and especially with comorbidities. In addition, patients greater than 74 years of age are more likely to bleed, have a positive FIT and require a colonoscopy follow-up.
# References
The decision to screen should be based on individual assessment of the risk/benefit ratio of colorectal cancer screening or surveillance for each patient. This includes results of previous screening tests, family history, any possible risks from the test, life expectancy and individual preferences. This risk/benefit ratio of screening should be discussed with and understood by the individual and the decision to screen is between the individual and provider. 2, Colorectal Cancer Screening | November 2013 (Revised 2020)
# APPENDIX B OTHER COLORECTAL CANCER SCREENING TESTS
Note: Availability and expertise of the following tests may vary across the province Flexible sigmoidoscopy: A recent Canadian expert panel on the evidence for the efficacy of flexible sigmoidoscopy in CRC screening concluded that the recently published results from four very large RCTs provide clear evidence that screening with flexible sigmoidoscopy reduces CRC incidence by about 20% and mortality by about 25% in average risk individuals. Authors of a recent metaanalysis of RCTs of sigmoidoscopy for CRC screening also came to the same conclusion based on the fact that, by intention to screen, sigmoidoscopy reduces incidence of CRC by 18% and mortality due to CRC by 28%, respectively, and by 32% and 50% respectively in those who actually received screening. 36 Limitations of flexible sigmoidoscopy include: it views only about a third of the colon and can miss small polyps. 37 The risks of complications are very low (.0018% for perforation and .0082% for bleeding). 20 Considerations that may affect compliance include: required bowel preparation, time away from work and the test may be uncomfortable.
Colonoscopy: Based on prospective observational studies and case-control studies, the reduction in CRC incidence and mortality in individuals undergoing colonoscopy compared to the general population, ranged from 0.45 to 0.77 for CRC incidence and from 0.31 to 0.65 for CRC mortality 38,43,44 There are concerns that colonoscopy might not be as effective in the right colon as in other segments of the colorectum. 40,43 Advantages of colonoscopy include: testing is done every 10 years, ability to biopsy and remove polyps, opportunity to diagnose other disease of the colon. The risk of complications reported is approximately 0.5%, 21 including bleeding, perforation, and cardiopulmonary complications. Considerations that may affect compliance include: required bowel preparation, sedation, time away from work, and the test may be uncomfortable.
CT Colonography: Evidence suggests CT Colonography has comparable sensitivity and specificity to colonoscopy for detecting large polyps but is less accurate than colonoscopy for detecting smaller (<1 cm) polyps according to one meta-analysis. 45 Considerations that may affect compliance include: exposure to radiation, required bowel preparation, time away from work, and the test may be uncomfortable. A colonoscopy is required if the CT colonoscopy is abnormal.
# Double contrast barium enema (DCBE):
The effectiveness of DCBE for polyp detection is less than CT colonography. Guidelines and publications reviewed do not support DCBE as a CRC screening test. 3,23,46 gFOBT: The gFOBT has lower sensitivity, specificity and test adherence rates when compared to the FIT 19 As of 2014, the gFOBT will be discontinued for screening in Alberta.
Carcinoembryonic antigen (CEA): The specificity of CEA for detecting colorectal cancer is high but the sensitivity is very low. Overall evidence does not support CEA as a screening test.
|
These recommendations are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. They should be used as an adjunct to sound clinical decision making. TARGET POPULATION Asymptomatic adult population EXCLUSIONS Individuals with signs or symptoms suggesting colorectal cancer (CRC) RECOMMENDATIONS RISK ASSESSMENT Assess risk for colorectal cancer (CRC) to determine when to start screening, the appropriate screening test and frequency An assessment of risk for CRC should occur earlier than age 50 Assess for indictors of increased risk including family and/or personal history of colorectal cancer, colonic adenomas or inflammatory bowel disease, and high risk CRC conditions, i.e., Lynch syndrome, familial adenoma polyposis (FAP) AVERAGE RISK POPULATION FECAL IMMUNOCHEMICAL TEST (FIT) 50 TO 74 YEARS OF AGE Screening is recommended with the Fecal Immunochemical Test (FIT) Screen with FIT every 1 to 2 years If the FIT result is positive, promptly refer for a colonoscopy. Referrals should be sent to a local CRC screening program (see Appendix A) or endoscopist, depending on available resources Wait 10 years after a normal colonoscopy to start or re-start screening with FIT. If the quality of the colonoscopy was uncertain, start or re-start screening with FIT five years after the colonoscopyFIT is the recommended screening test for average risk population, aged 50 to 74 years. Screen with FIT every 1 to 2 years.# WHEN NOT TO USE FIT
X DO NOT use as a diagnostic test for CRC in SYMPTOMATIC patients (e.g., reported bloody stools or recent change in bowel habit)
X DO NOT use to determine or exclude a cause for anemia X DO NOT use when an average risk patient has had a high quality colonoscopy within the past 10 years X DO NOT use as a CRC screening test when the patient has an acute gastrointestinal (GI) condition and/or where bleeding is occurring or highly likely:
# OTHER SCREENING TESTS
The FIT is the recommended method of screening for the average risk population. Appendix B summarizes the evidence for other CRC screening tests, e.g., colonoscopy, flexible sigmoidoscopy, CT colonography, and others. Expertise and availability varies across the province.
# INCREASED RISK POPULATIONS FAMILY HISTORY
Family history of colorectal cancer and/or high risk colonic adenomas are warning signs of increased risk (see Risk Assessment section for definition of high risk adenomas). Use clinical judgment.
One first degree relative > 60 years at diagnosis of colorectal cancer and/or high risk adenomas Screen with FIT every 1 to 2 years starting at age 40
# BACKGROUND RISK
CRC is the second most common cause of cancer death for males and the third most common cause of cancer death for females. 1 The probability of developing CRC increases with age and varies with sex. In Alberta, approximately one in 13 men and one in 16 women will develop invasive CRC within their lifetime. 2 Males have a greater chance of dying from CRC than females, i.e., 1 /32 males and 1/36 females will die of invasive CRC. 2 According to Alberta statistics, CRC mortality rates decreased over the period 1990 to 2010, for both males and females. 2 Declining rates may be attributed to screening's effect on early detection and management. CRC can be prevented by the detection and removal of precancerous polyps.
# AGE
The incidence of CRC increases with age. Rates are low until about age 40, with the incidence increasing in older age groups. 2 In Alberta, the probability of developing cancer at ages 30-40 years is one in 1,613 for males and one in 1,365 for females. 2 For those 50-60 years of age, the rate is one in 450 for males and one in 410 for females. 2 According to the United States Preventive Services Task Force, more than 80% of diagnosed cases of CRC occur in those older than 55 years. 3 (See Table 1). For the majority of those with CRC, age is the only risk factor.
# Age Group (Years) Males Females
Lifetime Risk (all ages) 1 in 13 1 in 16 0-20 Less than 1 in 10,000 Less than 1 in 10,000
# FAMILY HISTORY
Next to age, family history is the most common risk factor for CRC. 4 Risk of CRC increases as the number of affected relatives increases and the younger the age of the relative at diagnosis. [5][6][7] For
Colorectal Cancer Screening | November 2013 (Revised 2020)
Clinical Practice Guideline Page 5 of 14 Background example, having multiple family members with CRC prior to age 60 carries a higher risk than one family member with CRC at an advanced age. According to one meta-analysis, a population lifetime risk for a 50 year old was 1.8% but increased to 3.4% with at least one affected relative and 6.9% with two or more affected relatives. 6
# LYNCH SYNDROME
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), accounts for 1% to 3% of all colorectal cancers. 8,9 It carries a lifetime risk for CRC estimated at 50-80%, and is higher for men than for women. [9][10] Besides being associated with CRC, Lynch syndrome carries a 40-60% lifetime risk of endometrial cancer. 10 To a lesser degree (<19%), other cancers associated with Lynch syndrome include: gastric (11-19%), ovarian (9-12%), hepatobiliary (2-7%), upper urinary tract (4-5%), pancreatic (3-4%), small bowel (1-4%), and CNS -glioblastoma (1-3%). 10
# FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
FAP accounts for up to 1% of all CRC. 11 Almost all individuals with FAP will develop CRC if they are not identified and treated at an early stage. 11
# INFLAMMATORY BOWEL DISEASE (IBD)
IBD is associated with increased risk for CRC. For ulcerative colitis, the probability of developing CRC after 10 years of diagnosis is estimated at 2%, reaching 8% after 20 years and 18% after 30 years. 12
# DIABETES MELLITUS
A recent meta-analysis found that diabetes is associated with an increased risk of colon cancer (relative risk 1.38 for both men and women) and rectal cancer (relative risk 1.20 for men). 13 The association remained when the authors controlled for smoking and obesity, or for smoking, obesity and physical exercise.
# OBESITY
Body mass index (BMI) and waist circumference (WC) are positively associated with risk for CRC. In one meta-analysis the relative risks for the obese versus normal category of BMI were 1.334 and the relative risk for the highest versus lowest category of waist circumference were 1.455. 14 There was less heterogeneity among studies of waist circumference.
# LIFESTYLE
Physical activity: There is consistent evidence supporting an inverse relationship between physical activity and risk of CRC. The overall relative risk for those who are physically active is 0.76 with the relative risk at 0.76 for men and 0.79 for women. 15 The impact of physical activity in reducing CRC risk is supported by biological mechanisms, including: "decreased inflammation, reduced intestinal transit time, decreased insulin-like growth factor levels, reduced hyperinsulinemia and modulated immune function. Alcohol consumption: There is a strong link between alcohol consumption and CRC evident for those who drink two or more alcoholic beverages a day. A higher relative risk is observed when comparing moderate drinkers (two to three drinks a day) to heavy drinkers (four or more drinks a day), and there may be a stronger risk for men. 16 Smoking: Smoking is strongly associated with increased risk for colorectal cancer and mortality, including a significant dose-response relationship. 17 Diet: There is evidence that higher intake of processed and red meat are positively associated with CRC. 18
# RECOMMENDATIONS RISK ASSESSMENT
To determine the appropriate approach to CRC screening, it is important to assess an individual's risk considering age, family history, personal history and presence of high-risk conditions. These factors will determine when screening should be initiated, and the appropriate tests and frequency. Individuals considered at increased risk include:
• Family history of CRC or high risk colonic adenomas in a first degree relative or two or more affected relatives.
o A high risk colonic adenoma is defined as having one or more of the following:
# AVERAGE RISK POPULATION
The average risk population includes individuals ages 50 to 74 years with no signs or symptoms suggesting CRC, and the absence of family history, personal history or other high risk CRC conditions as described in the section on Increased Risk Population.
# Colorectal Cancer Screening | November 2013 (Revised 2020)
Clinical Practice Guideline Page 7 of 14 Background
Screening test: The Fecal Immunochemical Test (FIT) is the recommended method for screening those at average risk. This stool-based test relies on the detection of blood from adenomas or carcinomas. 3 The FIT uses an antibody against human globin -the protein part of hemoglobin. 19 In comparison to the guaiac fecal occult blood test (gFOBT), the FIT has higher sensitivity, specificity and test adherences rates. 19 A systematic review of randomized control trials (RCTs) comparing diagnostic accuracy of the gFOBT versus FIT, found better performance by the FIT, with positivity rates and sensitivities both higher than gFOBT. 19 One RCT reported the FIT to be twice as likely to find colorectal cancers and five times more likely to find advanced polyps. 20 The FIT does not have dietary restrictions and thus is not subject to false negative results in the presence of Vitamin C supplements. 20 RCTs have studied the likelihood of completing screening with FIT as compared to the gFOBT 20,21 and colonoscopy. 21 In both cases, compliance with the FIT is superior, i.e., 24.6% for colonoscopy versus 34.2% for FIT; 21 and 12% more favorable participation rate for FIT vs. gFOBT. 20 There are no RCTs available evaluating the outcomes of FIT screening to mortality from CRC. A 2007 Cochrane review 22 pooling RCT results of the gFOBT found that a CRC screening program with biennial gFOBT can lead to a 16% reduction in CRC mortality after 12 to 18 years of periodic screening and a 25% CRC mortality reduction for those attending at least one round of gFOBT screening. Given the increased test performance and adherence rates for FIT compared to the gFOBT, the effect of screening with the FIT is anticipated to produce even better outcomes.
Other guidelines support FIT over gFOBT because FIT has both superior test characteristics and adherence rates for the detection of CRC. [23][24][25] Screening interval: One and two year screening intervals are recommended in other CRC screening guidelines and are primarily based on modelling studies. 2,20,22 There is, however, strong evidence to support that the effectiveness of screening, for all screening modalities, will decrease substantially if adherence to the screening regimen declines. 3,26 This committee recommends a 1-2 year interval since it allows family physicians some flexibility to realistically meet this standard.
Screening following a normal colonoscopy: For individuals with a normal colonoscopy result, wait 10 years to start or re-start screening with FIT. This recommendation is based on the recommendations from other guidelines 24,27 and observational and case control studies suggesting that patients with colonoscopy have reduced CRC incidence or mortality for duration of effect of 10 years or more. 27 This recommendation is valid for high quality colonoscopy only. The quality of the colonoscopy depends on its completeness (reaching and inspecting the cecum), the quality of bowel preparation, and the degree of attention paid to mucosal details during the examination.
Positive FIT results: All individuals with a positive FIT result should be referred promptly for a colonoscopy. A repeat FIT test, just to be certain, is not recommended. One cancer is detected for every 20 positive FITs. 21 affected relatives increases and the younger the age of the relative at diagnosis. The evidence for a precise cut-off age is not strong so clinical judgment is called for.
# INCREASED RISK POPULATION
A first degree relative or two or more affected relatives with CRC or adenomatous polyps are warning signs of increased risk. Studies are increasingly showing that first degree relatives of individuals diagnosed with CRC had a risk of CRC at age 40 that was similar to the risk of CRC in average risk individuals at the age of 50. 6
Individuals with a first degree relative ≤ 60 years at diagnosis or two or more affected relatives should be referred for consideration of colonoscopy at age 40 or 10 years before the youngest index case, whichever comes first. Colonoscopy is the recommended screening modality as it affords opportunity for therapeutic intervention and biopsy. 4 Family history of a first degree relative > 60 years at diagnosis makes very little contribution to risk. A recent RCT illustrates FIT used for CRC screening (annual FIT for 3 years) detected all CRCs and was equivalent to colonoscopy for detecting advanced neoplasia in first-degree relatives of patients with CRC. 28 Therefore screening with FIT starting at age 40 is recommended.
In certain cases, an individuals anxiety and "need to know" may influence a referral.
Personal history: For individuals with a personal history of CRC, colonic adenomatous polyps or inflammatory bowel disease, regular surveillance colonoscopy is required. The recommended surveillance interval will depend on the number, type and size of colonic adenomas. Postpolypectomy surveillance recommendations are best made by the program or endoscopist that performed the colonoscopy, upon review of the pathology report. Provincial Post Polypectomy Surveillance guidelines are available at: https://screeningforlife.ca/wpcontent/uploads/2019/12/ACRCSP-Post-Polypectomy-Surveillance-Guidelines-June-2013.pdf Not all polyps require surveillance. For example, no follow up is required for small, single, hyperplastic polyps found in the distal colon. A personal history of ulcerative colitis or Crohn's colitis also necessitates an on-going relationship with a specialist for surveillance.
High risk conditions for CRC: It is important to identify individuals with high risk conditions for developing CRC, and ensure they have an established relationship with an endoscopist or surveillance program. These conditions include: Lynch syndrome (HNPCC) and Familial Adenomatous Polyposis (FAP). Consider Lynch syndrome in those with a personal or family history of multiple cancers, some of which include colorectal, endometrial, gastric, ovarian, hepatobiliary, upper urinary tract, pancreatic, small bowel and CNS -glioblastoma. 9 Consider FAP in those presenting with multiple colon polyps at young age.
# CRC SCREENING 75 YEARS OF AGE AND OLDER
# CRC SCREENING ON ASYMPTOMATIC PATIENTS WITH A LIFE EXPECTANCY OF LESS THAN 10 YEARS AND NO FAMILY OR PERSONAL HISTORY OF COLORECTAL NEOPLASIA
CRC screening and surveillance testing may not be appropriate for individuals over 74 years old when risk is greater than benefit. The risk from the colonoscopy procedure increases for patients of older ages and especially with comorbidities. In addition, patients greater than 74 years of age are more likely to bleed, have a positive FIT and require a colonoscopy follow-up.
# References
The decision to screen should be based on individual assessment of the risk/benefit ratio of colorectal cancer screening or surveillance for each patient. This includes results of previous screening tests, family history, any possible risks from the test, life expectancy and individual preferences. This risk/benefit ratio of screening should be discussed with and understood by the individual and the decision to screen is between the individual and provider. 2,[29][30][31] Colorectal Cancer Screening | November 2013 (Revised 2020)
# APPENDIX B OTHER COLORECTAL CANCER SCREENING TESTS
Note: Availability and expertise of the following tests may vary across the province Flexible sigmoidoscopy: A recent Canadian expert panel on the evidence for the efficacy of flexible sigmoidoscopy in CRC screening concluded that the recently published results from four very large RCTs [32][33][34][35] provide clear evidence that screening with flexible sigmoidoscopy reduces CRC incidence by about 20% and mortality by about 25% in average risk individuals. Authors of a recent metaanalysis of RCTs of sigmoidoscopy for CRC screening also came to the same conclusion based on the fact that, by intention to screen, sigmoidoscopy reduces incidence of CRC by 18% and mortality due to CRC by 28%, respectively, and by 32% and 50% respectively in those who actually received screening. 36 Limitations of flexible sigmoidoscopy include: it views only about a third of the colon and can miss small polyps. 37 The risks of complications are very low (.0018% for perforation and .0082% for bleeding). 20 Considerations that may affect compliance include: required bowel preparation, time away from work and the test may be uncomfortable.
Colonoscopy: Based on prospective observational studies and case-control studies, the reduction in CRC incidence and mortality in individuals undergoing colonoscopy compared to the general population, ranged from 0.45 to 0.77 for CRC [38][39][40][41][42] incidence and from 0.31 to 0.65 for CRC mortality 38,43,44 There are concerns that colonoscopy might not be as effective in the right colon as in other segments of the colorectum. 40,43 Advantages of colonoscopy include: testing is done every 10 years, ability to biopsy and remove polyps, opportunity to diagnose other disease of the colon. The risk of complications reported is approximately 0.5%, 21 including bleeding, perforation, and cardiopulmonary complications. Considerations that may affect compliance include: required bowel preparation, sedation, time away from work, and the test may be uncomfortable.
CT Colonography: Evidence suggests CT Colonography has comparable sensitivity and specificity to colonoscopy for detecting large polyps but is less accurate than colonoscopy for detecting smaller (<1 cm) polyps according to one meta-analysis. 45 Considerations that may affect compliance include: exposure to radiation, required bowel preparation, time away from work, and the test may be uncomfortable. A colonoscopy is required if the CT colonoscopy is abnormal.
# Double contrast barium enema (DCBE):
The effectiveness of DCBE for polyp detection is less than CT colonography. Guidelines and publications reviewed do not support DCBE as a CRC screening test. 3,23,46 gFOBT: The gFOBT has lower sensitivity, specificity and test adherence rates when compared to the FIT 19 As of 2014, the gFOBT will be discontinued for screening in Alberta.
Carcinoembryonic antigen (CEA): The specificity of CEA for detecting colorectal cancer is high but the sensitivity is very low. Overall evidence does not support CEA as a screening test. [47][48][49][50]
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The COVID- 19 Therapeutics Working Group (WG) has updated the evolving evidence base for this document as best as possible but recognizes that future updates will be required based on ongoing therapeutic trials and emerging evidence. Supportive care remains an important component of therapy for individuals infected with SARS-CoV-2. Updated COVID-19 management guidelines from the Public Health Agency of Canada (PHAC), Association of Medical Microbiology and Infectious Diseases (AMMI), Canada/Canadian Critical Care Society (August 21, 2020) 1 , the Infectious Diseases Society of America (IDSA) (March 23, 2022) 2 and the Alberta Health Services COVID-19 Scientific Advisory Group 3 have been reviewed in preparing this update. Full details are available in the hyperlinks above and the referenced documents below.
Consultation with other specialties (e.g. Infectious Diseases, Respiratory Medicine, Critical Care, General Internal Medicine) who are most likely to be familiar with the rapidly evolving literature can be considered to help assess the risks and benefits for an individual patient. As recommended by AHS Ethics, any off-label use of medication requires the prescriber's careful consideration of risk/benefit, consultation between experts and attending physician as needed, and documenting consent from the patient or alternate decision-maker after discussion of the current state of evidence of benefit and harms. Adverse events with respect to offlabel use of medications for inpatient treatment should be documented and reported by clinicians through the AHS Reporting and Learning System for Patient Safety.
The guidance provided in this document does not replace best clinical judgment and/or expert consultation but rather is meant to inform clinicians of the most current management guidelines to facilitate best use of therapeutic options for patients with COVID-19.
Current Guidance for the Management of Adult Hospitalized Patients with COVID-19 Document Owner: COVID-19 Therapeutics Working Group Current Practice Guidance
# General Considerations
- Patients with mild suspected or confirmed COVID-19 should not require hospitalization, unless there is a clinical concern for rapid deterioration, significant underlying co-morbidities, extenuating sociodemographic circumstances, or an inability to return promptly to hospital. Patients with mild COVID-19 and their caregivers should be provided with information on symptom management and informed of the signs and symptoms of complications that should prompt medical re-evaluation.
- Patients with moderate suspected or confirmed COVID-19 (i.e. with clinical signs of pneumonia, SpO2 ≥ 90% on room air, but no signs of severe pneumonia) who are not determined to be at high risk of deterioration may not require hospitalization, but they should self-monitor and be counseled along with their caregivers about the signs and symptoms of complications that should prompt medical reevaluation.
- Patients with severe suspected or confirmed COVID-19 and respiratory distress, hypoxemia, or shock should receive supplemental oxygen therapy immediately with target saturations of > 94% SpO2 during resuscitation. Patients with severe illness should be closely monitored for signs of clinical deterioration, specifically rapidly progressive respiratory failure, or shock.
# Guiding Principles
1) The use of antiviral or other immunomodulatory treatments, other than those recommended below, for patients with COVID-19 should occur within the context of controlled clinical trials wherever possible, given the currently available limited therapeutic options for which evidence-based data are available.
2) If the use of antiviral or immunomodulatory agents for COVID-19 outside of clinical trials is being considered, the potential risks (adverse reactions, drug interactions (see COVID drug interactions or Lexicomp) versus unverified benefits must be considered and discussed with the patient or caregiver, and consent documented on the chart.
3) Bacterial co-infection in patients with early COVID-19 is uncommon. Do NOT routinely add antibacterials unless bacterial infection is strongly suspected. If indicated, antibacterials should be reassessed within the first 3 days after initiation to determine if continuation is necessary, or to deescalate and/or optimize therapy in accordance with the principles of stewardship to avoid short-term adverse-effects and negative long-term consequences of increased microbial resistance.
- In hospitalized adult patients who meet criteria for severe disease (defined by the IDSA as SpO2 <94% on room air), and requiring supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation, clinicians should prescribe dexamethasone 6 mg IV/PO daily for 10 days (or equivalent glucocorticoid dose) 4 , or until off oxygen or discharged, whichever is earlier. Glucocorticoids are not recommended in patients who do not have hypoxemia requiring supplemental oxygen.
# Antibacterials
- For those patients with suspected or confirmed mild to moderate COVID-19, antibiotics should not be routinely prescribed unless there is clinical suspicion of a bacterial infection.
- For patients with severe COVID-19 but not critically ill, do NOT routinely add antibacterials unless bacterial infection is strongly suspected.
- For critically ill patients with suspected or confirmed severe COVID-19, empiric antibacterial agents to treat all likely pathogens causing severe acute respiratory bacterial infection and sepsis as soon as possible are reasonable, and optimally should be initiated within 1 hour of initial patient assessment for patients with sepsis.
- If indicated, empiric antibiotic treatment should be based on the working clinical diagnosis (e.g., community-acquired pneumonia, health care-associated pneumonia or sepsis), local epidemiology, and susceptibility data. See references such as Bugs & Drugs for empiric antibacterials.
- Use of antibacterial therapy should be judicious with reassessment after 3 days for de-escalation and/or optimization of therapy, in accordance with the principles of stewardship, after review of the clinical status, laboratory and imaging findings, and microbiology results.
# Antivirals/Immunomodulators
- Remdesivir has two approved formulary indications in AHS. Hospitalized patients with COVID-19 pneumonia, defined as having oxygen requirements above pre-hospitalization baseline (SpO2 less than 94% on room air, or requiring O2 supplementation to maintain SpO2 greater than 94%) and/or new infiltrates on chest X-ray not caused by other health conditions, who are not invasively mechanically ventilated, are eligible for a 5-day course of remdesivir (200 mg IV on day 1, followed by 100 mg IV daily on days 2-5) 5,6 . High risk inpatients admitted for non-COVID reasons with incidental or hospitalacquired COVID-19 are eligible for a 3-day course of remdesivir (200 mg IV on day 1, followed by 100 mg IV daily on days 2 and 3) 7 . See the AHS formulary for full eligibility criteria. In select clinical circumstances where multi-agent therapy including remdesivir, or extended duration remdesivir is being considered for highly immunocompromised people, Infectious Diseases consultation is required (in person or phone).
- Tocilizumab is approved for use in patients with severe COVID-19 pneumonia 8 . To be eligible, patients must have been admitted to hospital for COVID-19 pneumonia 7 or fewer days ago, or have developed symptoms from hospital-acquired COVID-19 pneumonia 7 or fewer days ago. They must also be experiencing significant progressive respiratory failure due to COVID-19 pneumonia that requires they receive ventilation (invasive or non-invasive) or supplemental oxygen to achieve a minimum SpO2 of 90%. Supplemental oxygen is defined as heated high flow oxygen with FiO2 > 0.5, nasal prong delivered oxygen at a rate of 6 L/minute, or mask delivered oxygen with FiO2 > 0.5. Furthermore, tocilizumab must be initiated within 24 hours of initiation of mechanical ventilation or, if not mechanically ventilated, as soon as possible. Tocilizumab is restricted for this indication to one dose per patient per hospitalization, dosed as follows: 40 kg: 400 mg Tocilizumab should not be used in patients who have received baricitinib for the treatment of COVID-19 during their current hospitalization. They each work on the same inflammatory pathway, so added benefit is unlikely. Due to their immunosuppressant effects, combination therapy may have adverse effects. 9
- Sarilumab is approved as an alternative to tocilizumab when tocilizumab is not available, using the same eligibility criteria as tocilizumab. It is available in Canada in a subcutaneous formulation, but is administered intravenously as a single 400mg dose for the treatment of COVID-19. It has the same mechanism of action as tocilizumab but has not been studied as widely. It was directly compared to tocilizumab in the REMAP-CAP trial 10 , and was found to lead to a similar reduction in mortality, albeit with less precision due to the much smaller number of patients given sarilumab. A network metaanalysis 11 done in support of the World Health Organization (WHO) living guidelines for COVID-19 therapeutics 12 concluded that sarilumab likely has similar effectiveness to tocilizumab, although their recommendation to use sarilumab has less certainty due to the smaller number of subjects and studies included in the meta-analysis. Approval of sarilumab was based on the similar mechanisms of action, direct trial evidence, and indirect network meta-analysis evidence. Sarilumab should not be used in patients who have received tocilizumab or baricitinib for the treatment of COVID-19 during their current hospitalization. They each work on the same inflammatory pathway, so added benefit is unlikely. Due to their immunosuppressant effects, combination therapy may have adverse effects. 9
- Baricitinib is approved for use in patients with severe COVID-19 pneumonia. To be eligible patients must be experiencing significant progressive respiratory failure due to COVID-19 pneumonia that requires they receive ventilation (invasive or non-invasive) or supplemental oxygen to achieve a minimum SpO2 of 90%. Supplemental oxygen is defined as heated high flow oxygen with FiO2 > 0.5, nasal prong delivered oxygen at a rate of 6 L/minute, or mask delivered oxygen with FiO2 > 0.5.
Baricitinib is an oral tablet given by mouth or enteral tube 4 mg once daily for 14 days or until discharge, whichever is sooner. The main trial 13 upon which approval of use was based excluded patients with eGFR < 30 mL/min/1.73m 2 . It was dosed at 2 mg daily for those with eGFR 30 to < 60 mL/min/1.73m 2 . However, the US Food and Drug Administration Emergency Use Authorization (FDA Current Guidance for the Management of Adult Hospitalized Patients with COVID-19 Document Owner: COVID-19 Therapeutics Working Group EUA) 14 also lists dosing of 1 mg for patients with eGFR 15 to < 30 mL/min/1.73m 2 . Baricitinib 1 mg tablets are not available in Canada, so for patients with eGFR in this range, the recommended dose is 2 mg every other day. Baricitinib should not be used in patients who have received tocilizumab or sarilumab for the treatment of COVID-19 during their current hospitalization. They each work on the same inflammatory pathway, so added benefit is unlikely and due to their immunosuppressant effects, combination therapy may have adverse effects. 9
- Casirivimab/imdevimab is no longer approved for use in hospitalized patients. Unfortunately, it fails to neutralize the Omicron variant in in vitro assays 15,16 . As Omicron constitutes nearly all cases of COVID in Alberta, and results from both COVID serology and variant of concern testing are required to determine the appropriateness of casirivimab/imdevimab, it is no longer appropriate as a treatment option. Variant of concern results take long enough to return that serology results may no longer be valid once variant status is known, as patients may have seroconverted in the meantime. Serology testing should no longer be ordered to help direct treatment for COVID-19 patients.
- Sotrovimab should only be used in patients who are confirmed to have the Omicron BA.1 variant, or any variants that emerged prior to Omicron (Alpha, Beta, Gamma, or Delta). As of May 13, 2022, the vast majority of new COVID cases in Alberta are from the Omicron BA.2 sub-variant, against which sotrovimab is unlikely to be effective. If a patient is confirmed to have one of the aforementioned approved variants, it can be used for outpatients, inpatients admitted for non-COVID reasons, and inpatients with hospital-acquired COVID-19, who are at high risk of progression to severe disease. See the AHS formulary for full eligibility criteria.
There is currently no clinical evidence to support the use of sotrovimab in patients hospitalized due to COVID-19. The ACTIV-3-TICO trial randomized 344 inpatients to receive either sotrovimab (n=169) or placebo (n=175). The trial was stopped early due to futility, meaning the evidence to date suggested it was of no benefit. Among sotrovimab recipients, there was one case of anaphylaxis and one case of cytokine release syndrome 17 .
- Nirmatrelvir-ritonavir (Paxlovid®) is an oral COVID-specific antiviral approved for use in for high risk outpatients, as well as inpatients admitted for non-COVID reasons with incidental or hospital-acquired COVID-19, if therapy can be initiated within 5 days of symptom onset. See the AHS formulary for full eligibility criteria. Published data suggests it significantly reduces risk of hospitalization or death in outpatients at high risk for progression to severe disease 18 . Paxlovid® has numerous significant drug interactions that may make patients ineligible for treatment. Outpatients who think they may be eligible for treatment with Paxlovid® are advised to call the dedicated Alberta HealthLink phone line at 1-844-343-0971. Centralized assessing and prescribing physicians will determine eligibility and arrange for treatment in the community, if appropriate.
- Bamlanivimab is no longer available within AHS. All available stock expired. No future purchases will be made due to greater than 10-fold reduction in neutralizing activity against variants of concern 19 .
- Consideration of all other investigational antivirals or immunomodulators (e.g. lopinavir/ritonavir, famotidine, and colchicine) should be only under ethics approved, controlled trials.
- There is currently insufficient evidence to recommend routine use of fluvoxamine in outpatients 2,20 . It is not recommended for inpatient use.
- The use of hydroxychloroquine, or any hydroxychloroquine combinations (e.g. hydroxychloroquine plus azithromycin), is not recommended as a treatment in patients with COVID-19.
- Ivermectin should not be used for the prevention or treatment of COVID-19. 21 Its use is not supported by evidence 22 .
- Convalescent plasma is not recommended as a treatment in patients with COVID-19. Evidence suggests it has no benefit 23 .
# General Investigations
Please note the listed investigations below are for clinical consideration and not required tests. Please use the laboratory tests and Investigations incorporated into care pathways and order sets if there are differences between those and the list below.
# General Laboratory tests:
Laboratory tests may not be required in otherwise ambulatory patients who are clinically stable, and not felt to be at elevated risk of decompensation. In the presence of higher clinical severity and/or comorbidities, the following laboratory tests may be considered:
- CBC & differential -
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#
The COVID- 19 Therapeutics Working Group (WG) has updated the evolving evidence base for this document as best as possible but recognizes that future updates will be required based on ongoing therapeutic trials and emerging evidence. Supportive care remains an important component of therapy for individuals infected with SARS-CoV-2. Updated COVID-19 management guidelines from the Public Health Agency of Canada (PHAC), Association of Medical Microbiology and Infectious Diseases (AMMI), Canada/Canadian Critical Care Society (August 21, 2020) 1 , the Infectious Diseases Society of America (IDSA) (March 23, 2022) 2 and the Alberta Health Services COVID-19 Scientific Advisory Group 3 have been reviewed in preparing this update. Full details are available in the hyperlinks above and the referenced documents below.
Consultation with other specialties (e.g. Infectious Diseases, Respiratory Medicine, Critical Care, General Internal Medicine) who are most likely to be familiar with the rapidly evolving literature can be considered to help assess the risks and benefits for an individual patient. As recommended by AHS Ethics, any off-label use of medication requires the prescriber's careful consideration of risk/benefit, consultation between experts and attending physician as needed, and documenting consent from the patient or alternate decision-maker after discussion of the current state of evidence of benefit and harms. Adverse events with respect to offlabel use of medications for inpatient treatment should be documented and reported by clinicians through the AHS Reporting and Learning System for Patient Safety.
The guidance provided in this document does not replace best clinical judgment and/or expert consultation but rather is meant to inform clinicians of the most current management guidelines to facilitate best use of therapeutic options for patients with COVID-19.
Current Guidance for the Management of Adult Hospitalized Patients with COVID-19 Document Owner: COVID-19 Therapeutics Working Group Current Practice Guidance
# General Considerations
• Patients with mild suspected or confirmed COVID-19 should not require hospitalization, unless there is a clinical concern for rapid deterioration, significant underlying co-morbidities, extenuating sociodemographic circumstances, or an inability to return promptly to hospital. Patients with mild COVID-19 and their caregivers should be provided with information on symptom management and informed of the signs and symptoms of complications that should prompt medical re-evaluation.
• Patients with moderate suspected or confirmed COVID-19 (i.e. with clinical signs of pneumonia, SpO2 ≥ 90% on room air, but no signs of severe pneumonia) who are not determined to be at high risk of deterioration may not require hospitalization, but they should self-monitor and be counseled along with their caregivers about the signs and symptoms of complications that should prompt medical reevaluation.
• Patients with severe suspected or confirmed COVID-19 and respiratory distress, hypoxemia, or shock should receive supplemental oxygen therapy immediately with target saturations of > 94% SpO2 during resuscitation. Patients with severe illness should be closely monitored for signs of clinical deterioration, specifically rapidly progressive respiratory failure, or shock.
# Guiding Principles
1) The use of antiviral or other immunomodulatory treatments, other than those recommended below, for patients with COVID-19 should occur within the context of controlled clinical trials wherever possible, given the currently available limited therapeutic options for which evidence-based data are available.
2) If the use of antiviral or immunomodulatory agents for COVID-19 outside of clinical trials is being considered, the potential risks (adverse reactions, drug interactions (see COVID drug interactions or Lexicomp) versus unverified benefits must be considered and discussed with the patient or caregiver, and consent documented on the chart.
3) Bacterial co-infection in patients with early COVID-19 is uncommon. Do NOT routinely add antibacterials unless bacterial infection is strongly suspected. If indicated, antibacterials should be reassessed within the first 3 days after initiation to determine if continuation is necessary, or to deescalate and/or optimize therapy in accordance with the principles of stewardship to avoid short-term adverse-effects and negative long-term consequences of increased microbial resistance.
• In hospitalized adult patients who meet criteria for severe disease (defined by the IDSA as SpO2 <94% on room air), and requiring supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation, clinicians should prescribe dexamethasone 6 mg IV/PO daily for 10 days (or equivalent glucocorticoid dose) 4 , or until off oxygen or discharged, whichever is earlier. Glucocorticoids are not recommended in patients who do not have hypoxemia requiring supplemental oxygen.
# Antibacterials
• For those patients with suspected or confirmed mild to moderate COVID-19, antibiotics should not be routinely prescribed unless there is clinical suspicion of a bacterial infection.
• For patients with severe COVID-19 but not critically ill, do NOT routinely add antibacterials unless bacterial infection is strongly suspected.
• For critically ill patients with suspected or confirmed severe COVID-19, empiric antibacterial agents to treat all likely pathogens causing severe acute respiratory bacterial infection and sepsis as soon as possible are reasonable, and optimally should be initiated within 1 hour of initial patient assessment for patients with sepsis.
• If indicated, empiric antibiotic treatment should be based on the working clinical diagnosis (e.g., community-acquired pneumonia, health care-associated pneumonia or sepsis), local epidemiology, and susceptibility data. See references such as Bugs & Drugs for empiric antibacterials.
• Use of antibacterial therapy should be judicious with reassessment after 3 days for de-escalation and/or optimization of therapy, in accordance with the principles of stewardship, after review of the clinical status, laboratory and imaging findings, and microbiology results.
# Antivirals/Immunomodulators
• Remdesivir has two approved formulary indications in AHS. Hospitalized patients with COVID-19 pneumonia, defined as having oxygen requirements above pre-hospitalization baseline (SpO2 less than 94% on room air, or requiring O2 supplementation to maintain SpO2 greater than 94%) and/or new infiltrates on chest X-ray not caused by other health conditions, who are not invasively mechanically ventilated, are eligible for a 5-day course of remdesivir (200 mg IV on day 1, followed by 100 mg IV daily on days 2-5) 5,6 . High risk inpatients admitted for non-COVID reasons with incidental or hospitalacquired COVID-19 are eligible for a 3-day course of remdesivir (200 mg IV on day 1, followed by 100 mg IV daily on days 2 and 3) 7 . See the AHS formulary for full eligibility criteria. In select clinical circumstances where multi-agent therapy including remdesivir, or extended duration remdesivir is being considered for highly immunocompromised people, Infectious Diseases consultation is required (in person or phone).
• Tocilizumab is approved for use in patients with severe COVID-19 pneumonia 8 . To be eligible, patients must have been admitted to hospital for COVID-19 pneumonia 7 or fewer days ago, or have developed symptoms from hospital-acquired COVID-19 pneumonia 7 or fewer days ago. They must also be experiencing significant progressive respiratory failure due to COVID-19 pneumonia that requires they receive ventilation (invasive or non-invasive) or supplemental oxygen to achieve a minimum SpO2 of 90%. Supplemental oxygen is defined as heated high flow oxygen with FiO2 > 0.5, nasal prong delivered oxygen at a rate of 6 L/minute, or mask delivered oxygen with FiO2 > 0.5. Furthermore, tocilizumab must be initiated within 24 hours of initiation of mechanical ventilation or, if not mechanically ventilated, as soon as possible. Tocilizumab is restricted for this indication to one dose per patient per hospitalization, dosed as follows: < 40 kg: 8 mg/kg > 40 kg: 400 mg Tocilizumab should not be used in patients who have received baricitinib for the treatment of COVID-19 during their current hospitalization. They each work on the same inflammatory pathway, so added benefit is unlikely. Due to their immunosuppressant effects, combination therapy may have adverse effects. 9
• Sarilumab is approved as an alternative to tocilizumab when tocilizumab is not available, using the same eligibility criteria as tocilizumab. It is available in Canada in a subcutaneous formulation, but is administered intravenously as a single 400mg dose for the treatment of COVID-19. It has the same mechanism of action as tocilizumab but has not been studied as widely. It was directly compared to tocilizumab in the REMAP-CAP trial 10 , and was found to lead to a similar reduction in mortality, albeit with less precision due to the much smaller number of patients given sarilumab. A network metaanalysis 11 done in support of the World Health Organization (WHO) living guidelines for COVID-19 therapeutics 12 concluded that sarilumab likely has similar effectiveness to tocilizumab, although their recommendation to use sarilumab has less certainty due to the smaller number of subjects and studies included in the meta-analysis. Approval of sarilumab was based on the similar mechanisms of action, direct trial evidence, and indirect network meta-analysis evidence. Sarilumab should not be used in patients who have received tocilizumab or baricitinib for the treatment of COVID-19 during their current hospitalization. They each work on the same inflammatory pathway, so added benefit is unlikely. Due to their immunosuppressant effects, combination therapy may have adverse effects. 9
• Baricitinib is approved for use in patients with severe COVID-19 pneumonia. To be eligible patients must be experiencing significant progressive respiratory failure due to COVID-19 pneumonia that requires they receive ventilation (invasive or non-invasive) or supplemental oxygen to achieve a minimum SpO2 of 90%. Supplemental oxygen is defined as heated high flow oxygen with FiO2 > 0.5, nasal prong delivered oxygen at a rate of 6 L/minute, or mask delivered oxygen with FiO2 > 0.5.
Baricitinib is an oral tablet given by mouth or enteral tube 4 mg once daily for 14 days or until discharge, whichever is sooner. The main trial 13 upon which approval of use was based excluded patients with eGFR < 30 mL/min/1.73m 2 . It was dosed at 2 mg daily for those with eGFR 30 to < 60 mL/min/1.73m 2 . However, the US Food and Drug Administration Emergency Use Authorization (FDA Current Guidance for the Management of Adult Hospitalized Patients with COVID-19 Document Owner: COVID-19 Therapeutics Working Group EUA) 14 also lists dosing of 1 mg for patients with eGFR 15 to < 30 mL/min/1.73m 2 . Baricitinib 1 mg tablets are not available in Canada, so for patients with eGFR in this range, the recommended dose is 2 mg every other day. Baricitinib should not be used in patients who have received tocilizumab or sarilumab for the treatment of COVID-19 during their current hospitalization. They each work on the same inflammatory pathway, so added benefit is unlikely and due to their immunosuppressant effects, combination therapy may have adverse effects. 9
• Casirivimab/imdevimab is no longer approved for use in hospitalized patients. Unfortunately, it fails to neutralize the Omicron variant in in vitro assays 15,16 . As Omicron constitutes nearly all cases of COVID in Alberta, and results from both COVID serology and variant of concern testing are required to determine the appropriateness of casirivimab/imdevimab, it is no longer appropriate as a treatment option. Variant of concern results take long enough to return that serology results may no longer be valid once variant status is known, as patients may have seroconverted in the meantime. Serology testing should no longer be ordered to help direct treatment for COVID-19 patients.
• Sotrovimab should only be used in patients who are confirmed to have the Omicron BA.1 variant, or any variants that emerged prior to Omicron (Alpha, Beta, Gamma, or Delta). As of May 13, 2022, the vast majority of new COVID cases in Alberta are from the Omicron BA.2 sub-variant, against which sotrovimab is unlikely to be effective. If a patient is confirmed to have one of the aforementioned approved variants, it can be used for outpatients, inpatients admitted for non-COVID reasons, and inpatients with hospital-acquired COVID-19, who are at high risk of progression to severe disease. See the AHS formulary for full eligibility criteria.
There is currently no clinical evidence to support the use of sotrovimab in patients hospitalized due to COVID-19. The ACTIV-3-TICO trial randomized 344 inpatients to receive either sotrovimab (n=169) or placebo (n=175). The trial was stopped early due to futility, meaning the evidence to date suggested it was of no benefit. Among sotrovimab recipients, there was one case of anaphylaxis and one case of cytokine release syndrome 17 .
• Nirmatrelvir-ritonavir (Paxlovid®) is an oral COVID-specific antiviral approved for use in for high risk outpatients, as well as inpatients admitted for non-COVID reasons with incidental or hospital-acquired COVID-19, if therapy can be initiated within 5 days of symptom onset. See the AHS formulary for full eligibility criteria. Published data suggests it significantly reduces risk of hospitalization or death in outpatients at high risk for progression to severe disease 18 . Paxlovid® has numerous significant drug interactions that may make patients ineligible for treatment. Outpatients who think they may be eligible for treatment with Paxlovid® are advised to call the dedicated Alberta HealthLink phone line at 1-844-343-0971. Centralized assessing and prescribing physicians will determine eligibility and arrange for treatment in the community, if appropriate.
• Bamlanivimab is no longer available within AHS. All available stock expired. No future purchases will be made due to greater than 10-fold reduction in neutralizing activity against variants of concern 19 .
• Consideration of all other investigational antivirals or immunomodulators (e.g. lopinavir/ritonavir, famotidine, and colchicine) should be only under ethics approved, controlled trials.
• There is currently insufficient evidence to recommend routine use of fluvoxamine in outpatients 2,20 . It is not recommended for inpatient use.
• The use of hydroxychloroquine, or any hydroxychloroquine combinations (e.g. hydroxychloroquine plus azithromycin), is not recommended as a treatment in patients with COVID-19.
• Ivermectin should not be used for the prevention or treatment of COVID-19. 21 Its use is not supported by evidence 22 .
• Convalescent plasma is not recommended as a treatment in patients with COVID-19. Evidence suggests it has no benefit 23 .
# General Investigations
Please note the listed investigations below are for clinical consideration and not required tests. Please use the laboratory tests and Investigations incorporated into care pathways and order sets if there are differences between those and the list below.
# General Laboratory tests:
Laboratory tests may not be required in otherwise ambulatory patients who are clinically stable, and not felt to be at elevated risk of decompensation. In the presence of higher clinical severity and/or comorbidities, the following laboratory tests may be considered:
• CBC & differential -
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55fb7244bf2d1dae106505bbcfd41c392748b252
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People who are living with HIV or hepatitis and have a viral load that is undetectable or unquantifiable are not infectious and pose no risk of cross-contamination in the ART laboratory. ART laboratories should process these gametes in the usual fashion without any special precautions needed to prevent infection.# INTRODUCTION
F ertility care providers have an obligation to provide safe and effective care to patients. When a user of assisted reproductive technology (ART) is living with a bloodborne viral infection (BBVI: human immunodeficiency virus , hepatitis C virus or hepatitis B virus ), physicians and ART laboratory personnel need to know the requirements for providing quality care.
ART laboratories routinely safeguard against risk of sample mix-up, equipment failure and contamination by other organisms. These processes that are standards of care are also important in the management of BBVI. This guideline provides an evidence-based approach to reduce the risk of BBVI transmission through horizontal transmission or cross-contamination when oocytes, spermatozoa or embryos from a person living with a BBVI are used.
The nature of ART inherently prevents female-to-male transmission, and intrauterine insemination (IUI) can be used to prevent horizontal spread when sexual intercourse is a source of potential infection. When having penilevaginal intercourse without a condom is considered acceptable with respect to the risk of BBVI transmission in the general population, this guideline recommends no additional processes in the ART laboratory.
Cross-contamination in ART is theoretically possible when a person with a BBVI is being treated. However, the mere presence of measurable viral DNA or RNA is not sufficient to cause infection. The risk of infection is commensurate with cell number or fluid volume. Human blastocysts contain fewer than 200 cells and are situated in less than 0.5 ml of media. Haematological samples, which are the more common sources of infection through crosscontamination, have volumes of 25-75 ml and millions of cells. As a general principle, BBVI require direct contact of blood (or semen) into a recipient. Thus, spread via fomite or environmental surface is not likely. With direct contact (i.e. spillage), a further requirement for infection is the presence of a host cell. The risk of cross-contamination in the incubator is based on the potential infectivity of the gamete, the likelihood of its media coming in direct contact with another gamete, and the potential of the recipient gamete to become infected.
Using human serum in culture media has been associated with crosscontamination when HBV-infected serum was used, when non-commercial media were made with the addition of patients' serum (Quint et al., 1994). Follow-up from such an event did not demonstrate any infection in offspring although there was acute hepatitis in most women affected (van Os et al., 1991). There have been no reported cases of BBVI occurring through cross-contamination in the ART laboratory in the two decades since the widespread use of commercial media. There is one report of hepatitis C transmission that occurred through contamination in the venepuncture setting and not through gametes or embryos (Lesourd et al., 2000).
The regular emergence of new pathogens underscores the need for constant best practices in infection control. In Canada, infection control guidelines are determined provincially, for example by Public Health Ontario (Ontario Agency for Health Protection and Promotion). When processes are not appropriate for the IVF setting, the specific provincial regulators may provide alternates. Options for sterilization processes for HIV are well described by Public Health authorities, for example Ontario (Agency for Health Protection and Promotion et al., 2013). This guideline does not address BBVI risks associated with (i) tissue (ovarian or testicular) procurement, (ii) perinatal transmission, or (iii) any other pathogens. For recommendations for HIV in pregnancy the Society of Obstetricians and Gynaecologists of Canada's (SOGC) (Money et al., 2014), and for hepatitides the Canadian Association for the Study of Liver Disease (CASL) and the Association of Medical Microbiology and Infectious Disease (AMMI), publications on HBV (Coffin et al., 2018) and HCV (Shah et al, 2018) can provide guidance. Specific considerations for general pregnancy planning are not included in this guideline but can be found in the SOGC's guidelines for those affected by HIV (Loutfy et al., 2018).
This document is intended to provide guidance only for autologous samples. The guideline does not pertain to the use of donor gametes. Health Canada regulations on third-party reproduction supersede this document. The accepted process for screening of and use of directed donors can be found in Health Canada guidance documents (https:// www.canada.ca/en/health-canada/ programs/consultation-safety-sperm-ovaregulations/document.html#a12).
# METHODS: GUIDELINE DEVELOPMENT
This guideline is informed by the available research data on transmission and empirical ART data relevant to managing BBVI in the ART setting. In accordance with Canadian Fertility and Andrology Society (CFAS) requirements, the guideline development working group used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) ('GRADE home,' n.d.) approach to development of recommendations when research was available. This provides a framework for the guideline development process, including assessment of the quality of evidence and recommendations.
# Literature search strategy
In July 2018, literature searches were performed by a librarian to identify issues related to BBVI ART transmission associated with cross-contamination, sperm washing and other ART-related procedures. Databases searched included Ovid MEDLINE, the Cochrane Central Register of Controlled Trials and Embase from the time of inception to the date of completion of searches. For the first search on cross-contamination, databases were searched using terms such as "HIV" or "HBV" or "HCV" and "IUI" or "IVF" or "Cryopreservation". For the second search on sperm washing, databases were searched with terms such as "Sperm" and "Wash" and "HIV" or "HBV" or "HCV". Full search terms can be provided on request. Titles and abstracts were screened for inclusion, followed by full-text review by two independent reviewers; a third reviewer was consulted to resolve discordance. A total of 11 articles for cross-contamination and eight articles for sperm washing were included for the final selection.
# PROVISION OF ART WHEN THERE IS HIV INFECTION
Background A total of 2402 new HIV cases were reported in Canada in 2017, a diagnosis rate of 6.5/100,000 (Haddad et al., 2019). The 30-39-year age group represents the highest number of new HIV cases. Although Caucasians accounted for the majority of reported diagnoses in 2017, both Indigenous and Black people were disproportionately represented, each making up less than 5% of the Canadian population but each accounting for more than 20% of new diagnoses (Centre for Infectious Disease Prevention and Control (Canada) and Public Health Agency of Canada, 2013).
The introduction of combination antiretroviral therapy in the mid-1990s led to significant positive changes in the natural history of HIV infection. With ongoing improvements in treatment and overall clinical management of HIV and its most common comorbidities, people with HIV in countries with accessible medical care now have life expectancies comparable to those of the general population. While the clinical management of HIV has led to longer life and improved overall health, stigma and discrimination remain pervasive issues in the lives of people with HIV in Canada and worldwide.
Combination antiretroviral therapy remains the greatest success in the field of HIV, and advances in HIV care have continued over the past 20 years. Today, HIV treatment includes seven classes of medications, more than 30 total medications and countless combinations to produce dozens of regimens that can meet the unique needs of a person with HIV (Cohen et al., 2016). Regimens typically include three medications from two different classes of antiretrovirals. Treatment has progressed to now include 10 single-tablet regimens that allow for one pill, once-a-day HIV treatment for many people with HIV, likely to be more in the future. The desired treatment outcome of combination antiretroviral therapy is full plasma viral suppression of HIV in the infected person. With an effective regimen, greater than 90% medication adherence and adequate support, this outcome is highly achievable.
The ability to achieve and sustain full viral suppression marks another paramount advancement for people with HIV because of the impact it has on transmission. By 2019, over 850 scientific agencies had endorsed the position that 'people living with HIV on antiretroviral therapy with an undetectable viral load in their blood have a negligible risk of sexual transmission of HIV' ('CONSENSUS STATEMENT | United States | Prevention Access Campaign,' n.d.). The statement continues with an explanation of negligible to mean 'so small or unimportant as to be not worth considering'. This follows the 2017 statement from the Centers for Disease Control (CDC): 'when antiretroviral therapy results in viral suppression, defined as less than 200 copies/ml or undetectable levels, it prevents sexual HIV transmission' (https:// www.cdc.gov/hiv/pdf/risk/art/cdc-hiv-artviral-suppression.pdf).
Across the two largest studies with heterosexual couples (HPTN 052 and PARTNER ) (TABLE 1), which included thousands of couples and many thousand acts of sex, mostly without condom use and none having received pre-exposure prophylaxis, no linked HIV transmissions to an HIV-negative partner were observed when the HIV-positive person was virally suppressed. This fact was further confirmed in two studies with large samples of same-sex male couples (Rodger et al., 2016). This means that people who take antiretroviral therapy daily as prescribed, and achieve and maintain an undetectable viral load, have effectively no risk of sexually transmitting the virus to an HIV-negative partner. This messaging has had significant impact on the lives of people with HIV and their partners, and has particular implications for conception. Canada's Department of Justice has issued a directive that federal prosecutors should not prosecute for HIV non-disclosure when the person living with HIV (Canada, 2018) has maintained a suppressed viral load (i.e. under 200 copies of the virus per millilitre of blood) because there is no realistic possibility of transmission (/ pub/fpsd-sfpg/fps-sfp/tpd/p5/ch12.html). This is based on the aforementioned studies and an additional meta-analysis commissioned by Public Health Canada (LeMessurier et al., 2018).
# Provision of ART when there is an undetectable HIV viral load
When an ejaculate is deemed noninfectious with intercourse, it is also non-infectious at all points of processing in the ART laboratory. This means that no additional precautions such as physical separation of patients or samples are required beyond universal precautions and standard IVF laboratory practice.
Concerns have been voiced regarding the applicability of these landmark HIV studies to the pragmatic world, as they only reported on patients in care, presumably adherent to treatment, with persistently undetectable viral loads. The rate of non-adherence varies among populations, and the possibility of nonadherence in the infertility population is real. The supplemental analysis from the PARTNER (Rodger et al., 2019) study provides reassurance as to the safety of this approach. It notes that if the periods of follow-up time (defined between two consecutive HIV tests) in which the HIV RNA was suppressed at the beginning of the period but during which the HIV RNA became elevated were included, the number of within-couple transmissions was still zero.
# Sensitivity Analysis
Sensitivity analysis was conducted including the period of follow-up time in which the HIV-RNA was suppressed at the beginning of the period, but during which became elevated (eTable 3). If we include the periods of follow-up time (defined between two © 2016 American Medical Association. All rights reserved. consecutive HIV tests), in which the HIV-RNA was suppressed at the beginning of the period but during which the HIV-RNA became elevated, the number of within-couple transmissions is still zero, therefore the estimated rate is zero. The estimates / confidence intervals included in the manuscript and the alternative described above are shown in the table below. This is consistent with previous data showing that the risk per individual sexual act is in the realm of 0.004-0.008% (LeMessurier et al., 2018). The implication of the CDC recommendation is that all providers of ART should provide all services to people with HIV who have a sustained undetectable viral load.
# Recommendations:
1 A person living with HIV should be under the regular care of an HIV-care provider prior to beginning fertility treatment. 2 A person living with HIV should be on combination antiretroviral therapy for a minimum of 3 months, preferably 6 months, and have two suppressed viral load results (i.e. <200 copies/ ml or 'target not detected') at least 1 month apart, and then every 6 months (or more frequently if questions of adherence arise or at the discretion of their HIV-care provider) prior to attempting conception. 3 ART laboratories should not offer sperm washing and IUI solely to reduce the risk of horizontal transmission if the spermatozoa come from a person living with HIV who has been on combination antiretroviral therapy for a minimum of 3 months (preferably 6 months) and has had two suppressed viral load results (i.e. <200 copies/ml or 'target not detected') at least 1 month apart.
# Provision of ART when there is a detectable HIV viral load
There is expert consensus that pregnancy should be deferred until infected partners are adequately treated (Loutfy et al., 2018). However, there may be circumstances where this is not possible, and ultimately it is the patient's decision. They should be supported in making informed, autonomous decisions about their health and be offered appropriate counselling to do so in the context of ART. When viral load in the female partner is not adequately suppressed, the SOGC guidelines for reducing perinatal transmission should be followed and IUI offered (Money et al., 2014).
# Managing the risk of horizontal transmission with HIV
There are several studies addressing the situation in which the male partner is living with HIV with a detectable serum viral load and IUI has been performed. For the purposes of this guideline, reports not written in English and those that did not separate IVF/ intracytoplasmic sperm injection from IUI were excluded. However, there are a number of meta-analyses including such papers that demonstrate the efficacy of sperm washing as a risk-reduction method when there is a detectable HIV viral load.
A 2011 meta-analysis found no reports of transmission across 3900 cycles of IUI in 1184 HIV-serodiscordant couples (Vitorino et al., 2011). In a 2014 meta-analysis based on 8212 seropositive male and seronegative female IUI cycles and 1254 seropositive male and seronegative female IVF cycles (Barnes et al., 2014), the authors found no reports of transmission. The 95% confidence interval (CI) would suggest an upper limit rate of 4.5 transmissions per 10,000. A larger meta-analysis published in 2016 reported on 11,237 cycles (Zafer et al., 2016). Of the couples treated, 27.7% of the males had not achieved viral suppression at the time of semen washing. There were no HIV seroconversions among this subset
# TABLE 1 PARTNER STUDY CHARACTERISTICS AND RESULTS
-f 1023 couples. The per-cycle risk of HIV seroconversion was zero. The 95% CI with this larger sample reduces the risk to a maximum of 0.0006% per cycle. The sperm preparation method varied among the studies, as such none is clearly proven to be superior. Today the standard protocol is gradient and swimup as described by Semprini and the European CREAThE network (Semprini et al., 1992). A double-tube method that allows the sperm pellet to be retrieved after centrifugation, without coming into contact with the gradient layers and seminal plasma, has also been developed but is not widely used (Fourie et al., 2015).
The aforementioned meta-analyses referenced papers that are not available in English. The four English language observational studies can be found in TABLE 2. While observational studies have weaknesses, the large sample size, the long period of use of the techniques and the multiple sites reporting outcomes leads to a strong recommendation for the use of gradient and swim-up techniques and IUI in serodiscordant couples.
# Recommendations:
4 ART providers should offer IUI to reduce the risk of female-to-male transmission if the female partner cannot achieve an undetectable HIV viral load. 5 ART laboratories should process ejaculates from men unable to achieve an undetectable HIV viral load using gradient and swim-up techniques to reduce the risk of horizontal transmission.
# Managing the risk of HIV crosscontamination and ART
As demonstrated by the PARTNER study (Rodgers et al., 2016), there is no risk of HIV infection or cross-contamination if the serum HIV viral load is suppressed. Thus, this section refers only to situations when there is a measurable HIV viral load.
# Managing the risk of HIV crosscontamination when processing spermatozoa
Double-washing has been well proven and universally used for HIV-positive specimens; thus, there are no clinical studies addressing the question of whether single-washing renders specimens non-infectious. There is potential for cross-contamination in the intermediary steps of sperm washing, with various semen fractions and with spent media. Small studies have found one sample wash positive after the initial process (Fiore et al., 2005;Savasi et al., 2010). By spiking samples with HIV, Fiori and colleagues demonstrated that, depending on the viral load, spent media may harbour HIV. Accurate estimates of the risk of cross-contamination based only on the risk of virus in spent media cannot be inferred but do provide a start. When a sample from a person known to have a detectable viral load is processed, the resulting sample is unlikely to harbour virus and the absolute load is
# Inconsistency
# Indirectness Imprecision Other considerations
Viral detection across different semen fractions 3 Observational studies Serious a Not serious Serious Serious None Semen samples from HIV-infected patients (n = 12); after density gradient centrifugation, one sample where virus was detected; after swim-up, all samples tested negative for viral detection (Hanabusa et al., 2000) Semen samples (n = 16) from HCV/ HIV-infected patients; detected virus in raw semen, seminal plasma and non-sperm cells, but not after density centrifugation or swim-up (Savasi et al., 2010) Semen samples (n = 62) with HIV/HBV/ HCV; washed with gradient centrifugation (no swim-up) and tested negative for viral detection (Molina et al., 2014) ⊕OOO Critical Very low a Risk of bias is inherent due to observational study design.
b Small sample: Hanabusa and colleagues (Hanabusa et al., 2000) had n = 12 semen samples from HIV infected patients, and Savasi and co-workers (Savasi et al., 2010) had n = 16 semen samples from HIV/HCV-infected patients.
HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus.
very low. This can cause infection only if it also comes into direct contact with a receptive host tissue; when samples are processed separately, this cannot happen. The studies in TABLE 3 provide only indirect evidence about the risk of cross-contamination but are nonetheless reassuring.
# Recommendations:
6 When recommendations 1 and 2 are met, and ART is being used for a fertility indication, ART laboratories should not provide any additional sperm processing solely to reduce the risk of cross-contamination. 7 When a person is unable to reach an undetectable HIV viral load, and ART is required, ART laboratories should process ejaculates as the only specimen in the hood or centrifuge in order to reduce the risk of crosscontamination, and should follow cleaning and disinfection procedures between samples as set by provincial regulations.
# Managing the risk of HIV crosscontamination when processing oocytes
Oocyte retrieval requires puncture of tissue with ensuing microscopic or macroscopic bleeding; thus, there is potential for contamination with the procedure. However, Health Canada clearly states that standard equipment and room cleansing is acceptable for reducing cross-contamination risk. This is likewise true in the laboratory, where follicular fluid and blood are washed from the oocyte. Standard preparation of the egg for insemination or vitrification has been demonstrated to effectively remove viral particles from the follicular fluid (Cobo et al., 2012). The rate of HIV DNA retrieval decreases from 89% to 25% by day 1 after oocyte retrieval, and DNA becomes undetectable after washing the embryos and refreshing the media, irrespective of the original bloody status of the follicular fluid.
There is no evidence to suggest that the oocyte of an HIV-positive woman can be infected by the virus, as CD4, and other HIV receptors, have never been demonstrated in mature oocytes or follicular cells (Baccetti et al., 1999). The oocyte is known to be a poor vector of pathogen agents because, in addition to the barrier effect of the zona pellucida, it is an isolated cell with no blood supply.
# Recommendation:
8 When a person is unable to reach an undetectable HIV viral load, and ART is required, ART laboratories should process oocytes as the only specimen in the hood in order to reduce the risk of cross-contamination, and should follow cleaning and disinfection procedures between samples as set by provincial regulations.
# Managing the risk of HIV crosscontamination with embryo culture
The risk of cross-contamination in the incubator is based on the potential infectivity of the gamete, the likelihood of its media coming into direct contact with another gamete, and the potential of the recipient gamete to become infected. As has been shown, washing for HIV-infected spermatozoa renders them non-infectious when a double process is used. Although there are not have the same large-scale observation studies for oocytes, the same appears to hold true (Cobo et al., 2012). Thus, embryos created from individuals and couples affected by HIV are themselves noninfectious. However, even in the unlikely event that the virus was not completely removed, the risk of cross-contamination in the incubator (i.e. coming into direct contact with another gamete) is also determined by the type of incubator (single chamber box versus individual chamber) and the number of patients per chamber. The use of one chamber per patient eliminates any risk of crosscontamination while in the incubator. However, the common practice of culturing under oil droplet also serves to minimize the chance of microbial contamination.
Finally, after removal from the incubator prior to fresh embryo transfer, trophectoderm biopsy or vitrification, the usual practice is to wash the embryo and replace the media. This final step would again provide an opportunity remove any potential contamination from the media.
In summary, given the many opportunities to wash gametes of virus before embryo transfer, the likelihood of contamination, even with the potential of spillage within the incubator, is negligible.
# Recommendation:
9 ART laboratories may culture embryos from a person with a detectable HIV viral load using standard processes in individual chambered incubators or box incubators.
# PROVISION OF ART WHEN THERE IS HEPATITIS C INFECTION Background
Approximately 0.67% of Canadians are infected with HCV. This varies from 3% in Indigenous populations to 0.8% in the cohort born from 1950 to 1975 and is extremely low in younger age groups (Shah et al., 2018). It is the most common newly diagnosed BBVI today in Canada, although there are more people living with chronic HBV infection (Canada, 2014).
The current understanding of diagnosing and managing HCV has altered dramatically since its discovery in 1989 (Choo et al.,1989). HCV is a blood-borne infectious disease that is caused by an RNA virus and primarily affects the liver. Often, patients are asymptomatic. If left untreated, 5-20% of individuals infected with HCV spontaneously clear the virus, and these individuals are non-infectious. However, for the remaining 80%, HCV becomes chronic and may lead to consequences such as cirrhosis of the liver, liver cancer and, after decades, even liver failure.
The first treatment for HCV became available in 1991, with a cure rate of less than 10% (Poynard, 2004). However, the treatment landscape has made tremendous advances with the use of direct-acting antivirals. HCV treatment is guided by factors such as viral genotype, prior antiviral use, liver cirrhosis, HIV or HBV co-infection and pregnancy. Current treatment with glecaprevir/pibrentasvir for as little as 8 weeks or with sofosbuvir/velpatasvir for 12 weeks can confer greater than 90% cure rates (Grover and Erlich, 2018). A person is considered cured of HCV, and un-infectious, if there is no detectable virus ('target not detected') in a serum sample 3 months after completing HCV treatment. HCVantibody positive but RNA-negative individuals do not need any specific intervention to reduce transmission as they are non-infectious.
# Recommendations:
10 A person with quantifiable HCV (detectable HCV RNA) should be treated for HCV before conceiving. 11 If/once the HCV RNA of a gamete provider is unquantifiable, ART laboratories should not use any additional spermatozoa, oocyte or embryo processing solely to reduce the risk of horizontal transmission. 12 If a gamete provider is HCV RNA unquantifiable, regardless of the HCV antigen or antibody status, ART providers should not offer specific processes solely to reduce the risk of cross-contamination in the laboratory.
# Managing the risk of horizontal transmission of HCV
It is recommended that people be cured of HCV before attempting conception. However, there may be circumstances when this is not possible, such as lack of drug access or advanced reproductive age. The presence of HCV in the semen of infected men is well documented. However, the presence of virus is not sufficient to cause infection. HCV is not a DNA virus (unlike HBV) and has no reverse transcriptase activity (unlike HIV); it therefore cannot integrate into spermatozoa or embryo DNA, which significantly reduces concern about horizontal transmission (Dodge and Terrault, 2014). Furthermore, several studies of thousands of people-years have documented negligible transmission rates in the absence of co-infection with HIV (Bresters et al., 1993;Terrault et al., 2013;Tohme and Holmberg, 2010). Thus, the recommendation is that a condom is not necessary for penile-vaginal intercourse in HCV serodiscordant couples, with the understanding that activities that have the potential for blood-to-blood contact do allow for transmission.
Despite laboratory evidence of the presence of virus, when unprotected intercourse is deemed safe, no additional measures are needed in the ART laboratory to prevent horizontal transmission.
# Recommendation:
13 If either partner has active HCV but no other BBVI, ART providers should not offer IUI solely to reduce the risk of horizontal transmission.
# Managing the risk of HCV crosscontamination when processing spermatozoa
In men infected with HCV, HCV RNA has been detected in different semen fractions (Garrido et al., 2005) but sperm washing has been shown to be effective at reducing the virus, as outlined for HIV above. In contrast to the HIV literature, preparation using only Percoll has been shown to eliminate HCV RNA (Halfon et al., 2006). The likelihood of cross-contamination, given the virus characteristics, is very small with routine processes.
# Recommendation:
14 If a sperm provider has quantifiable HCV and requires ART for fertility purposes, ART laboratories may process the ejaculate as the only specimen in the hood or centrifuge in order to reduce the risk of cross-contamination, and follow cleaning and disinfection procedures between samples as set by provincial regulations.
# Managing the risk of HCV crosscontamination with oocyte processing
Potential contamination with oocyte processing is likely as a result of blood in the follicular fluid, which is removed during the process identifying the oocyte and preparing for insemination (Cobo et al., 2012;Devaux, 2003;Levy, 2000).
# Recommendation:
15 If an egg provider has quantifiable HCV and requires ART for fertility purposes, ART laboratories should process oocytes as the only specimen in the hood in order to reduce the risk of cross-contamination, and should follow cleaning and disinfection procedures between samples as set by provincial regulations.
# Managing the risk of HCV crosscontamination with embryo culture
Despite the potential for HCV to be found in the follicular fluid, the likelihood of persistence in embryo culture is low. As for all BBVI, the risk of cross-contamination in the incubator is based on the potential infectivity of the gamete, the likelihood of its media coming in direct contact with another gamete, and the potential of the recipient gamete to become infected. As has been shown, washing HCVinfected spermatozoa or eggs renders them non-infectious, although there are few data for eggs (Cobo et al., 2012). Thus, embryos created from individuals and couples with HCV are likely to be non-infectious. However, even in the unlikely event that virus was not completely removed, the risk of crosscontamination in the incubator (i.e. coming into direct contact with another gamete) is also determined by the type of incubator (box versus individual chamber) and the number of patients per chamber. The use of one chamber per patient eliminates any risk of crosscontamination while in the incubator.
Another level of protection against cross-contamination during embryo incubation is attained by the culturing in media drops under oil.
Finally, after removal from the incubator prior to fresh embryo transfer, trophectoderm biopsy or vitrification, the usual practice is to wash the embryo and replace the media. This final step again would again provide opportunity remove any potential contamination from the media.
# Recommendation:
16 ART laboratories may culture embryos from a person with a detected HCV RNA using standard processes in individual chambered incubators or box incubators.
# PROVISION OF ART WHEN THERE IS HEPATITIS B INFECTION Background
The virus for hepatitis B, and the subsequent vaccine, was discovered by Nobel laureate Baruch Blumberg in 1965. More than 240 million individuals worldwide are chronically infected with HBV, which can lead to hepatitis, cirrhosis, fulminant liver failure and hepatic cancer. In Canada, cases of chronic HBV infection are falling, with an overall rate of 11/100,000 but one as high as 28/100,000 in men aged 20-29 years (Aparna et al., n.d.). HBV is most common in central and east Asia, sub-Saharan Africa and the Pacific (5-8% adults), as well as other developing countries and low-income communities without the resources or financial support for vaccination programmes, screening tools or treatment programmes. HBV continues to be an issue in Canada among immigrants from countries where HBV is endemic (Canada, 2019). Interpretation of hepatitis B testing can be found in TABLE 4.
Successful immunization provides effective protection against HBV infection. However, 5-15% of individuals do not respond to the vaccination and revaccination is recommended. If vaccination is still unsuccessful, these individuals should be counselled on prevention of acquiring and transmitting HBV.
Antiviral therapy is the primary form of treatment for those with chronic infection. HBV is most commonly transmitted sexually and perinatally. An infection rate of 20-40% is seen in the regular heterosexual partners of HBV-infected patients (Brook, 2002). HBV genotypes A and C are most common in individuals who acquire HBV sexually (Aparna et al., n.d.). The risk of horizontal transmission of HBV is completely eliminated when the partner is immune. However, the person carrying the pregnancy may not have been vaccinated or show immunity after vaccination (Bakker et al., 2016). Thus, the question of the infectivity of spermatozoa remains germane. HBV DNA or RNA can be extracted from spermatozoa and only occasionally from resulting embryos in humans (Ali et al., 2006).
HBV DNA can integrate into the germline. However, the presence of DNA in the germline does not necessarily result in vertical transmission (Hadchouel et al., 1985;Nie et al., 2011). Jin and colleagues (Jin et al., 2016) reported on excess embryos or unfertilized eggs and the babies resulting from sibling embryos, these babies being tested for HBV. Twelve babies were born to HBsAg-positive couples, and were all HBsAg-negative, even when unfertilized oocytes and non-viable embryos from these same couples were HBV positive. A study of HBV-negative pregnant women with a paternal HBV carrier (i.e. sperm provider) undergoing amniocentesis did not demonstrate any HBV infection in the livers of eight fetuses that were aborted (for other reasons) (Cai and Zhu, 2013). There was no evidence of paternal hepatitis antigen in over 100 samples, suggesting that paternal transmission is not a concern. This suggests that either the spermatozoa were not infective or the lack of liver development until 12 weeks of gestational age allowed for maternal clearance before any infection, or that infection was incompatible with ongoing pregnancy (Ye et al., 2013). The very small sample size precludes definitive conclusions about lack of sperm infectivity so this question remains.
# Managing the risk of horizontal transmission of HBV
# Recommendations:
17 If either reproductive partner is HBV surface antigen positive:
(a) The infected partner should be referred to an HBV-care provider. (b) The other partner must be tested for HBV surface antigen, surface antibody and core antibody, and be immunized if not immune. (c) The couple should be counselled to use condoms until the HBVsusceptible partner is immune. 18 When the gestating partner is HBV immune and the ejaculate is from a person infectious for HBV, ART providers should not offer IUI solely to reduce the risk of horizontal transmission. 19 When the gestating partner is HBV immune and the ejaculate is from a person infectious for HBV, and IUI is needed for fertility purposes, ART laboratories should prepare the spermatozoa in the usual fashion with a single wash.
If the sperm provider is HBV surface antigen positive and the gestating partner is non-immune (after vaccination), there are no data to guide the choice of single or double sperm washing to reduce horizontal transmission. HBV DNA or RNA can be extracted from spermatozoa and sometimes from resulting embryos in humans (Cai and Zhu, 2013). However, HBV is present in a much higher amount in the seminal fluid. Thus, sperm washing is still appropriate to reduce horizontal transmission. Alternatively, the person providing the spermatozoa can be considered for virus-reducing therapy.
20 When the gestating partner cannot achieve HBV immunity and the ejaculate is from a person infectious for HBV, ART providers may use gradient and swim-up for IUI to reduce the risk of horizontal transmission. 21 When the gestating partner is infectious for HBV, and the sperm provider is non-immune, IUI may be used to reduce the risk of horizontal transmission.
# Managing the risk of crosscontamination with HBV
We are not aware of any studies in which environmental surfaces have been clearly associated with the actual spread of HBV and HCV. However, it is well established that, without proper cleaning, HBV can survive outside the body for at least 7 days and is at least theoretically capable of causing infection (Sattar et al., 2001).
# Recommendations:
22 ART laboratories should process gametes from a person infectious for HBV separately, and follow cleaning and disinfection procedures between samples as set by provincial regulations. 23 ART laboratories may culture embryos from a person infectious for HBV using standard processes in individual chambered incubators or box incubators.
# Managing risk of cross-contamination with cryopreservation
Cryostorage has intrinsic risks, not only of microbiological contamination but also risks including, but not limited to, equipment failure, thawing and leakage of genetic material. The infectious risk is not limited to BBVI (Bielanski et al., 2003;Joaquim et al., 2017). As with the risk of embryo culture, opportunities for cross-contamination exist if the sample is infectious, if it can come into direct contact with the recipient gamete, and if the recipient gamete cannot be cleared of the BBVI before transfer.
However, there are fundamental differences between culture and storage. Embryo culture is for a duration of days. Cryopreservation may span years, so the cumulative risk of any problem is magnitudes bigger. Best practices mandate provisions for known and currently unknown risks. The addition of BBVI samples should not change risk management. As previously discussed with respect to embryo culture risk, it is unlikely that gametes that have been washed and prepared in the usual way for cryopreservation are infectious. Again, the preparation after thaw, and before transfer, further reduces the risk.
The storage of gametes or embryos in straws is akin to separate chambers of incubators. This is referenced in US regulatory standards. Of note, Pomery stated in 2010:
According to the FDA, storage is considered to be improper if unique specimens occupy the same location in such a way that provides the opportunity to mix, cross-contaminate, or be inadvertently distributed. It cannot be emphasized enough that it is permissible to physically locate specimens in the same storage tank provided that the aforementioned safeguards are assured. (Pomeroy et al., 2010) Health Canada has recently clarified their position, which is likewise that separation of specimens of unknown status is administrative, not physical, and does not require separate equipment. This means that samples of known positive BBVI status can be stored along with other samples.
A sample from individuals with a BBVI poses a theoretical risk with cryopreservation. Most microorganisms can survive storage at liquid nitrogen temperatures, and the cryoprotectants used in embryo and oocyte cryopreservation may also protect viruses. However, infection from liquid nitrogen in the ART setting has not been demonstrated. Liquid nitrogen tested from stored oocytes and embryos (n = 27) of HIV-, HBV-and HCV-infected patients did not demonstrate any virus in any sample (Cobo et al., 2012). This is likely to reflect the aforementioned ability to remove virus during the washing process. TABLE 5 summarizes the available studies.
The risk of cross-contamination from cryopreservation is also dependent on
# Risk of bias
# Inconsistency
# Indirectness Imprecision Other considerations
Risk of contamination into liquid nitrogen 1 Observational studies Serious a Not serious Not serious Serious b None Tested liquid nitrogen (n = 27) from oocyte (n = 14) and embryo vitrification (n = 10) and liquid nitrogen storage tank samples (n = 3) from HIV-, HBV-and HCV-infected patients; all samples tested negative for viral detection (Cobo et al., 2012). Very serious f None Report cross-contamination from leaked bag of HBV-infected bone marrow sample to six uninfected samples (Tedder et al., 1995) Leaking HBV blood product sample in combined storage with uninfected samples; testing of 115 uninfected samples showed negative for viral detection (Husebekk et al., 2004) ⊕OOO Critical Very low a Risk of bias is inherent due to observational study design.
b Small sample: n = 27 liquid nitrogen samples from vitrification and storage tanks tested.
c Used HIV-infected supernatant but not sperm samples from infected patients (Letur-Konirsch et al., 2003).
d Used sperm samples from uninfected patients spiked with blood plasma from HCV-infected patients but not sperm samples from infected patients (Maertens et al., 2004).
e Tedder and colleagues (Tedder et al., 1995) report cross-contamination to uninfected bone marrow samples from HBV-infected samples, and Husebekk and co-workers (Husebekk et al., 2004) report no contamination with shared storage of blood products. f Tedder and colleagues (Tedder et al., 1995) provide a case report of a single event of contamination from one HBV-infected sample to five other samples; Husebekk and co-workers (Husebekk et al., 2004) report no contamination from one leaked bag to 55 other samples.
HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus. PCR polymerase chain reaction an in vitro technique for rapidly synthesizing large quantities of a given DNA segment that involves separating the DNA into its two complementary strands, using DNA polymerase to synthesize two-stranded DNA from each single strand, and repeating the process -abbreviation PCR; PETG Polyvinyl chloride (PVC), polyethylene terephthalate glycol IR high-security ionomeric resin the type of storage method -liquid or vapour phase -and the type of strawopen or closed. Vapour-phase storage eliminates the vector for contamination. While it may be superior from an infection control perspective, it may present greater risk of compromise or loss of cryopreserved specimens (Vajta et al., 2015). Studies using washing techniques after thaw have demonstrated complete removal of bacteria and fungi, and this would be likely to be true of BBVI (Parmegiani et al, 2012).
In a closed liquid device, the nitrogen of the common container is never in direct contact with biological material frozen on the inside, so cross-contamination cannot occur unless there are several breaks in the system. If this were the case, the stored biological material would be at material risk. After loading in a closed system, the plastic straw can be heat-sealed on both ends, and consequently the solution containing the embryo and the liquid nitrogen are hermetically isolated during cooling and storage system. Closed systems reduce the potential danger of contamination through liquid nitrogen, but open systems provide direct contact for the required cooling and warming rates for vitrification. Contamination in animal models under experimental conditions has been shown (Bielanski et al., 2000). However, a review by the same authors acknowledges the differences between these studies and human practice (Bielanski and Vajta, 2009). The risk of direct contact may be ameliorated by the effects of the cryoprotectants against contamination.
Assessing risk of cross-contamination can only be done indirectly by measuring infectious material in liquid nitrogen after routine processing. There are no studies or reports of tank failure that have resulted in contamination. Sadly, there are reports of tank failure that have resulted in embryo demise.
# Managing cross-contamination with testing frequency
The current practice of many Canadian fertility clinics is mandatory annual testing for BBVI in all users of ART (IVF and IUI). This does not reflect evidencebased guidelines that base the frequency of testing on risk factors, but instead reflects a misplaced fear of crosscontamination between specimens in the ART setting, and an attempt at risk management on the part of the ART providers. An unintended consequence of this approach has been to perpetuate the stigma associated with BBVI, especially HIV, and limit the access to care of affected individuals.
Canadian Guidelines (HIV Screening and Testing Guide Canada.ca) recommend preconception BBVI testing of all individuals and repeat testing of low-risk individuals only if risk factors change, or at the request of the patient. Annual testing is unwarranted for the majority of ART patients, despite it being the practice of virtually all ART units, which believe it will reduce risk of cross-contamination.
Maintaining the mandatory BBVI testing in the ART setting but lengthening the time between testing possibly increases the number of undiagnosed cases that are being processed in an ART laboratory.
Eliminating repeat testing would increase the risk of undiagnosed cases over the whole period of fertility care, which may be years.
Data are not available on new cases of BBVI that have been diagnosed during fertility treatment in Canada. A UK study in 2001 demonstrated a baseline rate of HIV and HBV of 0.8% and 1.4%, respectively, in the infertile population, similar to the prenatal testing rates of 0.13% and 1.7 (Hart et al., 2001). A larger study demonstrated HBV and HIV baseline risks of 0.28% and 0.007% with no additional cases diagnosed over the course of treatment of 12,000 individuals (Abusheikha et al., 1999). Two smaller studies could not demonstrate any new cases among over 600 patients who had repeat testing within 3 years. These are summarized in TABLE 6. In Canada, the prevalence of HIV is 173/100,000 population (Haddad et al., 2019). In higher prevalence countries, rates in fertility clinics were found to be 1.7% (HIV), 7.9% (HBV) and 0.4% (HCV), similar to reported rates in their general populations (Yakass et al., 2016). exposure-prone procedures even though infected, undiagnosed surgeons pose a risk to patients through bloodborne contamination. In Ontario, these physicians are required to undergo testing every 3 years to reduce the risk of direct infection. The risk of indirect contamination (as might happen in other medical specialties) is deemed to be so low so as not to warrant testing. This is based on expert consensus and can be assumed to reflect Canadian values.
# Recommendations:
25 ART providers should test reproductive partners for HIV serology, HBV surface antigen and HCV antibody at intake. 26 ART providers should re-test individuals with any risk factors for these BBVI annually or biannually (TABLE 7). 27 In the absence of any BBVI risk factors (see TABLE 7), ART providers should not re-test for BBVI for the purpose of preventing cross-contamination.
# CONCLUSION
The management of individuals living with BBVI has advanced considerably, leading to improved prognosis and quality of life, and a greater desire to parent. Current practices in ART do not reflect these changes as many ART clinics inappropriately deny services to people living with BBVI. There remain important gaps in the availability of ART to those living with BBVI across Canada, often due to the unwarranted fears of those providing care.
The goal of this CFAS Clinical Practice Guideline is to address two important considerations with regard to BBVI in the ART setting: (i) managing male-tofemale transmission of BBVI, and (ii) preventing cross-contamination. This guideline interprets the best available evidence and considers the needs of the patient, the care providers and society. Individuals properly treated for HIV and HCV pose no infection risk to their partners or other patients using assisted reproduction. Laboratories can simply and effectively mitigate risk from individuals with active BBVI by individual preparation of gametes. Embryos in culture or in storage pose no threat in the absence of equipment failure and likely pose no threat even in the event of failure. The risk of both transmission and cross-contamination can effectively be eliminated by any and all ART laboratories while providing care to all who need it. Ultimately, the practices in this guideline are best practices for all ART patients regardless of BBVI status and we hope this guideline will expand ART access to people living with BBVI on the basis of the best available evidence.
|
People who are living with HIV or hepatitis and have a viral load that is undetectable or unquantifiable are not infectious and pose no risk of cross-contamination in the ART laboratory. ART laboratories should process these gametes in the usual fashion without any special precautions needed to prevent infection.# INTRODUCTION
F ertility care providers have an obligation to provide safe and effective care to patients. When a user of assisted reproductive technology (ART) is living with a bloodborne viral infection (BBVI: human immunodeficiency virus [HIV], hepatitis C virus [HCV] or hepatitis B virus [HBV]), physicians and ART laboratory personnel need to know the requirements for providing quality care.
ART laboratories routinely safeguard against risk of sample mix-up, equipment failure and contamination by other organisms. These processes that are standards of care are also important in the management of BBVI. This guideline provides an evidence-based approach to reduce the risk of BBVI transmission through horizontal transmission or cross-contamination when oocytes, spermatozoa or embryos from a person living with a BBVI are used.
The nature of ART inherently prevents female-to-male transmission, and intrauterine insemination (IUI) can be used to prevent horizontal spread when sexual intercourse is a source of potential infection. When having penilevaginal intercourse without a condom is considered acceptable with respect to the risk of BBVI transmission in the general population, this guideline recommends no additional processes in the ART laboratory.
Cross-contamination in ART is theoretically possible when a person with a BBVI is being treated. However, the mere presence of measurable viral DNA or RNA is not sufficient to cause infection. The risk of infection is commensurate with cell number or fluid volume. Human blastocysts contain fewer than 200 cells and are situated in less than 0.5 ml of media. Haematological samples, which are the more common sources of infection through crosscontamination, have volumes of 25-75 ml and millions of cells. As a general principle, BBVI require direct contact of blood (or semen) into a recipient. Thus, spread via fomite or environmental surface is not likely. With direct contact (i.e. spillage), a further requirement for infection is the presence of a host cell. The risk of cross-contamination in the incubator is based on the potential infectivity of the gamete, the likelihood of its media coming in direct contact with another gamete, and the potential of the recipient gamete to become infected.
Using human serum in culture media has been associated with crosscontamination when HBV-infected serum was used, when non-commercial media were made with the addition of patients' serum (Quint et al., 1994). Follow-up from such an event did not demonstrate any infection in offspring although there was acute hepatitis in most women affected (van Os et al., 1991). There have been no reported cases of BBVI occurring through cross-contamination in the ART laboratory in the two decades since the widespread use of commercial media. There is one report of hepatitis C transmission that occurred through contamination in the venepuncture setting and not through gametes or embryos (Lesourd et al., 2000).
The regular emergence of new pathogens underscores the need for constant best practices in infection control. In Canada, infection control guidelines are determined provincially, for example by Public Health Ontario (Ontario Agency for Health Protection and Promotion). When processes are not appropriate for the IVF setting, the specific provincial regulators may provide alternates. Options for sterilization processes for HIV are well described by Public Health authorities, for example Ontario (Agency for Health Protection and Promotion et al., 2013). This guideline does not address BBVI risks associated with (i) tissue (ovarian or testicular) procurement, (ii) perinatal transmission, or (iii) any other pathogens. For recommendations for HIV in pregnancy the Society of Obstetricians and Gynaecologists of Canada's (SOGC) (Money et al., 2014), and for hepatitides the Canadian Association for the Study of Liver Disease (CASL) and the Association of Medical Microbiology and Infectious Disease (AMMI), publications on HBV (Coffin et al., 2018) and HCV (Shah et al, 2018) can provide guidance. Specific considerations for general pregnancy planning are not included in this guideline but can be found in the SOGC's guidelines for those affected by HIV (Loutfy et al., 2018).
This document is intended to provide guidance only for autologous samples. The guideline does not pertain to the use of donor gametes. Health Canada regulations on third-party reproduction supersede this document. The accepted process for screening of and use of directed donors can be found in Health Canada guidance documents (https:// www.canada.ca/en/health-canada/ programs/consultation-safety-sperm-ovaregulations/document.html#a12).
# METHODS: GUIDELINE DEVELOPMENT
This guideline is informed by the available research data on transmission and empirical ART data relevant to managing BBVI in the ART setting. In accordance with Canadian Fertility and Andrology Society (CFAS) requirements, the guideline development working group used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) ('GRADE home,' n.d.) approach to development of recommendations when research was available. This provides a framework for the guideline development process, including assessment of the quality of evidence and recommendations.
# Literature search strategy
In July 2018, literature searches were performed by a librarian to identify issues related to BBVI ART transmission associated with cross-contamination, sperm washing and other ART-related procedures. Databases searched included Ovid MEDLINE, the Cochrane Central Register of Controlled Trials and Embase from the time of inception to the date of completion of searches. For the first search on cross-contamination, databases were searched using terms such as "HIV" or "HBV" or "HCV" and "IUI" or "IVF" or "Cryopreservation". For the second search on sperm washing, databases were searched with terms such as "Sperm" and "Wash" and "HIV" or "HBV" or "HCV". Full search terms can be provided on request. Titles and abstracts were screened for inclusion, followed by full-text review by two independent reviewers; a third reviewer was consulted to resolve discordance. A total of 11 articles for cross-contamination and eight articles for sperm washing were included for the final selection.
# PROVISION OF ART WHEN THERE IS HIV INFECTION
Background A total of 2402 new HIV cases were reported in Canada in 2017, a diagnosis rate of 6.5/100,000 (Haddad et al., 2019). The 30-39-year age group represents the highest number of new HIV cases. Although Caucasians accounted for the majority of reported diagnoses in 2017, both Indigenous and Black people were disproportionately represented, each making up less than 5% of the Canadian population but each accounting for more than 20% of new diagnoses (Centre for Infectious Disease Prevention and Control (Canada) and Public Health Agency of Canada, 2013).
The introduction of combination antiretroviral therapy in the mid-1990s led to significant positive changes in the natural history of HIV infection. With ongoing improvements in treatment and overall clinical management of HIV and its most common comorbidities, people with HIV in countries with accessible medical care now have life expectancies comparable to those of the general population. While the clinical management of HIV has led to longer life and improved overall health, stigma and discrimination remain pervasive issues in the lives of people with HIV in Canada and worldwide.
Combination antiretroviral therapy remains the greatest success in the field of HIV, and advances in HIV care have continued over the past 20 years. Today, HIV treatment includes seven classes of medications, more than 30 total medications and countless combinations to produce dozens of regimens that can meet the unique needs of a person with HIV (Cohen et al., 2016). Regimens typically include three medications from two different classes of antiretrovirals. Treatment has progressed to now include 10 single-tablet regimens that allow for one pill, once-a-day HIV treatment for many people with HIV, likely to be more in the future. The desired treatment outcome of combination antiretroviral therapy is full plasma viral suppression of HIV in the infected person. With an effective regimen, greater than 90% medication adherence and adequate support, this outcome is highly achievable.
The ability to achieve and sustain full viral suppression marks another paramount advancement for people with HIV because of the impact it has on transmission. By 2019, over 850 scientific agencies had endorsed the position that 'people living with HIV on antiretroviral therapy with an undetectable viral load in their blood have a negligible risk of sexual transmission of HIV' ('CONSENSUS STATEMENT | United States | Prevention Access Campaign,' n.d.). The statement continues with an explanation of negligible to mean 'so small or unimportant as to be not worth considering'. This follows the 2017 statement from the Centers for Disease Control (CDC): 'when antiretroviral therapy results in viral suppression, defined as less than 200 copies/ml or undetectable levels, it prevents sexual HIV transmission' (https:// www.cdc.gov/hiv/pdf/risk/art/cdc-hiv-artviral-suppression.pdf).
Across the two largest studies with heterosexual couples (HPTN 052 [Cohen et al., 2016] and PARTNER [Rodger et al., 2016]) (TABLE 1), which included thousands of couples and many thousand acts of sex, mostly without condom use and none having received pre-exposure prophylaxis, no linked HIV transmissions to an HIV-negative partner were observed when the HIV-positive person was virally suppressed. This fact was further confirmed in two studies with large samples of same-sex male couples (Rodger et al., 2016). This means that people who take antiretroviral therapy daily as prescribed, and achieve and maintain an undetectable viral load, have effectively no risk of sexually transmitting the virus to an HIV-negative partner. This messaging has had significant impact on the lives of people with HIV and their partners, and has particular implications for conception. Canada's Department of Justice has issued a directive that federal prosecutors should not prosecute for HIV non-disclosure when the person living with HIV (Canada, 2018) has maintained a suppressed viral load (i.e. under 200 copies of the virus per millilitre of blood) because there is no realistic possibility of transmission (https://ppsc-sppc.gc.ca/eng/ pub/fpsd-sfpg/fps-sfp/tpd/p5/ch12.html). This is based on the aforementioned studies and an additional meta-analysis commissioned by Public Health Canada (LeMessurier et al., 2018).
# Provision of ART when there is an undetectable HIV viral load
When an ejaculate is deemed noninfectious with intercourse, it is also non-infectious at all points of processing in the ART laboratory. This means that no additional precautions such as physical separation of patients or samples are required beyond universal precautions and standard IVF laboratory practice.
Concerns have been voiced regarding the applicability of these landmark HIV studies to the pragmatic world, as they only reported on patients in care, presumably adherent to treatment, with persistently undetectable viral loads. The rate of non-adherence varies among populations, and the possibility of nonadherence in the infertility population is real. The supplemental analysis from the PARTNER (Rodger et al., 2019) study provides reassurance as to the safety of this approach. It notes that if the periods of follow-up time (defined between two consecutive HIV tests) in which the HIV RNA was suppressed at the beginning of the period but during which the HIV RNA became elevated were included, the number of within-couple transmissions was still zero.
# Sensitivity Analysis
Sensitivity analysis was conducted including the period of follow-up time in which the HIV-RNA was suppressed at the beginning of the period, but during which became elevated (eTable 3). If we include the periods of follow-up time (defined between two © 2016 American Medical Association. All rights reserved. consecutive HIV tests), in which the HIV-RNA was suppressed at the beginning of the period but during which the HIV-RNA became elevated, the number of within-couple transmissions is still zero, therefore the estimated rate is zero. The estimates / confidence intervals included in the manuscript and the alternative described above are shown in the table below. This is consistent with previous data showing that the risk per individual sexual act is in the realm of 0.004-0.008% (LeMessurier et al., 2018). The implication of the CDC recommendation is that all providers of ART should provide all services to people with HIV who have a sustained undetectable viral load.
# Recommendations:
1 A person living with HIV should be under the regular care of an HIV-care provider prior to beginning fertility treatment. 2 A person living with HIV should be on combination antiretroviral therapy for a minimum of 3 months, preferably 6 months, and have two suppressed viral load results (i.e. <200 copies/ ml or 'target not detected') at least 1 month apart, and then every 6 months (or more frequently if questions of adherence arise or at the discretion of their HIV-care provider) prior to attempting conception. 3 ART laboratories should not offer sperm washing and IUI solely to reduce the risk of horizontal transmission if the spermatozoa come from a person living with HIV who has been on combination antiretroviral therapy for a minimum of 3 months (preferably 6 months) and has had two suppressed viral load results (i.e. <200 copies/ml or 'target not detected') at least 1 month apart.
# Provision of ART when there is a detectable HIV viral load
There is expert consensus that pregnancy should be deferred until infected partners are adequately treated (Loutfy et al., 2018). However, there may be circumstances where this is not possible, and ultimately it is the patient's decision. They should be supported in making informed, autonomous decisions about their health and be offered appropriate counselling to do so in the context of ART. When viral load in the female partner is not adequately suppressed, the SOGC guidelines for reducing perinatal transmission should be followed and IUI offered (Money et al., 2014).
# Managing the risk of horizontal transmission with HIV
There are several studies addressing the situation in which the male partner is living with HIV with a detectable serum viral load and IUI has been performed. For the purposes of this guideline, reports not written in English and those that did not separate IVF/ intracytoplasmic sperm injection from IUI were excluded. However, there are a number of meta-analyses including such papers that demonstrate the efficacy of sperm washing as a risk-reduction method when there is a detectable HIV viral load.
A 2011 meta-analysis found no reports of transmission across 3900 cycles of IUI in 1184 HIV-serodiscordant couples (Vitorino et al., 2011). In a 2014 meta-analysis based on 8212 seropositive male and seronegative female IUI cycles and 1254 seropositive male and seronegative female IVF cycles (Barnes et al., 2014), the authors found no reports of transmission. The 95% confidence interval (CI) would suggest an upper limit rate of 4.5 transmissions per 10,000. A larger meta-analysis published in 2016 reported on 11,237 cycles (Zafer et al., 2016). Of the couples treated, 27.7% of the males had not achieved viral suppression at the time of semen washing. There were no HIV seroconversions among this subset
# TABLE 1 PARTNER STUDY CHARACTERISTICS AND RESULTS
of 1023 couples. The per-cycle risk of HIV seroconversion was zero. The 95% CI with this larger sample reduces the risk to a maximum of 0.0006% per cycle. The sperm preparation method varied among the studies, as such none is clearly proven to be superior. Today the standard protocol is gradient and swimup as described by Semprini and the European CREAThE network (Semprini et al., 1992). A double-tube method that allows the sperm pellet to be retrieved after centrifugation, without coming into contact with the gradient layers and seminal plasma, has also been developed but is not widely used (Fourie et al., 2015).
The aforementioned meta-analyses referenced papers that are not available in English. The four English language observational studies can be found in TABLE 2. While observational studies have weaknesses, the large sample size, the long period of use of the techniques and the multiple sites reporting outcomes leads to a strong recommendation for the use of gradient and swim-up techniques and IUI in serodiscordant couples.
# Recommendations:
4 ART providers should offer IUI to reduce the risk of female-to-male transmission if the female partner cannot achieve an undetectable HIV viral load. 5 ART laboratories should process ejaculates from men unable to achieve an undetectable HIV viral load using gradient and swim-up techniques to reduce the risk of horizontal transmission.
# Managing the risk of HIV crosscontamination and ART
As demonstrated by the PARTNER study (Rodgers et al., 2016), there is no risk of HIV infection or cross-contamination if the serum HIV viral load is suppressed. Thus, this section refers only to situations when there is a measurable HIV viral load.
# Managing the risk of HIV crosscontamination when processing spermatozoa
Double-washing has been well proven and universally used for HIV-positive specimens; thus, there are no clinical studies addressing the question of whether single-washing renders specimens non-infectious. There is potential for cross-contamination in the intermediary steps of sperm washing, with various semen fractions and with spent media. Small studies have found one sample wash positive after the initial process (Fiore et al., 2005;Savasi et al., 2010). By spiking samples with HIV, Fiori and colleagues demonstrated that, depending on the viral load, spent media may harbour HIV. Accurate estimates of the risk of cross-contamination based only on the risk of virus in spent media cannot be inferred but do provide a start. When a sample from a person known to have a detectable viral load is processed, the resulting sample is unlikely to harbour virus and the absolute load is
# Inconsistency
# Indirectness Imprecision Other considerations
Viral detection across different semen fractions 3 Observational studies Serious a Not serious Serious Serious None Semen samples from HIV-infected patients (n = 12); after density gradient centrifugation, one sample where virus was detected; after swim-up, all samples tested negative for viral detection (Hanabusa et al., 2000) Semen samples (n = 16) from HCV/ HIV-infected patients; detected virus in raw semen, seminal plasma and non-sperm cells, but not after density centrifugation or swim-up (Savasi et al., 2010) Semen samples (n = 62) with HIV/HBV/ HCV; washed with gradient centrifugation (no swim-up) and tested negative for viral detection (Molina et al., 2014) ⊕OOO Critical Very low a Risk of bias is inherent due to observational study design.
b Small sample: Hanabusa and colleagues (Hanabusa et al., 2000) had n = 12 semen samples from HIV infected patients, and Savasi and co-workers (Savasi et al., 2010) had n = 16 semen samples from HIV/HCV-infected patients.
HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus.
very low. This can cause infection only if it also comes into direct contact with a receptive host tissue; when samples are processed separately, this cannot happen. The studies in TABLE 3 provide only indirect evidence about the risk of cross-contamination but are nonetheless reassuring.
# Recommendations:
6 When recommendations 1 and 2 are met, and ART is being used for a fertility indication, ART laboratories should not provide any additional sperm processing solely to reduce the risk of cross-contamination. 7 When a person is unable to reach an undetectable HIV viral load, and ART is required, ART laboratories should process ejaculates as the only specimen in the hood or centrifuge in order to reduce the risk of crosscontamination, and should follow cleaning and disinfection procedures between samples as set by provincial regulations.
# Managing the risk of HIV crosscontamination when processing oocytes
Oocyte retrieval requires puncture of tissue with ensuing microscopic or macroscopic bleeding; thus, there is potential for contamination with the procedure. However, Health Canada clearly states that standard equipment and room cleansing is acceptable for reducing cross-contamination risk. This is likewise true in the laboratory, where follicular fluid and blood are washed from the oocyte. Standard preparation of the egg for insemination or vitrification has been demonstrated to effectively remove viral particles from the follicular fluid (Cobo et al., 2012). The rate of HIV DNA retrieval decreases from 89% to 25% by day 1 after oocyte retrieval, and DNA becomes undetectable after washing the embryos and refreshing the media, irrespective of the original bloody status of the follicular fluid.
There is no evidence to suggest that the oocyte of an HIV-positive woman can be infected by the virus, as CD4, and other HIV receptors, have never been demonstrated in mature oocytes or follicular cells (Baccetti et al., 1999). The oocyte is known to be a poor vector of pathogen agents because, in addition to the barrier effect of the zona pellucida, it is an isolated cell with no blood supply.
# Recommendation:
8 When a person is unable to reach an undetectable HIV viral load, and ART is required, ART laboratories should process oocytes as the only specimen in the hood in order to reduce the risk of cross-contamination, and should follow cleaning and disinfection procedures between samples as set by provincial regulations.
# Managing the risk of HIV crosscontamination with embryo culture
The risk of cross-contamination in the incubator is based on the potential infectivity of the gamete, the likelihood of its media coming into direct contact with another gamete, and the potential of the recipient gamete to become infected. As has been shown, washing for HIV-infected spermatozoa renders them non-infectious when a double process is used. Although there are not have the same large-scale observation studies for oocytes, the same appears to hold true (Cobo et al., 2012). Thus, embryos created from individuals and couples affected by HIV are themselves noninfectious. However, even in the unlikely event that the virus was not completely removed, the risk of cross-contamination in the incubator (i.e. coming into direct contact with another gamete) is also determined by the type of incubator (single chamber box versus individual chamber) and the number of patients per chamber. The use of one chamber per patient eliminates any risk of crosscontamination while in the incubator. However, the common practice of culturing under oil droplet also serves to minimize the chance of microbial contamination.
Finally, after removal from the incubator prior to fresh embryo transfer, trophectoderm biopsy or vitrification, the usual practice is to wash the embryo and replace the media. This final step would again provide an opportunity remove any potential contamination from the media.
In summary, given the many opportunities to wash gametes of virus before embryo transfer, the likelihood of contamination, even with the potential of spillage within the incubator, is negligible.
# Recommendation:
9 ART laboratories may culture embryos from a person with a detectable HIV viral load using standard processes in individual chambered incubators or box incubators.
# PROVISION OF ART WHEN THERE IS HEPATITIS C INFECTION Background
Approximately 0.67% of Canadians are infected with HCV. This varies from 3% in Indigenous populations to 0.8% in the cohort born from 1950 to 1975 and is extremely low in younger age groups (Shah et al., 2018). It is the most common newly diagnosed BBVI today in Canada, although there are more people living with chronic HBV infection (Canada, 2014).
The current understanding of diagnosing and managing HCV has altered dramatically since its discovery in 1989 (Choo et al.,1989). HCV is a blood-borne infectious disease that is caused by an RNA virus and primarily affects the liver. Often, patients are asymptomatic. If left untreated, 5-20% of individuals infected with HCV spontaneously clear the virus, and these individuals are non-infectious. However, for the remaining 80%, HCV becomes chronic and may lead to consequences such as cirrhosis of the liver, liver cancer and, after decades, even liver failure.
The first treatment for HCV became available in 1991, with a cure rate of less than 10% (Poynard, 2004). However, the treatment landscape has made tremendous advances with the use of direct-acting antivirals. HCV treatment is guided by factors such as viral genotype, prior antiviral use, liver cirrhosis, HIV or HBV co-infection and pregnancy. Current treatment with glecaprevir/pibrentasvir for as little as 8 weeks or with sofosbuvir/velpatasvir for 12 weeks can confer greater than 90% cure rates (Grover and Erlich, 2018). A person is considered cured of HCV, and un-infectious, if there is no detectable virus ('target not detected') in a serum sample 3 months after completing HCV treatment. HCVantibody positive but RNA-negative individuals do not need any specific intervention to reduce transmission as they are non-infectious.
# Recommendations:
10 A person with quantifiable HCV (detectable HCV RNA) should be treated for HCV before conceiving. 11 If/once the HCV RNA of a gamete provider is unquantifiable, ART laboratories should not use any additional spermatozoa, oocyte or embryo processing solely to reduce the risk of horizontal transmission. 12 If a gamete provider is HCV RNA unquantifiable, regardless of the HCV antigen or antibody status, ART providers should not offer specific processes solely to reduce the risk of cross-contamination in the laboratory.
# Managing the risk of horizontal transmission of HCV
It is recommended that people be cured of HCV before attempting conception. However, there may be circumstances when this is not possible, such as lack of drug access or advanced reproductive age. The presence of HCV in the semen of infected men is well documented. However, the presence of virus is not sufficient to cause infection. HCV is not a DNA virus (unlike HBV) and has no reverse transcriptase activity (unlike HIV); it therefore cannot integrate into spermatozoa or embryo DNA, which significantly reduces concern about horizontal transmission (Dodge and Terrault, 2014). Furthermore, several studies of thousands of people-years have documented negligible transmission rates in the absence of co-infection with HIV (Bresters et al., 1993;Terrault et al., 2013;Tohme and Holmberg, 2010). Thus, the recommendation is that a condom is not necessary for penile-vaginal intercourse in HCV serodiscordant couples, with the understanding that activities that have the potential for blood-to-blood contact do allow for transmission.
Despite laboratory evidence of the presence of virus, when unprotected intercourse is deemed safe, no additional measures are needed in the ART laboratory to prevent horizontal transmission.
# Recommendation:
13 If either partner has active HCV but no other BBVI, ART providers should not offer IUI solely to reduce the risk of horizontal transmission.
# Managing the risk of HCV crosscontamination when processing spermatozoa
In men infected with HCV, HCV RNA has been detected in different semen fractions (Garrido et al., 2005) but sperm washing has been shown to be effective at reducing the virus, as outlined for HIV above. In contrast to the HIV literature, preparation using only Percoll has been shown to eliminate HCV RNA (Halfon et al., 2006). The likelihood of cross-contamination, given the virus characteristics, is very small with routine processes.
# Recommendation:
14 If a sperm provider has quantifiable HCV and requires ART for fertility purposes, ART laboratories may process the ejaculate as the only specimen in the hood or centrifuge in order to reduce the risk of cross-contamination, and follow cleaning and disinfection procedures between samples as set by provincial regulations.
# Managing the risk of HCV crosscontamination with oocyte processing
Potential contamination with oocyte processing is likely as a result of blood in the follicular fluid, which is removed during the process identifying the oocyte and preparing for insemination (Cobo et al., 2012;Devaux, 2003;Levy, 2000).
# Recommendation:
15 If an egg provider has quantifiable HCV and requires ART for fertility purposes, ART laboratories should process oocytes as the only specimen in the hood in order to reduce the risk of cross-contamination, and should follow cleaning and disinfection procedures between samples as set by provincial regulations.
# Managing the risk of HCV crosscontamination with embryo culture
Despite the potential for HCV to be found in the follicular fluid, the likelihood of persistence in embryo culture is low. As for all BBVI, the risk of cross-contamination in the incubator is based on the potential infectivity of the gamete, the likelihood of its media coming in direct contact with another gamete, and the potential of the recipient gamete to become infected. As has been shown, washing HCVinfected spermatozoa or eggs renders them non-infectious, although there are few data for eggs (Cobo et al., 2012). Thus, embryos created from individuals and couples with HCV are likely to be non-infectious. However, even in the unlikely event that virus was not completely removed, the risk of crosscontamination in the incubator (i.e. coming into direct contact with another gamete) is also determined by the type of incubator (box versus individual chamber) and the number of patients per chamber. The use of one chamber per patient eliminates any risk of crosscontamination while in the incubator.
Another level of protection against cross-contamination during embryo incubation is attained by the culturing in media drops under oil.
Finally, after removal from the incubator prior to fresh embryo transfer, trophectoderm biopsy or vitrification, the usual practice is to wash the embryo and replace the media. This final step again would again provide opportunity remove any potential contamination from the media.
# Recommendation:
16 ART laboratories may culture embryos from a person with a detected HCV RNA using standard processes in individual chambered incubators or box incubators.
# PROVISION OF ART WHEN THERE IS HEPATITIS B INFECTION Background
The virus for hepatitis B, and the subsequent vaccine, was discovered by Nobel laureate Baruch Blumberg in 1965. More than 240 million individuals worldwide are chronically infected with HBV, which can lead to hepatitis, cirrhosis, fulminant liver failure and hepatic cancer. In Canada, cases of chronic HBV infection are falling, with an overall rate of 11/100,000 but one as high as 28/100,000 in men aged 20-29 years (Aparna et al., n.d.). HBV is most common in central and east Asia, sub-Saharan Africa and the Pacific (5-8% adults), as well as other developing countries and low-income communities without the resources or financial support for vaccination programmes, screening tools or treatment programmes. HBV continues to be an issue in Canada among immigrants from countries where HBV is endemic (Canada, 2019). Interpretation of hepatitis B testing can be found in TABLE 4.
Successful immunization provides effective protection against HBV infection. However, 5-15% of individuals do not respond to the vaccination and revaccination is recommended. If vaccination is still unsuccessful, these individuals should be counselled on prevention of acquiring and transmitting HBV.
Antiviral therapy is the primary form of treatment for those with chronic infection. HBV is most commonly transmitted sexually and perinatally. An infection rate of 20-40% is seen in the regular heterosexual partners of HBV-infected patients (Brook, 2002). HBV genotypes A and C are most common in individuals who acquire HBV sexually (Aparna et al., n.d.). The risk of horizontal transmission of HBV is completely eliminated when the partner is immune. However, the person carrying the pregnancy may not have been vaccinated or show immunity after vaccination (Bakker et al., 2016). Thus, the question of the infectivity of spermatozoa remains germane. HBV DNA or RNA can be extracted from spermatozoa and only occasionally from resulting embryos in humans (Ali et al., 2006).
HBV DNA can integrate into the germline. However, the presence of DNA in the germline does not necessarily result in vertical transmission (Hadchouel et al., 1985;Nie et al., 2011). Jin and colleagues (Jin et al., 2016) reported on excess embryos or unfertilized eggs and the babies resulting from sibling embryos, these babies being tested for HBV. Twelve babies were born to HBsAg-positive couples, and were all HBsAg-negative, even when unfertilized oocytes and non-viable embryos from these same couples were HBV positive. A study of HBV-negative pregnant women with a paternal HBV carrier (i.e. sperm provider) undergoing amniocentesis did not demonstrate any HBV infection in the livers of eight fetuses that were aborted (for other reasons) (Cai and Zhu, 2013). There was no evidence of paternal hepatitis antigen in over 100 samples, suggesting that paternal transmission is not a concern. This suggests that either the spermatozoa were not infective or the lack of liver development until 12 weeks of gestational age allowed for maternal clearance before any infection, or that infection was incompatible with ongoing pregnancy (Ye et al., 2013). The very small sample size precludes definitive conclusions about lack of sperm infectivity so this question remains.
# Managing the risk of horizontal transmission of HBV
# Recommendations:
17 If either reproductive partner is HBV surface antigen positive:
(a) The infected partner should be referred to an HBV-care provider. (b) The other partner must be tested for HBV surface antigen, surface antibody and core antibody, and be immunized if not immune. (c) The couple should be counselled to use condoms until the HBVsusceptible partner is immune. 18 When the gestating partner is HBV immune and the ejaculate is from a person infectious for HBV, ART providers should not offer IUI solely to reduce the risk of horizontal transmission. 19 When the gestating partner is HBV immune and the ejaculate is from a person infectious for HBV, and IUI is needed for fertility purposes, ART laboratories should prepare the spermatozoa in the usual fashion with a single wash.
If the sperm provider is HBV surface antigen positive and the gestating partner is non-immune (after vaccination), there are no data to guide the choice of single or double sperm washing to reduce horizontal transmission. HBV DNA or RNA can be extracted from spermatozoa and sometimes from resulting embryos in humans (Cai and Zhu, 2013). However, HBV is present in a much higher amount in the seminal fluid. Thus, sperm washing is still appropriate to reduce horizontal transmission. Alternatively, the person providing the spermatozoa can be considered for virus-reducing therapy.
20 When the gestating partner cannot achieve HBV immunity and the ejaculate is from a person infectious for HBV, ART providers may use gradient and swim-up for IUI to reduce the risk of horizontal transmission. 21 When the gestating partner is infectious for HBV, and the sperm provider is non-immune, IUI may be used to reduce the risk of horizontal transmission.
# Managing the risk of crosscontamination with HBV
We are not aware of any studies in which environmental surfaces have been clearly associated with the actual spread of HBV and HCV. However, it is well established that, without proper cleaning, HBV can survive outside the body for at least 7 days and is at least theoretically capable of causing infection (Sattar et al., 2001).
# Recommendations:
22 ART laboratories should process gametes from a person infectious for HBV separately, and follow cleaning and disinfection procedures between samples as set by provincial regulations. 23 ART laboratories may culture embryos from a person infectious for HBV using standard processes in individual chambered incubators or box incubators.
# Managing risk of cross-contamination with cryopreservation
Cryostorage has intrinsic risks, not only of microbiological contamination but also risks including, but not limited to, equipment failure, thawing and leakage of genetic material. The infectious risk is not limited to BBVI (Bielanski et al., 2003;Joaquim et al., 2017). As with the risk of embryo culture, opportunities for cross-contamination exist if the sample is infectious, if it can come into direct contact with the recipient gamete, and if the recipient gamete cannot be cleared of the BBVI before transfer.
However, there are fundamental differences between culture and storage. Embryo culture is for a duration of days. Cryopreservation may span years, so the cumulative risk of any problem is magnitudes bigger. Best practices mandate provisions for known and currently unknown risks. The addition of BBVI samples should not change risk management. As previously discussed with respect to embryo culture risk, it is unlikely that gametes that have been washed and prepared in the usual way for cryopreservation are infectious. Again, the preparation after thaw, and before transfer, further reduces the risk.
The storage of gametes or embryos in straws is akin to separate chambers of incubators. This is referenced in US regulatory standards. Of note, Pomery stated in 2010:
According to the FDA, storage is considered to be improper if unique specimens occupy the same location in such a way that provides the opportunity to mix, cross-contaminate, or be inadvertently distributed. It cannot be emphasized enough that it is permissible to physically locate specimens in the same storage tank provided that the aforementioned safeguards are assured. (Pomeroy et al., 2010) Health Canada has recently clarified their position, which is likewise that separation of specimens of unknown status is administrative, not physical, and does not require separate equipment. This means that samples of known positive BBVI status can be stored along with other samples.
A sample from individuals with a BBVI poses a theoretical risk with cryopreservation. Most microorganisms can survive storage at liquid nitrogen temperatures, and the cryoprotectants used in embryo and oocyte cryopreservation may also protect viruses. However, infection from liquid nitrogen in the ART setting has not been demonstrated. Liquid nitrogen tested from stored oocytes and embryos (n = 27) of HIV-, HBV-and HCV-infected patients did not demonstrate any virus in any sample (Cobo et al., 2012). This is likely to reflect the aforementioned ability to remove virus during the washing process. TABLE 5 summarizes the available studies.
The risk of cross-contamination from cryopreservation is also dependent on
# Risk of bias
# Inconsistency
# Indirectness Imprecision Other considerations
Risk of contamination into liquid nitrogen 1 Observational studies Serious a Not serious Not serious Serious b None Tested liquid nitrogen (n = 27) from oocyte (n = 14) and embryo vitrification (n = 10) and liquid nitrogen storage tank samples (n = 3) from HIV-, HBV-and HCV-infected patients; all samples tested negative for viral detection (Cobo et al., 2012). Very serious f None Report cross-contamination from leaked bag of HBV-infected bone marrow sample to six uninfected samples (Tedder et al., 1995) Leaking HBV blood product sample in combined storage with uninfected samples; testing of 115 uninfected samples showed negative for viral detection (Husebekk et al., 2004) ⊕OOO Critical Very low a Risk of bias is inherent due to observational study design.
b Small sample: n = 27 liquid nitrogen samples from vitrification and storage tanks tested.
c Used HIV-infected supernatant but not sperm samples from infected patients (Letur-Konirsch et al., 2003).
d Used sperm samples from uninfected patients spiked with blood plasma from HCV-infected patients but not sperm samples from infected patients (Maertens et al., 2004).
e Tedder and colleagues (Tedder et al., 1995) report cross-contamination to uninfected bone marrow samples from HBV-infected samples, and Husebekk and co-workers (Husebekk et al., 2004) report no contamination with shared storage of blood products. f Tedder and colleagues (Tedder et al., 1995) provide a case report of a single event of contamination from one HBV-infected sample to five other samples; Husebekk and co-workers (Husebekk et al., 2004) report no contamination from one leaked bag to 55 other samples.
HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus. PCR polymerase chain reaction an in vitro technique for rapidly synthesizing large quantities of a given DNA segment that involves separating the DNA into its two complementary strands, using DNA polymerase to synthesize two-stranded DNA from each single strand, and repeating the process -abbreviation PCR; PETG Polyvinyl chloride (PVC), polyethylene terephthalate glycol IR high-security ionomeric resin the type of storage method -liquid or vapour phase -and the type of strawopen or closed. Vapour-phase storage eliminates the vector for contamination. While it may be superior from an infection control perspective, it may present greater risk of compromise or loss of cryopreserved specimens (Vajta et al., 2015). Studies using washing techniques after thaw have demonstrated complete removal of bacteria and fungi, and this would be likely to be true of BBVI (Parmegiani et al, 2012).
In a closed liquid device, the nitrogen of the common container is never in direct contact with biological material frozen on the inside, so cross-contamination cannot occur unless there are several breaks in the system. If this were the case, the stored biological material would be at material risk. After loading in a closed system, the plastic straw can be heat-sealed on both ends, and consequently the solution containing the embryo and the liquid nitrogen are hermetically isolated during cooling and storage system. Closed systems reduce the potential danger of contamination through liquid nitrogen, but open systems provide direct contact for the required cooling and warming rates for vitrification. Contamination in animal models under experimental conditions has been shown (Bielanski et al., 2000). However, a review by the same authors acknowledges the differences between these studies and human practice (Bielanski and Vajta, 2009). The risk of direct contact may be ameliorated by the effects of the cryoprotectants against contamination.
Assessing risk of cross-contamination can only be done indirectly by measuring infectious material in liquid nitrogen after routine processing. There are no studies or reports of tank failure that have resulted in contamination. Sadly, there are reports of tank failure that have resulted in embryo demise.
# Managing cross-contamination with testing frequency
The current practice of many Canadian fertility clinics is mandatory annual testing for BBVI in all users of ART (IVF and IUI). This does not reflect evidencebased guidelines that base the frequency of testing on risk factors, but instead reflects a misplaced fear of crosscontamination between specimens in the ART setting, and an attempt at risk management on the part of the ART providers. An unintended consequence of this approach has been to perpetuate the stigma associated with BBVI, especially HIV, and limit the access to care of affected individuals.
Canadian Guidelines (HIV Screening and Testing Guide Canada.ca) recommend preconception BBVI testing of all individuals and repeat testing of low-risk individuals only if risk factors change, or at the request of the patient. Annual testing is unwarranted for the majority of ART patients, despite it being the practice of virtually all ART units, which believe it will reduce risk of cross-contamination.
Maintaining the mandatory BBVI testing in the ART setting but lengthening the time between testing possibly increases the number of undiagnosed cases that are being processed in an ART laboratory.
Eliminating repeat testing would increase the risk of undiagnosed cases over the whole period of fertility care, which may be years.
Data are not available on new cases of BBVI that have been diagnosed during fertility treatment in Canada. A UK study in 2001 demonstrated a baseline rate of HIV and HBV of 0.8% and 1.4%, respectively, in the infertile population, similar to the prenatal testing rates of 0.13% and 1.7 (Hart et al., 2001). A larger study demonstrated HBV and HIV baseline risks of 0.28% and 0.007% with no additional cases diagnosed over the course of treatment of 12,000 individuals (Abusheikha et al., 1999). Two smaller studies could not demonstrate any new cases among over 600 patients who had repeat testing within 3 years. These are summarized in TABLE 6. In Canada, the prevalence of HIV is 173/100,000 population (Haddad et al., 2019). In higher prevalence countries, rates in fertility clinics were found to be 1.7% (HIV), 7.9% (HBV) and 0.4% (HCV), similar to reported rates in their general populations (Yakass et al., 2016). exposure-prone procedures even though infected, undiagnosed surgeons pose a risk to patients through bloodborne contamination. In Ontario, these physicians are required to undergo testing every 3 years to reduce the risk of direct infection. The risk of indirect contamination (as might happen in other medical specialties) is deemed to be so low so as not to warrant testing. This is based on expert consensus and can be assumed to reflect Canadian values.
# Recommendations:
25 ART providers should test reproductive partners for HIV serology, HBV surface antigen and HCV antibody at intake. 26 ART providers should re-test individuals with any risk factors for these BBVI annually or biannually (TABLE 7). 27 In the absence of any BBVI risk factors (see TABLE 7), ART providers should not re-test for BBVI for the purpose of preventing cross-contamination.
# CONCLUSION
The management of individuals living with BBVI has advanced considerably, leading to improved prognosis and quality of life, and a greater desire to parent. Current practices in ART do not reflect these changes as many ART clinics inappropriately deny services to people living with BBVI. There remain important gaps in the availability of ART to those living with BBVI across Canada, often due to the unwarranted fears of those providing care.
The goal of this CFAS Clinical Practice Guideline is to address two important considerations with regard to BBVI in the ART setting: (i) managing male-tofemale transmission of BBVI, and (ii) preventing cross-contamination. This guideline interprets the best available evidence and considers the needs of the patient, the care providers and society. Individuals properly treated for HIV and HCV pose no infection risk to their partners or other patients using assisted reproduction. Laboratories can simply and effectively mitigate risk from individuals with active BBVI by individual preparation of gametes. Embryos in culture or in storage pose no threat in the absence of equipment failure and likely pose no threat even in the event of failure. The risk of both transmission and cross-contamination can effectively be eliminated by any and all ART laboratories while providing care to all who need it. Ultimately, the practices in this guideline are best practices for all ART patients regardless of BBVI status and we hope this guideline will expand ART access to people living with BBVI on the basis of the best available evidence.
# ACKNOWLEDGEMENTS
We would like to thank the librarian, Teruko Kishibe, for carrying out the search, and Reilly Jones who acted as the second reviewer.
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16% to 30% of women with gestational diabetes develop type 2 diabetes by 5 to 10 years postpartum 3.4% 10% 10%The postpartum period is a significant time for the mother, baby, partner, and family. It is a time of transition and adaptation and is formative for everyone. There are physiological adjustments for both mother and baby, and significant social and emotional adjustments for the entire family. Providing family-centred care to women, their partners, and families during the postpartum period is an essential component of the care offered by all institutions, agencies, and programs. While the postpartum period is a normal, healthy time of life, it is challenging for families even as parents get comfortable with their roles. It is important that HCPs who are working with mothers, partners, newborns, and families focus on their individual needs and values. Key family-centred care recommendations: - Treat families with respect, dignity, and kindness, and learn about and respect their values and beliefs, using them to guide their care. - Maintain open and ongoing communication with the woman and her partner/family; - Plan the timing and purpose of each postpartum contact in partnership with the woman and her partner/family based on their individual needs. - Provide culturally competent and safe care with cultural humility. - Provide information and support in a timely fashion, according to the needs of the woman, her partner, and family. Information should be evidence-based and accessible according to their culture, language, and abilities so that they can promote their own and their baby's health and make informed decisions about their care and any necessary treatment. - Support and promote the physical well-being of mother and baby and enable the mother to rest and recover from the physical demands of pregnancy and birth. - Foster the developing relationship between the baby and their mother as well as the mother's partner and family. - Support the mother's and her partner's emotional and mental health needs.#
Complex and finely tuned adjustments have physical and psychological benefits for the mother and her baby. It is important that everyone involved in the care of mothers and babies knows and acknowledges these benefits so that systems are planned and organized around the mother/baby unit and not around health care providers (HCPs).
The goals of care during the postpartum period are to:
- Support and promote the physical well-being of mother and baby and enable the mother to rest and recover from the physical demands of pregnancy and birth;
- Support the developing relationship between the baby and their mother as well as the mother's partner and family;
- Support the mother's and her partner's emotional and mental health needs;
- Support infant feeding;
- Support the mother's confidence in herself and in her baby's health and well-being, enabling her to fulfill her mothering role within her particular family and culture; and
- Support partners and other family members to enable them to develop confidence in their new role.
According to the principles of family-centred care, it is incumbent on HCPs to:
- Treat families with respect, dignity, and kindness, and learn about and respect their values and beliefs, using them to guide their care;
- Maintain open and ongoing communication with the woman and her partner/family;
- Plan the timing and purpose of each postpartum contact in partnership with the woman and her partner/family based on their individual needs;
- Provide culturally competent and safe care with cultural humility;
- Provide information and support in a timely fashion, according to the needs of the woman, her partner, and family. Ensure that information is evidence-based and accessible according to their culture, language, and abilities so that they can promote their own and their baby's health and make informed decisions about their care and any necessary treatment.
# > ADDITIONAL RESOURCES ON POSTPARTUM CARE: SEE APPENDIX A
The postpartum period is a significant time for the mother, baby, partner, and family. It is a time of transition and adaptation and is formative for everyone. There are physiological adjustments for both mother and baby, and significant social and emotional adjustments for the entire family.
# FAMILIES WITH SPECIAL CONSIDERATIONS
# CULTURAL CONSIDERATIONS
Canadians are ethnoculturally diverse. Women from different cultures, whether Canadian-born or newcomers, may be influenced to a greater or lesser extent by their background.
HCPs will want to assess each woman's background-if they are newcomers, their place of birth, how long they have been in Canadaand their support networks. 1 It is important to understand how the woman's culture influences her unique needs, hopes, and postpartum expectations. Even when the necessary services are available and they are made aware of them, immigrant women may face language barriers and difficulties in access because of differences in cultural practices and expectations. 2 Most women who are newcomers to Canada face challenges of some sort: 2
- The Canadian health care system may feel foreign and strange, and they may have different expectations from those of their HCPs.
- They may not know about the available supports in the health care system.
- They may not share a common language with available HCPs, and their communities may not have access to culturally sensitive health care or translation services.
Each family is unique; they adapt their cultural traditions and practices to their own experience and needs, and they will interpret the parameters of the Canadian health care system within this context. As such, it is important to assess each situation individually. While HCPs may not always agree with certain cultural practices, respecting families' needs and decisions is paramount.
Listening to the women's and families' stories about their own culture, childbearing practices, and needs helps accomplish this approach. 1 Giving Birth in a New Land: Strategies for service providers working with newcomers suggests specific strategies that promote family-centred, culturally competent postpartum care. 3 HCPs can use these to engage in a dialogue with women and families and learn about their values and beliefs and how these apply to their situation.
HCPs need to consider the personal values they bring to their relationship with families. Cultural competence includes working collaboratively with families and communicating effectively.
Communication with families from different cultural backgrounds involves not only translating words, but also understanding subtle variations in meaning, style, volume, and gestures. 1 As such, it is important to find the best possible interpreter for the specific situation.
Interpreters must be trustworthy regarding access to private information and, ideally, have specific health-related language skills. Using children or other family members as interpreters is not recommended. 1,3 If families are newcomers to Canada, ask about their place of birth, how long they have been in Canada, and their support systems. To ensure that women have an opportunity to express their needs, helpful questions include:
# QUESTIONS TO FACILITATE COMMUNICATION ABOUT VALUES AND BELIEFS
- How is health care different in your homeland or culture?
- What do you and your family believe you should do to remain healthy postpartum?
- What are the things you do to improve your health and the health of your baby? What can't you do?
- Do you have beliefs about caring for your baby and yourself that I need to know about?
- Do you have any practices and faith rituals to do with your role as a mother?
- Are there any specific foods that you might eat/drink (or prefer to avoid)?
- Are there any home remedies that you may use during the postpartum period?
- Who do you want involved in decision-making?
Adapted from Giving Birth in a New Land: Strategies for service providers working with newcomers (2014), and Maternal Child Nursing Care Canada (2017).
# CARING FOR INDIGENOUS WOMEN, NEWBORNS, AND THEIR FAMILIES
The history of residential schools and colonization, which caused the loss of traditional values and practices, languages, and family/community kinship, continues to affect Indigenous women, families, and communities. Indigenous Peoples have poorer health outcomes and higher rates of poverty, food insecurity, and unsafe and overcrowded housing. These social determinants of health take a toll on the physical, emotional, mental, and spiritual health of Indigenous women in Canada.
The health and well-being of many Indigenous women and families have been further undermined by racism, sexism, and culturally inappropriate or inaccessible health serviceswhich also affect Indigenous women and their babies during the postpartum period. Indigenous women in Canada are diverse in their culture, ancestry, beliefs, and practices. Each Indigenous community has its own traditions, values, language, and communication styles. Many Indigenous women want to incorporate their cultural and societal values and beliefs into their lives and parenting. Integrating cultural safety in the care of Indigenous women during the postpartum period involves providing an environment of respect and open communication, which is consistent with the principles of familycentred care. Indigenous women, as all women, need to feel safe in order to build a trusting relationship with their HCPs.
HCPs should engage with, and familiarize themselves with, the community and work with women to understand their individual values, beliefs, and needs. 7 An Indigenous doula can assist in honouring traditional and spiritual practices and beliefs associated with postpartum care and support the woman and her family's language and cultural needs while providing emotional and physical assistance during pregnancy, labour, and the postpartum period. 8 Indigenous women may have to leave their communities to give birth in larger centres.
Being away from their families and support systems affects their postpartum experience, including breastfeeding, and recovery. It is important to consider their needs and re-connect them with families and communities as quickly as possible.
Indigenous-specific postpartum and parenting programs are ideal-particularly group formats that allow Indigenous women to meet each other and develop supportive friendships during their pregnancies. Programs that support Indigenous fathers so that they feel equipped to help their partners and children are also necessary. Better systems of referrals and communication between different services and organizations would ensure continuity and comprehensiveness in care. 9 Training and Education of Healthcare Providers
There is a need for better training of HCPs on how to create culturally safe, stigma-free, and respectful care for Indigenous mothers, babies, and families during the postpartum period. 9 A nationwide survey of residents and program directors of all accredited obstetrics and gynecology residency programs in Canada demonstrated a lack of curriculum and a significant deficit in knowledge in Indigenous women's health. 10 As a result, a nationwide curriculum initiative is underway for residents and other health care practitioners. This will facilitate the provision of education in Indigenous women's health while decreasing the burden on individual programs.
# CARING FOR LGBTQ2 FAMILIES
Family-centred maternity and newborn care is based on individual needs and a mutually respectful and trusting relationship. While progress has been made in providing equitable health care to the LGBTQ2 community i , these families often continue to face barriers in health care.
People in the LGBTQ2 community identify 3 major barriers when dealing with the health care system-invisibility, lack of information, and negative beliefs. Invisibility refers to the fact that they do not see themselves in the institutions/ programs-for example, the posters on the walls, the forms they complete-or in conversations with HCPs. The HCPs they encounter often do not understand their experiences as an LGBTQ2 family, their unique and diverse needs, and may have negative beliefs about them. 11 Sexual minority women (including lesbian, bisexual, and other non-heterosexual women) have a greater prevalence of depression and depressive symptoms compared with heterosexual women, likely because of the impact of sexual orientation-based discrimination, stigma, lack of social support and exposure to additional stress due to heterosexism from their families and some HCPs. Invisible sexual minority women (i.e., women who have a history of sexual relationships with women but are currently partnered with men) are at higher risk for postpartum depression than both visible sexual minority women (women partnered with women) and heterosexual women. 14,17 i The acronym LGBTQ2 is commonly used to include people who identify their sexual orientation as lesbian, gay, bisexual, queer or questioning, and/or who identify their gender identity as transgender. These guidelines recognize that sexual orientation and gender identity exist along a continuum that may change over time, and that the LGBTQ2 community is diverse. 334 Ongoing education for HCPs on the unique needs of LGTBQ2 families is essential to improving the health care LGTBQ2 families receive. 18 HCPs caring for LGBTQ2 families will want to confront any negative beliefs they may have and aim for ease in approaching the topics of gender, sexuality, and families. It is important that HCPs reflect on their beliefs about LGBTQ2 people and be willing to challenge these beliefs to develop their practice. 11 HCPs can facilitate inclusivity when caring for LGBTQ2 families, including during the postpartum period, by: 11 - Paying attention to words and language. Words can empower people and they can hurt.
- Being aware of non-verbal communication and tone of voice-these express emotions and attitudes.
- Using non-biased, inclusive language and open-ended questions.
- Asking questions that express openness to all families-and not making assumptions about gender identity, sexual orientation, or behaviour.
- Making sure forms and questionnaires are inclusive.
- Ensuring that visuals, such as posters, in a clinic or program area signal acceptance of diversity.
- Posting a non-discrimination policy and communicating an environment of respect.
# POSTPARTUM CARE
# IMMEDIATELY AFTER CHILDBIRTH (BIRTH TO 2 HOURS)
# INTEGRATED CARE OF THE MOTHER AND BABY
The mother and newborn should be considered a unit during the immediate postpartum period (0-2 hours). It is important to avoid disrupting this close relationship during these crucial few hours and to encourage skin-to-skin contact between the baby and the mother (or partner if the mother is unable). The International MotherBaby Childbirth Organization refers to this as motherbaby care to emphasize the importance of recognizing that mothers and babies are a unit.
The parent-baby bond-the first step in the baby's subsequent attachments-is formative to a child's sense of security and has long-lasting effects. 19 Having early physical contact with the baby can affirm parents' sense of accomplishment and promote their self-confidence as parents. Keeping babies and parents together is of the highest priority. Institutional policies should only disrupt this contact in the event of a necessary, evidence-based medical reason.
All major organizations concerned with newborn health, including the Society of Obstetricians and Gynaecologists of Canada (SOGC), the Breastfeeding Committee for Canada, the Canadian Paediatric Society (CPS), the Canadian Association of Midwives, the American Academy of Pediatrics, the World Health Organization (WHO), and the United Nations Children's Fund (UNICEF), recommend that healthy babies have direct skin-to-skin contact with their mothers immediately following birth. Skin-to-skin contact involves placing the newborn babies on their mothers' bare chest immediately after she gives birth, covering the baby with a blanket, and ensuring that contact is uninterrupted for at least an hour or at least until the first feeding is completed or the mother wishes. 20 It is essential to prepare mothers for skin-to-skin contact before birth. Since some cultures may not practise this contact, information, encouragement and support are called for.
Being held by their mother helps the baby normalize his or her temperature, breathing, heart rate, and blood sugar and reduces the pain of medical procedures. Babies who have skin-to-skin contact interact more with their mothers and cry less than those who do not have this contact. The vast majority of babies go to the breast within an hour of birth if they are kept skin-to-skin with their mother. Mothers are more likely to breastfeed in the 4 months postpartum and tend to breastfeed for longer if they have early skin-to-skin contact with their babies. 22 Nevertheless, skin-to-skin contact is important for all mothers and babies regardless of the mother's decision about feeding. If the mother herself is unable to have skin-to-skin contact with her baby, she should choose another person to hold, warm, and comfort the baby, for example, her partner or another family member.
HCPs can demonstrate respect for the family by interfering as little as possible during interactions between the mother and baby. Observations, assessments, and interventions can be completed with minimal intrusion, while skin-to-skin contact is maintained. Anything that is not essential to the immediate well-being of the baby or mother can wait for 2 hours or after the first breastfeeding. Even medically necessary procedures can be done while the baby remains in skin-to-skin contact as long as it is medically safe to do so. 23,24 Skin-to-skin contact should continue during transfer from the birthing unit to the postpartum unit or neonatal intensive care unit (NICU). 25 At this time, babies should be observed for abnormal respiratory effort, colour, activity or tone-signs of instability that call for urgent evaluation. Separating a mother from a baby requiring special care can make adjustment to motherhood more difficult, and HCPs are called upon to provide even more intensive support at such times. There are continued benefits to skin-toskin contact past the immediate first few hours of birth, as well as benefits to initiating skin-to-skin contact later, if this was not possible immediately following birth. 23,24,26 In some Canadian and European centres, preterm babies stay with their parents during assessments, and couplet care is practised within the NICU. 27 Many centres are advocating for skin-to-skin contact, even of very preterm, ventilated, and low birth-weight babies, because of the clinical and psychological benefits to both baby and parents. 28
# FAMILY-INTEGRATED CARE IN THE NEONATAL INTENSIVE CARE UNIT
Recent Canadian research has found that a family-integrated care (FICare) model of care for preterm babies in neonatal intensive care units (NICU) is feasible and safe in the Canadian health care setting and results in improved weight gain by these babies. The FICare model of care, which is based on the original work of Dr. Adik Levin in Estonia, also has the potential to improve other short-and long-term outcomes for babies and families. 29 In this model, parents provide most of the care for their baby, while nurses and other HCPs guide and counsel parents. 29,30 FICare is more than just the physical setting; the model recognizes that parents are the primary caregivers and decision-makers for their babies. FICare can be accomplished even in older units, and HCP teams are expected to adapt to that reality whenever possible.
Innovative examples of this model of care in Canada include the following:
- BC Women's hospital offers intensive care for newborns and postpartum care for mothers in the same room. Mothers are able to recover from vaginal or caesarean births and pump breast milk without leaving their babies. All newborn babies have their own sound-proofed rooms, and 12 of the 70 rooms are spacious mom-and-baby rooms equipped with a breast-pumping station, reclining chair, and hospital bed for the mother as well as an incubator and infant-monitoring machines. The mom-andbaby rooms are for babies born at 33 weeks or later at low risk of complications.
- In Nova Scotia, the IWK Health Centre is caring for mothers and babies together in their NICU. Each room has a full setup to care for a baby as well as a suite for the family to stay in. The family is given a double bed, a closet with a safe, and a private washroom with a shower. Babies are continuously monitored and, if an alarm is triggered, a signal is sent to a nurse's smartphone. The rooms are also equipped with everything from milk fridges to special sinks that help families bathe their babies. Rooms without windows have skylights that mimic clouds in the sky, and every room has artwork.
In the event of a caesarean birth, it is important to provide all possible opportunities for immediate (defined as within 5 minutes) and uninterrupted skin-to-skin contact as well as breastfeeding when babies cue to feed. This can be done in the operating and recovery rooms. In fact, skin-to-skin care should be considered the norm for caesarean births in the operating room, decreasing the need for early supplemental feedings. 31 It is important to provide time alone for the family in those critical first hours, with opportunities for both parents to interact with the baby in the birth and recovery rooms. Parents should be encouraged to spend as much time as possible with their baby, including in the NICU, ideally while rooming-in together. If the woman's partner chooses not to be present for the caesarean birth, the family should be re-united as soon as possible. 32
# CARE OF THE MOTHER
The immediate postpartum period is a time of joyful celebration for the vast majority of families, but it is also a time of considerable physiological adaptation for the mother-and for the baby.
As such, careful observation and, at times, intervention is required.
Women have different responses on giving birth. Some feel excited, uplifted, and energetic. Others are exhausted and want to sleep. A woman's response may depend on the length, difficulty, and pain during labour, blood loss, anesthesia/ analgesia, complications, and whether she had an operative vaginal birth or caesarean birth. Another determining factor is the woman's experience of labour and birth compared with her expectations of these events.
Physical adjustments in the immediate postpartum period-including blood loss, weight loss, and displacement of internal organs-require a significant expenditure of energy. Immediate postpartum care centers on the need for hydration, nutrition, and rest. It is a time to replenish energy.
Begin each postpartum contact by asking the woman how she feels, physically and emotionally, and identifying any concerns that she may have.
The physical observation of the mother at each postpartum contact should be individualized and guided by her unique history and situation.
The assessment can include the following, depending on the mother's feelings, sensations, and expressed needs: 24
- Vital signs (temperature, pulse, respiratory rate, blood pressure);
- Uterine tone and condition of perineum;
- Lochia;
- Bladder and bowel function;
- Breasts and nipples;
- Physical comfort;
- Emotional and psychological response to labour and birth, for the woman and her partner. Starting this conversation is particularly important in certain circumstances (e.g., when the baby is sick, the mother had complications, or the birth did not go as planned);
- Skin-to-skin contact with baby; and
- Learning needs.
Document the findings according to the institution's policy.
# CARE OF THE NEWBORN
The baby's transition to life outside the uterus involves:
- Establishment of effective respiration and circulation;
- Maintenance of an adequate body temperature;
- Contact with his/her mother and family; and
- Initiation of feeding.
# POSTPARTUM HEMORRHAGE
Postpartum hemorrhage is the most common complication in the immediate postpartum period.
It affects approximately 6% of women globally and is the leading cause of maternal mortality worldwide. 33 In Canada, a diagnosis of postpartum hemorrhage was associated with 1.6 maternal deaths per 100,000 hospital births from 2002 to 2010. 34 From 2006 to 2010, it was the second most common severe maternal morbidity, at a rate of 465.4 per 100 000 hospital births. 34 Postpartum hemorrhage is defined as blood loss of more than 500 mL during vaginal birth or more than 1000 mL during caesarean birth. The primary cause of immediate postpartum hemorrhage is uterine atony. Other causes include uterine rupture, morbidly adherent placenta, and uterine artery extension/laceration during caesarean birth.
Refer to the Society of Obstetricians and Gynaecologists of Canada (SOGC) guideline Active Management of the Third Stage of Labour: Prevention and treatment of postpartum hemorrhage. 35 Postpartum hemorrhage has many implications for the woman, including orthostatic hypotension, anemia, fatigue, and fear-all of which affect her ability to care for herself and her baby. It may also result in a lack of immediate skin-to-skin contact with her infant and an increase in the risk of postpartum depression. A blood transfusion may be necessary, which has risks. 36,37 Delayed, or secondary, postpartum hemorrhage (between 24 hours and 6 weeks postpartum), may occur after the woman and baby have been transferred to a postpartum unit or at home.
It is important to educate women of the signs and symptoms of concern relating to delayed postpartum hemorrhage before discharge and after a homebirth.
The postpartum period is a critical transition time for the baby. This period requires thorough and ongoing assessment and monitoring. An initial, head-to-toe examination of the baby in the birthing area ensures that he or she is adapting to the extrauterine environment. This examination would also identify any abnormal clinical findings. These observations can be completed when the baby is skin-to-skin, which promotes intimacy while helping to maintain a calm environment.
# Neonatal Resuscitation
The Neonatal Resuscitation Program (NRP) acknowledges that at least 90% of newborns are vigorous, term babies who do not need to be separated from their mothers for the initial steps of resuscitation. Care for these babies includes:
- Managing the umbilical cord (i.e., avoidance, where possible, of immediate clamping);
- Providing warmth by encouraging direct skin-to-skin contact, ideally with the mother;
- Drying the baby's skin with a warm, dry towel, stimulating breathing, and repositioning the head to open the airway;
- Clearing mucus from the upper airway, if necessary, by wiping the baby's mouth and nose; and
- Ongoing observation of breathing, heart rate, activity, and colour. 38 Refer to NRP guidelines for the management of specific clinical situations. 23,39 HCPs obtain skills in neonatal resuscitation through NRP training coordinated by the CPS, which has set the educational standards for Canadian practice. The Society recommends that an individual trained in neonatal resuscitation be assigned to this role at every birth. The CPS also recommends that all personnel likely to care for babies at birth have training and registration at the Provider or Instructor level and undergo periodic re-registration. 39 While the primary care provider at the birth is responsible for the woman's care, a second HCP should have the primary role of assisting the baby through transition-one able to provide positive pressure ventilation and perform chest compressions, if necessary. 38 Another person with the skills to perform a complete resuscitation (including intubation and chest compressions) should be readily available to assist. 38,40 The CPS also advises that local/regional health authorities have in place a program that supports the implementation of current neonatal resuscitation guidelines, educational programs for HCPs involved in care during labour and birth, and policies that take into account the educational needs, roles, and responsibilities of professionals involved in care during labour and birth/care of the newborn.
# Neonatal Stabilization
A proportion of newly born babies are identified as at risk or unwell during the minutes or hours following birth, often due to prematurity or poor cardiorespiratory transition. All delivering facilities and practitioners should have a plan that addresses these babies' clinical needs (such as respiratory support or glucose management), communication with referral centres, and support of the family.
The CPS's Acute-Care of at-Risk Newborns (ACoRN) program specifically addresses the needs of babies who are challenged by the transition to extrauterine life. Facilities may find this program useful in preparing for the possibility that a newborn is unwell or at risk.
# EARLY POSTPARTUM CARE (AFTER 2 HOURS)
The key goals of early postpartum care are to:
- maintain and promote the health and wellbeing of mother and baby;
- support the mother in caring for herself and her baby;
- foster attachment between the baby and the mother, her partner, and other significant family members;
- support the physical and psychological adjustment of the mother and her partner, the baby, and the family; and
- promote effective feeding.
Every postpartum interaction should be carried out in accordance with the principles of familycentred care, basing care and support on evidence of individual needs and not routines.
The benefits of skin-to-skin contact continue through the early postpartum period, facilitating attachment, increasing the duration of breastfeeding, and decreased crying and expression of pain during procedures such as heel prick blood sampling. 23 Although no national guidelines on labour, birthing, and postpartum rooms exist, the Provincial Council for Maternal and Child Health (PCMCH) recommends that mothers who give birth in hospital have a spacious room, preferably a private one, where they can labour, give birth, and stay with their babies until discharged. Rooming-in 24 hours a day should be the norm for all mother-baby dyads unless there is a justifiable reason for separation. 20 As many interventions as possible should occur in the mother's room to avoid separation. Admissions to nurseries should be based on established criteria and guidelinesand be the exception rather than the rule. 23 A personalized postpartum care plan should be developed in partnership with the mother and her family as soon as possible following the birth. It includes: 24
- the mother's concerns and needs;
- important factors in the pregnancy, birth, and immediate postpartum period;
- assessment of infant feeding;
- the names and contact information of the professionals involved in the mother's and baby's care; and
- planned follow-ups/appointments with HCPs for mother and baby during the postpartum period.
The plan needs to be reviewed and adjusted with the mother and family after every postpartum interaction.
Each mother should be assigned an HCP who is responsible for coordinating the care of the family and their transition into the community. This HCP consults with others, as necessary, as the needs of the mother and baby evolve. When birth takes place in hospital or a birthing centre, it is critical that systems, policies, and protocols ensure families are discharged only after followup care in the community is established. 41,42 Optimal family-centred care during the early postpartum period requires seamless continuity of care and information-sharing between HCPs. How this is accomplished depends on the type of provider and the jurisdiction. Successful coordination of early postpartum care depends upon clear communication between institutions, community HCPs, and families. Hospitals, birth centres, physicians, nurse practitioners, and midwives need a strategy to facilitate effective communication of health information as mothers and babies transition into the community. A comprehensive discharge summary or maternalnewborn passport program may be useful. Secure electronic communication facilitates this process. 43 The Breastfeeding Committee of Canada and WHO recommend assessing newborn babies for breastfeeding issues within 24 to 48 hours of discharge from a hospital/birthing centre with routine follow-up of all mothers within 48 hours of discharge; 20,44 this care may be provided by the hospital, community health centre, a breastfeeding clinic, midwife, etc.
Most newborn care guidelines recommend that an HCP assess the mother and baby during the first week of life. 45 The American Academy of Pediatrics specifies that this assessment takes place 48 to 72 hours after discharge if discharge occurs less than 48 hours following birth. 46 The CPS states:
"At time of discharge, infants must have an appropriate follow-up plan in place that includes: contact information for a primary health care provider; a scheduled follow-up visit 24 h to 72 h post discharge-in hospital, clinic or at homewith a qualified health care provider. Hearing and newborn screens have been scheduled (if they were not conducted in-hospital); appropriate follow-up for jaundice; vitamin D supplementation if breast-fed; other follow-up, as required. 45 "
Even though the same principles and philosophy of care underpin all postpartum care, postpartum services should be organized locally to maximize effectiveness and efficiency for women and their babies.
# HOSPITAL BIRTHS: LENGTH OF HOSPITAL STAY AND DISCHARGE
In 1993, the average length of stay after a vaginal birth was 3.2 days, decreasing to 2.0 days by 2012. During the same period, the length of hospital stay following Caesarean birth decreased from 5.0 days to 3.4 days. The safety of a shortened hospital stay (averaging 2.2 days in 2017/2018 47 ) has been debated with regards to the needs of the mother and particularly the newborn. What research says about shorter hospital stays can differ from various organizations' guidelines for both mother and baby. 48,49 Each family needs to discuss with their HCP the risks and benefits of a stay that is shorter than the institutional standard. Base this discussion on the baby's and the mother's needs and not on routine policies. From the perspective of family-centred care, leaving the hospital as early as possible has a number of potential benefits: the opportunity for the entire family to get to know the baby together, resulting in greater attachment; more involvement for the partner and less sibling rivalry; better rest and sleep for the mother in her own environment, without constant interruptions from hospital staff; reduced exposure of mother and baby to hospital-acquired infections; and greater confidence on the mother's part in her ability to care for her baby. 49 A shortened hospital or birthing centre stay is favoured by: the physiological stability of the mother and baby; family readiness to care for the baby at home; and a greater level of community, family, and institutional support upon discharge. In all situations, including those where mothers and babies are discharged early, mothers need to understand the signs of potential problems. In addition, it is important that the family knows where and when the mother and baby will next see an HCP and who they can contact with any questions.
The Canadian Medical Protective Association (CMPA) recommends reviewing test results and looking for signs of postpartum complications (e.g., infection, hemorrhage, excessive pain, bladder distention, difficulty walking) before discharging the mother and baby. The family should receive clear written or verbal instructions describing the steps and precautions to take when there are concerns, as well as the symptoms or signs that indicate that further medical attention is necessary. 50 Women and families should be told about community programs for postpartum care and peer supports for themselves and their babieswhat they are, where they are located, and how to access them. These may include homevisiting programs, clinics, community-based programs and telephone support. Since it may be difficult for new mothers to remember all of the information shared with them, it is best to provide written information and also make it available on the facility's website.
Regularly reviewing communication and coordination mechanisms will help to ensure a consistent and effective transition into the community and follow-up for the mother, baby, and family. The question of how best to arrange mother and baby's discharge is an opportunity to revisit institutional and community resources for new families.
Refer to the following CPS guidelines related to infant discharge: " The family should receive clear written or verbal instructions describing the steps and precautions to take when there are concerns, as well as the symptoms or signs that indicate that further medical attention is necessary.
# CARE OF THE MOTHER
Care and support during the early postpartum period should enable the mother to take charge of her own health and that of her baby-and to become confident in her ability to care for herself and her baby. This assumes that she is an autonomous adult and that HCPs have confidence in her ability to be a partner in her own care. Her values, situation, and needs are unique.
# The Mother's Well-being and Needs
Begin each postpartum contact with the mother and family by asking the woman how she feels, physically and emotionally, and identify any concerns she may have. Topics to explore include her experiences with her baby, breastfeeding/ feeding, how much rest she is getting, and any pain or discomfort she may be experiencing. A physical examination may be performed as needed. The mother's care is aimed at maintaining her health and helping her adapt to her new role as a mother.
Women need information, advice, and reassurance about postpartum physiological adaptations-such as normal lochia, perineal healing, incision healing (following caesarean birth), and changes to the breasts and nipples. They also need information on any potential issues, such as infection, hemorrhoids, cramping, constipation, urinary incontinence, painful urination, perineal pain and hygiene, headaches, back pain, pain medication, anemia, late postpartum hemorrhage, separation of the abdominal muscles, and breastfeeding challenges. The emotional and social changes she is likely to experience as a result of becoming a parent also require discussion.
# Mother's Adjustment and Emotional Health
Research shows that the mother's emotional adjustment affects her well-being as well as that of the baby and the family. 51 Mothers may experience a range of emotions postpartum, including baby blues, depression, anxiety disorders, obsessive-compulsive disorders, trauma and stressor-related disorders, and postpartum psychosis.
Compassion and vigilance are the key approaches to effective support for the new mother and family during this period of transition. HCPs will want to attune themselves to the thoughts and experiences of new mothers and their partners in order to help them explore their feelings and emotional health, rather than rely on tasks or checklists. As always, the goal is to empower the mother in her own capacity to adjust and adapt. It is important that HCPs develop assessment skills to monitor symptoms for mental disorders and stay alert for signs of concern so they can provide appropriate information and support. Providers need to be aware of the various types of responses and sufficiently knowledgeable about emotional health to identify psychiatric disorders in the immediate postpartum phase and beyond (as these disorders do not always present in early postpartum).
# Caesarean Birth
Caesarean births are common-in 2016/17, 28% of all births in Canada were by caesarean births. These rates range from 18.5% to 35.3% across the provinces and territories. 56,57 Mothers and families who have an emergency caesarean birth after a long and difficult labour have special needs. They may be experiencing depression, anxiety, guilt, sense of loss of control, less satisfaction with the birth experience, and loss of self-esteem. 58 Mothers and families who undergo planned, scheduled caesarean births can use coping mechanisms to prepare for the surgery; women undergoing an unplanned caesarean birth do not have this preparation time. 32 If a woman has an unplanned caesarean birth but feels respect and compassion and that her caregivers are collaborating with her during her labour, her outcomes will likely be optimized.
If a woman has an unanticipated caesarean birth and is not supported, she could develop posttraumatic stress disorder (PTSD). 51 HCPs are well-positioned to help mothers and their families resolve their feelings about the caesarean birth, and connect families to support and services in the community, if needed.
Women who have a caesarean birth need more care and support in their postpartum recovery and greater support caring for themselves and their babies. They experience higher levels of fatigue, constipation, depression, anemia, headache, difficulty voiding, abnormal bleeding, urinary tract infection, abdominal pain, and vaginal discharge than women who have a spontaneous vaginal birth. Primarily because of pain, mothers may need extra help with breastfeeding, especially during the first few days, and they have increased difficulties caring for their babies due to painful or reduced mobility. 59 It is vital that women and their partners/families understand what to expect during the recovery period, such as the importance of rest, fluids, support for mobility, and adequate diet for recovery. They also need to plan for support with lifting, driving, and household chores.
The average length of hospital stay is longer for women who have caesarean births than for those who have vaginal births. Family support is imperative after a caesarean birth. Mothers and babies should be cared for as a unit, with her partner, if available, including in the NICU.
# CARE OF THE NEWBORN
During the early postpartum period, care of the newborn usually involves celebrating and rejoicing with the family and respecting and supporting their needs. The care is based on nurturing the developing mother-baby-family relationship and caring for mother and baby as a unit. It includes asking the mother and her partner about their concerns and feelings, observing the baby, and supporting his or her health and well-being.
HCPs will want to ensure that the information and advice they share is clear, consistent and tailored to the mother's specific needs. By focusing on the expressed concerns of the family, rather than on predetermined teaching lists, HCPs will avoid overwhelming them with information. Opportunities to share information about the health and care of babies, including signs of concern, are maximized by caring for mother, baby, and the family together. The mother or partner should be present any time the newborn is being examined, and then made aware of the findings.
There are no Canadian guidelines on the development of newborn care plans. The National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG) recommend developing a documented, individualized postnatal care plan with the woman, ideally in the antenatal period or as soon as possible after the birth. The plan would list the HCPs involved in her and her baby's care, including their roles and contact details. NICE and ACOG recommend that parents be offered information and advice to enable them to assess their baby's general condition, identify signs and symptoms of common health problems in babies, and contact an HCP or emergency service if required. 24,60 For babies born in hospitals or birthing centres, the length of their stay varies from a few hours to about 72 hours. Appropriate postpartum follow-up, including a physical examination by a skilled HCP is essential. This physical examination should include observing feeding. The CPS guideline Facilitating Discharge from Hospital of the Healthy Term Infant provides recommendations for discharge and newborn follow-up. 45 Midwives carry their own caseload and follow their clients regardless of place of birth. They commonly provide three home visits during the first weeks of life.
# Baby-friendly Environment and Exclusive Breastfeeding
Breastfeeding is recognized as the unequalled way to provide optimal nutritional, immunological, and emotional nurturing of infants. Consistent with WHO global recommendations, Health Canada recommends exclusive breastfeeding for the first 6 months that is sustained for up to 2 years or longer with appropriate complementary feeding. This is important for the nutrition, immunologic protection, growth, and development of infants and toddlers. 66 It is also important that hospitals, birthing centres, and community health facilities protect, promote, and support breastfeeding, strive for Baby-Friendly status, and achieve the Ten Steps to Successful Breastfeeding.
# Infant Mental Health
Infant and early childhood mental health has been defined as "the infant's/young child's capacity to experience, regulate, and express emotions, form close and secure relationships, and explore the environment and learn. 19 "
Infants form attachments, learn about social interactions and relationships, take in information from the world around them through their five senses, and as they grow, explore their world. Infant mental health is impacted by a number of factors-biology, genetics, brain development, temperament, the prenatal environment, illness or disability, relationships, attachment, their parents' mental health, parenting, their environment, the social determinants of health, violence, stress and trauma and resiliency. 67 The basis for mental health starts early in life. Early experiences, including infants' relationships with parents and caregivers, affect the architecture of their developing brains. 68 The infant's brain is growing very fast-and nurturing and responsive caregiving is the key to supporting healthy brain development. 67 Disruptions in this process can influence stress regulation, emotional health and immune system development throughout life. 68 Infants are totally dependent on their parents and other caregivers, and when parents and caregivers are responsive, consistent, and nurturing, and they live in safe and economically secure environments, their infants are more likely to have strong emotional health. Parenting and caregiving affect the infant's/ young child's brain development and mental health through a number of mechanisms. One is attachment. When infants are nurtured and looked after responsively by their parents and other caregivers, their physical and mental health is affected for life through the formation of strong, positive bonds with adults-or attachment. Babies who are securely attached demonstrate less anxiety and more positive emotion in young childhood and are more capable of forming relationships with peers and adults. 67,69 Consistent, high quality and timely daily routines also shape the baby's developing regulatory system. The predictability and quality of routines influence the biological rhythms related to waking, eating, eliminating, and sleeping. 67,69 On the other hand, if babies experience persistent, toxic stress, the architecture of their brains is weakened. This can lead to mental health issues and physical, learning and behaviour problems throughout life. While stress is an important part of healthy development, when babies without supportive relationships experience high levels of stress for long periods of time, the result is toxic stress. 70 If parents (or other caregivers) struggle with depression or problematic substance use, for example, they may have difficulty being responsive to their infants. 71,72 Furthermore, if parents have high levels of stress themselves due to precarious economic, housing, or safety conditions, they may struggle to respond to their infants as needed. 73 Parents in these situations need particular support.
Optimal growth and development requires a continuum of services for infants, toddlers, and their families, delivered by trained professionals. Early investment can support infant mental health and prevent the need for more expensive interventions down the road. 67 Developing a strong system of informal and formal services is necessary in order to support parents who are struggling to care for their children. In addition, infants/children who are experiencing abnormal stress need assessment and treatment, along with expert support, before this stress has long-lasting effects. 73 Breastfeeding supports neurodevelopment. This may be due to the breastmilk nutrients or the mother-baby interaction-or both. Neuroscientific evidence strongly supports that infants be exclusively breastfed for 6 months and that hospitalized preterm infants either be breastfed or receive breast milk. 74,75 Consistent with the WHO global recommendation for public health, Health Canada recommends exclusive breastfeeding for the first 6 months that is sustained for up to 2 years or longer, with appropriate complementary feeding to support nutrition needs, for immunological protection and growth and development of infants and toddlers. 66 Mothers and their families need breastfeeding information and support to encourage exclusive breastfeeding.
Programs that are offered before, during, and after pregnancy as well as during early childhood, have shown benefits for supporting positive infant and child mental health. 76 These include home-visiting and other family support strategies.
Nobody's Perfect is a facilitated, communitybased parenting program for parents of children from birth to age 5. The program is designed to meet the needs of parents who are young, single, socially or geographically isolated, or who have low income or limited formal education.
Several studies have shown that participants in the Nobody's Perfect parenting program experience increased: 77
- Confidence in their parenting skills;
- Ability to cope with stress;
- Ability to problem solve;
- Resiliency;
- Self-sufficiency and independence;
- Frequency of positive parent-child interactions;
- Use of positive discipline techniques; and
- Access to peer/social/community support.
# Ophthalmia Neonatorum
Prophylaxis for neonatal gonococcal ophthalmia remains mandatory in some provinces and territories. The CPS states that "erythromycin, the only ophthalmic antibiotic eye ointment currently available for use in newborns, is of questionable efficacy. 81 " Furthermore, the Society considers that eye prophylaxis is not effective in preventing chlamydial conjunctivitis, and that applying medication to the eyes of newborns may result in mild eye irritation. 81 They no longer recommend prophylaxis for ophthalmia neonatorum but recommend screening all pregnant women for gonorrhea and chlamydia infection, with treatment and follow-up of those found to be infected. The CPS suggests that mothers who were not screened should be tested at birth, and babies of mothers with untreated gonococcal infection should receive ceftriaxone. 81 The Public Health Agency of Canada (PHAC) states that "all pregnant women at risk should be screened at the first prenatal visit or at the time of delivery if not previously screened," and provides guidance for the management of ophthalmia neonatorum. 82
# Skin Care
Mothers look at their baby's skin regularly, and HCPs can help them understand transient benign skin conditions such as acrocyanosis, baby acne, cutis marmorata (mottling), milia, erythema toxicum neonatorum, and dermal melanocytosis (Mongolian spots). 83,84 For detailed information on valid and reliable skin assessment tools for babies at risk of impaired skin integrity, refer to the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) guideline Neonatal Skin Care. 83 It is important to share information about skin creams or barriers with parents. While routine application of skin creams or lotions is not necessary for newborns, petroleum emollients have been demonstrated to prevent dermatitis and skin breakdown without increasing the risk of infection. 24,83 Barrier creams or ointments can be applied to the diaper area if reddening is noted.
Parents of both newborn boys and girls need to be made aware of how to properly clean and care for their child's genitals. For example, in the case of uncircumcised newborn boys, normal foreskin can remain nonretractile until puberty. 84
# Bathing
Newborn babies are often bathed for aesthetic and hygiene reasons, as opposed to medical indications (i.e., to prevent transmitting certain infectious diseases). 83,85 Vernix caseosa, the waxy white substance found coating the skin of newborn babies, moisturizes the baby's skin and prevents bacterial cutaneous infections. It should not be washed off, but should be allowed to dry naturally.
The priorities at birth and in the early postpartum period are skin-to-skin contact, breastfeeding, and promoting attachment; the first bath can be postponed. Some families bathe their baby for the first time at home, when the baby is a few days old. Ultimately, "decisions about the frequency of bathing and time of day should be based on the individual baby's need and consideration of family values and beliefs of the local culture. 83 " Newborns do not require daily bathing. Encourage parents to wash their baby with a warm wet cloth between baths, and to wipe the baby's face and hands frequently. 83,84 Umbilical Cord Care
Parents need to be informed about care of the umbilical cord. Natural drying is recommended, that is, putting nothing on the cord. Topical drying agents (including isopropyl alcohol) and antibiotics do not reduce cord separation time or frequency of cord infections, and in some cases, they can harm the newborn. 24,83,85 Newborns can be bathed with the umbilical cord intact so long as the cord is dried thoroughly afterwards.
Fold down diapers to provide maximum exposure to air and prevent contamination with stool or urine. If the umbilical cord or stump is soiled with urine or stool, the area should be washed with water and dried. Parents need to recognize that fever (38 °C or higher), redness, swelling, drainage (yellow pus), foul-smelling discharge, and bleeding (more than a few spots on the diaper shirt or sleeper) are abnormal findings that they should report to their HCP. 83,84
# Circumcision
Parents require accurate, up-to-date, evidencebased information about circumcision so they can make an informed choice for their baby. There is considerable controversy in medical communities regarding circumcision. In their position paper, the CPS outlines the benefits and risks, and does not recommend routine circumcision. 86 According to the American Academy of Pediatrics, the health benefits of newborn male circumcision outweigh the risks. However, the health benefits are not great enough to recommend universal newborn circumcision. 87 The Journal of Medical Ethics has an exclusive edition exploring the medical, religious, and social reasons for and against circumcision. 88 Religious, cultural, and social factors play an important part in the decision to circumcise male babies-these should be considered and respected.
# Early Immunization
In most parts of Canada, routine immunizations are not given to newborns. As of 2014, only New Brunswick, the Northwest Territories, and Nunavut include hepatitis B vaccine as part of the immunization schedule at birth. 89 PHAC recommends that hepatitis B vaccine be given at months 0, 1, and 6 with at least 4 weeks between the first and second dose, at least 2 months between the second and third dose, and at least 4 months between the first and third dose. Alternatively, it can be given as DTaP-HB-IPV-Hib vaccine, which protects against diphtheria, tetanus, pertussis (whooping cough), hepatitis B, polio, and Haemophilus influenzae type b, with the first dose at 2 months of age. 89 It is recommended that a baby whose mother has tested positive for the hepatitis B surface antigen (HBsAg) receive hepatitis B immunoglobulin and a vaccine within 12 hours of birth. If the mother's hepatitis B status is not known, and will not be known within 12 hours of birth, HCPs might consider administering the vaccine and the immunoglobulin based on risk factors, erring on the side of caution and administering both when uncertain. If the mother is HBsAg negative, it is reasonable to administer the vaccine to babies who may be at increased risk of exposure to HbsAg-positive household members or those at high risk of being positive. 89 Parents, grandparents, family, and friends who are in regular contact with a baby should have all their recommended immunizations and these should be up-to-date. Anyone requiring a booster vaccine should get it at least 2 weeks before contact with the baby. 89 This is particularly important for diphtheria, tetanus, and acellular pertussis adult vaccine, as well as for influenza vaccine.
# Vitamin D
Cases of vitamin D deficiency still occur in babies in Canada who do not receive vitamin D as a supplement. 90 Without supplementation, a baby's vitamin D stores will be depleted, particularly if the mother's vitamin D stores are low. 91,92 Nutrition for Healthy Term Infants, a joint statement by Health Canada, CPS, Dietitians of Canada, and the Breastfeeding Committee for Canada, recommends a daily vitamin D supplement of 10 µg (400 IU) for exclusively and partially breastfed babies, from birth to 1 year of age. Children aged 12 to 24 months of age who are breastfed or receive breastmilk should continue to receive this daily vitamin D supplement of 10 µg (400 IU). 66,93 Breastfed babies living in northern latitudes require special attention. In this situation, the CPS suggests that vitamin D supplementation within a range of 400 IU/day to 800 IU/day appears to be safe. 94 Continuing this supplement is a conservative approach to achieving adequate vitamin D intakes. It also provides a consistent and straightforward public health message. In individual practice, the decision to discontinue the supplement beyond 12 months of age can be informed by a dietary assessment of other contributors of vitamin D, such as cow milk. 93
# Newborn Screening
Newborn screening has been one of the most successful public health programs of this century. It has achieved the goal of detecting hereditary disorders that can result in death or severe long-term disability if not identified prior to the onset of signs. 95 Current Canadian standards are set at the provincial and territorial level, resulting in variations in the number of screening tests performed in the general categories of endocrine disorders, hemoglobinopathies, fatty acid, amino acid and organic acid disorders, cystic fibrosis, galactosemia, and other disorders. 96 HCPs would be expected to discuss screening the newborn with parents before and soon after the birth, emphasizing that this is a routine part of their baby's care that can prevent serious health problems. The newborn screening blood specimen card is completed between 1 and 7 days of age -and ideally between 2 and 3 days of age.
If testing is conducted earlier, before 24 hours, repeat the test within 5 days. In Quebec, in addition to blood sampling, a urine sample is obtained at 3 weeks for screening of a number of hereditary conditions.
According to the CPS, all newborns should be screened for hyperbilirubinemia, using a predictive nomogram. The Society recommends measuring bilirubin at the same time as having the metabolic screening test, unless it is required earlier, or at discharge or within 72 hours of birth, whichever comes earlier. This is particularly important if babies go home early, since bilirubin levels will peak at home. 97 The incidence of critical congenital heart disease (CCHD) in Canada is 3/1000 live births. CCHD accounts for more deaths than any other congenital malformation. Between 10% and 30% of CCHD diagnoses are not made prior to discharge from hospital although early diagnosis and follow-up are essential first steps in preventing infant mortality and morbidity. 98 Some centres now perform routine pulse oximetry screening to identify babies with CCHD. Used in conjunction with prenatal ultrasound and a physical examination, pulse oximetry screening is the best approach to detecting CCHD in newborns. 99 The CPS recommends that pulse oximetry screening be performed between 24 and 36 hours after the birth, using the baby's right hand and either foot to minimize false-positive results. The Society recommends that newborns with abnormal results undergo a thorough evaluation by the most responsible HCP. If a cardiac diagnosis cannot be excluded, newborns with abnormal results would be referred to a pediatric cardiologist. 100
# Hearing Screening
Hearing loss is not a common disorder in the newborn. Profound hearing loss (>70 dB) occurs in approximately 1 to 3 infants per 1000 live births. Together with moderate loss (>40 dB), the prevalence increases to 6 per 1000. 101 Universal screening for hearing results in earlier diagnosis and intervention and improved language outcomes for children. 102 The CPS and Speech-Language and Audiology Canada recommend universal screening for all newborns. 102,103 Speech-Language and Audiology Canada recommends that screening be conducted by 1 month of age, in either a hospital or communitybased setting. Any suspected hearing loss should be confirmed by 3 months of age, and an intervention implemented by 6 months of age. 104 Screening policies, however, vary between provinces, with some offering universal screening and others screening only high-risk populations. 96 HCPs will want to discuss the hearing tests with parents and explain the rationale, how they are performed, and the implications of test results that show possible hearing loss. It is also important to explain the efficacy of the test and the occurrence and meaning of false positives.
# Pain
Newborns, both preterm and term, have a hypersensitivity to stimuli and are more prone to pain and the consequences of pain. It is critical that they receive effective pain relief. As newborns cannot verbalize, it is up to their caregivers to assess and alleviate their pain.
Always keep the number of painful procedures to a minimum; those that are conducted should be evidence-based.
Some effective pain management strategies have been identified for newborns during bedside procedures. 105 Breastfeeding and skin-to-skin contact together are effective at reducing pain, and this is the first line of pain reduction for procedures such as injections, heel lancing, or venipuncture. 106 - Skin-to-skin contact reduces pain responses in preterm and term babies. 107 Skin-to-skin contact should be started approximately 10 to 15 minutes prior to the procedure. 105 - Breastfeeding should be started approximately 5 minutes before the procedure. Ensure that the baby achieves an effective latch with sustained sucking and swallowing. 105 Sweet solutions, including breast milk, have analgesic effects on babies. 108 Refer to the CPS guideline Prevention and Management of Pain in the Neonate on bedside procedure pain management as well as surgery and major procedures. 109 " Breastfeeding and skin-to-skin contact together are effective at reducing pain, and this is the first line of pain reduction for procedures.
# Safe Sleep
An optimal amount of sleep for both babies and parents is a priority for parents. Deciding where a baby sleeps is personal and highly variable. The decision may be based on cultural or personal values or the desire to facilitate breastfeeding. Alternatively, it may reflect socioeconomic realities such as unstable housing or poverty resulting in a lack of resources such as a crib. 110 It is incumbent on all HCPs to work closely with the families to promote safe sleep for their babies.
HCPs and parents should discuss the following modifiable risk factors, which reduce the risk of Sudden Infant Death Syndrome (SIDS): 111 - Breastfeeding of any duration, which provides a protective effect, with exclusive breastfeeding offering greater protection;
- Placing infants to sleep in a crib, cradle, or bassinet-one that meets current Canadian regulations-in the same room and near the parent or caregiver's bed;
- Providing a smoke-free environment-both before and after the birth; and
- Placing infants on their backs to sleep, for every sleep.
PHAC recognizes SIDS and other infant deaths that occur during sleep as major public health concerns. 111 According to Statistics Canada, 10 babies aged less than 1 year died from SIDS in 2018. 112 While it is important to differentiate between SIDS and accidental suffocation and strangulation in bed, the American Academy of Pediatrics notes that many of the modifiable and non-modifiable risk factors for SIDS and other sleep-related infant deaths are similar. 113 There is some confusion around the meaning of the term "co-sleeping." Sometimes it refers to sleeping in the same bed and sometimes to sleeping in the same room. Room sharing occurs when the baby and adult caregiver sleep on separate surfaces in the same room-a practice that is recommended. 111,113 Bed sharing, when the baby and caregiver share the same sleep surface, is not recommended by either CPS or PHAC.
Parental fatigue can play a significant role in creating unsafe sleep environments for babies and, infrequently, extreme parental fatigue can contribute to accidental suffocation. 110 A more likely scenario is that parents become so tired that they are less capable of making evidencebased decisions about sleep for either themselves or their babies. HCPs should take a proactive approach when it comes to discussing sleep strategies with parents.
# Growth Monitoring
Monitoring a baby's growth helps identify health or nutrition problems early enough for corrective action to be effective. 66,93 Measurement of growth over time should be combined with clinical, developmental, and behavioural assessments.
The WHO Child Growth Standards are based on the growth of breastfed babies. 116 Standard growth charts show the gradual change in growth velocity.
Babies who are feeding well typically regain their birth weight by 10 to 14 days, double their weight by about 5 months, triple it by 12 months and quadruple it by 2 years of age. 117 Babies grow quickly during the first 3 months, gaining 20 to 30 g per day in the first 4 weeks, or an average of 0.6 to 1.4 kg per month. 118 At-risk or Unwell Babies 121 Since postpartum women can experience mental health problems for a long time (more than a year in some cases), having one person coordinate integrated care can help ensure that the care is consistent and ongoing.
If the mother agrees, her partner and family may also be involved in decisions regarding her care.
# Postpartum Blues
The most common type of postpartum mood change is the postpartum blues, or baby blues.
Estimates of prevalence range dramatically, from 15% to 84%. 122 The postpartum blues are thought to be an effect of the rapid post-childbirth hormonal drop on the neurotransmitter systems involved in mood disorders. The challenges of caring for the baby and interrupted sleep are also likely to contribute to the blues. 128,129 Common symptoms of postpartum blues are low mood, emotional lability, tearfulness, fatigue, and irritability. These symptoms are usually transient, beginning shortly after childbirth and resolving on their own within the first few weeks postpartum. 123 The transient nature of the symptoms helps distinguish postpartum blues from a major depressive episode. Other features that distinguish postpartum blues from a major depressive episode are the lack of severe symptoms, such as persistent insomnia, thoughts of guilt or worthlessness, or suicidal ideation.
The reason some women have postpartum blues, while others develop major depression is unknown, but research suggests that genetic predisposition is a factor. 130,131 Postpartum blues are self-limiting and require no treatment other than reassurance and support. 132 However, early onset, severe, or prolonged blues is associated with postpartum depression, and requires medical attention. 133
# Postpartum Depression
Postpartum depression can affect a woman at any age or socioeconomic status and from any culture. Biological risk factors may include history of depression or untreated depression in pregnancy, while psychosocial risk factors may include poor social support and stressful life events, including issues related to the health of the baby. 134 Some women are at a higher risk of postpartum depression such as Indigenous women, younger mothers, sexual minority women, and women who are recent immigrants to Canada.
# SUPPORTING WOMEN WITH POSTPARTUM MENTAL ILLNESS 51
Supporting women with postpartum mental illness requires a multifaceted, family-centred approach based on the individual needs and experiences of the woman and her family.
Effective treatments for postpartum mental health disorders may require referral to a mental health professional. HCPs can support new mothers and families by:
- Knowing how to differentiate between postpartum depression and other anxiety disorders or mental illnesses, including posttraumatic stress disorder (PTSD);
- Being familiar with risk factors associated with postpartum depression and mental illnesses;
- Being able to identify women at risk of developing postpartum emotional disorders and those in difficulty;
- Recognizing the symptoms of mental disorders, from baby blues to postpartum psychosis;
- Knowing about the range of treatment options available for the various postpartum mood disorders, and providing women and their families ways to access the appropriate resources;
- Helping to debunk the "motherhood equals joy and complete fulfillment" myth; and
- Encouraging women to talk about their negative emotions to do with motherhood.
The Diagnostic and Statistical Manual of Mental Disorders, version 5 (DSM-5) qualifies a major depressive episode with peripartum onset when symptoms start in late pregnancy or within the first 4 weeks postpartum. 135 However, most clinicians define postpartum depression as depression during the first year postpartum. According to 2019 Canadian data, almost onequarter (23%) of mothers who recently gave birth reported depressive and anxiety symptoms that might or might not be postpartum depression or anxiety because these were just very general screening scales. Prevalence of such feelings was higher among mothers aged under 25 years (30%) than all other age groups. Of the mothers who had these feelings, 31% had been told by an HCP that they had depression or a mood disorder before pregnancy. Almost one-third (32%) of mothers who had these feelings reported that they received mental health treatment since the birth of their baby-39% had counselling, 38% medication (such as anti-depressants), and 23% counselling plus medication. 139 Women with bipolar disorder are at particularly high risk of developing a depressive episode postpartum. 140 Recent Canadian research indicates that First Nations mothers had a 20% increase in the mean scores of depressive symptoms compared to White Caucasian mothers in Canada. 141 A systematic review of the evidence on the prevalence of postpartum mental health disorders in Indigenous women confirmed this finding. 142 Chronic life stress and trauma are considered key causes of prenatal and postpartum depression among Indigenous women. This life stress is influenced by racism, sexism, domestic and sexual violence, and intergenerational trauma from residential schools and other legacies of colonization. 9
# SYMPTOMS OF A MAJOR DEPRESSIVE EPISODE 135
- Persistently low mood and/or loss of interest While the symptoms of postpartum depression are similar to those of a major depressive episode outside of the postpartum year, the negative thoughts and images associated with postpartum depression can focus on feelings of failure as a mother, anxiety about the baby's health and well-being, and guilt about having difficulty with the transition to parenthood. While perinatal suicide is extremely rare, as many as 20% of women report thoughts of self-harm or suicide. 143 The Canadian Task Force on Preventive Health Care guideline Recommendations on Screening for Depression in Adults does not recommend screening for depression in perinatal and postpartum women. 52 However, there are tools that can be used to help detect anxiety and depression in the postpartum period.
Refer to the Registered Nurses' Association of Ontario best practice guidelines for effective interventions when caring for mothers with postpartum depression. 53
# Anxiety and Related Disorders
Anxiety is a primary feature of perinatal depression, with the prevalence of anxiety symptoms ranging from 14% to 20% in the postpartum period. Parents often feel anxious about the welfare of the baby, insecure about their parenting abilities, or worry about being alone. However, women can also have anxiety and related disorders, including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder and PTSD. 134 The Generalized Anxiety Disorder 2-item (GAD-2) questionnaire is a useful tool for identifying generalized anxiety disorder. 150 The tool has just 2 questions with four possible answers per question: 151 "Over the last 2 weeks, how often have you been bothered by the following problems?
- Feeling nervous, anxious or on edge?
- Not at all/Several days/More than half the days/Nearly every day 2. Not being able to stop or control worrying
- Not at all/Several days/More than half the days/Nearly every day" New parents are naturally nervous when they are beginning to care for their newborn baby. Generalized anxiety disorder, however, is characterized by excessive worry about anticipated events or activities in a way that is difficult to control or interferes with daily functioning. The anxiety can be clustered worries about finances, appearances, maintenance of household duties, and the well-being of the baby, for example. 152 Panic disorder, affecting about 1% to 3% of new mothers, may cause significant impairment. It can result in the mother experiencing isolation due to her difficulty in leaving the home or being in groups of people. 152,153 Obsessive-compulsive symptoms occur in 4% to 9% of new mothers. These most often include obsessions about contamination, compulsions about checking and ordering, and in some cases, thoughts about the baby being harmed. The latter can be distinguished from psychosis because women with obsessive-compulsive symptoms have no intention of harming their child and are significantly distressed by these types of thoughts.
Obsessive-compulsive symptoms commonly co-exist with a depressive episode. 155
# TOOLS TO DETECT ANXIETY AND DEPRESSION POSTPARTUM
The Edinburgh Postnatal Depression Scale (EPDS) This 10-item depression scale:
- Can be used in clinical care or for women at risk of, or showing, symptoms of postpartum depression;
- Can be used any time postpartum, including at regular maternal or baby checks;
- Has an anxiety subscale (items 3, 4, and 5);
- Asks about self-harm thoughts (item 10).
Women with a score higher than 12 (out of 30) have 10 times the likelihood of being diagnosed with postpartum depression than women with a lower score.
# Whooley Questions for Depression Screening 121
There are two Whooley questions for depression:
- During the past month, have you often been bothered by feeling down, depressed, or hopeless?
- During the past month, have you often been bothered by little interest or pleasure in doing things?
If a woman answers yes to either of these questions, it signifies need for further follow-up to determine whether she has depression.
Trauma-and stressor-related disorders, including PTSD, affect about 3% of postpartum women and up to 15% of high-risk women 158 . Important risk factors included a history of psychopathology, current depression, and complications during pregnancy, labor and delivery. While it is rare that a stressful birth experience leads to PTSD, risk factors do include having a birth experience different from what was expected and ineffective communication where HCPs do not listen to the woman. 158 Severe Postpartum Mental Disorders
# Bipolar Disorder and Schizophrenia
About 2% of pregnant women have a preexisting bipolar disorder, and less than 1% have a pre-existing psychotic disorder such as schizophrenia. 159 Women with severe mental disorders are at particularly high risk of relapse in the postpartum period and usually require special mental health care. They are also at high risk of developing postpartum depression. 140 Evidence suggests that there is a relationship between bipolar disorder and postpartum psychosis, with the majority of cases thought to be variants of bipolar disorder. The risk of relapse in women with primary psychotic disorders increases during the postpartum period. 160,161 Sometimes postpartum psychosis is preceded by hypomanic or manic symptoms. 162 Women with severe mental disorders and their families require support from professionals and family/friends as well as appropriate treatment to promote optimal health and parenting.
# Postpartum Psychosis
Postpartum psychosis, the most severe postpartum psychiatric disorder, is a medical emergency.
Postpartum psychosis occurs in approximately 1 in every 600 postpartum women. 161 It most often occurs during the first week or the first month postpartum, but it can occur later in the postpartum period or at weaning, although the latter is rare.
The primary symptoms of postpartum psychosis reflect a significant change from the woman's usual personality, with confusion and clouding of consciousness considered classic symptoms. These symptoms may be accompanied by an inability to distinguish thoughts from reality and delusions about herself, her baby, or others. 163,164 Women with a history of bipolar and psychotic illnesses are at increased risk for postpartum psychosis, particularly if they stopped taking medication during pregnancy or in the early postpartum period. Other risk factors include a family history of psychiatric illness (particularly bipolar affective disorder) and sleep deprivation among women with a previous bipolar mood disorder diagnosis. 140 Women with postpartum psychosis require urgent psychiatric consultation, pharmacological treatment, ongoing support to facilitate the recovery process, and usually hospitalization. 165 They should not be left to care for their babies alone until the psychosis has resolved. Assess and support safety of the mother and her baby on an individual basis, as delusions may increase the risk of harm to either or both. Family members should be educated and engaged, and ongoing support provided by professionals, community organizations, and family/friends. 166,167 Women who develop postpartum psychosis are at increased risk for reoccurrence during subsequent pregnancies. 168,169
# LATE POSTPARTUM HEMORRHAGE
Late postpartum hemorrhage, also called secondary postpartum hemorrhage, can occur 24 hours to 12 weeks after childbirth. The potential causes of late postpartum hemorrhage include retained fragments of the placenta or membranes, sub-involution of the placental site, uterine infection, and coagulation defects.
Treatment involves controlling bleeding with medications such as oxytocin, as well as possible blood replacement or surgical intervention.
As most cases of late postpartum hemorrhage occur after women leave birthing facilities, focus the discharge information on expected changes, what amount of bleeding is normal and what amount of bleeding is not normal, causes for concern, and when to contact an HCP or emergency department. If a mother needs to be re-admitted to hospital for late postpartum hemorrhage, it is very important not to separate the mother and baby and to provide support for breastfeeding.
# INFECTIONS Endometritis
Endometritis is an infection of the reproductive tract. It can occur at any time from birth to 6 weeks postpartum. Endometritis occurs after 1% to 3% of vaginal births and up to 27% of caesarean births. 170 Endometritis is limited to the uterine cavity but can spread.
A woman with mild endometritis has discharge that is scant or profuse, bloody, and foul smelling.
In more severe situations, she has fever, chills, lower abdominal pain or uterine tenderness, anorexia, lethargy, and rapid pulse. Treatment includes administration of antibiotics and can also include rest, a high fluid intake, analgesia as needed, and administration of oxytocics to keep the uterus contracted. Comfort measures are important to relieve the symptoms. 170,171 Women need to be informed about what to expect with regard to normal lochia and vaginal discharge, and should call their HCP if they develop symptoms of endometritis.
# Mastitis
Mastitis is an inflammation of the breast that may involve an infection. It is characterized by localized tenderness, redness, and heat, and systemic symptoms of fever, malaise, and occasionally nausea and vomiting. 172 Mastitis commonly occurs within the first 6 weeks postpartum, but can occur at any point during lactation. It can start as engorgement, develop into non-infective mastitis, and then become infective mastitis. 172 While the breast is congested/engorged, the most effective treatment is breast emptying-by an electric pump if necessary-and increased water intake.
Mastitis occurs in 10% of breastfeeding women, but some studies have reported the incidence to be as high as 33%. 173 Encourage mothers to continue breastfeeding.
It is important that mothers know their milk is safe for their baby even if they require antibiotics.
Frequent feeding and good positioning and latching, with effective milk flow from breast to baby, are preventive factors for mastitis.
# CARDIOVASCULAR AND HYPERTENSIVE DISORDERS OF PREGNANCY
Hypertension affects 6% to 10% of pregnant women, but few studies have reported the incidence of postpartum hypertension. Women who have had chronic hypertension, gestational hypertension, preeclampsia, and eclampsia may have preeclampsia postpartum-and may develop preeclampsia for the first time postpartum. 174 As such, if a mother has hypertensive disorder of pregnancy (HPD), postpartum monitoring is important.
Refer to the SOGC guideline Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy for information on care in the first 6 weeks postpartum and beyond. The Working Group recommends checking blood pressure 3 to 6 days following birth, especially if the woman has had a pregnancy complicated by high blood pressure. 175 During pregnancy, women may develop conditions such as preeclampsia and gestational diabetes mellitus (GDM) that put them at higher risk of heart disease and stroke. Pregnancy-related stroke can happen at any stage of pregnancy, but the greatest risk is during birth and the first few months postpartum. It is usually the result of a pre-existing blood vessel malformation or eclampsia. Peripartum cardiomyopathy (PPCM) is a rare-and often misdiagnosed-form of cardiomyopathy that occurs in the last month of pregnancy and up to 5 months postpartum.
There are a number of risk factors for peripartum cardiomyopathy: multiple pregnancies, twins, preeclampsia and eclampsia, a history of heart problems, excessive alcohol consumption, smoking, diabetes, obesity, unhealthy diet, and African heritage. 176 It is important to describe the signs and symptoms of heart disease and stroke to women and their families and explain when to talk to an HCP or seek emergency care.
# EXTENSIVE PERINEAL TEARS
Approximately 53% to 79% of women experience some form of laceration during vaginal birthmost often in the perineal body and commonly first-and second-degree lacerations. The more severe third-and fourth-degree lacerations that result in obstetrical anal sphincter injuries (OASIS) may occur in up to 11% of women who have vaginal births. 177 OASIS may result in significant problems, including anal incontinence, rectovaginal fistula, and pain, along with increased risk of postpartum urinary retention.
Women who have lacerations during birth need to be made comfortable and helped to recover-and be supported in their confidence in caring for their baby. Provide information so that the woman understands what happened during the birth and the extent of the laceration/injury. Focus on what can help recuperation and healing; that is, rest, hygiene, prevention of constipation, and pain management, as needed, so that they can be actively involved in caring for their babies. Helpful measures include sitz baths, using the side-lying breastfeeding position, avoiding sitting or standing for long periods of time, and seeking and accepting support from family and friends.
The SOGC recommends that HCPs carefully examine all women for perineal or vaginal tears and that anyone with a tear that is more than superficial has a systematic rectal exam for OASIS. 178 The SOGC guidelines provide recommendations on prophylactic antibiotic administration, the use of laxatives, as well as analgesics for pain, in the case of OASIS. 178 Refer women who have OASIS to a physiotherapist skilled in helping with this condition. 178,179 The benefits relate to wound healing as well as rehabilitation to restore local and integrated muscle function following the muscle trauma. Scar management may be required to help the woman have intercourse without fear and pain. These considerations may also be relevant for first-and second-degree tears, although in this case referral to physiotherapy is not always necessary.
# FEMALE GENITAL MUTILATION/ CUTTING (FGM/C)
Women who have experienced female genital mutilation/cutting (FGM/C), also known as circumcision, need particularly sensitive postpartum care. Learning about the cultural, social, psychological, and physical implications of this centuries-old traditional practice will help HCPs talk to mothers appropriately and provide care that is culturally aware and respectful. The perineal area may be extremely painful due to repeated cutting and laceration throughout life compounded by a recent vaginal birth, making even walking difficult. This all makes caring for their baby more problematic. 180 Following birth, women need additional advice on perineal hygiene. Perineal infections may occur if culturally acceptable methods of cleanliness are not understood by HCPs. For example, using water may be considered impure on religious grounds. Instead, a diluted antiseptic wash may be used for cleaning after voiding.
HCPs will want to address birth control methods, as choice may be limited for women with FGM/C. They may have been taught that touching their genitals is forbidden, and because the vaginal area is sensitive, the use of diaphragms, cervical caps, and sponges is usually not suitable. The most acceptable and reliable method of birth control for women with FGM/C may be intrauterine contraception (IUC, also known as an intrauterine device or IUD). Hormonal contraceptives, either oral or implanted, are also possible. As for all women, the different contraceptive options should be explained carefully and clearly.
HCPs also need to discuss FGM/C with parents and inform them that performing FGM/C is illegal in Canada.
# DIASTASIS OF THE RECTUS ABDOMINIS MUSCLE
Diastasis recti abdominis (DRA) is defined as a separation of the two sides of the rectus abdominis muscles. 181 The onset of DRA occurs during pregnancy and the first weeks following birth. 182 The literature on the prevalence and risk factors for development of this condition is limited. 181,182 A prospective cohort study of 300 first-time pregnant women found the prevalence of mild DRA to be high both during pregnancy and after childbirth: 33% at 21 weeks gestation; 60% at 6 weeks postpartum; 45% at 6 months postpartum; and 33% at 12 months postpartum.
There was no difference in reported lumbopelvic pain in women with and without DRA. 181 In another prospective study of 84 first-time pregnant women, the prevalence of DRA decreased from 100% at gestational week 35 to 39% at 6 months postpartum. Women with DRA at 6 months postpartum were equally likely to report lumbopelvic pain as women without DRA. 182 A widening of greater than 2.7 cm at the level of the umbilicus is considered to be pathological diastasis of the rectus abdominis muscle. 183 It can have negative health consequences for women during pregnancy and the postpartum period and beyond, including altered body mechanics and posture, injury of the lumbar spine and pelvis, and impaired pelvic stability. 184,185 Exercise is a protective factor in the development of DRA. 186 Exercise may reduce the risk of developing DRA as it helps to maintain tone, strength, and control of the abdominal muscle.
In addition, women who exercise during and after pregnancy most likely exercised before pregnancy and have better-conditioned abdominal muscles than women who do not exercise. The type of exercise also affects DRA width and recovery time. 186 It is important to refer women with DRA to pelvic floor physiotherapy. 187 Physiotherapy or exercises for diastasis recti should not only address the separation but retrain the pelvic floor muscles. More than 70% of women with rectus diastasis cannot do a pelvic floor contraction and therefore are more likely to experience incontinence, prolapse, and pelvic pain. 188 Consider as well physiotherapy or exercises that address posture, body mechanics, and restricted tissues that may be causing poor movement. A corset or binder is often recommended for separations of 4 finger widths or more. Neuromuscular electrical stimulation also helps to reduce DRA, and if combined with abdominal exercises, can augment the effects. 189 Some women may meet the criteria for surgery (abdominoplasty) if they have unresolved symptoms that have not responded to exercise. 187
# GESTATIONAL DIABETES MELLITUS
It is important to encourage women who have had gestational diabetes mellitus (GDM) to breastfeed immediately after childbirth. Breastfeeding helps to lower the risk of neonatal hypoglycemia. 190 Women with GDM require information about the associated health risks:
- Between 16% and 30% of women with GDM develop type 2 diabetes by 5 to 10 years postpartum, and some women develop type 1 diabetes. 191 - Metabolic syndrome is more common in women with GDM. Women should be counselled about lifestyle modifications to prevent diabetes and cardiovascular disease.
Lifestyle changes can prevent the onset of type 2 diabetes. 191 - The recurrence rate of GDM in subsequent pregnancies is about 30% to 84%. 192 For most women with GDM, diabetes goes away soon after childbirth. However, only 50% of women return for postpartum testing due to time pressures, lack of childcare, lack of awareness of the importance of postpartum screening, the unpleasantness of the test, and other factors. The SOGC guideline Diabetes in Pregnancy recommends that women with GDM be screened with a 75 g oral glucose tolerance test (OGTT) between 6 weeks and 6 months postpartum to detect prediabetes and diabetes. 194 Women with GDM may benefit from the support of a lactation consultant or specialist in case of delayed onset of breastmilk secretion. 195,196 The Canadian Diabetes Association Clinical Practice Guideline Expert Committee recommends that after childbirth women with pregestational diabetes: 197 - Breastfeed for the many benefits it offers;
- Be carefully monitored as they have a high risk of hypoglycemia postpartum;
- Use metformin and glyburide, if needed, as they can be used during breastfeeding; and
- Have their triglycerides assessed late postpartum.
In addition, women with type 1 diabetes in pregnancy should be screened for postpartum thyroiditis with a thyroid-stimulating hormone (TSH) test at 6 to 8 weeks postpartum.
# THYROID CONDITIONS
# SYMPHYSIS PUBIC DYSFUNCTION, PELVIC GIRDLE PAIN, AND DIASTASIS SYMPHYSIS PUBIS
Symphysis pubic dysfunction (SPD) has been described as a collection of signs and symptoms of discomfort and pain in the pelvic area, including pelvic pain radiating to the upper thighs and perineum. While this term has been used to describe pregnancy-associated pain and instability and dysfunction of the symphysis pubis joint (SPJ) or sacroiliac joint (SIJ), the European Guidelines recommend pelvic girdle pain (PGP) as the accepted umbrella term. 201 PGP symptoms occur due to pelvic ligament relaxation and increased joint mobility in pregnancy, and can vary from mild discomfort to severely debilitating pain. 202 About 20% of pregnant women experience PGP. 201,203 Risk factors for developing PGP during pregnancy include a history of previous low back pain and previous trauma to the pelvis. 201 Prolonged and difficult births, often with larger babies, with the women's legs widely abducted, and possibly assisted by forceps, can also be contributing factors. The reported incidence of clinically persistent PGP from the postpartum stage to 2 years after childbirth ranges from 5% to 8.5%. 204 In severe cases, the symphysis pubis may partially or completely rupture. Diastasis of the symphysis pubis (DSP), where the gap in the symphysis pubis increases to more than 10 mm, can only be confirmed by diagnostic imaging. 205,206 DSP can occur during pregnancy, childbirth, or the postpartum period. 206 Although specific recurrences are difficult to predict, women need to be made aware of the high recurrence rate (68-85%) in subsequent pregnancies. 207 A small subgroup of patients with PGP can develop chronic pain leading to high disability with resistance to physical interventions. These women should receive multidisciplinary care involving medical and psychological intervention.
There are no Canadian guidelines on diagnosing and managing PGP. Guidelines from Ireland and the United Kingdom are consistent in their message that symptoms of pelvic girdle pain are often mild but can be seriously disabling. 206,208 Women should be asked at every postpartum contact whether they are experiencing pelvic girdle or lower back pain. 206,209 Indications of pain and difficulty with walking after giving birth may indicate pubic symphysis diastasis and should not be discounted as a "minor discomfort of childbearing," but investigated. Do not discount any level of pain-rather, undertake a careful clinical assessment to determine the extent of the pain and any symphysis pubis dysfunction. Assessments should include determining what occurred during pregnancy and childbirth, and running diagnostics and making timely referrals, including to physiotherapy, to avoid long-term and potentially permanent disability. 201,209
# ASSISTED VAGINAL BIRTH
In 2016/2017, 13% of women who gave birth in Canada had an assisted vaginal birth, 9% had a vacuum birth, and 4% had a forceps-assisted birth. 210 Recent evidence reviews have shown that women who had an assisted vaginal birth were more likely than those who had a spontaneous birth to have at least one health problem during the early postpartum period, for example, painful perineum, constipation, hemorrhoids, breakdown of stitches, and urinary or fecal incontinence.
They were also more likely to have a painful perineum at 8 weeks postpartum, regardless of whether they had an episiotomy. 59,177 Forceps-assisted and vacuum-assisted births are associated with an increased risk of injury to the vagina, perineum, and anus. Tears are more severe, which may require prolonged healing. 211 Women who have a forceps-assisted birth have a significantly greater decrease in intra-anal pressure and a greater incidence of a weak pelvic floor. 212 It is important to focus on the woman's comfort during the postpartum period, determining if she has any concerns about perineal comfort or healing, as well as pain, discomfort or stinging, odour, incontinence, or dyspareunia. 24 The integrity and progress in healing of the perineum needs to be assessed, with pain relief or comfort measures offered and their effectiveness assessed. Women need information on the use of ice packs to decrease swelling, care of the perineum, self-inspection, warm water sitz baths, and Kegel exercises to improve perineal tone. 41
# URINARY OR FECAL INCONTINENCE AND URINARY RETENTION
A significant number of women experience urinary and fecal incontinence following childbirth. The condition is both physically and psychologically challenging, and can influence many aspects of women's lives and recovery.
# Urinary Incontinence
During pregnancy and childbirth, the pelvic floor muscles are stretched and weakened, placing women at risk for the development of urinary incontinence. 213 While urinary incontinence can happen during pregnancy, stress urinary incontinence results from pelvic floor trauma during vaginal birth, especially the first birth.
Although antenatal urinary incontinence, obesity, and significant perineal trauma are risk factors, clinical studies have not identified any single responsible event, suggesting that the problem is multifactoral. Some women have temporary urinary incontinence, but others have long-term problems. 213 According to the Maternity Experiences Survey, 3.4% of all women who gave birth reported urinary incontinence as "a great deal of a problem" in the first 3 months postpartum. 215 Women who had vaginal births were more likely to report this problem (4.2%) than women who had caesarean births (1.1%). First-time mothers were also more likely to report this problem (4.0%) than multiparous women (2.9%). 215 Research indicates that women who had a forceps-assisted birth (with or without an episiotomy) were 10 times more likely to have significant perineal trauma than women who delivered by vacuum extraction without an episiotomy. Moreover, 5 years later, almost half of the women who had assisted vaginal births had some degree of urinary incontinence. 59 When talking with women about urinary incontinence, focus on prevention, muscle toning techniques, and other interventions. Pelvic floor muscle training can prevent urinary incontinence for up to 6 months after first-time mothers have given birth. 216 There is also evidence that pelvic floor muscle training is appropriate for women with persistent postpartum urinary incontinence. 216 The effectiveness might be increased with targeted approaches.
The SOGC recommends Kegel exercises for incontinence with follow-up to assess their effectiveness. Combining any necessary lifestyle changes with bladder training plus pelvic muscle exercises is highly effective. Refer to the SOGC guidelines Conservative Management of Urinary Incontinence. 217
# Urinary Retention
Urinary retention is a sudden inability to spontaneously void the bladder or where a woman passes small amounts of urine but is unable to fully empty her bladder. Symptoms of urinary retention include urinary frequency, voiding small amounts, bladder discomfort or pain, straining to void, reduced sensation to void, incomplete emptying of the bladder and urinary incontinence. 221 Postpartum voiding dysfunction is defined as failure to pass urine spontaneously within 6 hours of vaginal delivery or the removal of a catheter. 218 If urinary retention is not detected and managed, it can lead to bladder distention or underactivity and longer-term problems such as incontinence and urinary tract infections. 222,223 The causes of urinary retention are not well understood, but likely mechanical, physiological, and neurological factors are involved. 220 There are no national Canadian guidelines on postpartum urinary retention, but NICE guidelines recommend that if a woman has not passed urine within 6 hours of childbirth, she has warm baths or showers to assist urination. If these actions are not successful, bladder volume should be assessed and catheterization considered. 24
# Fecal Incontinence
According to the Maternity Experiences Survey, 1.8% of all women who gave birth reported that loss of bowel control was most pronounced in the first 3 months postpartum. 215 First-time mothers were more likely to report this problem (2.2%) than multiparous women (1.4%). 215 Anal incontinence after childbirth is more prevalent among women who have had a forceps-assisted birth and laceration of the anal sphincter. 224,225 In addition, women who have anal sphincter tears are more than twice as likely to report postpartum fecal incontinence than women without sphincter tears. 224,225 For women who had an OASIS repair, the SOGC recommends prescribing laxatives and nonsteroidal anti-inflammatories and acetaminophen as first-line agents, and a single dose of an intravenous antibiotic. HCPs will want to discuss the degree of injury and arrange for appropriate follow-up. The SOGC also recommends that women with anal incontinence be referred for pelvic floor physiotherapy. 178
# PROLONGED STAY IN HOSPITAL
Having to remain in hospital for a prolonged period after childbirth can be extremely stressful for families. Mothers may be distanced from their support circle of friends and family. Concerns regarding contact with and care of other children may be a source of stress. Families may be worrying about the mother's health and the care of siblings; contact with other children and grandparents; travelling logistics to and from the hospital; and work obligations of partners. It is important that HCPs explore these issues with the family and support them as much as possible.
Consider referrals to social services if needed and innovative technology-based programs and resources to help keep families connected.
When women are sole-parenting, prolonged stay situations can escalate their stress and anxiety and interfere with their recovery.
A prolonged hospital stay requires compassionate and individualized care. Policies should focus on enabling skin-to-skin contact, supporting breastfeeding, and allowing mothers and babies to be together (rooming-in/mother-baby care). 23 Mothers who are breastfeeding should have the opportunity to feed frequently and on cue for as long as they want and receive help with breastmilk expression, if needed. 226 If the baby cannot be given their mother's breastmilk, pasteurized human donor milk is the next best choice. 20,93,227 It is incumbent upon HCPs to consult expert resources to determine the effects on the breastfeeding mother and breastfed baby of any medications the mothers is taking. Only a small number of medications are contraindicated while breastfeeding. 228 " Policies should focus on enabling skin-to-skin contact, supporting breastfeeding, and allowing mothers and babies to be together (rooming-in/mother-baby care).
# COMPLICATIONS RELATED TO THE NEWBORN
According to findings from the ACoRN program, complications related to the newborn fall into eight areas of concern:
- Infection - Cardiovascular - Respiratory - Neurological
- Gastrointestinal or surgical
- Glucose and electrolytes
- Jaundice
# - Thermoregulation
Refer to the CPS ACoRN program for guidance on neonatal stabilization, support for multidisciplinary teams, and identifying and caring for babies who are unwell or at risk of becoming unwell in the first few hours or days after childbirth. 119
# INFECTION
If the baby has an infection, supportive care with adequate time to share information is essential. The mother and baby should be considered a unit-with non-separation the goal at all times.
Refer to the CPS guidelines for the diagnosis and treatment of infectious disease in newborns.
# Sepsis
With the introduction of guidelines for systematic maternal screening and increased use of intrapartum antibiotics, the incidence of group B streptococcal (GBS) sepsis has decreased from 1.7 cases per 1000 live births in 1993 to 0.22 cases per 1000 live births in 2016. 229,230 Despite this, GBS remains the leading cause of neonatal infection in Canada. In 2012, 48% of the cases of early onset neonatal sepsis were due to GBS, while Escherichia coli accounted for 31%. 231 Evaluating the risk of sepsis is an important part of the newborn assessment. Prompt treatment prevents the progression to severe disease. Babies at risk for sepsis are those where the mother has maternal GBS colonization in the current pregnancy or GBS bacteriuria; a previous baby with invasive GBS disease; prolonged rupture of membranes (≥18 hours); and maternal fever (temperature ≥38 °C).
# CARDIORESPIRATORY DISTRESS AND CARDIAC CONCERNS
Cardiorespiratory distress in the newborn may occur immediately after childbirth or later in the postpartum period. All HCPs caring for newborns must be able to assess respiratory distress, cyanosis, and perfusion. The CPS recommends that all centres in which babies are born have personnel capable of initiating assisted ventilation. 232 They also recommend following Neonatal Resuscitation Program guidelines for specific resuscitation procedures immediately after the birth and having a written policy regarding the initial care of a baby with respiratory distress outside of each birthing room in each facility. 232 Regular simulation sessions or other forms of practice scenarios are useful opportunities for continuing education and maintenance of skills.
Heart murmurs are common in the first few days of life and do not normally indicate a significant problem. In the first 24 hours, murmurs are often indicative of flow through the patent ductus arteriosus and disappear following the closure of the ductus. However, any murmur, even within the first 24 hours, must be assessed in the context of the entire physical examination. If a murmur persists or is symptomatic, a more complete evaluation is recommended. 233,234 The incidence of CCHD in Canada is 3/1,000 live births and accounts for more deaths than any other congenital malformation. Between 10% and 30% of CCHD diagnoses are not made prior to discharge from hospital. Early diagnosis and follow-up are essential first steps in preventing infant mortality and morbidity. 98 Pulse oximetry screening, used in conjunction with prenatal ultrasound and physical examination, is the best approach to detecting CCHD in newborns. 99
# HYPOGLYCEMIA
The definition of hypoglycemia in the newborn is controversial. Multiple reviews have concluded that no specific glucose concentration can be linked to clinical signs or neurological injury. 235 Approximately 12% to 14% of healthy, appropriatefor-gestational-age (AGA), breastfed, term newborns have blood glucose levels of less than 2.6 mmol/L in the first 72 hours of life. 236 The CPS does not recommend routine blood glucose monitoring in healthy term babies. 237,238 However, it is important to routinely screen babies at risk for hypoglycemia, including babies of mothers with diabetes (gestational and preconception), preterm babies, and both small-for-gestational-age (SGA) (weight 90 th percentile). The general recommendation for this population is that glucose levels be maintained at 2.6 mmol/L or higher after the first 2 hours of age.
Blood glucose screening of asymptomatic at-risk babies should begin at 2 hours of age and continue at a frequency and duration that depends upon the specific risk factors and until pre-feeding glucose levels have been consistently documented. 235,238 Babies who are unwell or show signs of hypoglycemia, such as jitteriness, lethargy, poor feeding, apnea, or tachypnea, require immediate testing.
Approaches to the management of hypoglycemia depend upon whether it is asymptomatic or symptomatic. Early and frequent skin-to-skin contact and breastfeeding is encouraged in asymptomatic babies, with supplementation with expressed breast milk the next best approach.
A breast milk substitute may be considered, if essential. 238 Refer to the CPS guideline Screening and Management of Newborns At Risk for Low Blood Glucose for information on diagnosis, monitoring, and management of hypoglycemia. 238
# PRENATAL ANTIDEPRESSANT USE
Selective serotonin reuptake inhibitors (SSRIs) are the antidepressant medications most frequently prescribed for the general population and pregnant women. 239 When considering prescribing or discontinuing SSRIs, HCPs are expected to weigh the potential harms of untreated depression or anxiety against potential risks to the fetus or newborn. SSRIs as a group have not been found to increase risk of major congenital malformations when used in the first trimester. However, paroxetine use in the first trimester may increase the risk of cardiovascular malformation, and other SSRIs may increase the risk of specific birth defects. 240 Third trimester use of SSRIs has been linked to a constellation of neonatal signs including prolonged crying, jitteriness, increased tone, tachypnea, cyanosis and feeding difficulty. 241 These signs occur in 10% to 30% of babies exposed to SSRIs in utero, usually within several hours of birth. The signs are usually mildsometimes so mild they are difficult to identifyand resolve over several weeks. 242,243 The mother is the best person to settle her baby with skin-toskin contact, breastfeeding, and holding and comforting-the HCP's role is to support her in caring for her baby and to provide a calm, quiet environment.
The CPS recommends observing the baby in hospital for 48 hours when SSRIs have been used during the third trimester. 240 However, since the majority of babies exposed to SSRIs are born healthy, Perinatal Services BC recommends considering discharge after 24 hours for babies who show no adverse signs or symptoms and who meet the following criteria:
- normal vital signs and oxygen saturation levels for the first 24 hours and at discharge;
- a normal physical exam;
- established feeding;
- well-regulating temperature; and
- no signs or symptoms of neonatal abstinence syndrome (NAS). 244 It is important to inform families about the possible effects of SSRIs on their baby and about strategies to support babies with symptoms. Postpartum use of SSRIs is not a contraindication to breastfeeding. 240 While information about long-term neurodevelopmental outcomes after prenatal SSRI exposure is largely reassuring, evidence in this area is limited.
Refer to the CPS guideline Selective Serotonin Reuptake Inhibitors in pregnancy and infant outcomes on caring for babies with SSRI exposure. 240
# SMALL-FOR-GESTATIONAL-AGE BABIES AND MACROSOMIA
# Small for Gestational Age
Babies who are born small for gestational a ge (SGA) have a birth weight below the 10 th percentile of the age-and gestation-specific birth weight. The rate of SGA births has increased steadily between 2008 and 2014, from 8.2 to 9.1 per 100 singleton live births in Canada. 245 Intrauterine growth restriction (IUGR) describes genetic or environmental factors preventing a fetus reaching its growth potential. Low birthweight is defined as weight at birth of less than 2500 grams (5.5 pounds) irrespective of gestational age. 246 Babies with SGA have physical characteristics (behaviour, alertness, spontaneous activity, and feeding ability) similar to those of normal-sized babies of like gestational age. They may look small and thin because they have decreased subcutaneous fat tissue and muscle mass, but they do not have the complications related to organ system immaturity that preterm babies of similar size have. Any complications are usually a function of the underlying cause of the SGA. 247 Parents and families of babies who are born SGA are anxious about their baby's well-being and require supportive care, counselling, and reassurance. Caring for the mother-baby unit, non-separation, and supporting breastfeeding are all essential aspects of care.
# Macrosomia
There is no consensus on the definition of fetal macrosomia, which some define as birth weight of more than 4000, 4500, or 5000 g, regardless of the baby's gestational age. Others define macrosomia as a baby above the 90 th birth-weight percentile for gestational age of a reference population-also known as large-for-gestationalage (LGA) babies. 248 The description normal birth weight depends on the population of reference.
In Canada, the LGA birth rate among singleton babies decreased from 11.6 to 10.2 per 100 singleton live births between 2005 and 2014. 245 Babies born with macrosomia are at higher risk of perinatal mortality (stillbirth and early neonatal, late neonatal, and post-neonatal mortality) and have a higher risk of shoulder dystocia, asphyxia, congenital anomalies, infection, and SIDS. 248 In addition, these babies are more likely to be born with a lower than normal blood sugar level, have a higher risk of childhood obesity, and a higher risk of metabolic syndrome during childhood. 249 Babies with macrosomia should be assessed for low blood sugar and jaundice and be encouraged to feed soon after the birth to prevent low blood sugar. 250
# NEONATAL OPIOID WITHDRAWAL SYMPTOMS
Neonatal opioid withdrawal symptoms are a group of possible symptoms experienced by babies whose mothers used opioids during pregnancy. From 48% to 94% of babies exposed to opioids in utero have opioid withdrawal symptoms. 251 While their symptoms vary, babies who have been exposed to opioids in utero may feed poorly and have diarrhea and weight loss. They may demonstrate tremors, tight muscle tone, excessive crying, hyperactive Moro reflex (sometimes called the startle reflex), irritability, vomiting and convulsions, hyperthermia and tachypnea. 252,253 If these signs become sufficiently severe, and depending on the drug that the baby was exposed to, the baby may require pharmacotherapy.
The CPS recommends that all babies exposed to opioids be assessed using a scoring system that measures the severity of withdrawal symptoms and helps determine the need for additional monitoring, nursing, medical intervention, or pharmacological therapy.
# Refer to the CPS practice point Managing Infants Born to Mothers Who Have Used Opioids During
Pregnancy for details. 253 The CPS also notes that the length of stay in hospital varies depending on exposure to opioids prenatally, severity of withdrawal, symptoms, treatment, and social factors. The Society recommends observing babies for a minimum of 72 to 120 hours, depending on their exposure to opioids. If the treatment threshold is not reached within that time, the baby can be discharged. The key to a successful transition home is to ensure continuity of care by an interprofessional team, with anticipatory planning for when the baby meets criteria for discharge. 253 It is important that babies be cared for in their mothers' rooms. Having in place a protocol for rooming-in and use of morphine (if required) for opioid-exposed babies helps to reassure staff about the safety of this treatment modality and supports them in caring jointly for the mothers and their babies. The BC Perinatal Services and British Columbia Centre on Substance Use guideline Treatment of Opioid Use Disorder During Pregnancy Guideline Supplement offers a sample rooming-in protocol for opioidexposed neonates. 252 Encourage mothers to hold and cuddle their baby as much as possible, as this helps to settle the baby and minimize withdrawal. In addition, if the mother is relaxed, the baby is more likely to relax. Also encourage breastfeeding, as this can delay the onset and decrease the severity of withdrawal symptoms as well as decrease the need for pharmacological treatment. 253,254 Consider that even babies who do not have in utero exposure to opioids usually take at least 36 to 72 hours to settle until the mother's breast milk comes in and breastfeeding is established.
If the baby requires pharmacotherapy, the mother and baby may be subject to a prolonged hospital stay. It is important to inform the mother during her pregnancy that she and her baby may need to stay longer at the hospital so that she has a realistic understanding of the early postnatal period and be better prepared for any additional care her baby may require. Note that rooming-in and non-pharmacological care often reduce withdrawal signs to the extent that pharmacotherapy treatment is not required. 252,253 Mothers who used opioids during pregnancy may experience a range of emotions; for example, anxiety over the well-being of their baby, concerns about withdrawal signs the baby is showing, and worries about maintaining custody, or they may be confident and relaxed. It is essential to individualize care to support the mother and other caregivers.
# The CPS practice point Managing Infants Born to Mothers Who Have Used Opioids During
Pregnancy discusses discharge criteria relating to the newborn and referral to support services and family services be considered. 253 In the Treatment of Opioid Use Disorder During Pregnancy Guideline Supplement, the BC Perinatal Services and British Columbia Centre on Substance Use advise that maternal opioid use alone is not grounds for the apprehension of a baby by authorities or referral to child protection. Make the decision to report on a case-by-case basis, in consultation with the entire health care team, although HCPs should be aware of their legal obligations in this regard. 252
# LATE PRETERM BABIES
Late preterm babies (34 +0 to 36 +6 weeks of gestation) vary widely in physiological maturity. The late preterm baby may have inadequate thermoregulation, immature and weak suck and swallow patterns, incomplete adaptation of certain enzyme systems, and poor immunological and respiratory defence systems. 255 These factors contribute to increased risk of death and morbidity compared to full-term babies. Common problems are hypoglycemia, hypothermia, respiratory distress, infections, increased risk and delayed onset of hyperbilirubinemia, feeding issues, increased hospital readmission rates, and growth failure. 256 Early term babies (37 +0 to 38 +6 weeks of gestation) are at increased risk for the same problems as late preterm babies, with increased likelihood of admission to NICU. 257 An assessment at birth to confirm the baby's gestational age and ongoing monitoring are important to determine the treatment plan. Delay in adaptation might require admission to NICU, while mature late preterm babies can be cared for in regular postpartum care. In both situations, it is important to avoid separating the mother and baby. 255
Screen for hypoglycemia and hyperbilirubinemia according to the CPS Screening Guidelines for Newborns at Risk for Low Blood Glucose and Guidelines for Detection, Management and Prevention of Hyperbilirubinemia in Term and Late Preterm Newborn Infants. Continued breastfeeding support is necessary to establish feeding and prevent readmission.
The CPS guideline Safe Discharge of the Late Preterm Infant provides detailed criteria for hospital discharge and post-discharge followup. 255 Some key criteria include stable vital signs for at least 12 hours prior to discharge, 24 hours of successful feeding, and avoidance of motherbaby separation before discharge by providing flexible accommodation arrangements for parents. Arrange for a follow-up appointment within 24 to 48 hours of discharge with a community-based HCP, prior to the baby being discharged home.
# ASSISTED VAGINAL BIRTH
Instrumental birth involves use of a vacuum extractor or obstetrical forceps. Trauma is the major complication of instrument-assisted birth in the newborn. Trauma may be caused by head compression and traction on the fetal intracranial structures, face, and scalp or by suboptimal instrument placement. 258 The most serious sequelae of trauma is intracranial hemorrhage, which occurs in 16 to 17 per 10 000 births. 259,260 The overall risk to the newborn from assisted vaginal birth is low. The risks that could occur include bumps, bruises, or marks on the baby's head or face that heal in a few days or weeks; cone-shaping of the head, which returns to normal within a day or two; injuries to the baby's scalp, head, and eye; injuries to the nerves in the arm or face-the baby's face muscles may droop if the nerves are injured but go back to normal when the nerves heal. 177,211 Subgaleal hemorrhage is a very rare but serious outcome. 177,211 If the baby has any trauma from an assisted birth, it is important that the mother and family understand the cause, the care required, and the anticipated outcome.
Refer to the SOGC Advances in Labour and Risk Management (ALARM) course for assessment, monitoring, and care of the newborn with subgaleal hemorrhage.
# ANOMALIES OR RARE CONDITIONS
Along with the joy of birth and the delight of welcoming a baby into the family, parents whose babies are born with congenital anomalies or rare conditions have special needs and may feel a sense of loss. Many factors influence parents' experience of having a baby with an anomaly: their personal beliefs, culture, and support network; their HCPs' knowledge and attitude; how the diagnosis is communicated; the information that they are given about their baby's diagnosis and what they can expect; and their connection to appropriate services and support groups. 261 In these situations, base all communication on compassion, using clear and simple terms. 262 Parents require access to the most current information about their baby's condition in a form they can understand. 263 They need to understand the immediate care plan and know what to expect in the future. 261 They should also be told about the necessary resources availablemedical services, clinics, specialists, therapy (e.g., physical, occupational, speech, vision), breastfeeding support, dietitians, mental health services, recreation services, and support groups.
When babies are born with anomalies or rare conditions, a team approach to the family's care is always required. Parents will often be referred to genetics services to help in the diagnosis of their baby. They could also be referred to genetics counselling if they have concerns about future pregnancies.
" Parents require access to the most current information about their baby's condition in a form they can understand.
HCPs are encouraged to take extra time to communicate with the parents and familyincluding significant family members such as grandparents and siblings. Show compassion, listen carefully as the parents and family express their concerns and feelings, and communicate in a way that everyone can understand. It is also important to ensure privacy when discussing the baby with the parents or family.
It is critical to remind parents and family (often repeatedly) about what to expect when they are caring for their baby. When parents are first told about their baby's diagnosis, they are often overwhelmed to the point that they are unable to retain information. A designated HCP should follow up with parents through the postpartum period and to repeat information in subsequent meetings, to assess their ability to cope, and to refer them to appropriate services. 261 Referrals to peer support can be helpful to provide parents with a shared social identity and contribute to feelings of hope. 264 Peer support can include face-to-face or online support groups relevant to the baby's specific condition.
# PROLONGED STAY IN HOSPITAL OR NEONATAL INTENSIVE CARE UNIT
A baby remaining in hospital (especially in the NICU) for an extended period can create a great deal of stress for parents and families. The kind of care that the baby receives, and the approach to care, affects not only the baby's physical well-being but also parent-baby attachment, feeding, neurodevelopmental outcomes, and the overall health and well-being of the baby, parents, and family. The parents and family may be experiencing extreme emotions such as anxiety or depression, or conflicting feelings such as the joy at the birth of their baby and the fears for the baby's well-being and their ability to provide care.
NICU environments that facilitate shared decision-making and partnerships between parents and professionals and enable parents to be their baby's primary caregiver, create a more consistent care for the baby. They also protect the baby from trauma associated with the NICU, such as isolation, stress, and lack of support during painful procedures, and provide parents with the opportunity to develop confidence and skill in caring for their babies. 30,265,266 Critical elements of family-centred care include: unrestricted presence of the parents, 24/7; parents and family as primary caregivers for their babies with the support and guidance of HCPs; and open, continuous communication 267 . The basic principles of family-centred care in this context are the same as all family-centred caredignity and respect, shared decision-making, choice, information exchange, empowerment, and collaboration. 267,268 Improvements in the baby's weight gain, decreased parental stress and anxiety, and increased high frequency exclusive breastfeeding at discharge are some of the demonstrated benefits of family-centred care in the NICU. 269,270 Others include decreased length of stay, enhanced attachment between parents and babies, and greater family satisfaction. 267,270 Family involvement is critical to enabling all babies to reach their full physical, cognitive, and psychosocial development-including those babies in the NICU. 270,271 The Family-Integrated Care (FICare) model is an extension of the principles of family-centred care, with parents as true partners in their baby's care within the NICU. This model was developed by a health care team that included parents whose babies had been in the NICU and follows research in Estonia. 29 Integrating parents into the care team in FICare goes well beyond merely allowing parents to be present and observing their baby's care. 272 Rather, parents provide most of the care for their baby while HCPs guide and counsel parents. 29,30 Single-family NICU rooms are now in use in a few centres in Canada as well as in the USA and Europe. The single-room setting has a number of benefits: it provides optimal environmental support to parents; reduces neonatal sepsis; improves baby weight gain; improves breastfeeding rates; improves control of excessive noise and light; improves staff and parental satisfaction with care; reduces parental and staff stress and anxiety; and costs the same, or possibly less, than standard NICUs. 269, Single-room care has not been associated with any increase in adverse outcomes. 275 The stressful environment of the NICU may add to the risks facing preterm or sick babies due to their physiological vulnerabilities, negatively impacting their growth, with the brain particularly affected. Developmental care refers to a range of strategies designed to reduce the stresses of the NICU and include control of external stimuli, improved clustering of care activities, and positioning or swaddling of the preterm baby. 278,279 While more research is needed, developmental care interventions has demonstrated benefits to the outcomes of preterm babies. 279 Some families, including Indigenous families and those living in rural and remote areas, may be far from home and have to travel for the birth or if the mother and child are transferred to another facility after the baby is born. Prolonged hospital stays can be particularly stressful for these parents, as they are away from extended family members, friends, and support networks. They may have other children back home, which can cause additional stress.
PROVIDING FAMILY-CENTRED CARE IN THE NICU 29,280,281 Parents
- Are full partners in decision-making and caregiving and are integrated into the NICU team;
- Have unlimited access to their babies and rooming-in, 24/7;
- Are supported by HCPs in aspects of care, such as prolonged skin-to-skin contact, breastfeeding, and providing developmentally appropriate care so that they become competent in their caregiving;
- Are supported in their baby's care to minimize their baby's stress and pain, to safeguard their sleep, and protect their baby's skin;
- Participate in care planning-in rounds and having access to their baby's records;
- Receive psychosocial support from the interprofessional team, including psychologists, and peers; and
- Are enabled to express their emotions and fears.
Health care providers: 29,267, - Provide care based on interprofessional collaboration and partnerships with family and other professional providers;
- Include parents as full partners in decision-making and care;
- Shift their role from skilled provider to one of guidance, supporting parents in their role as primary caregivers, 24/7;
- Focus on promoting baby-parent interactions, stressing the critical importance of parents' presence and rooming-in, and assuring them of unlimited 24-hour information and access to their baby;
- Support parents in a compassionate, respectful way, recognizing their individual needs;
- Support parents in skin-to-skin contact with their babies;
- Support mothers in breastfeeding and feeding their babies breast milk;
- Communicate with families openly and honestly, and spend time listening to the families' experiences, fears, and concerns;
- Communicate warmly, regularly, in an understandable fashion, and in a culturally appropriate and safe manner;
- Share information between themselves and with parents;
- Are aware of the possibility of posttraumatic stress disorder (PTSD), and screen for depression; and
- Are supported by system leadership who are committed to an integrated team approach to the needs of babies, families, and staff.
PROVIDING FAMILY-CENTRED CARE IN THE NICU 29,280,281 Policies: 29,267,280,284 - Are supported by a clear vision;
- Have full leadership and administrative support;
- Stipulate unlimited access and preferably rooming-in 24/7 and information for parents;
- Stipulate that parents are integral members of the care team, not visitors, and are their babies' primary caregivers, sharing in decision-making;
- Create opportunities for the participation of parents in support systems;
- Stipulate that HCPs communicate regularly with parents and provide mechanisms to do so;
- Ensure adequate staffing for the model of care in the unit;
- Support ongoing professional development for NICU staff;
- Actively involve parent partners and advocates in the development and monitoring of policies to inform quality improvement, and develop systems to accommodate this; and
- Support early and frequent breastfeeding or breast milk expression, meetings with lactation consultants and adequate follow-up-with a written policy.
Infrastructure and supports 267,271,283,285,286 - The physical setting is supportive of the baby's well-being and neurodevelopment, i.e., in a single room with enough space and resources to support parents' presence (e.g., with showers, kitchen, laundry, lounge, etc.) so that the parents can stay in the room with their baby 24/7 (or sleeping rooms available).
- The interprofessional team give the parents psychological and social support, and they have access to peer support.
- The physical environment supports the breastfeeding mother, e.g., provides for intimacy and means of expressing breastmilk, etc.
- Educational materials are available in plain language in a variety of formats (e.g., in writing, video, apps, etc.).
- Mechanisms in place enable parents' involvement in their baby's care and inform them of their baby's well-being, even when they are not present (e.g., by using web cameras).
- Preparation for the transition home begins at the baby's admission to the NICU, by providing information on the criteria for discharge and baby care, supporting parents to care for their baby, assessing the parents' social supports, and providing referrals to appropriate services.
- Care planning for the transition to home includes coordination of health and social care plans with any applicable community services, which may require multi-agency collaboration.
# LATE POSTPARTUM
New parents have many different emotions after the birth of their baby. They may feel full of joy and wonder, anxious, overwhelmed, worried and tired. Having a baby brings a myriad of changesand is very demanding. It takes months or even years to adapt to these changes. Becoming a parent is a deeply significant personal and social transition that involves a change of identity.
When caring for the new mother and her family, the goal of HCPs is to assist her in this transition and recognize and support her role in caring for her baby and nurturing their interdependent relationship. It is critical to spend time listening to mothers and families and to provide support based on their individual needs and experiences.
Providers should let new mothers know that they have faith in them and their ability to care for themselves and their baby. Providers can also help them listen to their intuitions and learn from their experiences so they become more and more confident in their new role. With time, the mother can discover her strengths and her own way of doing things. 287 Relationships with a partner and family are also undergoing transition. Communication is the key to nurturing these relationships. Talking about feelings, worries, and happiness during this intense period can help keep couples and/or families close. 287 Healthy early childhood development includes the physical, social/emotional, and language/ cognitive domains. 288 Many health, social, and justice issues later in life have their roots in early childhood. Parents need the supports of HCPs and community programs to assist them in fostering the optimal growth and development of their baby starting from birth.
# SYSTEMS TO FOLLOW FAMILIES POSTPARTUM
Postpartum support in the community should be planned according to a family-centred approach to care, based on women's experiences and needs, while respecting their diversity in the social and cultural contexts of their postnatal experience. 289 The woman and her partner and newborn belong at the centre of care, with strategies planned and provided to meet their needs, respecting the woman's preferences and decisions, while ensuring she is treated with kindness, respect, and dignity. 29,289,290 Women, newborns, and families have different points of access to postpartum care in the community. These often involve numerous HCPs (e.g., physicians, nurses, and midwives; lactation consultants and registered dieticians; social workers and psychologists) and communitybased providers (e.g., postpartum doulas and maternal child health home visitors). They also seek and receive support from their family members and peers.
Successful postpartum support strategies in the community are holistic and comprehensive, applying an efficient and effective interdisciplinary approach to care. 289 Women should have multiple choices for the kind of supports that meet their needs. It is critical that women be provided with a first/consistent point of contact (for example, a public health nurse, midwife, or nurse practitioner) for when they need to reach out for support.
Hospitals, health centres, community-based organizations, and public health and primary care providers offer postpartum services in Canada. Some jurisdictions have centres that provide education, support, and programming for new mothers and young families. Various models are used, including phone calls, telephone triage services, clinic visits (drop-in and by appointment), and home visits. 215 With many providers and many groups providing care, and with a lack of coordination across settings, postpartum care runs the risk of fragmentation.
As most women who give birth return home after a very short stay in the hospital or birthing centre, the coordination of support in the community is critical.
Planning postpartum care locally allows for the greatest efficiency and effectiveness. NICE guidelines recommend having a coordinating health care professional for each postpartum case and a documented, individualized care plan developed with the woman. 24 It is essential that mothers and families know about the specific community supports that are available to them in their area, perhaps in the form of a handout or website that lists the information.
While access to professional postpartum support within the community is essential for positive health outcomes for women, children, and families, social support networks have been identified as one of the key determinants of health. 291 It is also important that women have access to their own social support networks. Social media provides the opportunity for women to form virtual groups for support and information sharing. They can also access a variety of websites with evidence-based information, such as those of PHAC, provincial/ territorial governments, and professional organizations, that can provide answers to questions on self and baby care. HCPs can help women identify the websites or social media sites that may be helpful and those that would be best to avoid because they are neither helpful nor evidence-based.
Optimally, planning for the postpartum period starts during pregnancy. Prenatal education classes may provide a source of postpartum support from other families going through the same experiences. 292 Appendix B provides descriptions of innovative international and Canadian postpartum care models and guidelines. Refer to Appendix C for an outline of the various methods used to deliver postpartum care in the community.
# ONGOING POSTPARTUM CARE OF THE MOTHER AND BABY
Continued postpartum support and care needs to be provided according to the principles of familycentred care. It is important to determine and respect the woman's and family's views, beliefs, and values. The mother should be fully involved in determining the timing and content of each postpartum contact with HCPs so that the care she receives meets her and her baby's needs and is flexible. 24,41 At each postpartum encounter, the mother and her partner should have the opportunity to express their feelings and concerns and talk about their physical and emotional well-being, breastfeeding, rest, pain or discomfort and any concerns to do with the baby. These encounters provide HCPs with the opportunity to explore how the mother is coping with her daily experiences and her family and social supports, and to encourage women and their families or partners to talk about any changes in mood, emotional state, and behaviour that are outside of the woman's normal pattern. 24 HCPs will want to be aware of and look out for the signs of emotional health problems that occur during the weeks and months following birth.
Professionals have developed a number of methods-written standards of care, care plans, maps or paths, managed care, among others-to ensure that criteria for maternal and newborn health and adjustment are observed during the postpartum period. These criteria, also called indicators or outcomes, include specifics about the mother, the baby, and the family's social or home support system. While these tools are useful, the focus should always be on supporting the mother and baby's transition based on their individual needs and experiences.
# INTIMATE PARTNER VIOLENCE AND CHILD MALTREATMENT
HCPs are ideally positioned to recognize signs of family violence, including intimate partner violence, as well as child exposure to intimate partner violence and other types of child maltreatment. These forms of violence can negatively impact the health of mother and child, and the effects can persist over time.
It is important that providers be equipped to recognize and respond safely to situations involving family violence, and to ensure that their interactions or interventions do not revictimize the mother or child.
According to the Maternity Experiences Survey, about 1 in 10 women who have given birth reported experiencing one or more acts of violence in the past 2 years, most often being pushed, grabbed, or shoved in a way that could have hurt them. 215 Over half (52%) identified their partner, husband, or boyfriend as the perpetrator of this violence. One-third (31%) experienced the violence during pregnancy, and 16% reported that the violence increased after the birth of the baby, 52% that it decreased, and 32% that it stayed the same. Of those women who experienced abuse, 61% reported discussing or receiving information about what to do if they experienced abuse. 215 Intimate partner violence has been associated with mental health disorders for women, most commonly depression and anxiety disorders, and PTSD. Other effects on mental health include poor self-esteem, sleep disorders, eating disorders, phobias and panic disorders, substance dependence, antisocial personality disorders, and psychosis. 293 Intimate partner violence is also associated with postpartum depression. 294 Child maltreatment includes physical, sexual, and emotional/psychological abuse as well as neglect. Exposure to intimate partner violence is also a form of child maltreatment. 295 Child maltreatment is a major public health issue associated with a broad range of negative health outcomes across the life course. Approximately one-third of Canadian adults (32%) report experiencing physical abuse, sexual abuse, and/or exposure to intimate partner violence before the age of 16 years. 296 Provincial/territorial child welfare legislation considers exposing a child to intimate partner violence/family violence a form of maltreatment, and HCPs are required to report it. 296 Violence in the home has a negative impact on babies, whether they experience it directly, for example, receive an injury while held during physical violence, or indirectly, due to their dependence on their primary caregivers for emotional support. 297 When the primary caregiver is involved in a stressful event, the child's main source of comfort is a source of fear and distress. This repeated pattern can result in disorders of attachment, which may contribute to behaviour problems in later childhood. Babies and young children who experience repeated violence in the home have reduced capacity to regulate their emotions and behaviour because of their lack of emotional security. 297 Adverse Childhood Experiences (ACEs) research has shown that traumatic childhood events such as abuse, neglect, and household dysfunction are linked to an increased likelihood of developing physical, behavioural, and social problems in adulthood. 298 Canadian and WHO guidance do not recommend universal screening for intimate partner violence. 299,300
# MOTHER'S NUTRITION AND HEALTHY WEIGHT
Postpartum nutrition and achieving a healthy weight following a pregnancy can impact maternal and child health both in the short and the long term. The SOGC states that postpartum women can achieve optimal nutrition by eating a variety of high quality foods and following the advice in Canada's Food Guide.
Breastfeeding women have higher energy needs and should therefore eat a little more food each day than non-breastfeeding women. Canada's Food Guide recommends regular intake of vegetables, fruit, whole grains, and protein foods. Deficiency of certain nutrients, including thiamin, riboflavin, vitamin B6, vitamin B12, choline, vitamin A, vitamin D, selenium, and iodine, can adversely affect the concentration in breastmilk. 302 Health Canada recommends that all women who could become pregnant, including breastfeeding women, take a daily multivitamin containing 400 mcg (0.4 mg) of folic acid. 302 Some women, for example those who live in low income, Indigenous women or women who are newly arrived in Canada or refugees, may be at higher risk of nutritional challenges. 303,304 A lack of access to nutritious food, or to knowledge about nutritious food, can compromise women's and families' abilities to eat adequately. It is important that women receive nutritional counselling that is relevant to their specific needs and culture.
Refer to the SOGC guideline Canadian Consensus on Female Nutrition: Adolescence, reproduction, menopause, and beyond for components of the maternal diet that may affect those babies who are breastfeeding. 305
# Postpartum weight
Weight loss during the postpartum period should be gradual. There is little evidence that gradual weight loss affects the volume and quality of breastmilk once lactation is established. 305 The SOGC emphasizes the need for optimal nutrition to achieve a healthy body weight postpartum. Postpartum visits can be opportunities to check on weight retention/reduction, healthy eating habits, and exercise.
Refer to the SOGC guideline Canadian Consensus on Female Nutrition: Adolescence, reproduction, menopause, and beyond for more information. 305 HCPs are well positioned to recognize circumstances that are cause for concern; for example, a sudden, rapid weight loss or, conversely, if a woman is living with obesity.
The scientific knowledge about obesity and its treatment has led to the recognition that obesity is an illness and not a product of an inadequate lifestyle. It is important to avoid shaming and stigma. 306 Refer to the SOGC guideline Obesity in Pregnancy for recommendations on the counselling and care of women who have obesity.
# SEXUALITY AND CONTRACEPTION
Many factors influence a woman's sexuality during the postpartum period: her culture, her experience before and during pregnancy, her relationship, her physiology, and her emotional and psychological state. 307 This is compounded by the experience of giving birth, fatigue, the physical recovery from labour and birth, the changes her body is undergoing postpartum, caring for her baby, and perineal pain or discomfort.
Faced with the physiological and emotional changes of becoming new parents, intimacy may be challenging for women and their partners to maintain postpartum, but it remains important for the health of their relationship. Both women and providers often find it difficult to discuss postpartum sexual changes, adjustment, and intimacy. However, sexual concerns are common among women, and they welcome their HCP raising the topic and offering support regarding any concerns that she and her partner may have. 308,309 Low or no sexual desire is very common during the postpartum period. A lesser interest in sexual activity than before or during pregnancy is the norm during the first few months to a year after childbirth. 310,311 Between 22% and 86% of women experience changes in sexual functioning postpartum, especially those who have had an assisted vaginal birth as opposed to a spontaneous vaginal birth or caesarean birth. 312 A number of studies have linked episiotomy or perineal lacerations and operative vaginal birth with dyspareunia, which can persist for a number of months. 313,314 Women who have had a caesarean birth may also have discomfort with intercourse. 312,315
# Contraception and Prevention of Sexually Transmitted Infection
Postpartum women need information about contraception and preventing sexually transmitted infections (STIs), and about what methods are compatible with breastfeeding.
In this regard, the SOGC recommends the following: 316,317 - Lactational amenorrhea method (LAM) can be used for the first 6 months if the woman's periods have not returned and the baby is exclusively breastfed on demand day and night and is not fed other foods or liquids. 318 The woman will need to use another form of birth control once her period returns or the baby is older than 6 months, is no longer exclusively breastfeeding, is sleeping through the night, or has long intervals between breastfeeding. 318
- Postpartum women may be candidates for an IUC, which can be inserted immediately after delivery. However, women are at a higher risk for uterine perforation during insertion of the IUC in the first postpartum year.
- Hormonal contraceptives can be used by non-breastfeeding women from 3 to 4 weeks after they give birth. Some hormonal birth control methods may decrease milk production, but the progestin-only birth control pill does not appear to interfere with lactation. Currently available combined estrogen-progestin birth control pills do not interfere with the quantity or quality of breast milk once feeding is established.
- Condoms are an effective contraceptive option for breastfeeding and non-breastfeeding women. Condoms also protect both partners from STIs.
Refer to the SOGC guidelines The Canadian Contraception Consensus Guidelines for guidance on the use of contraceptive methods in postpartum and breastfeeding women to prevent pregnancy and STIs.
# IMMUNIZATION
Immunization is a proven cost-effective public health intervention that prevents significant illness, disability, and death. 319 Vaccines work best when they are given on time, beginning in infancy. Children are immunized early in life because they are vulnerable to diseases and the consequences can be very serious. The vaccination schedule is designed to protect babies and children before they are exposed to vaccine-preventable diseases.
Periodic outbreaks of illnesses such as measles, which can cause death or disability, can result because not all Canadians are immunized. 320 PHAC reports that 23% of children have not received the full four recommended doses of the diphtheria, whooping cough (pertussis), and tetanus vaccine by the time they are 2 years old. 321 In the last 10 years, the number of measles outbreaks has increased in several provinces, with five of the outbreaks involving more than 10 cases. These outbreaks are largely a result of the importation of the virus from other countries, with vulnerable children, including those who are not immunized, contracting the illness. 322 Some parents may be hesitant or resistant to immunizing their babies. The reasons behind children not being fully immunized are complex and context-specific and often community-specific.
A vocal few hold anti-vaccine views; they are not the main reason for the lack of coverage, although the number of vaccine-hesitant parents is growing. Some are complacent, taking vaccination rates and herd immunity for granted; some have doubts about the safety or necessity of vaccines, having been convinced by misinformation about adverse effects; while others do not get their children immunized because of the time and effort it can take to do so or they are concerned about the injections causing pain. 323 The CPS recommends that HCPs acquire the knowledge and skill to work with parents who are hesitant about immunization. Parents often look to HCPs for answers to their questions about immunization. HCPs will want to share evidencebased information about babies' vaccinations in a manner that is easy for parents to understand and explore any reasons families may have for not immunizing. 324 Connecting with parents in order to maintain trust and keep the lines of communication open is critical. Each parent requires different information geared to his or her specific needs.
It is important to understand a parent's specific concerns and to demonstrate care and compassion for both the child and the family. Telling stories about vaccine-preventable disease cases in Canada can help educate parents. Taking the time to convey information clearly, calmly, and effectively can make the difference whether a child is immunized. 325 Refer to the CPS practice point Working with vaccine-hesitant parents for more information.
The Canadian Immunization Guide, based on guidance from the National Advisory Committee on Immunization (NACI), provides guidelines for immunization of babies, children, youth, and adults, as well as specific recommendations for postpartum and breastfeeding women. The Canadian Immunization Guide includes the schedule for the following vaccinations for babies and toddlers up to 18 months:
- Diphtheria, tetanus, pertussis, polio
- Haemophilus influenza type b
- Rotavirus - Pneumococcal disease - Influenza - Meningococcal disease - Measles - Mumps - Rubella - Varicella - Hepatitis B
Although NACI makes recommendations at the national level, provinces and territories determine specific programs and schedules.
As such, HCPs need to refer to the immunization schedules of their respective jurisdictions.
It is critical that all siblings, parents, grandparents, other family members, and visitors have all their immunizations up-to-date when a baby comes home. This is particularly important if the baby or mother have underlying medical conditions or vulnerabilities that would increase their risk of communicable diseases like whooping cough and influenza.
# CONCLUSION
The birth of a baby involves many transitions and adaptations for the woman, the baby, and the family. Parents feel many different things following the birth of their baby-joy, wonder and happiness, as well as anxiety, worry and fatigue. These are all normal feelings. Mothers adapt physically and psychologically following birth as they face lack of sleep, physical discomfort or pain and relationship changes. Caring for a baby is demanding, requiring many adaptations for parents. While the postpartum period is a normal, healthy time of life, it is also challenging for families, even as parents get comfortable with their roles.
Providing family-centred maternity and newborn care to women, their partners, and families during the postpartum period is an essential component of the care offered by all institutions, agencies, and programs. It is important that HCPs focus on the individual needs and values of the mothers, partners, newborns, and families they are working with. As women, their partners, and immediate families develop attachment and confidence in caring for their newborn babies, they will also require support from extended family and friends, in addition to providers and community programs.
# APPENDIX B-LEARNING FROM OTHERS'-POSTPARTUM CARE MODELS AND GUIDANCE
The Netherlands
The Netherlands has a system for postpartum care provided by kraamverzorgenden-maternity home care assistants. Trained caregivers visit the home of new parents and observe the mother and her baby, offer information in baby care and feeding, and even help in household chores, shopping, and if necessary, cooking. The service is popular and, because of a recent shortage of kraamverzorgenden, the average number of hours of maternity home care assistance over the first 8 days after normal childbirth has decreased from 64 to 44 hours. 326 As a result of guidelines developed by government, insurance companies, and professional organizations, maternity care in the Netherlands is considered "remarkable for its degree of cooperation between caregivers at different levels and locations in the system. 326 " Pregnant women can move freely between care settings and caregivers, including midwives, general practitioners, and specialists.
# France
Most babies are born in hospital in France. When families leave the hospital, they are given the telephone number of the nursery nurse in their area and are encouraged to call with any questions or concerns. Newborn babies are issued with a health record book that contains all their medical informationincluding vaccinations-up to age 16 years. The health record book is considered an essential document, and it aids the communication process between HCPs and families. 327 Compulsory medical examinations of children are carried out regularly. The first is within 8 days of birth, another is in month 9 or 10, and the last during month 24 or 25. Mothers and children can access interdisciplinary mother and baby care ("Protection maternelle et infantile") at local maternal and child health clinics. Clinic staff conduct postnatal checks, provide nutritional and health advice, and can administer vaccinations. 327
# Canada
# Nova Scotia-Healthy Babies, Healthy Families: Postpartum & Postnatal Guidelines
The Government of Nova Scotia's Healthy Babies, Healthy Families: Postpartum & Postnatal Guidelines provide guidance for the organization of postpartum services. These guidelines were developed to enhance and support the provision of high quality care to women, their babies, and their families across Nova Scotia in the first 6 weeks postpartum. They contain recommendations that focus on physiological stability, infant feeding or nutrition and growth monitoring, psychosocial/family adjustment, parent-child attachment/parenting, building on capacities and strengths, transition to home and community, family access to community support, healthy lifestyles and environments, collaborative practice, and professional competency. 328
# Ontario-Standards of Postnatal Care
The Standards of Postnatal Care articulate the criteria of postnatal care for mothers and babies in Ontario in immediately postpartum. The Standards identify models, methods, or systems for improving coordination of care along with an evaluation framework to monitor their impact. To support the implementation of the Standards of Postnatal Care, another report was developed: Standards of Postnatal Care for Mothers and Newborns in Ontario (Part II): A focus on implementation and evaluation. This report provides an overview of implementation recommendations to enhance the delivery of postnatal care. It also includes a suggested evaluation framework that identifies priority standards for monitoring across the province. 42
# Ontario-Monarch Centre-Ottawa
The Monarch Centre is a multidisciplinary maternal and newborn health clinic providing evidencebased comprehensive care. Following the birth and discharge from hospital, babies born at the Ottawa Hospital and their mothers can be referred to the Monarch Centre for their first 24-to 48-hour check-up.
The registered nurses, board-certified lactation consultants, and family doctors at the Monarch Centre specialize in maternal and newborn care, and provide all the necessary breastfeeding support, bilirubin checks for jaundice, newborn screening and full postpartum check-ups, services and follow-up for mother and baby.
The Monarch Centre coordinates discharge directly with hospital providers to make sure that mother and baby are discharged when ready-and when it is medically appropriate. Upon coordinated discharge from hospital, Monarch supports the transition home for the new family. 329
# British Columbia-The Nurse-Family Partnership
The Nurse-Family Partnership (NFP) is an intensive home-visiting program designed to help young first-time mothers and their children. A public health nurse visits women enrolled in the program throughout their pregnancy and until their child reaches 2 years of age. The goals are to improve children's health and development while improving mothers' life situations.
McMaster University in Ontario ran a pilot study of the NFP program, and British Columbia is conducting a randomized controlled trial evaluation. In the USA, the program has demonstrated improved parenting, reduced injuries and poisonings, and improved emotional and language development by babies. The mothers have also been found to have benefitted, with greater participation in the workforce and less reliance on social assistance. 330,331
# APPENDIX C-METHODS USED TO DELIVER POSTPARTUM CARE IN THE COMMUNITY
Drop-In Clinics: Usually staffed by nurses, midwives, and lactation consultants, postpartum clinics are geared to mother/baby drop-ins or scheduled visits. The clinic program can be structured for health assessment, health concerns, breastfeeding support, and advice.
Home Visits: A traditional follow-up component of maternal and newborn care is the home visit by either a nurse or midwife. The length and frequency of visits vary according to the needs of the family and the program specifications. Referrals for home visits are made by the hospital or community liaison staff or by the mother herself; often, they are governed by the "urgency" rating of the assessed need.
In some areas, home visiting has been discontinued or replaced with community-based supports that the mother must transit to. Some hospitals have initiated home follow-up by their childbirth staff for mothers in need, as identified by risk criteria or need for additional support. Some home-visiting models use a combination of professional and paraprofessional visitors.
Online: Online resources for postpartum information include social media, websites, and blogs. Online resources enable mothers to engage with other mothers, share experiences, and attain information on caring for themselves and their newborn.
Parenting Courses: As with prenatal classes, some parents benefit from group or individual discussions on parenting during the postpartum period and learn more about their roles as parents through these.
Peer Support: Mother-to-mother support provided in various ways-in person, over the phone, via social media or texts. The supporter is or was in a similar situation to the peer. Some peer-to-peer support deals with specific topics such as breastfeeding or postpartum depression, while others provide general postpartum support.
Phone Lines: Some provinces and communities have initiated phone support and advice for new parents. Parents can ask questions, sometimes day or night, about personal, parenting, and postpartum health concerns. Questions usually relate to breastfeeding, crying, coping at home, and community resources. Phone lines can be connected to general health lines or hospital postpartum wards, or run by public health units or community-based organizations.
Physician/Midwife: Follow-up assessments by the physician, midwife, or other HCP in the community or home. Scheduling/timing of visits depends on general maternal and newborn health; complications of pregnancy, birth, and the postpartum period; and available family/community supports.
Telephone Follow-up: A phone call from public/community health nurses or midwives can ensure that the postpartum plan is in place and working well. Specific outcomes related to feeding and mother and baby well-being can be addressed. The telephone interview may result in a referral to a community agency for service, such as a home visit or other follow-up.
The Canada Prenatal Nutrition Program (CPNP) is a Government of Canada program that provides funding to community groups to help improve the health of pregnant women and new mothers and their babies who face, for example, poverty, teen pregnancy, social and geographical isolation, substance use, or family violence, which put their health at risk. CPNP aims to improve the health of women and their babies by increasing the number of babies born at a healthy weight and promoting and supporting breastfeeding. It ensures culturally sensitive prenatal support for Indigenous women and women who have recently immigrated.
The program provides nutrition counselling, prenatal vitamins, food, food coupons and food preparation training, counselling in prenatal health and lifestyle, breastfeeding education and support, education and support on baby care and child development, and referrals to other agencies and services. 332 The Community Action Program for Children (CAPC) is another Government of Canada program that provides funding to community groups whose focus is the promotion of the healthy development of families (with children from birth to 6 years old) who face challenges that put their health at risk-poverty, teen parenting, social and geographical isolation, substance use, and family violence.
# APPENDIX A-ADDITIONAL RESOURCES
# CLINICAL PRACTICE GUIDELINES RELATING TO POSTPARTUM HEALTH
|
16% to 30% of women with gestational diabetes develop type 2 diabetes by 5 to 10 years postpartum 3.4% 10% 10%The postpartum period is a significant time for the mother, baby, partner, and family. It is a time of transition and adaptation and is formative for everyone. There are physiological adjustments for both mother and baby, and significant social and emotional adjustments for the entire family. Providing family-centred care to women, their partners, and families during the postpartum period is an essential component of the care offered by all institutions, agencies, and programs. While the postpartum period is a normal, healthy time of life, it is challenging for families even as parents get comfortable with their roles. It is important that HCPs who are working with mothers, partners, newborns, and families focus on their individual needs and values. Key family-centred care recommendations: • Treat families with respect, dignity, and kindness, and learn about and respect their values and beliefs, using them to guide their care. • Maintain open and ongoing communication with the woman and her partner/family; • Plan the timing and purpose of each postpartum contact in partnership with the woman and her partner/family based on their individual needs. • Provide culturally competent and safe care with cultural humility. • Provide information and support in a timely fashion, according to the needs of the woman, her partner, and family. Information should be evidence-based and accessible according to their culture, language, and abilities so that they can promote their own and their baby's health and make informed decisions about their care and any necessary treatment. • Support and promote the physical well-being of mother and baby and enable the mother to rest and recover from the physical demands of pregnancy and birth. • Foster the developing relationship between the baby and their mother as well as the mother's partner and family. • Support the mother's and her partner's emotional and mental health needs.#
Complex and finely tuned adjustments have physical and psychological benefits for the mother and her baby. It is important that everyone involved in the care of mothers and babies knows and acknowledges these benefits so that systems are planned and organized around the mother/baby unit and not around health care providers (HCPs).
The goals of care during the postpartum period are to:
• Support and promote the physical well-being of mother and baby and enable the mother to rest and recover from the physical demands of pregnancy and birth;
• Support the developing relationship between the baby and their mother as well as the mother's partner and family;
• Support the mother's and her partner's emotional and mental health needs;
• Support infant feeding;
• Support the mother's confidence in herself and in her baby's health and well-being, enabling her to fulfill her mothering role within her particular family and culture; and
• Support partners and other family members to enable them to develop confidence in their new role.
According to the principles of family-centred care, it is incumbent on HCPs to:
• Treat families with respect, dignity, and kindness, and learn about and respect their values and beliefs, using them to guide their care;
• Maintain open and ongoing communication with the woman and her partner/family;
• Plan the timing and purpose of each postpartum contact in partnership with the woman and her partner/family based on their individual needs;
• Provide culturally competent and safe care with cultural humility;
• Provide information and support in a timely fashion, according to the needs of the woman, her partner, and family. Ensure that information is evidence-based and accessible according to their culture, language, and abilities so that they can promote their own and their baby's health and make informed decisions about their care and any necessary treatment.
# > ADDITIONAL RESOURCES ON POSTPARTUM CARE: SEE APPENDIX A
The postpartum period is a significant time for the mother, baby, partner, and family. It is a time of transition and adaptation and is formative for everyone. There are physiological adjustments for both mother and baby, and significant social and emotional adjustments for the entire family.
# FAMILIES WITH SPECIAL CONSIDERATIONS
# CULTURAL CONSIDERATIONS
Canadians are ethnoculturally diverse. Women from different cultures, whether Canadian-born or newcomers, may be influenced to a greater or lesser extent by their background.
HCPs will want to assess each woman's background-if they are newcomers, their place of birth, how long they have been in Canadaand their support networks. 1 It is important to understand how the woman's culture influences her unique needs, hopes, and postpartum expectations. Even when the necessary services are available and they are made aware of them, immigrant women may face language barriers and difficulties in access because of differences in cultural practices and expectations. 2 Most women who are newcomers to Canada face challenges of some sort: 2
• The Canadian health care system may feel foreign and strange, and they may have different expectations from those of their HCPs.
• They may not know about the available supports in the health care system.
• They may not share a common language with available HCPs, and their communities may not have access to culturally sensitive health care or translation services.
Each family is unique; they adapt their cultural traditions and practices to their own experience and needs, and they will interpret the parameters of the Canadian health care system within this context. As such, it is important to assess each situation individually. While HCPs may not always agree with certain cultural practices, respecting families' needs and decisions is paramount.
Listening to the women's and families' stories about their own culture, childbearing practices, and needs helps accomplish this approach. 1 Giving Birth in a New Land: Strategies for service providers working with newcomers suggests specific strategies that promote family-centred, culturally competent postpartum care. 3 HCPs can use these to engage in a dialogue with women and families and learn about their values and beliefs and how these apply to their situation.
HCPs need to consider the personal values they bring to their relationship with families. Cultural competence includes working collaboratively with families and communicating effectively.
Communication with families from different cultural backgrounds involves not only translating words, but also understanding subtle variations in meaning, style, volume, and gestures. 1 As such, it is important to find the best possible interpreter for the specific situation.
Interpreters must be trustworthy regarding access to private information and, ideally, have specific health-related language skills. Using children or other family members as interpreters is not recommended. 1,3 If families are newcomers to Canada, ask about their place of birth, how long they have been in Canada, and their support systems. To ensure that women have an opportunity to express their needs, helpful questions include:
# 5-3
# QUESTIONS TO FACILITATE COMMUNICATION ABOUT VALUES AND BELIEFS
• How is health care different in your homeland or culture?
• What do you and your family believe you should do to remain healthy postpartum?
• What are the things you do to improve your health and the health of your baby? What can't you do?
• Do you have beliefs about caring for your baby and yourself that I need to know about?
• Do you have any practices and faith rituals to do with your role as a mother?
• Are there any specific foods that you might eat/drink (or prefer to avoid)?
• Are there any home remedies that you may use during the postpartum period?
• Who do you want involved in decision-making?
Adapted from Giving Birth in a New Land: Strategies for service providers working with newcomers (2014), and Maternal Child Nursing Care Canada (2017).
# CARING FOR INDIGENOUS WOMEN, NEWBORNS, AND THEIR FAMILIES
The history of residential schools and colonization, which caused the loss of traditional values and practices, languages, and family/community kinship, continues to affect Indigenous women, families, and communities. Indigenous Peoples have poorer health outcomes and higher rates of poverty, food insecurity, and unsafe and overcrowded housing. These social determinants of health take a toll on the physical, emotional, mental, and spiritual health of Indigenous women in Canada.
The health and well-being of many Indigenous women and families have been further undermined by racism, sexism, and culturally inappropriate or inaccessible health serviceswhich also affect Indigenous women and their babies during the postpartum period. [4][5][6] Indigenous women in Canada are diverse in their culture, ancestry, beliefs, and practices. Each Indigenous community has its own traditions, values, language, and communication styles. Many Indigenous women want to incorporate their cultural and societal values and beliefs into their lives and parenting. Integrating cultural safety in the care of Indigenous women during the postpartum period involves providing an environment of respect and open communication, which is consistent with the principles of familycentred care. Indigenous women, as all women, need to feel safe in order to build a trusting relationship with their HCPs.
HCPs should engage with, and familiarize themselves with, the community and work with women to understand their individual values, beliefs, and needs. 7 An Indigenous doula can assist in honouring traditional and spiritual practices and beliefs associated with postpartum care and support the woman and her family's language and cultural needs while providing emotional and physical assistance during pregnancy, labour, and the postpartum period. 8 Indigenous women may have to leave their communities to give birth in larger centres.
Being away from their families and support systems affects their postpartum experience, including breastfeeding, and recovery. It is important to consider their needs and re-connect them with families and communities as quickly as possible.
Indigenous-specific postpartum and parenting programs are ideal-particularly group formats that allow Indigenous women to meet each other and develop supportive friendships during their pregnancies. Programs that support Indigenous fathers so that they feel equipped to help their partners and children are also necessary. Better systems of referrals and communication between different services and organizations would ensure continuity and comprehensiveness in care. 9 Training and Education of Healthcare Providers
There is a need for better training of HCPs on how to create culturally safe, stigma-free, and respectful care for Indigenous mothers, babies, and families during the postpartum period. 9 A nationwide survey of residents and program directors of all accredited obstetrics and gynecology residency programs in Canada demonstrated a lack of curriculum and a significant deficit in knowledge in Indigenous women's health. 10 As a result, a nationwide curriculum initiative is underway for residents and other health care practitioners. This will facilitate the provision of education in Indigenous women's health while decreasing the burden on individual programs.
# CARING FOR LGBTQ2 FAMILIES
Family-centred maternity and newborn care is based on individual needs and a mutually respectful and trusting relationship. While progress has been made in providing equitable health care to the LGBTQ2 community i , these families often continue to face barriers in health care.
People in the LGBTQ2 community identify 3 major barriers when dealing with the health care system-invisibility, lack of information, and negative beliefs. Invisibility refers to the fact that they do not see themselves in the institutions/ programs-for example, the posters on the walls, the forms they complete-or in conversations with HCPs. The HCPs they encounter often do not understand their experiences as an LGBTQ2 family, their unique and diverse needs, and may have negative beliefs about them. 11 Sexual minority women (including lesbian, bisexual, and other non-heterosexual women) have a greater prevalence of depression and depressive symptoms compared with heterosexual women, likely because of the impact of sexual orientation-based discrimination, stigma, lack of social support and exposure to additional stress due to heterosexism from their families and some HCPs. [12][13][14][15][16] Invisible sexual minority women (i.e., women who have a history of sexual relationships with women but are currently partnered with men) are at higher risk for postpartum depression than both visible sexual minority women (women partnered with women) and heterosexual women. 14,17 i The acronym LGBTQ2 is commonly used to include people who identify their sexual orientation as lesbian, gay, bisexual, queer or questioning, and/or who identify their gender identity as transgender. These guidelines recognize that sexual orientation and gender identity exist along a continuum that may change over time, and that the LGBTQ2 community is diverse. 334 Ongoing education for HCPs on the unique needs of LGTBQ2 families is essential to improving the health care LGTBQ2 families receive. 18 HCPs caring for LGBTQ2 families will want to confront any negative beliefs they may have and aim for ease in approaching the topics of gender, sexuality, and families. It is important that HCPs reflect on their beliefs about LGBTQ2 people and be willing to challenge these beliefs to develop their practice. 11 HCPs can facilitate inclusivity when caring for LGBTQ2 families, including during the postpartum period, by: 11 • Paying attention to words and language. Words can empower people and they can hurt.
• Being aware of non-verbal communication and tone of voice-these express emotions and attitudes.
• Using non-biased, inclusive language and open-ended questions.
• Asking questions that express openness to all families-and not making assumptions about gender identity, sexual orientation, or behaviour.
• Making sure forms and questionnaires are inclusive.
• Ensuring that visuals, such as posters, in a clinic or program area signal acceptance of diversity.
• Posting a non-discrimination policy and communicating an environment of respect.
# POSTPARTUM CARE
# IMMEDIATELY AFTER CHILDBIRTH (BIRTH TO 2 HOURS)
# INTEGRATED CARE OF THE MOTHER AND BABY
The mother and newborn should be considered a unit during the immediate postpartum period (0-2 hours). It is important to avoid disrupting this close relationship during these crucial few hours and to encourage skin-to-skin contact between the baby and the mother (or partner if the mother is unable). The International MotherBaby Childbirth Organization refers to this as motherbaby care to emphasize the importance of recognizing that mothers and babies are a unit.
The parent-baby bond-the first step in the baby's subsequent attachments-is formative to a child's sense of security and has long-lasting effects. 19 Having early physical contact with the baby can affirm parents' sense of accomplishment and promote their self-confidence as parents. Keeping babies and parents together is of the highest priority. Institutional policies should only disrupt this contact in the event of a necessary, evidence-based medical reason.
All major organizations concerned with newborn health, including the Society of Obstetricians and Gynaecologists of Canada (SOGC), the Breastfeeding Committee for Canada, the Canadian Paediatric Society (CPS), the Canadian Association of Midwives, the American Academy of Pediatrics, the World Health Organization (WHO), and the United Nations Children's Fund (UNICEF), recommend that healthy babies have direct skin-to-skin contact with their mothers immediately following birth. Skin-to-skin contact involves placing the newborn babies on their mothers' bare chest immediately after she gives birth, covering the baby with a blanket, and ensuring that contact is uninterrupted for at least an hour or at least until the first feeding is completed or the mother wishes. 20 It is essential to prepare mothers for skin-to-skin contact before birth. Since some cultures may not practise this contact, information, encouragement and support are called for.
Being held by their mother helps the baby normalize his or her temperature, breathing, heart rate, and blood sugar and reduces the pain of medical procedures. Babies who have skin-to-skin contact interact more with their mothers and cry less than those who do not have this contact. [21][22][23] The vast majority of babies go to the breast within an hour of birth if they are kept skin-to-skin with their mother. Mothers are more likely to breastfeed in the 4 months postpartum and tend to breastfeed for longer if they have early skin-to-skin contact with their babies. 22 Nevertheless, skin-to-skin contact is important for all mothers and babies regardless of the mother's decision about feeding. If the mother herself is unable to have skin-to-skin contact with her baby, she should choose another person to hold, warm, and comfort the baby, for example, her partner or another family member.
HCPs can demonstrate respect for the family by interfering as little as possible during interactions between the mother and baby. Observations, assessments, and interventions can be completed with minimal intrusion, while skin-to-skin contact is maintained. Anything that is not essential to the immediate well-being of the baby or mother can wait for 2 hours or after the first breastfeeding. Even medically necessary procedures can be done while the baby remains in skin-to-skin contact as long as it is medically safe to do so. 23,24 Skin-to-skin contact should continue during transfer from the birthing unit to the postpartum unit or neonatal intensive care unit (NICU). 25 At this time, babies should be observed for abnormal respiratory effort, colour, activity or tone-signs of instability that call for urgent evaluation. Separating a mother from a baby requiring special care can make adjustment to motherhood more difficult, and HCPs are called upon to provide even more intensive support at such times. There are continued benefits to skin-toskin contact past the immediate first few hours of birth, as well as benefits to initiating skin-to-skin contact later, if this was not possible immediately following birth. 23,24,26 In some Canadian and European centres, preterm babies stay with their parents during assessments, and couplet care is practised within the NICU. 27 Many centres are advocating for skin-to-skin contact, even of very preterm, ventilated, and low birth-weight babies, because of the clinical and psychological benefits to both baby and parents. 28
# FAMILY-INTEGRATED CARE IN THE NEONATAL INTENSIVE CARE UNIT
Recent Canadian research has found that a family-integrated care (FICare) model of care for preterm babies in neonatal intensive care units (NICU) is feasible and safe in the Canadian health care setting and results in improved weight gain by these babies. The FICare model of care, which is based on the original work of Dr. Adik Levin in Estonia, also has the potential to improve other short-and long-term outcomes for babies and families. 29 In this model, parents provide most of the care for their baby, while nurses and other HCPs guide and counsel parents. 29,30 FICare is more than just the physical setting; the model recognizes that parents are the primary caregivers and decision-makers for their babies. FICare can be accomplished even in older units, and HCP teams are expected to adapt to that reality whenever possible.
Innovative examples of this model of care in Canada include the following:
• BC Women's hospital offers intensive care for newborns and postpartum care for mothers in the same room. Mothers are able to recover from vaginal or caesarean births and pump breast milk without leaving their babies. All newborn babies have their own sound-proofed rooms, and 12 of the 70 rooms are spacious mom-and-baby rooms equipped with a breast-pumping station, reclining chair, and hospital bed for the mother as well as an incubator and infant-monitoring machines. The mom-andbaby rooms are for babies born at 33 weeks or later at low risk of complications.
• In Nova Scotia, the IWK Health Centre is caring for mothers and babies together in their NICU. Each room has a full setup to care for a baby as well as a suite for the family to stay in. The family is given a double bed, a closet with a safe, and a private washroom with a shower. Babies are continuously monitored and, if an alarm is triggered, a signal is sent to a nurse's smartphone. The rooms are also equipped with everything from milk fridges to special sinks that help families bathe their babies. Rooms without windows have skylights that mimic clouds in the sky, and every room has artwork.
In the event of a caesarean birth, it is important to provide all possible opportunities for immediate (defined as within 5 minutes) and uninterrupted skin-to-skin contact as well as breastfeeding when babies cue to feed. This can be done in the operating and recovery rooms. In fact, skin-to-skin care should be considered the norm for caesarean births in the operating room, decreasing the need for early supplemental feedings. 31 It is important to provide time alone for the family in those critical first hours, with opportunities for both parents to interact with the baby in the birth and recovery rooms. Parents should be encouraged to spend as much time as possible with their baby, including in the NICU, ideally while rooming-in together. If the woman's partner chooses not to be present for the caesarean birth, the family should be re-united as soon as possible. 32
# CARE OF THE MOTHER
The immediate postpartum period is a time of joyful celebration for the vast majority of families, but it is also a time of considerable physiological adaptation for the mother-and for the baby.
As such, careful observation and, at times, intervention is required.
Women have different responses on giving birth. Some feel excited, uplifted, and energetic. Others are exhausted and want to sleep. A woman's response may depend on the length, difficulty, and pain during labour, blood loss, anesthesia/ analgesia, complications, and whether she had an operative vaginal birth or caesarean birth. Another determining factor is the woman's experience of labour and birth compared with her expectations of these events.
Physical adjustments in the immediate postpartum period-including blood loss, weight loss, and displacement of internal organs-require a significant expenditure of energy. Immediate postpartum care centers on the need for hydration, nutrition, and rest. It is a time to replenish energy.
Begin each postpartum contact by asking the woman how she feels, physically and emotionally, and identifying any concerns that she may have.
The physical observation of the mother at each postpartum contact should be individualized and guided by her unique history and situation.
The assessment can include the following, depending on the mother's feelings, sensations, and expressed needs: 24
• Vital signs (temperature, pulse, respiratory rate, blood pressure);
• Uterine tone and condition of perineum;
• Lochia;
• Bladder and bowel function;
• Breasts and nipples;
• Physical comfort;
• Emotional and psychological response to labour and birth, for the woman and her partner. Starting this conversation is particularly important in certain circumstances (e.g., when the baby is sick, the mother had complications, or the birth did not go as planned);
• Skin-to-skin contact with baby; and
• Learning needs.
Document the findings according to the institution's policy.
# CARE OF THE NEWBORN
The baby's transition to life outside the uterus involves:
• Establishment of effective respiration and circulation;
• Maintenance of an adequate body temperature;
• Contact with his/her mother and family; and
• Initiation of feeding.
# POSTPARTUM HEMORRHAGE
Postpartum hemorrhage is the most common complication in the immediate postpartum period.
It affects approximately 6% of women globally and is the leading cause of maternal mortality worldwide. 33 In Canada, a diagnosis of postpartum hemorrhage was associated with 1.6 maternal deaths per 100,000 hospital births from 2002 to 2010. 34 From 2006 to 2010, it was the second most common severe maternal morbidity, at a rate of 465.4 per 100 000 hospital births. 34 Postpartum hemorrhage is defined as blood loss of more than 500 mL during vaginal birth or more than 1000 mL during caesarean birth. The primary cause of immediate postpartum hemorrhage is uterine atony. Other causes include uterine rupture, morbidly adherent placenta, and uterine artery extension/laceration during caesarean birth.
Refer to the Society of Obstetricians and Gynaecologists of Canada (SOGC) guideline Active Management of the Third Stage of Labour: Prevention and treatment of postpartum hemorrhage. 35 Postpartum hemorrhage has many implications for the woman, including orthostatic hypotension, anemia, fatigue, and fear-all of which affect her ability to care for herself and her baby. It may also result in a lack of immediate skin-to-skin contact with her infant and an increase in the risk of postpartum depression. A blood transfusion may be necessary, which has risks. 36,37 Delayed, or secondary, postpartum hemorrhage (between 24 hours and 6 weeks postpartum), may occur after the woman and baby have been transferred to a postpartum unit or at home.
It is important to educate women of the signs and symptoms of concern relating to delayed postpartum hemorrhage before discharge and after a homebirth.
The postpartum period is a critical transition time for the baby. This period requires thorough and ongoing assessment and monitoring. An initial, head-to-toe examination of the baby in the birthing area ensures that he or she is adapting to the extrauterine environment. This examination would also identify any abnormal clinical findings. These observations can be completed when the baby is skin-to-skin, which promotes intimacy while helping to maintain a calm environment.
# Neonatal Resuscitation
The Neonatal Resuscitation Program (NRP) acknowledges that at least 90% of newborns are vigorous, term babies who do not need to be separated from their mothers for the initial steps of resuscitation. Care for these babies includes:
• Managing the umbilical cord (i.e., avoidance, where possible, of immediate clamping);
• Providing warmth by encouraging direct skin-to-skin contact, ideally with the mother;
• Drying the baby's skin with a warm, dry towel, stimulating breathing, and repositioning the head to open the airway;
• Clearing mucus from the upper airway, if necessary, by wiping the baby's mouth and nose; and
• Ongoing observation of breathing, heart rate, activity, and colour. 38 Refer to NRP guidelines for the management of specific clinical situations. 23,39 HCPs obtain skills in neonatal resuscitation through NRP training coordinated by the CPS, which has set the educational standards for Canadian practice. The Society recommends that an individual trained in neonatal resuscitation be assigned to this role at every birth. The CPS also recommends that all personnel likely to care for babies at birth have training and registration at the Provider or Instructor level and undergo periodic re-registration. 39 While the primary care provider at the birth is responsible for the woman's care, a second HCP should have the primary role of assisting the baby through transition-one able to provide positive pressure ventilation and perform chest compressions, if necessary. 38 Another person with the skills to perform a complete resuscitation (including intubation and chest compressions) should be readily available to assist. 38,40 The CPS also advises that local/regional health authorities have in place a program that supports the implementation of current neonatal resuscitation guidelines, educational programs for HCPs involved in care during labour and birth, and policies that take into account the educational needs, roles, and responsibilities of professionals involved in care during labour and birth/care of the newborn.
# Neonatal Stabilization
A proportion of newly born babies are identified as at risk or unwell during the minutes or hours following birth, often due to prematurity or poor cardiorespiratory transition. All delivering facilities and practitioners should have a plan that addresses these babies' clinical needs (such as respiratory support or glucose management), communication with referral centres, and support of the family.
The CPS's Acute-Care of at-Risk Newborns (ACoRN) program specifically addresses the needs of babies who are challenged by the transition to extrauterine life. Facilities may find this program useful in preparing for the possibility that a newborn is unwell or at risk.
# EARLY POSTPARTUM CARE (AFTER 2 HOURS)
The key goals of early postpartum care are to:
• maintain and promote the health and wellbeing of mother and baby;
• support the mother in caring for herself and her baby;
• foster attachment between the baby and the mother, her partner, and other significant family members;
• support the physical and psychological adjustment of the mother and her partner, the baby, and the family; and
• promote effective feeding.
Every postpartum interaction should be carried out in accordance with the principles of familycentred care, basing care and support on evidence of individual needs and not routines.
The benefits of skin-to-skin contact continue through the early postpartum period, facilitating attachment, increasing the duration of breastfeeding, and decreased crying and expression of pain during procedures such as heel prick blood sampling. 23 Although no national guidelines on labour, birthing, and postpartum rooms exist, the Provincial Council for Maternal and Child Health (PCMCH) recommends that mothers who give birth in hospital have a spacious room, preferably a private one, where they can labour, give birth, and stay with their babies until discharged. Rooming-in 24 hours a day should be the norm for all mother-baby dyads unless there is a justifiable reason for separation. 20 As many interventions as possible should occur in the mother's room to avoid separation. Admissions to nurseries should be based on established criteria and guidelinesand be the exception rather than the rule. 23 A personalized postpartum care plan should be developed in partnership with the mother and her family as soon as possible following the birth. It includes: 24
• the mother's concerns and needs;
• important factors in the pregnancy, birth, and immediate postpartum period;
• assessment of infant feeding;
• the names and contact information of the professionals involved in the mother's and baby's care; and
• planned follow-ups/appointments with HCPs for mother and baby during the postpartum period.
The plan needs to be reviewed and adjusted with the mother and family after every postpartum interaction.
Each mother should be assigned an HCP who is responsible for coordinating the care of the family and their transition into the community. This HCP consults with others, as necessary, as the needs of the mother and baby evolve. When birth takes place in hospital or a birthing centre, it is critical that systems, policies, and protocols ensure families are discharged only after followup care in the community is established. 41,42 Optimal family-centred care during the early postpartum period requires seamless continuity of care and information-sharing between HCPs. How this is accomplished depends on the type of provider and the jurisdiction. Successful coordination of early postpartum care depends upon clear communication between institutions, community HCPs, and families. Hospitals, birth centres, physicians, nurse practitioners, and midwives need a strategy to facilitate effective communication of health information as mothers and babies transition into the community. A comprehensive discharge summary or maternalnewborn passport program may be useful. Secure electronic communication facilitates this process. 43 The Breastfeeding Committee of Canada and WHO recommend assessing newborn babies for breastfeeding issues within 24 to 48 hours of discharge from a hospital/birthing centre with routine follow-up of all mothers within 48 hours of discharge; 20,44 this care may be provided by the hospital, community health centre, a breastfeeding clinic, midwife, etc.
Most newborn care guidelines recommend that an HCP assess the mother and baby during the first week of life. 45 The American Academy of Pediatrics specifies that this assessment takes place 48 to 72 hours after discharge if discharge occurs less than 48 hours following birth. 46 The CPS states:
"At time of discharge, infants must have an appropriate follow-up plan in place that includes: contact information for a primary health care provider; a scheduled follow-up visit 24 h to 72 h post discharge-in hospital, clinic or at homewith a qualified health care provider. Hearing and newborn screens have been scheduled (if they were not conducted in-hospital); appropriate follow-up for jaundice; vitamin D supplementation if breast-fed; other follow-up, as required. 45 "
Even though the same principles and philosophy of care underpin all postpartum care, postpartum services should be organized locally to maximize effectiveness and efficiency for women and their babies.
# HOSPITAL BIRTHS: LENGTH OF HOSPITAL STAY AND DISCHARGE
In 1993, the average length of stay after a vaginal birth was 3.2 days, decreasing to 2.0 days by 2012. [5] During the same period, the length of hospital stay following Caesarean birth decreased from 5.0 days to 3.4 days. The safety of a shortened hospital stay (averaging 2.2 days in 2017/2018 47 ) has been debated with regards to the needs of the mother and particularly the newborn. What research says about shorter hospital stays can differ from various organizations' guidelines for both mother and baby. 48,49 Each family needs to discuss with their HCP the risks and benefits of a stay that is shorter than the institutional standard. Base this discussion on the baby's and the mother's needs and not on routine policies. From the perspective of family-centred care, leaving the hospital as early as possible has a number of potential benefits: the opportunity for the entire family to get to know the baby together, resulting in greater attachment; more involvement for the partner and less sibling rivalry; better rest and sleep for the mother in her own environment, without constant interruptions from hospital staff; reduced exposure of mother and baby to hospital-acquired infections; and greater confidence on the mother's part in her ability to care for her baby. 49 A shortened hospital or birthing centre stay is favoured by: the physiological stability of the mother and baby; family readiness to care for the baby at home; and a greater level of community, family, and institutional support upon discharge. In all situations, including those where mothers and babies are discharged early, mothers need to understand the signs of potential problems. In addition, it is important that the family knows where and when the mother and baby will next see an HCP and who they can contact with any questions.
The Canadian Medical Protective Association (CMPA) recommends reviewing test results and looking for signs of postpartum complications (e.g., infection, hemorrhage, excessive pain, bladder distention, difficulty walking) before discharging the mother and baby. The family should receive clear written or verbal instructions describing the steps and precautions to take when there are concerns, as well as the symptoms or signs that indicate that further medical attention is necessary. 50 Women and families should be told about community programs for postpartum care and peer supports for themselves and their babieswhat they are, where they are located, and how to access them. These may include homevisiting programs, clinics, community-based programs and telephone support. Since it may be difficult for new mothers to remember all of the information shared with them, it is best to provide written information and also make it available on the facility's website.
Regularly reviewing communication and coordination mechanisms will help to ensure a consistent and effective transition into the community and follow-up for the mother, baby, and family. The question of how best to arrange mother and baby's discharge is an opportunity to revisit institutional and community resources for new families.
Refer to the following CPS guidelines related to infant discharge: " The family should receive clear written or verbal instructions describing the steps and precautions to take when there are concerns, as well as the symptoms or signs that indicate that further medical attention is necessary.
•
# CARE OF THE MOTHER
Care and support during the early postpartum period should enable the mother to take charge of her own health and that of her baby-and to become confident in her ability to care for herself and her baby. This assumes that she is an autonomous adult and that HCPs have confidence in her ability to be a partner in her own care. Her values, situation, and needs are unique.
# The Mother's Well-being and Needs
Begin each postpartum contact with the mother and family by asking the woman how she feels, physically and emotionally, and identify any concerns she may have. Topics to explore include her experiences with her baby, breastfeeding/ feeding, how much rest she is getting, and any pain or discomfort she may be experiencing. A physical examination may be performed as needed. The mother's care is aimed at maintaining her health and helping her adapt to her new role as a mother.
Women need information, advice, and reassurance about postpartum physiological adaptations-such as normal lochia, perineal healing, incision healing (following caesarean birth), and changes to the breasts and nipples. They also need information on any potential issues, such as infection, hemorrhoids, cramping, constipation, urinary incontinence, painful urination, perineal pain and hygiene, headaches, back pain, pain medication, anemia, late postpartum hemorrhage, separation of the abdominal muscles, and breastfeeding challenges. The emotional and social changes she is likely to experience as a result of becoming a parent also require discussion.
# Mother's Adjustment and Emotional Health
Research shows that the mother's emotional adjustment affects her well-being as well as that of the baby and the family. 51 Mothers may experience a range of emotions postpartum, including baby blues, depression, anxiety disorders, obsessive-compulsive disorders, trauma and stressor-related disorders, and postpartum psychosis.
Compassion and vigilance are the key approaches to effective support for the new mother and family during this period of transition. HCPs will want to attune themselves to the thoughts and experiences of new mothers and their partners in order to help them explore their feelings and emotional health, rather than rely on tasks or checklists. As always, the goal is to empower the mother in her own capacity to adjust and adapt. It is important that HCPs develop assessment skills to monitor symptoms for mental disorders and stay alert for signs of concern so they can provide appropriate information and support. Providers need to be aware of the various types of responses and sufficiently knowledgeable about emotional health to identify psychiatric disorders in the immediate postpartum phase and beyond (as these disorders do not always present in early postpartum).
# Caesarean Birth
Caesarean births are common-in 2016/17, 28% of all births in Canada were by caesarean births. These rates range from 18.5% to 35.3% across the provinces and territories. 56,57 Mothers and families who have an emergency caesarean birth after a long and difficult labour have special needs. They may be experiencing depression, anxiety, guilt, sense of loss of control, less satisfaction with the birth experience, and loss of self-esteem. 58 Mothers and families who undergo planned, scheduled caesarean births can use coping mechanisms to prepare for the surgery; women undergoing an unplanned caesarean birth do not have this preparation time. 32 If a woman has an unplanned caesarean birth but feels respect and compassion and that her caregivers are collaborating with her during her labour, her outcomes will likely be optimized.
If a woman has an unanticipated caesarean birth and is not supported, she could develop posttraumatic stress disorder (PTSD). 51 HCPs are well-positioned to help mothers and their families resolve their feelings about the caesarean birth, and connect families to support and services in the community, if needed.
Women who have a caesarean birth need more care and support in their postpartum recovery and greater support caring for themselves and their babies. They experience higher levels of fatigue, constipation, depression, anemia, headache, difficulty voiding, abnormal bleeding, urinary tract infection, abdominal pain, and vaginal discharge than women who have a spontaneous vaginal birth. Primarily because of pain, mothers may need extra help with breastfeeding, especially during the first few days, and they have increased difficulties caring for their babies due to painful or reduced mobility. 59 It is vital that women and their partners/families understand what to expect during the recovery period, such as the importance of rest, fluids, support for mobility, and adequate diet for recovery. They also need to plan for support with lifting, driving, and household chores.
The average length of hospital stay is longer for women who have caesarean births than for those who have vaginal births. Family support is imperative after a caesarean birth. Mothers and babies should be cared for as a unit, with her partner, if available, including in the NICU.
5-15
# CARE OF THE NEWBORN
During the early postpartum period, care of the newborn usually involves celebrating and rejoicing with the family and respecting and supporting their needs. The care is based on nurturing the developing mother-baby-family relationship and caring for mother and baby as a unit. It includes asking the mother and her partner about their concerns and feelings, observing the baby, and supporting his or her health and well-being.
HCPs will want to ensure that the information and advice they share is clear, consistent and tailored to the mother's specific needs. By focusing on the expressed concerns of the family, rather than on predetermined teaching lists, HCPs will avoid overwhelming them with information. Opportunities to share information about the health and care of babies, including signs of concern, are maximized by caring for mother, baby, and the family together. The mother or partner should be present any time the newborn is being examined, and then made aware of the findings.
There are no Canadian guidelines on the development of newborn care plans. The National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG) recommend developing a documented, individualized postnatal care plan with the woman, ideally in the antenatal period or as soon as possible after the birth. The plan would list the HCPs involved in her and her baby's care, including their roles and contact details. NICE and ACOG recommend that parents be offered information and advice to enable them to assess their baby's general condition, identify signs and symptoms of common health problems in babies, and contact an HCP or emergency service if required. 24,60 For babies born in hospitals or birthing centres, the length of their stay varies from a few hours to about 72 hours. Appropriate postpartum follow-up, including a physical examination by a skilled HCP is essential. This physical examination should include observing feeding. The CPS guideline Facilitating Discharge from Hospital of the Healthy Term Infant provides recommendations for discharge and newborn follow-up. 45 Midwives carry their own caseload and follow their clients regardless of place of birth. They commonly provide three home visits during the first weeks of life.
# Baby-friendly Environment and Exclusive Breastfeeding
Breastfeeding is recognized as the unequalled way to provide optimal nutritional, immunological, and emotional nurturing of infants. [61][62][63][64][65] Consistent with WHO global recommendations, Health Canada recommends exclusive breastfeeding for the first 6 months that is sustained for up to 2 years or longer with appropriate complementary feeding. This is important for the nutrition, immunologic protection, growth, and development of infants and toddlers. 66 It is also important that hospitals, birthing centres, and community health facilities protect, promote, and support breastfeeding, strive for Baby-Friendly status, and achieve the Ten Steps to Successful Breastfeeding.
# Infant Mental Health
Infant and early childhood mental health has been defined as "the infant's/young child's capacity to experience, regulate, and express emotions, form close and secure relationships, and explore the environment and learn. 19 "
Infants form attachments, learn about social interactions and relationships, take in information from the world around them through their five senses, and as they grow, explore their world. Infant mental health is impacted by a number of factors-biology, genetics, brain development, temperament, the prenatal environment, illness or disability, relationships, attachment, their parents' mental health, parenting, their environment, the social determinants of health, violence, stress and trauma and resiliency. 67 The basis for mental health starts early in life. Early experiences, including infants' relationships with parents and caregivers, affect the architecture of their developing brains. 68 The infant's brain is growing very fast-and nurturing and responsive caregiving is the key to supporting healthy brain development. 67 Disruptions in this process can influence stress regulation, emotional health and immune system development throughout life. 68 Infants are totally dependent on their parents and other caregivers, and when parents and caregivers are responsive, consistent, and nurturing, and they live in safe and economically secure environments, their infants are more likely to have strong emotional health. [67][68][69] Parenting and caregiving affect the infant's/ young child's brain development and mental health through a number of mechanisms. One is attachment. When infants are nurtured and looked after responsively by their parents and other caregivers, their physical and mental health is affected for life through the formation of strong, positive bonds with adults-or attachment. Babies who are securely attached demonstrate less anxiety and more positive emotion in young childhood and are more capable of forming relationships with peers and adults. 67,69 Consistent, high quality and timely daily routines also shape the baby's developing regulatory system. The predictability and quality of routines influence the biological rhythms related to waking, eating, eliminating, and sleeping. 67,69 On the other hand, if babies experience persistent, toxic stress, the architecture of their brains is weakened. This can lead to mental health issues and physical, learning and behaviour problems throughout life. While stress is an important part of healthy development, when babies without supportive relationships experience high levels of stress for long periods of time, the result is toxic stress. 70 If parents (or other caregivers) struggle with depression or problematic substance use, for example, they may have difficulty being responsive to their infants. 71,72 Furthermore, if parents have high levels of stress themselves due to precarious economic, housing, or safety conditions, they may struggle to respond to their infants as needed. 73 Parents in these situations need particular support.
Optimal growth and development requires a continuum of services for infants, toddlers, and their families, delivered by trained professionals. Early investment can support infant mental health and prevent the need for more expensive interventions down the road. 67 Developing a strong system of informal and formal services is necessary in order to support parents who are struggling to care for their children. In addition, infants/children who are experiencing abnormal stress need assessment and treatment, along with expert support, before this stress has long-lasting effects. 73 Breastfeeding supports neurodevelopment. This may be due to the breastmilk nutrients or the mother-baby interaction-or both. Neuroscientific evidence strongly supports that infants be exclusively breastfed for 6 months and that hospitalized preterm infants either be breastfed or receive breast milk. 74,75 Consistent with the WHO global recommendation for public health, Health Canada recommends exclusive breastfeeding for the first 6 months that is sustained for up to 2 years or longer, with appropriate complementary feeding to support nutrition needs, for immunological protection and growth and development of infants and toddlers. 66 Mothers and their families need breastfeeding information and support to encourage exclusive breastfeeding.
Programs that are offered before, during, and after pregnancy as well as during early childhood, have shown benefits for supporting positive infant and child mental health. 76 These include home-visiting and other family support strategies.
Nobody's Perfect is a facilitated, communitybased parenting program for parents of children from birth to age 5. The program is designed to meet the needs of parents who are young, single, socially or geographically isolated, or who have low income or limited formal education.
Several studies have shown that participants in the Nobody's Perfect parenting program experience increased: 77
• Confidence in their parenting skills;
• Ability to cope with stress;
• Ability to problem solve;
• Resiliency;
• Self-sufficiency and independence;
• Frequency of positive parent-child interactions;
• Use of positive discipline techniques; and
• Access to peer/social/community support.
# Ophthalmia Neonatorum
Prophylaxis for neonatal gonococcal ophthalmia remains mandatory in some provinces and territories. The CPS states that "erythromycin, the only ophthalmic antibiotic eye ointment currently available for use in newborns, is of questionable efficacy. 81 " Furthermore, the Society considers that eye prophylaxis is not effective in preventing chlamydial conjunctivitis, and that applying medication to the eyes of newborns may result in mild eye irritation. 81 They no longer recommend prophylaxis for ophthalmia neonatorum but recommend screening all pregnant women for gonorrhea and chlamydia infection, with treatment and follow-up of those found to be infected. The CPS suggests that mothers who were not screened should be tested at birth, and babies of mothers with untreated gonococcal infection should receive ceftriaxone. 81 The Public Health Agency of Canada (PHAC) states that "all pregnant women at risk should be screened at the first prenatal visit or at the time of delivery if not previously screened," and provides guidance for the management of ophthalmia neonatorum. 82
# Skin Care
Mothers look at their baby's skin regularly, and HCPs can help them understand transient benign skin conditions such as acrocyanosis, baby acne, cutis marmorata (mottling), milia, erythema toxicum neonatorum, and dermal melanocytosis (Mongolian spots). 83,84 For detailed information on valid and reliable skin assessment tools for babies at risk of impaired skin integrity, refer to the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) guideline Neonatal Skin Care. 83 It is important to share information about skin creams or barriers with parents. While routine application of skin creams or lotions is not necessary for newborns, petroleum emollients have been demonstrated to prevent dermatitis and skin breakdown without increasing the risk of infection. 24,83 Barrier creams or ointments can be applied to the diaper area if reddening is noted.
Parents of both newborn boys and girls need to be made aware of how to properly clean and care for their child's genitals. For example, in the case of uncircumcised newborn boys, normal foreskin can remain nonretractile until puberty. 84
# Bathing
Newborn babies are often bathed for aesthetic and hygiene reasons, as opposed to medical indications (i.e., to prevent transmitting certain infectious diseases). 83,85 Vernix caseosa, the waxy white substance found coating the skin of newborn babies, moisturizes the baby's skin and prevents bacterial cutaneous infections. It should not be washed off, but should be allowed to dry naturally.
The priorities at birth and in the early postpartum period are skin-to-skin contact, breastfeeding, and promoting attachment; the first bath can be postponed. Some families bathe their baby for the first time at home, when the baby is a few days old. Ultimately, "decisions about the frequency of bathing and time of day should be based on the individual baby's need and consideration of family values and beliefs of the local culture. 83 " Newborns do not require daily bathing. Encourage parents to wash their baby with a warm wet cloth between baths, and to wipe the baby's face and hands frequently. 83,84 Umbilical Cord Care
Parents need to be informed about care of the umbilical cord. Natural drying is recommended, that is, putting nothing on the cord. Topical drying agents (including isopropyl alcohol) and antibiotics do not reduce cord separation time or frequency of cord infections, and in some cases, they can harm the newborn. 24,83,85 Newborns can be bathed with the umbilical cord intact so long as the cord is dried thoroughly afterwards.
Fold down diapers to provide maximum exposure to air and prevent contamination with stool or urine. If the umbilical cord or stump is soiled with urine or stool, the area should be washed with water and dried. Parents need to recognize that fever (38 °C or higher), redness, swelling, drainage (yellow pus), foul-smelling discharge, and bleeding (more than a few spots on the diaper shirt or sleeper) are abnormal findings that they should report to their HCP. 83,84
# Circumcision
Parents require accurate, up-to-date, evidencebased information about circumcision so they can make an informed choice for their baby. There is considerable controversy in medical communities regarding circumcision. In their position paper, the CPS outlines the benefits and risks, and does not recommend routine circumcision. 86 According to the American Academy of Pediatrics, the health benefits of newborn male circumcision outweigh the risks. However, the health benefits are not great enough to recommend universal newborn circumcision. 87 The Journal of Medical Ethics has an exclusive edition exploring the medical, religious, and social reasons for and against circumcision. 88 Religious, cultural, and social factors play an important part in the decision to circumcise male babies-these should be considered and respected.
# Early Immunization
In most parts of Canada, routine immunizations are not given to newborns. As of 2014, only New Brunswick, the Northwest Territories, and Nunavut include hepatitis B vaccine as part of the immunization schedule at birth. 89 PHAC recommends that hepatitis B vaccine be given at months 0, 1, and 6 with at least 4 weeks between the first and second dose, at least 2 months between the second and third dose, and at least 4 months between the first and third dose. Alternatively, it can be given as DTaP-HB-IPV-Hib vaccine, which protects against diphtheria, tetanus, pertussis (whooping cough), hepatitis B, polio, and Haemophilus influenzae type b, with the first dose at 2 months of age. 89 It is recommended that a baby whose mother has tested positive for the hepatitis B surface antigen (HBsAg) receive hepatitis B immunoglobulin and a vaccine within 12 hours of birth. If the mother's hepatitis B status is not known, and will not be known within 12 hours of birth, HCPs might consider administering the vaccine and the immunoglobulin based on risk factors, erring on the side of caution and administering both when uncertain. If the mother is HBsAg negative, it is reasonable to administer the vaccine to babies who may be at increased risk of exposure to HbsAg-positive household members or those at high risk of being positive. 89 Parents, grandparents, family, and friends who are in regular contact with a baby should have all their recommended immunizations and these should be up-to-date. Anyone requiring a booster vaccine should get it at least 2 weeks before contact with the baby. 89 This is particularly important for diphtheria, tetanus, and acellular pertussis adult vaccine, as well as for influenza vaccine.
# Vitamin D
Cases of vitamin D deficiency still occur in babies in Canada who do not receive vitamin D as a supplement. 90 Without supplementation, a baby's vitamin D stores will be depleted, particularly if the mother's vitamin D stores are low. 91,92 Nutrition for Healthy Term Infants, a joint statement by Health Canada, CPS, Dietitians of Canada, and the Breastfeeding Committee for Canada, recommends a daily vitamin D supplement of 10 µg (400 IU) for exclusively and partially breastfed babies, from birth to 1 year of age. Children aged 12 to 24 months of age who are breastfed or receive breastmilk should continue to receive this daily vitamin D supplement of 10 µg (400 IU). 66,93 Breastfed babies living in northern latitudes require special attention. In this situation, the CPS suggests that vitamin D supplementation within a range of 400 IU/day to 800 IU/day appears to be safe. 94 Continuing this supplement is a conservative approach to achieving adequate vitamin D intakes. It also provides a consistent and straightforward public health message. In individual practice, the decision to discontinue the supplement beyond 12 months of age can be informed by a dietary assessment of other contributors of vitamin D, such as cow milk. 93
# Newborn Screening
Newborn screening has been one of the most successful public health programs of this century. It has achieved the goal of detecting hereditary disorders that can result in death or severe long-term disability if not identified prior to the onset of signs. 95 Current Canadian standards are set at the provincial and territorial level, resulting in variations in the number of screening tests performed in the general categories of endocrine disorders, hemoglobinopathies, fatty acid, amino acid and organic acid disorders, cystic fibrosis, galactosemia, and other disorders. 96 HCPs would be expected to discuss screening the newborn with parents before and soon after the birth, emphasizing that this is a routine part of their baby's care that can prevent serious health problems. The newborn screening blood specimen card is completed between 1 and 7 days of age -and ideally between 2 and 3 days of age.
If testing is conducted earlier, before 24 hours, repeat the test within 5 days. In Quebec, in addition to blood sampling, a urine sample is obtained at 3 weeks for screening of a number of hereditary conditions.
According to the CPS, all newborns should be screened for hyperbilirubinemia, using a predictive nomogram. The Society recommends measuring bilirubin at the same time as having the metabolic screening test, unless it is required earlier, or at discharge or within 72 hours of birth, whichever comes earlier. This is particularly important if babies go home early, since bilirubin levels will peak at home. 97 The incidence of critical congenital heart disease (CCHD) in Canada is 3/1000 live births. CCHD accounts for more deaths than any other congenital malformation. Between 10% and 30% of CCHD diagnoses are not made prior to discharge from hospital although early diagnosis and follow-up are essential first steps in preventing infant mortality and morbidity. 98 Some centres now perform routine pulse oximetry screening to identify babies with CCHD. Used in conjunction with prenatal ultrasound and a physical examination, pulse oximetry screening is the best approach to detecting CCHD in newborns. 99 The CPS recommends that pulse oximetry screening be performed between 24 and 36 hours after the birth, using the baby's right hand and either foot to minimize false-positive results. The Society recommends that newborns with abnormal results undergo a thorough evaluation by the most responsible HCP. If a cardiac diagnosis cannot be excluded, newborns with abnormal results would be referred to a pediatric cardiologist. 100
# Hearing Screening
Hearing loss is not a common disorder in the newborn. Profound hearing loss (>70 dB) occurs in approximately 1 to 3 infants per 1000 live births. Together with moderate loss (>40 dB), the prevalence increases to 6 per 1000. 101 Universal screening for hearing results in earlier diagnosis and intervention and improved language outcomes for children. 102 The CPS and Speech-Language and Audiology Canada recommend universal screening for all newborns. 102,103 Speech-Language and Audiology Canada recommends that screening be conducted by 1 month of age, in either a hospital or communitybased setting. Any suspected hearing loss should be confirmed by 3 months of age, and an intervention implemented by 6 months of age. 104 Screening policies, however, vary between provinces, with some offering universal screening and others screening only high-risk populations. 96 HCPs will want to discuss the hearing tests with parents and explain the rationale, how they are performed, and the implications of test results that show possible hearing loss. It is also important to explain the efficacy of the test and the occurrence and meaning of false positives.
# Pain
Newborns, both preterm and term, have a hypersensitivity to stimuli and are more prone to pain and the consequences of pain. It is critical that they receive effective pain relief. As newborns cannot verbalize, it is up to their caregivers to assess and alleviate their pain.
Always keep the number of painful procedures to a minimum; those that are conducted should be evidence-based.
Some effective pain management strategies have been identified for newborns during bedside procedures. 105 Breastfeeding and skin-to-skin contact together are effective at reducing pain, and this is the first line of pain reduction for procedures such as injections, heel lancing, or venipuncture. 106 • Skin-to-skin contact reduces pain responses in preterm and term babies. 107 Skin-to-skin contact should be started approximately 10 to 15 minutes prior to the procedure. 105 • Breastfeeding should be started approximately 5 minutes before the procedure. Ensure that the baby achieves an effective latch with sustained sucking and swallowing. 105 Sweet solutions, including breast milk, have analgesic effects on babies. 108 Refer to the CPS guideline Prevention and Management of Pain in the Neonate on bedside procedure pain management as well as surgery and major procedures. 109 " Breastfeeding and skin-to-skin contact together are effective at reducing pain, and this is the first line of pain reduction for procedures.
# Safe Sleep
An optimal amount of sleep for both babies and parents is a priority for parents. Deciding where a baby sleeps is personal and highly variable. The decision may be based on cultural or personal values or the desire to facilitate breastfeeding. Alternatively, it may reflect socioeconomic realities such as unstable housing or poverty resulting in a lack of resources such as a crib. 110 It is incumbent on all HCPs to work closely with the families to promote safe sleep for their babies.
HCPs and parents should discuss the following modifiable risk factors, which reduce the risk of Sudden Infant Death Syndrome (SIDS): 111 • Breastfeeding of any duration, which provides a protective effect, with exclusive breastfeeding offering greater protection;
• Placing infants to sleep in a crib, cradle, or bassinet-one that meets current Canadian regulations-in the same room and near the parent or caregiver's bed;
• Providing a smoke-free environment-both before and after the birth; and
• Placing infants on their backs to sleep, for every sleep.
PHAC recognizes SIDS and other infant deaths that occur during sleep as major public health concerns. 111 According to Statistics Canada, 10 babies aged less than 1 year died from SIDS in 2018. 112 While it is important to differentiate between SIDS and accidental suffocation and strangulation in bed, the American Academy of Pediatrics notes that many of the modifiable and non-modifiable risk factors for SIDS and other sleep-related infant deaths are similar. 113 There is some confusion around the meaning of the term "co-sleeping." Sometimes it refers to sleeping in the same bed and sometimes to sleeping in the same room. Room sharing occurs when the baby and adult caregiver sleep on separate surfaces in the same room-a practice that is recommended. 111,113 Bed sharing, when the baby and caregiver share the same sleep surface, is not recommended by either CPS or PHAC.
Parental fatigue can play a significant role in creating unsafe sleep environments for babies and, infrequently, extreme parental fatigue can contribute to accidental suffocation. 110 A more likely scenario is that parents become so tired that they are less capable of making evidencebased decisions about sleep for either themselves or their babies. HCPs should take a proactive approach when it comes to discussing sleep strategies with parents.
# Growth Monitoring
Monitoring a baby's growth helps identify health or nutrition problems early enough for corrective action to be effective. 66,93 Measurement of growth over time should be combined with clinical, developmental, and behavioural assessments.
The WHO Child Growth Standards are based on the growth of breastfed babies. 116 Standard growth charts show the gradual change in growth velocity.
Babies who are feeding well typically regain their birth weight by 10 to 14 days, double their weight by about 5 months, triple it by 12 months and quadruple it by 2 years of age. 117 Babies grow quickly during the first 3 months, gaining 20 to 30 g per day in the first 4 weeks, or an average of 0.6 to 1.4 kg per month. 118 At-risk or Unwell Babies 121 Since postpartum women can experience mental health problems for a long time (more than a year in some cases), having one person coordinate integrated care can help ensure that the care is consistent and ongoing.
If the mother agrees, her partner and family may also be involved in decisions regarding her care.
# 5-25
# Postpartum Blues
The most common type of postpartum mood change is the postpartum blues, or baby blues.
Estimates of prevalence range dramatically, from 15% to 84%. 122 The postpartum blues are thought to be an effect of the rapid post-childbirth hormonal drop on the neurotransmitter systems involved in mood disorders. [123][124][125][126][127] The challenges of caring for the baby and interrupted sleep are also likely to contribute to the blues. 128,129 Common symptoms of postpartum blues are low mood, emotional lability, tearfulness, fatigue, and irritability. These symptoms are usually transient, beginning shortly after childbirth and resolving on their own within the first few weeks postpartum. 123 The transient nature of the symptoms helps distinguish postpartum blues from a major depressive episode. Other features that distinguish postpartum blues from a major depressive episode are the lack of severe symptoms, such as persistent insomnia, thoughts of guilt or worthlessness, or suicidal ideation.
The reason some women have postpartum blues, while others develop major depression is unknown, but research suggests that genetic predisposition is a factor. 130,131 Postpartum blues are self-limiting and require no treatment other than reassurance and support. 132 However, early onset, severe, or prolonged blues is associated with postpartum depression, and requires medical attention. 133
# Postpartum Depression
Postpartum depression can affect a woman at any age or socioeconomic status and from any culture. Biological risk factors may include history of depression or untreated depression in pregnancy, while psychosocial risk factors may include poor social support and stressful life events, including issues related to the health of the baby. 134 Some women are at a higher risk of postpartum depression such as Indigenous women, younger mothers, sexual minority women, and women who are recent immigrants to Canada.
# SUPPORTING WOMEN WITH POSTPARTUM MENTAL ILLNESS 51
Supporting women with postpartum mental illness requires a multifaceted, family-centred approach based on the individual needs and experiences of the woman and her family.
Effective treatments for postpartum mental health disorders may require referral to a mental health professional. HCPs can support new mothers and families by:
• Knowing how to differentiate between postpartum depression and other anxiety disorders or mental illnesses, including posttraumatic stress disorder (PTSD);
• Being familiar with risk factors associated with postpartum depression and mental illnesses;
• Being able to identify women at risk of developing postpartum emotional disorders and those in difficulty;
• Recognizing the symptoms of mental disorders, from baby blues to postpartum psychosis;
• Knowing about the range of treatment options available for the various postpartum mood disorders, and providing women and their families ways to access the appropriate resources;
• Helping to debunk the "motherhood equals joy and complete fulfillment" myth; and
• Encouraging women to talk about their negative emotions to do with motherhood.
The Diagnostic and Statistical Manual of Mental Disorders, version 5 (DSM-5) qualifies a major depressive episode with peripartum onset when symptoms start in late pregnancy or within the first 4 weeks postpartum. 135 However, most clinicians define postpartum depression as depression during the first year postpartum. [136][137][138] According to 2019 Canadian data, almost onequarter (23%) of mothers who recently gave birth reported depressive and anxiety symptoms that might or might not be postpartum depression or anxiety because these were just very general screening scales. Prevalence of such feelings was higher among mothers aged under 25 years (30%) than all other age groups. Of the mothers who had these feelings, 31% had been told by an HCP that they had depression or a mood disorder before pregnancy. Almost one-third (32%) of mothers who had these feelings reported that they received mental health treatment since the birth of their baby-39% had counselling, 38% medication (such as anti-depressants), and 23% counselling plus medication. 139 Women with bipolar disorder are at particularly high risk of developing a depressive episode postpartum. 140 Recent Canadian research indicates that First Nations mothers had a 20% increase in the mean scores of depressive symptoms compared to White Caucasian mothers in Canada. 141 A systematic review of the evidence on the prevalence of postpartum mental health disorders in Indigenous women confirmed this finding. 142 Chronic life stress and trauma are considered key causes of prenatal and postpartum depression among Indigenous women. This life stress is influenced by racism, sexism, domestic and sexual violence, and intergenerational trauma from residential schools and other legacies of colonization. 9
# SYMPTOMS OF A MAJOR DEPRESSIVE EPISODE 135
• Persistently low mood and/or loss of interest While the symptoms of postpartum depression are similar to those of a major depressive episode outside of the postpartum year, the negative thoughts and images associated with postpartum depression can focus on feelings of failure as a mother, anxiety about the baby's health and well-being, and guilt about having difficulty with the transition to parenthood. While perinatal suicide is extremely rare, as many as 20% of women report thoughts of self-harm or suicide. 143 The Canadian Task Force on Preventive Health Care guideline Recommendations on Screening for Depression in Adults does not recommend screening for depression in perinatal and postpartum women. 52 However, there are tools that can be used to help detect anxiety and depression in the postpartum period.
Refer to the Registered Nurses' Association of Ontario best practice guidelines for effective interventions when caring for mothers with postpartum depression. 53
# Anxiety and Related Disorders
Anxiety is a primary feature of perinatal depression, with the prevalence of anxiety symptoms ranging from 14% to 20% in the postpartum period. [147][148][149] Parents often feel anxious about the welfare of the baby, insecure about their parenting abilities, or worry about being alone. However, women can also have anxiety and related disorders, including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder and PTSD. 134 The Generalized Anxiety Disorder 2-item (GAD-2) questionnaire is a useful tool for identifying generalized anxiety disorder. 150 The tool has just 2 questions with four possible answers per question: 151 "Over the last 2 weeks, how often have you been bothered by the following problems?
1. Feeling nervous, anxious or on edge?
• Not at all/Several days/More than half the days/Nearly every day 2. Not being able to stop or control worrying
• Not at all/Several days/More than half the days/Nearly every day" New parents are naturally nervous when they are beginning to care for their newborn baby. Generalized anxiety disorder, however, is characterized by excessive worry about anticipated events or activities in a way that is difficult to control or interferes with daily functioning. The anxiety can be clustered worries about finances, appearances, maintenance of household duties, and the well-being of the baby, for example. 152 Panic disorder, affecting about 1% to 3% of new mothers, may cause significant impairment. It can result in the mother experiencing isolation due to her difficulty in leaving the home or being in groups of people. 152,153 Obsessive-compulsive symptoms occur in 4% to 9% of new mothers. These most often include obsessions about contamination, compulsions about checking and ordering, and in some cases, thoughts about the baby being harmed. [154][155][156][157] The latter can be distinguished from psychosis because women with obsessive-compulsive symptoms have no intention of harming their child and are significantly distressed by these types of thoughts.
Obsessive-compulsive symptoms commonly co-exist with a depressive episode. 155
# TOOLS TO DETECT ANXIETY AND DEPRESSION POSTPARTUM
The Edinburgh Postnatal Depression Scale (EPDS) [144][145][146] This 10-item depression scale:
• Can be used in clinical care or for women at risk of, or showing, symptoms of postpartum depression;
• Can be used any time postpartum, including at regular maternal or baby checks;
• Has an anxiety subscale (items 3, 4, and 5);
• Asks about self-harm thoughts (item 10).
Women with a score higher than 12 (out of 30) have 10 times the likelihood of being diagnosed with postpartum depression than women with a lower score.
# Whooley Questions for Depression Screening 121
There are two Whooley questions for depression:
• During the past month, have you often been bothered by feeling down, depressed, or hopeless?
• During the past month, have you often been bothered by little interest or pleasure in doing things?
If a woman answers yes to either of these questions, it signifies need for further follow-up to determine whether she has depression.
Trauma-and stressor-related disorders, including PTSD, affect about 3% of postpartum women and up to 15% of high-risk women 158 . Important risk factors included a history of psychopathology, current depression, and complications during pregnancy, labor and delivery. While it is rare that a stressful birth experience leads to PTSD, risk factors do include having a birth experience different from what was expected and ineffective communication where HCPs do not listen to the woman. 158 Severe Postpartum Mental Disorders
# Bipolar Disorder and Schizophrenia
About 2% of pregnant women have a preexisting bipolar disorder, and less than 1% have a pre-existing psychotic disorder such as schizophrenia. 159 Women with severe mental disorders are at particularly high risk of relapse in the postpartum period and usually require special mental health care. They are also at high risk of developing postpartum depression. 140 Evidence suggests that there is a relationship between bipolar disorder and postpartum psychosis, with the majority of cases thought to be variants of bipolar disorder. The risk of relapse in women with primary psychotic disorders increases during the postpartum period. 160,161 Sometimes postpartum psychosis is preceded by hypomanic or manic symptoms. 162 Women with severe mental disorders and their families require support from professionals and family/friends as well as appropriate treatment to promote optimal health and parenting.
# Postpartum Psychosis
Postpartum psychosis, the most severe postpartum psychiatric disorder, is a medical emergency.
Postpartum psychosis occurs in approximately 1 in every 600 postpartum women. 161 It most often occurs during the first week or the first month postpartum, but it can occur later in the postpartum period or at weaning, although the latter is rare.
The primary symptoms of postpartum psychosis reflect a significant change from the woman's usual personality, with confusion and clouding of consciousness considered classic symptoms. These symptoms may be accompanied by an inability to distinguish thoughts from reality and delusions about herself, her baby, or others. 163,164 Women with a history of bipolar and psychotic illnesses are at increased risk for postpartum psychosis, particularly if they stopped taking medication during pregnancy or in the early postpartum period. Other risk factors include a family history of psychiatric illness (particularly bipolar affective disorder) and sleep deprivation among women with a previous bipolar mood disorder diagnosis. 140 Women with postpartum psychosis require urgent psychiatric consultation, pharmacological treatment, ongoing support to facilitate the recovery process, and usually hospitalization. 165 They should not be left to care for their babies alone until the psychosis has resolved. Assess and support safety of the mother and her baby on an individual basis, as delusions may increase the risk of harm to either or both. Family members should be educated and engaged, and ongoing support provided by professionals, community organizations, and family/friends. 166,167 Women who develop postpartum psychosis are at increased risk for reoccurrence during subsequent pregnancies. 168,169
# LATE POSTPARTUM HEMORRHAGE
Late postpartum hemorrhage, also called secondary postpartum hemorrhage, can occur 24 hours to 12 weeks after childbirth. The potential causes of late postpartum hemorrhage include retained fragments of the placenta or membranes, sub-involution of the placental site, uterine infection, and coagulation defects.
Treatment involves controlling bleeding with medications such as oxytocin, as well as possible blood replacement or surgical intervention.
As most cases of late postpartum hemorrhage occur after women leave birthing facilities, focus the discharge information on expected changes, what amount of bleeding is normal and what amount of bleeding is not normal, causes for concern, and when to contact an HCP or emergency department. If a mother needs to be re-admitted to hospital for late postpartum hemorrhage, it is very important not to separate the mother and baby and to provide support for breastfeeding.
# INFECTIONS Endometritis
Endometritis is an infection of the reproductive tract. It can occur at any time from birth to 6 weeks postpartum. Endometritis occurs after 1% to 3% of vaginal births and up to 27% of caesarean births. 170 Endometritis is limited to the uterine cavity but can spread.
A woman with mild endometritis has discharge that is scant or profuse, bloody, and foul smelling.
In more severe situations, she has fever, chills, lower abdominal pain or uterine tenderness, anorexia, lethargy, and rapid pulse. Treatment includes administration of antibiotics and can also include rest, a high fluid intake, analgesia as needed, and administration of oxytocics to keep the uterus contracted. Comfort measures are important to relieve the symptoms. 170,171 Women need to be informed about what to expect with regard to normal lochia and vaginal discharge, and should call their HCP if they develop symptoms of endometritis.
# Mastitis
Mastitis is an inflammation of the breast that may involve an infection. It is characterized by localized tenderness, redness, and heat, and systemic symptoms of fever, malaise, and occasionally nausea and vomiting. 172 Mastitis commonly occurs within the first 6 weeks postpartum, but can occur at any point during lactation. It can start as engorgement, develop into non-infective mastitis, and then become infective mastitis. 172 While the breast is congested/engorged, the most effective treatment is breast emptying-by an electric pump if necessary-and increased water intake.
Mastitis occurs in 10% of breastfeeding women, but some studies have reported the incidence to be as high as 33%. 173 Encourage mothers to continue breastfeeding.
It is important that mothers know their milk is safe for their baby even if they require antibiotics.
Frequent feeding and good positioning and latching, with effective milk flow from breast to baby, are preventive factors for mastitis.
# CARDIOVASCULAR AND HYPERTENSIVE DISORDERS OF PREGNANCY
Hypertension affects 6% to 10% of pregnant women, but few studies have reported the incidence of postpartum hypertension. Women who have had chronic hypertension, gestational hypertension, preeclampsia, and eclampsia may have preeclampsia postpartum-and may develop preeclampsia for the first time postpartum. 174 As such, if a mother has hypertensive disorder of pregnancy (HPD), postpartum monitoring is important.
Refer to the SOGC guideline Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy for information on care in the first 6 weeks postpartum and beyond. The Working Group recommends checking blood pressure 3 to 6 days following birth, especially if the woman has had a pregnancy complicated by high blood pressure. 175 During pregnancy, women may develop conditions such as preeclampsia and gestational diabetes mellitus (GDM) that put them at higher risk of heart disease and stroke. Pregnancy-related stroke can happen at any stage of pregnancy, but the greatest risk is during birth and the first few months postpartum. It is usually the result of a pre-existing blood vessel malformation or eclampsia. Peripartum cardiomyopathy (PPCM) is a rare-and often misdiagnosed-form of cardiomyopathy that occurs in the last month of pregnancy and up to 5 months postpartum.
There are a number of risk factors for peripartum cardiomyopathy: multiple pregnancies, twins, preeclampsia and eclampsia, a history of heart problems, excessive alcohol consumption, smoking, diabetes, obesity, unhealthy diet, and African heritage. 176 It is important to describe the signs and symptoms of heart disease and stroke to women and their families and explain when to talk to an HCP or seek emergency care.
# EXTENSIVE PERINEAL TEARS
Approximately 53% to 79% of women experience some form of laceration during vaginal birthmost often in the perineal body and commonly first-and second-degree lacerations. The more severe third-and fourth-degree lacerations that result in obstetrical anal sphincter injuries (OASIS) may occur in up to 11% of women who have vaginal births. 177 OASIS may result in significant problems, including anal incontinence, rectovaginal fistula, and pain, along with increased risk of postpartum urinary retention.
Women who have lacerations during birth need to be made comfortable and helped to recover-and be supported in their confidence in caring for their baby. Provide information so that the woman understands what happened during the birth and the extent of the laceration/injury. Focus on what can help recuperation and healing; that is, rest, hygiene, prevention of constipation, and pain management, as needed, so that they can be actively involved in caring for their babies. Helpful measures include sitz baths, using the side-lying breastfeeding position, avoiding sitting or standing for long periods of time, and seeking and accepting support from family and friends.
The SOGC recommends that HCPs carefully examine all women for perineal or vaginal tears and that anyone with a tear that is more than superficial has a systematic rectal exam for OASIS. 178 The SOGC guidelines provide recommendations on prophylactic antibiotic administration, the use of laxatives, as well as analgesics for pain, in the case of OASIS. 178 Refer women who have OASIS to a physiotherapist skilled in helping with this condition. 178,179 The benefits relate to wound healing as well as rehabilitation to restore local and integrated muscle function following the muscle trauma. Scar management may be required to help the woman have intercourse without fear and pain. These considerations may also be relevant for first-and second-degree tears, although in this case referral to physiotherapy is not always necessary.
# FEMALE GENITAL MUTILATION/ CUTTING (FGM/C)
Women who have experienced female genital mutilation/cutting (FGM/C), also known as circumcision, need particularly sensitive postpartum care. Learning about the cultural, social, psychological, and physical implications of this centuries-old traditional practice will help HCPs talk to mothers appropriately and provide care that is culturally aware and respectful. The perineal area may be extremely painful due to repeated cutting and laceration throughout life compounded by a recent vaginal birth, making even walking difficult. This all makes caring for their baby more problematic. 180 Following birth, women need additional advice on perineal hygiene. Perineal infections may occur if culturally acceptable methods of cleanliness are not understood by HCPs. For example, using water may be considered impure on religious grounds. Instead, a diluted antiseptic wash may be used for cleaning after voiding.
HCPs will want to address birth control methods, as choice may be limited for women with FGM/C. They may have been taught that touching their genitals is forbidden, and because the vaginal area is sensitive, the use of diaphragms, cervical caps, and sponges is usually not suitable. The most acceptable and reliable method of birth control for women with FGM/C may be intrauterine contraception (IUC, also known as an intrauterine device or IUD). Hormonal contraceptives, either oral or implanted, are also possible. As for all women, the different contraceptive options should be explained carefully and clearly.
HCPs also need to discuss FGM/C with parents and inform them that performing FGM/C is illegal in Canada.
# DIASTASIS OF THE RECTUS ABDOMINIS MUSCLE
Diastasis recti abdominis (DRA) is defined as a separation of the two sides of the rectus abdominis muscles. 181 The onset of DRA occurs during pregnancy and the first weeks following birth. 182 The literature on the prevalence and risk factors for development of this condition is limited. 181,182 A prospective cohort study of 300 first-time pregnant women found the prevalence of mild DRA to be high both during pregnancy and after childbirth: 33% at 21 weeks gestation; 60% at 6 weeks postpartum; 45% at 6 months postpartum; and 33% at 12 months postpartum.
There was no difference in reported lumbopelvic pain in women with and without DRA. 181 In another prospective study of 84 first-time pregnant women, the prevalence of DRA decreased from 100% at gestational week 35 to 39% at 6 months postpartum. Women with DRA at 6 months postpartum were equally likely to report lumbopelvic pain as women without DRA. 182 A widening of greater than 2.7 cm at the level of the umbilicus is considered to be pathological diastasis of the rectus abdominis muscle. 183 It can have negative health consequences for women during pregnancy and the postpartum period and beyond, including altered body mechanics and posture, injury of the lumbar spine and pelvis, and impaired pelvic stability. 184,185 Exercise is a protective factor in the development of DRA. 186 Exercise may reduce the risk of developing DRA as it helps to maintain tone, strength, and control of the abdominal muscle.
In addition, women who exercise during and after pregnancy most likely exercised before pregnancy and have better-conditioned abdominal muscles than women who do not exercise. The type of exercise also affects DRA width and recovery time. 186 It is important to refer women with DRA to pelvic floor physiotherapy. 187 Physiotherapy or exercises for diastasis recti should not only address the separation but retrain the pelvic floor muscles. More than 70% of women with rectus diastasis cannot do a pelvic floor contraction and therefore are more likely to experience incontinence, prolapse, and pelvic pain. 188 Consider as well physiotherapy or exercises that address posture, body mechanics, and restricted tissues that may be causing poor movement. A corset or binder is often recommended for separations of 4 finger widths or more. Neuromuscular electrical stimulation also helps to reduce DRA, and if combined with abdominal exercises, can augment the effects. 189 Some women may meet the criteria for surgery (abdominoplasty) if they have unresolved symptoms that have not responded to exercise. 187
# GESTATIONAL DIABETES MELLITUS
It is important to encourage women who have had gestational diabetes mellitus (GDM) to breastfeed immediately after childbirth. Breastfeeding helps to lower the risk of neonatal hypoglycemia. 190 Women with GDM require information about the associated health risks:
• Between 16% and 30% of women with GDM develop type 2 diabetes by 5 to 10 years postpartum, and some women develop type 1 diabetes. 191 • Metabolic syndrome is more common in women with GDM. Women should be counselled about lifestyle modifications to prevent diabetes and cardiovascular disease.
Lifestyle changes can prevent the onset of type 2 diabetes. 191 • The recurrence rate of GDM in subsequent pregnancies is about 30% to 84%. 192 For most women with GDM, diabetes goes away soon after childbirth. However, only 50% of women return for postpartum testing due to time pressures, lack of childcare, lack of awareness of the importance of postpartum screening, the unpleasantness of the test, and other factors. [191][192][193] The SOGC guideline Diabetes in Pregnancy recommends that women with GDM be screened with a 75 g oral glucose tolerance test (OGTT) between 6 weeks and 6 months postpartum to detect prediabetes and diabetes. 194 Women with GDM may benefit from the support of a lactation consultant or specialist in case of delayed onset of breastmilk secretion. 195,196 The Canadian Diabetes Association Clinical Practice Guideline Expert Committee recommends that after childbirth women with pregestational diabetes: 197 • Breastfeed for the many benefits it offers;
• Be carefully monitored as they have a high risk of hypoglycemia postpartum;
• Use metformin and glyburide, if needed, as they can be used during breastfeeding; and
• Have their triglycerides assessed late postpartum.
In addition, women with type 1 diabetes in pregnancy should be screened for postpartum thyroiditis with a thyroid-stimulating hormone (TSH) test at 6 to 8 weeks postpartum.
# THYROID CONDITIONS
# SYMPHYSIS PUBIC DYSFUNCTION, PELVIC GIRDLE PAIN, AND DIASTASIS SYMPHYSIS PUBIS
Symphysis pubic dysfunction (SPD) has been described as a collection of signs and symptoms of discomfort and pain in the pelvic area, including pelvic pain radiating to the upper thighs and perineum. [199][200][201] While this term has been used to describe pregnancy-associated pain and instability and dysfunction of the symphysis pubis joint (SPJ) or sacroiliac joint (SIJ), the European Guidelines recommend pelvic girdle pain (PGP) as the accepted umbrella term. 201 PGP symptoms occur due to pelvic ligament relaxation and increased joint mobility in pregnancy, and can vary from mild discomfort to severely debilitating pain. 202 About 20% of pregnant women experience PGP. 201,203 Risk factors for developing PGP during pregnancy include a history of previous low back pain and previous trauma to the pelvis. 201 Prolonged and difficult births, often with larger babies, with the women's legs widely abducted, and possibly assisted by forceps, can also be contributing factors. The reported incidence of clinically persistent PGP from the postpartum stage to 2 years after childbirth ranges from 5% to 8.5%. 204 In severe cases, the symphysis pubis may partially or completely rupture. Diastasis of the symphysis pubis (DSP), where the gap in the symphysis pubis increases to more than 10 mm, can only be confirmed by diagnostic imaging. 205,206 DSP can occur during pregnancy, childbirth, or the postpartum period. 206 Although specific recurrences are difficult to predict, women need to be made aware of the high recurrence rate (68-85%) in subsequent pregnancies. 207 A small subgroup of patients with PGP can develop chronic pain leading to high disability with resistance to physical interventions. These women should receive multidisciplinary care involving medical and psychological intervention.
There are no Canadian guidelines on diagnosing and managing PGP. Guidelines from Ireland and the United Kingdom are consistent in their message that symptoms of pelvic girdle pain are often mild but can be seriously disabling. 206,208 Women should be asked at every postpartum contact whether they are experiencing pelvic girdle or lower back pain. 206,209 Indications of pain and difficulty with walking after giving birth may indicate pubic symphysis diastasis and should not be discounted as a "minor discomfort of childbearing," but investigated. Do not discount any level of pain-rather, undertake a careful clinical assessment to determine the extent of the pain and any symphysis pubis dysfunction. Assessments should include determining what occurred during pregnancy and childbirth, and running diagnostics and making timely referrals, including to physiotherapy, to avoid long-term and potentially permanent disability. 201,209
# ASSISTED VAGINAL BIRTH
In 2016/2017, 13% of women who gave birth in Canada had an assisted vaginal birth, 9% had a vacuum birth, and 4% had a forceps-assisted birth. 210 Recent evidence reviews have shown that women who had an assisted vaginal birth were more likely than those who had a spontaneous birth to have at least one health problem during the early postpartum period, for example, painful perineum, constipation, hemorrhoids, breakdown of stitches, and urinary or fecal incontinence.
They were also more likely to have a painful perineum at 8 weeks postpartum, regardless of whether they had an episiotomy. 59,177 Forceps-assisted and vacuum-assisted births are associated with an increased risk of injury to the vagina, perineum, and anus. Tears are more severe, which may require prolonged healing. 211 Women who have a forceps-assisted birth have a significantly greater decrease in intra-anal pressure and a greater incidence of a weak pelvic floor. 212 It is important to focus on the woman's comfort during the postpartum period, determining if she has any concerns about perineal comfort or healing, as well as pain, discomfort or stinging, odour, incontinence, or dyspareunia. 24 The integrity and progress in healing of the perineum needs to be assessed, with pain relief or comfort measures offered and their effectiveness assessed. Women need information on the use of ice packs to decrease swelling, care of the perineum, self-inspection, warm water sitz baths, and Kegel exercises to improve perineal tone. 41
# URINARY OR FECAL INCONTINENCE AND URINARY RETENTION
A significant number of women experience urinary and fecal incontinence following childbirth. The condition is both physically and psychologically challenging, and can influence many aspects of women's lives and recovery.
# Urinary Incontinence
During pregnancy and childbirth, the pelvic floor muscles are stretched and weakened, placing women at risk for the development of urinary incontinence. 213 While urinary incontinence can happen during pregnancy, stress urinary incontinence results from pelvic floor trauma during vaginal birth, especially the first birth.
Although antenatal urinary incontinence, obesity, and significant perineal trauma are risk factors, clinical studies have not identified any single responsible event, suggesting that the problem is multifactoral. [212][213][214] Some women have temporary urinary incontinence, but others have long-term problems. 213 According to the Maternity Experiences Survey, 3.4% of all women who gave birth reported urinary incontinence as "a great deal of a problem" in the first 3 months postpartum. 215 Women who had vaginal births were more likely to report this problem (4.2%) than women who had caesarean births (1.1%). First-time mothers were also more likely to report this problem (4.0%) than multiparous women (2.9%). 215 Research indicates that women who had a forceps-assisted birth (with or without an episiotomy) were 10 times more likely to have significant perineal trauma than women who delivered by vacuum extraction without an episiotomy. Moreover, 5 years later, almost half of the women who had assisted vaginal births had some degree of urinary incontinence. 59 When talking with women about urinary incontinence, focus on prevention, muscle toning techniques, and other interventions. Pelvic floor muscle training can prevent urinary incontinence for up to 6 months after first-time mothers have given birth. 216 There is also evidence that pelvic floor muscle training is appropriate for women with persistent postpartum urinary incontinence. 216 The effectiveness might be increased with targeted approaches.
The SOGC recommends Kegel exercises for incontinence with follow-up to assess their effectiveness. Combining any necessary lifestyle changes with bladder training plus pelvic muscle exercises is highly effective. Refer to the SOGC guidelines Conservative Management of Urinary Incontinence. 217
# Urinary Retention
Urinary retention is a sudden inability to spontaneously void the bladder or where a woman passes small amounts of urine but is unable to fully empty her bladder. [218][219][220] Symptoms of urinary retention include urinary frequency, voiding small amounts, bladder discomfort or pain, straining to void, reduced sensation to void, incomplete emptying of the bladder and urinary incontinence. 221 Postpartum voiding dysfunction is defined as failure to pass urine spontaneously within 6 hours of vaginal delivery or the removal of a catheter. 218 If urinary retention is not detected and managed, it can lead to bladder distention or underactivity and longer-term problems such as incontinence and urinary tract infections. 222,223 The causes of urinary retention are not well understood, but likely mechanical, physiological, and neurological factors are involved. 220 There are no national Canadian guidelines on postpartum urinary retention, but NICE guidelines recommend that if a woman has not passed urine within 6 hours of childbirth, she has warm baths or showers to assist urination. If these actions are not successful, bladder volume should be assessed and catheterization considered. 24
# Fecal Incontinence
According to the Maternity Experiences Survey, 1.8% of all women who gave birth reported that loss of bowel control was most pronounced in the first 3 months postpartum. 215 First-time mothers were more likely to report this problem (2.2%) than multiparous women (1.4%). 215 Anal incontinence after childbirth is more prevalent among women who have had a forceps-assisted birth and laceration of the anal sphincter. 224,225 In addition, women who have anal sphincter tears are more than twice as likely to report postpartum fecal incontinence than women without sphincter tears. 224,225 For women who had an OASIS repair, the SOGC recommends prescribing laxatives and nonsteroidal anti-inflammatories and acetaminophen as first-line agents, and a single dose of an intravenous antibiotic. HCPs will want to discuss the degree of injury and arrange for appropriate follow-up. The SOGC also recommends that women with anal incontinence be referred for pelvic floor physiotherapy. 178
# PROLONGED STAY IN HOSPITAL
Having to remain in hospital for a prolonged period after childbirth can be extremely stressful for families. Mothers may be distanced from their support circle of friends and family. Concerns regarding contact with and care of other children may be a source of stress. Families may be worrying about the mother's health and the care of siblings; contact with other children and grandparents; travelling logistics to and from the hospital; and work obligations of partners. It is important that HCPs explore these issues with the family and support them as much as possible.
Consider referrals to social services if needed and innovative technology-based programs and resources to help keep families connected.
When women are sole-parenting, prolonged stay situations can escalate their stress and anxiety and interfere with their recovery.
A prolonged hospital stay requires compassionate and individualized care. Policies should focus on enabling skin-to-skin contact, supporting breastfeeding, and allowing mothers and babies to be together (rooming-in/mother-baby care). 23 Mothers who are breastfeeding should have the opportunity to feed frequently and on cue for as long as they want and receive help with breastmilk expression, if needed. 226 If the baby cannot be given their mother's breastmilk, pasteurized human donor milk is the next best choice. 20,93,227 It is incumbent upon HCPs to consult expert resources to determine the effects on the breastfeeding mother and breastfed baby of any medications the mothers is taking. Only a small number of medications are contraindicated while breastfeeding. 228 " Policies should focus on enabling skin-to-skin contact, supporting breastfeeding, and allowing mothers and babies to be together (rooming-in/mother-baby care).
# COMPLICATIONS RELATED TO THE NEWBORN
According to findings from the ACoRN program, complications related to the newborn fall into eight areas of concern:
• Infection • Cardiovascular • Respiratory • Neurological
• Gastrointestinal or surgical
• Glucose and electrolytes
• Jaundice
# • Thermoregulation
Refer to the CPS ACoRN program for guidance on neonatal stabilization, support for multidisciplinary teams, and identifying and caring for babies who are unwell or at risk of becoming unwell in the first few hours or days after childbirth. 119
# INFECTION
If the baby has an infection, supportive care with adequate time to share information is essential. The mother and baby should be considered a unit-with non-separation the goal at all times.
Refer to the CPS guidelines for the diagnosis and treatment of infectious disease in newborns.
# Sepsis
With the introduction of guidelines for systematic maternal screening and increased use of intrapartum antibiotics, the incidence of group B streptococcal (GBS) sepsis has decreased from 1.7 cases per 1000 live births in 1993 to 0.22 cases per 1000 live births in 2016. 229,230 Despite this, GBS remains the leading cause of neonatal infection in Canada. In 2012, 48% of the cases of early onset neonatal sepsis were due to GBS, while Escherichia coli accounted for 31%. 231 Evaluating the risk of sepsis is an important part of the newborn assessment. Prompt treatment prevents the progression to severe disease. Babies at risk for sepsis are those where the mother has maternal GBS colonization in the current pregnancy or GBS bacteriuria; a previous baby with invasive GBS disease; prolonged rupture of membranes (≥18 hours); and maternal fever (temperature ≥38 °C).
# CARDIORESPIRATORY DISTRESS AND CARDIAC CONCERNS
Cardiorespiratory distress in the newborn may occur immediately after childbirth or later in the postpartum period. All HCPs caring for newborns must be able to assess respiratory distress, cyanosis, and perfusion. The CPS recommends that all centres in which babies are born have personnel capable of initiating assisted ventilation. 232 They also recommend following Neonatal Resuscitation Program guidelines for specific resuscitation procedures immediately after the birth and having a written policy regarding the initial care of a baby with respiratory distress outside of each birthing room in each facility. 232 Regular simulation sessions or other forms of practice scenarios are useful opportunities for continuing education and maintenance of skills.
Heart murmurs are common in the first few days of life and do not normally indicate a significant problem. In the first 24 hours, murmurs are often indicative of flow through the patent ductus arteriosus and disappear following the closure of the ductus. However, any murmur, even within the first 24 hours, must be assessed in the context of the entire physical examination. If a murmur persists or is symptomatic, a more complete evaluation is recommended. 233,234 The incidence of CCHD in Canada is 3/1,000 live births and accounts for more deaths than any other congenital malformation. Between 10% and 30% of CCHD diagnoses are not made prior to discharge from hospital. Early diagnosis and follow-up are essential first steps in preventing infant mortality and morbidity. 98 Pulse oximetry screening, used in conjunction with prenatal ultrasound and physical examination, is the best approach to detecting CCHD in newborns. 99
# HYPOGLYCEMIA
The definition of hypoglycemia in the newborn is controversial. Multiple reviews have concluded that no specific glucose concentration can be linked to clinical signs or neurological injury. 235 Approximately 12% to 14% of healthy, appropriatefor-gestational-age (AGA), breastfed, term newborns have blood glucose levels of less than 2.6 mmol/L in the first 72 hours of life. 236 The CPS does not recommend routine blood glucose monitoring in healthy term babies. 237,238 However, it is important to routinely screen babies at risk for hypoglycemia, including babies of mothers with diabetes (gestational and preconception), preterm babies, and both small-for-gestational-age (SGA) (weight < 10 th percentile) and large-for-gestational-age (LGA) babies (weight > 90 th percentile). The general recommendation for this population is that glucose levels be maintained at 2.6 mmol/L or higher after the first 2 hours of age.
Blood glucose screening of asymptomatic at-risk babies should begin at 2 hours of age and continue at a frequency and duration that depends upon the specific risk factors and until pre-feeding glucose levels have been consistently documented. 235,238 Babies who are unwell or show signs of hypoglycemia, such as jitteriness, lethargy, poor feeding, apnea, or tachypnea, require immediate testing.
Approaches to the management of hypoglycemia depend upon whether it is asymptomatic or symptomatic. Early and frequent skin-to-skin contact and breastfeeding is encouraged in asymptomatic babies, with supplementation with expressed breast milk the next best approach.
A breast milk substitute may be considered, if essential. 238 Refer to the CPS guideline Screening and Management of Newborns At Risk for Low Blood Glucose for information on diagnosis, monitoring, and management of hypoglycemia. 238
# PRENATAL ANTIDEPRESSANT USE
Selective serotonin reuptake inhibitors (SSRIs) are the antidepressant medications most frequently prescribed for the general population and pregnant women. 239 When considering prescribing or discontinuing SSRIs, HCPs are expected to weigh the potential harms of untreated depression or anxiety against potential risks to the fetus or newborn. SSRIs as a group have not been found to increase risk of major congenital malformations when used in the first trimester. However, paroxetine use in the first trimester may increase the risk of cardiovascular malformation, and other SSRIs may increase the risk of specific birth defects. 240 Third trimester use of SSRIs has been linked to a constellation of neonatal signs including prolonged crying, jitteriness, increased tone, tachypnea, cyanosis and feeding difficulty. 241 These signs occur in 10% to 30% of babies exposed to SSRIs in utero, usually within several hours of birth. The signs are usually mildsometimes so mild they are difficult to identifyand resolve over several weeks. 242,243 The mother is the best person to settle her baby with skin-toskin contact, breastfeeding, and holding and comforting-the HCP's role is to support her in caring for her baby and to provide a calm, quiet environment.
The CPS recommends observing the baby in hospital for 48 hours when SSRIs have been used during the third trimester. 240 However, since the majority of babies exposed to SSRIs are born healthy, Perinatal Services BC recommends considering discharge after 24 hours for babies who show no adverse signs or symptoms and who meet the following criteria:
• normal vital signs and oxygen saturation levels for the first 24 hours and at discharge;
• a normal physical exam;
• established feeding;
• well-regulating temperature; and
• no signs or symptoms of neonatal abstinence syndrome (NAS). 244 It is important to inform families about the possible effects of SSRIs on their baby and about strategies to support babies with symptoms. Postpartum use of SSRIs is not a contraindication to breastfeeding. 240 While information about long-term neurodevelopmental outcomes after prenatal SSRI exposure is largely reassuring, evidence in this area is limited.
Refer to the CPS guideline Selective Serotonin Reuptake Inhibitors in pregnancy and infant outcomes on caring for babies with SSRI exposure. 240
# SMALL-FOR-GESTATIONAL-AGE BABIES AND MACROSOMIA
# Small for Gestational Age
Babies who are born small for gestational a ge (SGA) have a birth weight below the 10 th percentile of the age-and gestation-specific birth weight. The rate of SGA births has increased steadily between 2008 and 2014, from 8.2 to 9.1 per 100 singleton live births in Canada. 245 Intrauterine growth restriction (IUGR) describes genetic or environmental factors preventing a fetus reaching its growth potential. Low birthweight is defined as weight at birth of less than 2500 grams (5.5 pounds) irrespective of gestational age. 246 Babies with SGA have physical characteristics (behaviour, alertness, spontaneous activity, and feeding ability) similar to those of normal-sized babies of like gestational age. They may look small and thin because they have decreased subcutaneous fat tissue and muscle mass, but they do not have the complications related to organ system immaturity that preterm babies of similar size have. Any complications are usually a function of the underlying cause of the SGA. 247 Parents and families of babies who are born SGA are anxious about their baby's well-being and require supportive care, counselling, and reassurance. Caring for the mother-baby unit, non-separation, and supporting breastfeeding are all essential aspects of care.
# Macrosomia
There is no consensus on the definition of fetal macrosomia, which some define as birth weight of more than 4000, 4500, or 5000 g, regardless of the baby's gestational age. Others define macrosomia as a baby above the 90 th birth-weight percentile for gestational age of a reference population-also known as large-for-gestationalage (LGA) babies. 248 The description normal birth weight depends on the population of reference.
In Canada, the LGA birth rate among singleton babies decreased from 11.6 to 10.2 per 100 singleton live births between 2005 and 2014. 245 Babies born with macrosomia are at higher risk of perinatal mortality (stillbirth and early neonatal, late neonatal, and post-neonatal mortality) and have a higher risk of shoulder dystocia, asphyxia, congenital anomalies, infection, and SIDS. 248 In addition, these babies are more likely to be born with a lower than normal blood sugar level, have a higher risk of childhood obesity, and a higher risk of metabolic syndrome during childhood. 249 Babies with macrosomia should be assessed for low blood sugar and jaundice and be encouraged to feed soon after the birth to prevent low blood sugar. 250
# NEONATAL OPIOID WITHDRAWAL SYMPTOMS
Neonatal opioid withdrawal symptoms are a group of possible symptoms experienced by babies whose mothers used opioids during pregnancy. From 48% to 94% of babies exposed to opioids in utero have opioid withdrawal symptoms. 251 While their symptoms vary, babies who have been exposed to opioids in utero may feed poorly and have diarrhea and weight loss. They may demonstrate tremors, tight muscle tone, excessive crying, hyperactive Moro reflex (sometimes called the startle reflex), irritability, vomiting and convulsions, hyperthermia and tachypnea. 252,253 If these signs become sufficiently severe, and depending on the drug that the baby was exposed to, the baby may require pharmacotherapy.
The CPS recommends that all babies exposed to opioids be assessed using a scoring system that measures the severity of withdrawal symptoms and helps determine the need for additional monitoring, nursing, medical intervention, or pharmacological therapy.
# Refer to the CPS practice point Managing Infants Born to Mothers Who Have Used Opioids During
Pregnancy for details. 253 The CPS also notes that the length of stay in hospital varies depending on exposure to opioids prenatally, severity of withdrawal, symptoms, treatment, and social factors. The Society recommends observing babies for a minimum of 72 to 120 hours, depending on their exposure to opioids. If the treatment threshold is not reached within that time, the baby can be discharged. The key to a successful transition home is to ensure continuity of care by an interprofessional team, with anticipatory planning for when the baby meets criteria for discharge. 253 It is important that babies be cared for in their mothers' rooms. Having in place a protocol for rooming-in and use of morphine (if required) for opioid-exposed babies helps to reassure staff about the safety of this treatment modality and supports them in caring jointly for the mothers and their babies. The BC Perinatal Services and British Columbia Centre on Substance Use guideline Treatment of Opioid Use Disorder During Pregnancy Guideline Supplement offers a sample rooming-in protocol for opioidexposed neonates. 252 Encourage mothers to hold and cuddle their baby as much as possible, as this helps to settle the baby and minimize withdrawal. In addition, if the mother is relaxed, the baby is more likely to relax. Also encourage breastfeeding, as this can delay the onset and decrease the severity of withdrawal symptoms as well as decrease the need for pharmacological treatment. 253,254 Consider that even babies who do not have in utero exposure to opioids usually take at least 36 to 72 hours to settle until the mother's breast milk comes in and breastfeeding is established.
If the baby requires pharmacotherapy, the mother and baby may be subject to a prolonged hospital stay. It is important to inform the mother during her pregnancy that she and her baby may need to stay longer at the hospital so that she has a realistic understanding of the early postnatal period and be better prepared for any additional care her baby may require. Note that rooming-in and non-pharmacological care often reduce withdrawal signs to the extent that pharmacotherapy treatment is not required. 252,253 Mothers who used opioids during pregnancy may experience a range of emotions; for example, anxiety over the well-being of their baby, concerns about withdrawal signs the baby is showing, and worries about maintaining custody, or they may be confident and relaxed. It is essential to individualize care to support the mother and other caregivers.
# The CPS practice point Managing Infants Born to Mothers Who Have Used Opioids During
Pregnancy discusses discharge criteria relating to the newborn and referral to support services and family services be considered. 253 In the Treatment of Opioid Use Disorder During Pregnancy Guideline Supplement, the BC Perinatal Services and British Columbia Centre on Substance Use advise that maternal opioid use alone is not grounds for the apprehension of a baby by authorities or referral to child protection. Make the decision to report on a case-by-case basis, in consultation with the entire health care team, although HCPs should be aware of their legal obligations in this regard. 252
# LATE PRETERM BABIES
Late preterm babies (34 +0 to 36 +6 weeks of gestation) vary widely in physiological maturity. The late preterm baby may have inadequate thermoregulation, immature and weak suck and swallow patterns, incomplete adaptation of certain enzyme systems, and poor immunological and respiratory defence systems. 255 These factors contribute to increased risk of death and morbidity compared to full-term babies. Common problems are hypoglycemia, hypothermia, respiratory distress, infections, increased risk and delayed onset of hyperbilirubinemia, feeding issues, increased hospital readmission rates, and growth failure. 256 Early term babies (37 +0 to 38 +6 weeks of gestation) are at increased risk for the same problems as late preterm babies, with increased likelihood of admission to NICU. 257 An assessment at birth to confirm the baby's gestational age and ongoing monitoring are important to determine the treatment plan. Delay in adaptation might require admission to NICU, while mature late preterm babies can be cared for in regular postpartum care. In both situations, it is important to avoid separating the mother and baby. 255
# 5-41
Screen for hypoglycemia and hyperbilirubinemia according to the CPS Screening Guidelines for Newborns at Risk for Low Blood Glucose and Guidelines for Detection, Management and Prevention of Hyperbilirubinemia in Term and Late Preterm Newborn Infants. Continued breastfeeding support is necessary to establish feeding and prevent readmission.
The CPS guideline Safe Discharge of the Late Preterm Infant provides detailed criteria for hospital discharge and post-discharge followup. 255 Some key criteria include stable vital signs for at least 12 hours prior to discharge, 24 hours of successful feeding, and avoidance of motherbaby separation before discharge by providing flexible accommodation arrangements for parents. Arrange for a follow-up appointment within 24 to 48 hours of discharge with a community-based HCP, prior to the baby being discharged home.
# ASSISTED VAGINAL BIRTH
Instrumental birth involves use of a vacuum extractor or obstetrical forceps. Trauma is the major complication of instrument-assisted birth in the newborn. Trauma may be caused by head compression and traction on the fetal intracranial structures, face, and scalp or by suboptimal instrument placement. 258 The most serious sequelae of trauma is intracranial hemorrhage, which occurs in 16 to 17 per 10 000 births. 259,260 The overall risk to the newborn from assisted vaginal birth is low. The risks that could occur include bumps, bruises, or marks on the baby's head or face that heal in a few days or weeks; cone-shaping of the head, which returns to normal within a day or two; injuries to the baby's scalp, head, and eye; injuries to the nerves in the arm or face-the baby's face muscles may droop if the nerves are injured but go back to normal when the nerves heal. 177,211 Subgaleal hemorrhage is a very rare but serious outcome. 177,211 If the baby has any trauma from an assisted birth, it is important that the mother and family understand the cause, the care required, and the anticipated outcome.
Refer to the SOGC Advances in Labour and Risk Management (ALARM) course for assessment, monitoring, and care of the newborn with subgaleal hemorrhage.
# ANOMALIES OR RARE CONDITIONS
Along with the joy of birth and the delight of welcoming a baby into the family, parents whose babies are born with congenital anomalies or rare conditions have special needs and may feel a sense of loss. Many factors influence parents' experience of having a baby with an anomaly: their personal beliefs, culture, and support network; their HCPs' knowledge and attitude; how the diagnosis is communicated; the information that they are given about their baby's diagnosis and what they can expect; and their connection to appropriate services and support groups. 261 In these situations, base all communication on compassion, using clear and simple terms. 262 Parents require access to the most current information about their baby's condition in a form they can understand. 263 They need to understand the immediate care plan and know what to expect in the future. 261 They should also be told about the necessary resources availablemedical services, clinics, specialists, therapy (e.g., physical, occupational, speech, vision), breastfeeding support, dietitians, mental health services, recreation services, and support groups.
When babies are born with anomalies or rare conditions, a team approach to the family's care is always required. Parents will often be referred to genetics services to help in the diagnosis of their baby. They could also be referred to genetics counselling if they have concerns about future pregnancies.
" Parents require access to the most current information about their baby's condition in a form they can understand.
HCPs are encouraged to take extra time to communicate with the parents and familyincluding significant family members such as grandparents and siblings. Show compassion, listen carefully as the parents and family express their concerns and feelings, and communicate in a way that everyone can understand. It is also important to ensure privacy when discussing the baby with the parents or family.
It is critical to remind parents and family (often repeatedly) about what to expect when they are caring for their baby. When parents are first told about their baby's diagnosis, they are often overwhelmed to the point that they are unable to retain information. A designated HCP should follow up with parents through the postpartum period and to repeat information in subsequent meetings, to assess their ability to cope, and to refer them to appropriate services. 261 Referrals to peer support can be helpful to provide parents with a shared social identity and contribute to feelings of hope. 264 Peer support can include face-to-face or online support groups relevant to the baby's specific condition.
# PROLONGED STAY IN HOSPITAL OR NEONATAL INTENSIVE CARE UNIT
A baby remaining in hospital (especially in the NICU) for an extended period can create a great deal of stress for parents and families. The kind of care that the baby receives, and the approach to care, affects not only the baby's physical well-being but also parent-baby attachment, feeding, neurodevelopmental outcomes, and the overall health and well-being of the baby, parents, and family. The parents and family may be experiencing extreme emotions such as anxiety or depression, or conflicting feelings such as the joy at the birth of their baby and the fears for the baby's well-being and their ability to provide care.
NICU environments that facilitate shared decision-making and partnerships between parents and professionals and enable parents to be their baby's primary caregiver, create a more consistent care for the baby. They also protect the baby from trauma associated with the NICU, such as isolation, stress, and lack of support during painful procedures, and provide parents with the opportunity to develop confidence and skill in caring for their babies. 30,265,266 Critical elements of family-centred care include: unrestricted presence of the parents, 24/7; parents and family as primary caregivers for their babies with the support and guidance of HCPs; and open, continuous communication 267 . The basic principles of family-centred care in this context are the same as all family-centred caredignity and respect, shared decision-making, choice, information exchange, empowerment, and collaboration. 267,268 Improvements in the baby's weight gain, decreased parental stress and anxiety, and increased high frequency exclusive breastfeeding at discharge are some of the demonstrated benefits of family-centred care in the NICU. 269,270 Others include decreased length of stay, enhanced attachment between parents and babies, and greater family satisfaction. 267,270 Family involvement is critical to enabling all babies to reach their full physical, cognitive, and psychosocial development-including those babies in the NICU. 270,271 The Family-Integrated Care (FICare) model is an extension of the principles of family-centred care, with parents as true partners in their baby's care within the NICU. This model was developed by a health care team that included parents whose babies had been in the NICU and follows research in Estonia. 29 Integrating parents into the care team in FICare goes well beyond merely allowing parents to be present and observing their baby's care. 272 Rather, parents provide most of the care for their baby while HCPs guide and counsel parents. 29,30 Single-family NICU rooms are now in use in a few centres in Canada as well as in the USA and Europe. The single-room setting has a number of benefits: it provides optimal environmental support to parents; reduces neonatal sepsis; improves baby weight gain; improves breastfeeding rates; improves control of excessive noise and light; improves staff and parental satisfaction with care; reduces parental and staff stress and anxiety; and costs the same, or possibly less, than standard NICUs. 269,[273][274][275][276][277] Single-room care has not been associated with any increase in adverse outcomes. 275 The stressful environment of the NICU may add to the risks facing preterm or sick babies due to their physiological vulnerabilities, negatively impacting their growth, with the brain particularly affected. Developmental care refers to a range of strategies designed to reduce the stresses of the NICU and include control of external stimuli, improved clustering of care activities, and positioning or swaddling of the preterm baby. 278,279 While more research is needed, developmental care interventions has demonstrated benefits to the outcomes of preterm babies. 279 Some families, including Indigenous families and those living in rural and remote areas, may be far from home and have to travel for the birth or if the mother and child are transferred to another facility after the baby is born. Prolonged hospital stays can be particularly stressful for these parents, as they are away from extended family members, friends, and support networks. They may have other children back home, which can cause additional stress.
PROVIDING FAMILY-CENTRED CARE IN THE NICU 29,[268][269][270][271]280,281 Parents
• Are full partners in decision-making and caregiving and are integrated into the NICU team;
• Have unlimited access to their babies and rooming-in, 24/7;
• Are supported by HCPs in aspects of care, such as prolonged skin-to-skin contact, breastfeeding, and providing developmentally appropriate care so that they become competent in their caregiving;
• Are supported in their baby's care to minimize their baby's stress and pain, to safeguard their sleep, and protect their baby's skin;
• Participate in care planning-in rounds and having access to their baby's records;
• Receive psychosocial support from the interprofessional team, including psychologists, and peers; and
• Are enabled to express their emotions and fears.
Health care providers: 29,267,[269][270][271][280][281][282][283] • Provide care based on interprofessional collaboration and partnerships with family and other professional providers;
• Include parents as full partners in decision-making and care;
• Shift their role from skilled provider to one of guidance, supporting parents in their role as primary caregivers, 24/7;
• Focus on promoting baby-parent interactions, stressing the critical importance of parents' presence and rooming-in, and assuring them of unlimited 24-hour information and access to their baby;
• Support parents in a compassionate, respectful way, recognizing their individual needs;
• Support parents in skin-to-skin contact with their babies;
• Support mothers in breastfeeding and feeding their babies breast milk;
• Communicate with families openly and honestly, and spend time listening to the families' experiences, fears, and concerns;
• Communicate warmly, regularly, in an understandable fashion, and in a culturally appropriate and safe manner;
• Share information between themselves and with parents;
• Are aware of the possibility of posttraumatic stress disorder (PTSD), and screen for depression; and
• Are supported by system leadership who are committed to an integrated team approach to the needs of babies, families, and staff.
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PROVIDING FAMILY-CENTRED CARE IN THE NICU 29,[268][269][270][271]280,281 Policies: 29,267,[269][270][271]280,284 • Are supported by a clear vision;
• Have full leadership and administrative support;
• Stipulate unlimited access and preferably rooming-in 24/7 and information for parents;
• Stipulate that parents are integral members of the care team, not visitors, and are their babies' primary caregivers, sharing in decision-making;
• Create opportunities for the participation of parents in support systems;
• Stipulate that HCPs communicate regularly with parents and provide mechanisms to do so;
• Ensure adequate staffing for the model of care in the unit;
• Support ongoing professional development for NICU staff;
• Actively involve parent partners and advocates in the development and monitoring of policies to inform quality improvement, and develop systems to accommodate this; and
• Support early and frequent breastfeeding or breast milk expression, meetings with lactation consultants and adequate follow-up-with a written policy.
Infrastructure and supports 267,271,283,285,286 • The physical setting is supportive of the baby's well-being and neurodevelopment, i.e., in a single room with enough space and resources to support parents' presence (e.g., with showers, kitchen, laundry, lounge, etc.) so that the parents can stay in the room with their baby 24/7 (or sleeping rooms available).
• The interprofessional team give the parents psychological and social support, and they have access to peer support.
• The physical environment supports the breastfeeding mother, e.g., provides for intimacy and means of expressing breastmilk, etc.
• Educational materials are available in plain language in a variety of formats (e.g., in writing, video, apps, etc.).
• Mechanisms in place enable parents' involvement in their baby's care and inform them of their baby's well-being, even when they are not present (e.g., by using web cameras).
• Preparation for the transition home begins at the baby's admission to the NICU, by providing information on the criteria for discharge and baby care, supporting parents to care for their baby, assessing the parents' social supports, and providing referrals to appropriate services.
• Care planning for the transition to home includes coordination of health and social care plans with any applicable community services, which may require multi-agency collaboration.
# LATE POSTPARTUM
New parents have many different emotions after the birth of their baby. They may feel full of joy and wonder, anxious, overwhelmed, worried and tired. Having a baby brings a myriad of changesand is very demanding. It takes months or even years to adapt to these changes. Becoming a parent is a deeply significant personal and social transition that involves a change of identity.
When caring for the new mother and her family, the goal of HCPs is to assist her in this transition and recognize and support her role in caring for her baby and nurturing their interdependent relationship. It is critical to spend time listening to mothers and families and to provide support based on their individual needs and experiences.
Providers should let new mothers know that they have faith in them and their ability to care for themselves and their baby. Providers can also help them listen to their intuitions and learn from their experiences so they become more and more confident in their new role. With time, the mother can discover her strengths and her own way of doing things. 287 Relationships with a partner and family are also undergoing transition. Communication is the key to nurturing these relationships. Talking about feelings, worries, and happiness during this intense period can help keep couples and/or families close. 287 Healthy early childhood development includes the physical, social/emotional, and language/ cognitive domains. 288 Many health, social, and justice issues later in life have their roots in early childhood. Parents need the supports of HCPs and community programs to assist them in fostering the optimal growth and development of their baby starting from birth.
# SYSTEMS TO FOLLOW FAMILIES POSTPARTUM
Postpartum support in the community should be planned according to a family-centred approach to care, based on women's experiences and needs, while respecting their diversity in the social and cultural contexts of their postnatal experience. 289 The woman and her partner and newborn belong at the centre of care, with strategies planned and provided to meet their needs, respecting the woman's preferences and decisions, while ensuring she is treated with kindness, respect, and dignity. 29,289,290 Women, newborns, and families have different points of access to postpartum care in the community. These often involve numerous HCPs (e.g., physicians, nurses, and midwives; lactation consultants and registered dieticians; social workers and psychologists) and communitybased providers (e.g., postpartum doulas and maternal child health home visitors). They also seek and receive support from their family members and peers.
Successful postpartum support strategies in the community are holistic and comprehensive, applying an efficient and effective interdisciplinary approach to care. 289 Women should have multiple choices for the kind of supports that meet their needs. It is critical that women be provided with a first/consistent point of contact (for example, a public health nurse, midwife, or nurse practitioner) for when they need to reach out for support.
Hospitals, health centres, community-based organizations, and public health and primary care providers offer postpartum services in Canada. Some jurisdictions have centres that provide education, support, and programming for new mothers and young families. Various models are used, including phone calls, telephone triage services, clinic visits (drop-in and by appointment), and home visits. 215 With many providers and many groups providing care, and with a lack of coordination across settings, postpartum care runs the risk of fragmentation.
As most women who give birth return home after a very short stay in the hospital or birthing centre, the coordination of support in the community is critical.
Planning postpartum care locally allows for the greatest efficiency and effectiveness. NICE guidelines recommend having a coordinating health care professional for each postpartum case and a documented, individualized care plan developed with the woman. 24 It is essential that mothers and families know about the specific community supports that are available to them in their area, perhaps in the form of a handout or website that lists the information.
While access to professional postpartum support within the community is essential for positive health outcomes for women, children, and families, social support networks have been identified as one of the key determinants of health. 291 It is also important that women have access to their own social support networks. Social media provides the opportunity for women to form virtual groups for support and information sharing. They can also access a variety of websites with evidence-based information, such as those of PHAC, provincial/ territorial governments, and professional organizations, that can provide answers to questions on self and baby care. HCPs can help women identify the websites or social media sites that may be helpful and those that would be best to avoid because they are neither helpful nor evidence-based.
Optimally, planning for the postpartum period starts during pregnancy. Prenatal education classes may provide a source of postpartum support from other families going through the same experiences. 292 Appendix B provides descriptions of innovative international and Canadian postpartum care models and guidelines. Refer to Appendix C for an outline of the various methods used to deliver postpartum care in the community.
# ONGOING POSTPARTUM CARE OF THE MOTHER AND BABY
Continued postpartum support and care needs to be provided according to the principles of familycentred care. It is important to determine and respect the woman's and family's views, beliefs, and values. The mother should be fully involved in determining the timing and content of each postpartum contact with HCPs so that the care she receives meets her and her baby's needs and is flexible. 24,41 At each postpartum encounter, the mother and her partner should have the opportunity to express their feelings and concerns and talk about their physical and emotional well-being, breastfeeding, rest, pain or discomfort and any concerns to do with the baby. These encounters provide HCPs with the opportunity to explore how the mother is coping with her daily experiences and her family and social supports, and to encourage women and their families or partners to talk about any changes in mood, emotional state, and behaviour that are outside of the woman's normal pattern. 24 HCPs will want to be aware of and look out for the signs of emotional health problems that occur during the weeks and months following birth.
Professionals have developed a number of methods-written standards of care, care plans, maps or paths, managed care, among others-to ensure that criteria for maternal and newborn health and adjustment are observed during the postpartum period. These criteria, also called indicators or outcomes, include specifics about the mother, the baby, and the family's social or home support system. While these tools are useful, the focus should always be on supporting the mother and baby's transition based on their individual needs and experiences.
# INTIMATE PARTNER VIOLENCE AND CHILD MALTREATMENT
HCPs are ideally positioned to recognize signs of family violence, including intimate partner violence, as well as child exposure to intimate partner violence and other types of child maltreatment. These forms of violence can negatively impact the health of mother and child, and the effects can persist over time.
It is important that providers be equipped to recognize and respond safely to situations involving family violence, and to ensure that their interactions or interventions do not revictimize the mother or child.
According to the Maternity Experiences Survey, about 1 in 10 women who have given birth reported experiencing one or more acts of violence in the past 2 years, most often being pushed, grabbed, or shoved in a way that could have hurt them. 215 Over half (52%) identified their partner, husband, or boyfriend as the perpetrator of this violence. One-third (31%) experienced the violence during pregnancy, and 16% reported that the violence increased after the birth of the baby, 52% that it decreased, and 32% that it stayed the same. Of those women who experienced abuse, 61% reported discussing or receiving information about what to do if they experienced abuse. 215 Intimate partner violence has been associated with mental health disorders for women, most commonly depression and anxiety disorders, and PTSD. Other effects on mental health include poor self-esteem, sleep disorders, eating disorders, phobias and panic disorders, substance dependence, antisocial personality disorders, and psychosis. 293 Intimate partner violence is also associated with postpartum depression. 294 Child maltreatment includes physical, sexual, and emotional/psychological abuse as well as neglect. Exposure to intimate partner violence is also a form of child maltreatment. 295 Child maltreatment is a major public health issue associated with a broad range of negative health outcomes across the life course. Approximately one-third of Canadian adults (32%) report experiencing physical abuse, sexual abuse, and/or exposure to intimate partner violence before the age of 16 years. 296 Provincial/territorial child welfare legislation considers exposing a child to intimate partner violence/family violence a form of maltreatment, and HCPs are required to report it. 296 Violence in the home has a negative impact on babies, whether they experience it directly, for example, receive an injury while held during physical violence, or indirectly, due to their dependence on their primary caregivers for emotional support. 297 When the primary caregiver is involved in a stressful event, the child's main source of comfort is a source of fear and distress. This repeated pattern can result in disorders of attachment, which may contribute to behaviour problems in later childhood. Babies and young children who experience repeated violence in the home have reduced capacity to regulate their emotions and behaviour because of their lack of emotional security. 297 Adverse Childhood Experiences (ACEs) research has shown that traumatic childhood events such as abuse, neglect, and household dysfunction are linked to an increased likelihood of developing physical, behavioural, and social problems in adulthood. 298 Canadian and WHO guidance do not recommend universal screening for intimate partner violence. 299,300
# MOTHER'S NUTRITION AND HEALTHY WEIGHT
Postpartum nutrition and achieving a healthy weight following a pregnancy can impact maternal and child health both in the short and the long term. The SOGC states that postpartum women can achieve optimal nutrition by eating a variety of high quality foods and following the advice in Canada's Food Guide.
Breastfeeding women have higher energy needs and should therefore eat a little more food each day than non-breastfeeding women. Canada's Food Guide recommends regular intake of vegetables, fruit, whole grains, and protein foods. Deficiency of certain nutrients, including thiamin, riboflavin, vitamin B6, vitamin B12, choline, vitamin A, vitamin D, selenium, and iodine, can adversely affect the concentration in breastmilk. 302 Health Canada recommends that all women who could become pregnant, including breastfeeding women, take a daily multivitamin containing 400 mcg (0.4 mg) of folic acid. 302 Some women, for example those who live in low income, Indigenous women or women who are newly arrived in Canada or refugees, may be at higher risk of nutritional challenges. 303,304 A lack of access to nutritious food, or to knowledge about nutritious food, can compromise women's and families' abilities to eat adequately. It is important that women receive nutritional counselling that is relevant to their specific needs and culture.
Refer to the SOGC guideline Canadian Consensus on Female Nutrition: Adolescence, reproduction, menopause, and beyond for components of the maternal diet that may affect those babies who are breastfeeding. 305
# Postpartum weight
Weight loss during the postpartum period should be gradual. There is little evidence that gradual weight loss affects the volume and quality of breastmilk once lactation is established. 305 The SOGC emphasizes the need for optimal nutrition to achieve a healthy body weight postpartum. Postpartum visits can be opportunities to check on weight retention/reduction, healthy eating habits, and exercise.
Refer to the SOGC guideline Canadian Consensus on Female Nutrition: Adolescence, reproduction, menopause, and beyond for more information. 305 HCPs are well positioned to recognize circumstances that are cause for concern; for example, a sudden, rapid weight loss or, conversely, if a woman is living with obesity.
The scientific knowledge about obesity and its treatment has led to the recognition that obesity is an illness and not a product of an inadequate lifestyle. It is important to avoid shaming and stigma. 306 Refer to the SOGC guideline Obesity in Pregnancy for recommendations on the counselling and care of women who have obesity.
# SEXUALITY AND CONTRACEPTION
Many factors influence a woman's sexuality during the postpartum period: her culture, her experience before and during pregnancy, her relationship, her physiology, and her emotional and psychological state. 307 This is compounded by the experience of giving birth, fatigue, the physical recovery from labour and birth, the changes her body is undergoing postpartum, caring for her baby, and perineal pain or discomfort.
Faced with the physiological and emotional changes of becoming new parents, intimacy may be challenging for women and their partners to maintain postpartum, but it remains important for the health of their relationship. Both women and providers often find it difficult to discuss postpartum sexual changes, adjustment, and intimacy. However, sexual concerns are common among women, and they welcome their HCP raising the topic and offering support regarding any concerns that she and her partner may have. 308,309 Low or no sexual desire is very common during the postpartum period. A lesser interest in sexual activity than before or during pregnancy is the norm during the first few months to a year after childbirth. 310,311 Between 22% and 86% of women experience changes in sexual functioning postpartum, especially those who have had an assisted vaginal birth as opposed to a spontaneous vaginal birth or caesarean birth. 312 A number of studies have linked episiotomy or perineal lacerations and operative vaginal birth with dyspareunia, which can persist for a number of months. 313,314 Women who have had a caesarean birth may also have discomfort with intercourse. 312,315
# Contraception and Prevention of Sexually Transmitted Infection
Postpartum women need information about contraception and preventing sexually transmitted infections (STIs), and about what methods are compatible with breastfeeding.
In this regard, the SOGC recommends the following: 316,317 • Lactational amenorrhea method (LAM) can be used for the first 6 months if the woman's periods have not returned and the baby is exclusively breastfed on demand day and night and is not fed other foods or liquids. 318 The woman will need to use another form of birth control once her period returns or the baby is older than 6 months, is no longer exclusively breastfeeding, is sleeping through the night, or has long intervals between breastfeeding. 318
• Postpartum women may be candidates for an IUC, which can be inserted immediately after delivery. However, women are at a higher risk for uterine perforation during insertion of the IUC in the first postpartum year.
• Hormonal contraceptives can be used by non-breastfeeding women from 3 to 4 weeks after they give birth. Some hormonal birth control methods may decrease milk production, but the progestin-only birth control pill does not appear to interfere with lactation. Currently available combined estrogen-progestin birth control pills do not interfere with the quantity or quality of breast milk once feeding is established.
• Condoms are an effective contraceptive option for breastfeeding and non-breastfeeding women. Condoms also protect both partners from STIs.
Refer to the SOGC guidelines The Canadian Contraception Consensus Guidelines for guidance on the use of contraceptive methods in postpartum and breastfeeding women to prevent pregnancy and STIs.
# IMMUNIZATION
Immunization is a proven cost-effective public health intervention that prevents significant illness, disability, and death. 319 Vaccines work best when they are given on time, beginning in infancy. Children are immunized early in life because they are vulnerable to diseases and the consequences can be very serious. The vaccination schedule is designed to protect babies and children before they are exposed to vaccine-preventable diseases.
Periodic outbreaks of illnesses such as measles, which can cause death or disability, can result because not all Canadians are immunized. 320 PHAC reports that 23% of children have not received the full four recommended doses of the diphtheria, whooping cough (pertussis), and tetanus vaccine by the time they are 2 years old. 321 In the last 10 years, the number of measles outbreaks has increased in several provinces, with five of the outbreaks involving more than 10 cases. These outbreaks are largely a result of the importation of the virus from other countries, with vulnerable children, including those who are not immunized, contracting the illness. 322 Some parents may be hesitant or resistant to immunizing their babies. The reasons behind children not being fully immunized are complex and context-specific and often community-specific.
A vocal few hold anti-vaccine views; they are not the main reason for the lack of coverage, although the number of vaccine-hesitant parents is growing. Some are complacent, taking vaccination rates and herd immunity for granted; some have doubts about the safety or necessity of vaccines, having been convinced by misinformation about adverse effects; while others do not get their children immunized because of the time and effort it can take to do so or they are concerned about the injections causing pain. 323 The CPS recommends that HCPs acquire the knowledge and skill to work with parents who are hesitant about immunization. Parents often look to HCPs for answers to their questions about immunization. HCPs will want to share evidencebased information about babies' vaccinations in a manner that is easy for parents to understand and explore any reasons families may have for not immunizing. 324 Connecting with parents in order to maintain trust and keep the lines of communication open is critical. Each parent requires different information geared to his or her specific needs.
It is important to understand a parent's specific concerns and to demonstrate care and compassion for both the child and the family. Telling stories about vaccine-preventable disease cases in Canada can help educate parents. Taking the time to convey information clearly, calmly, and effectively can make the difference whether a child is immunized. 325 Refer to the CPS practice point Working with vaccine-hesitant parents for more information.
The Canadian Immunization Guide, based on guidance from the National Advisory Committee on Immunization (NACI), provides guidelines for immunization of babies, children, youth, and adults, as well as specific recommendations for postpartum and breastfeeding women. The Canadian Immunization Guide includes the schedule for the following vaccinations for babies and toddlers up to 18 months:
• Diphtheria, tetanus, pertussis, polio
• Haemophilus influenza type b
• Rotavirus • Pneumococcal disease • Influenza • Meningococcal disease • Measles • Mumps • Rubella • Varicella • Hepatitis B
Although NACI makes recommendations at the national level, provinces and territories determine specific programs and schedules.
As such, HCPs need to refer to the immunization schedules of their respective jurisdictions.
It is critical that all siblings, parents, grandparents, other family members, and visitors have all their immunizations up-to-date when a baby comes home. This is particularly important if the baby or mother have underlying medical conditions or vulnerabilities that would increase their risk of communicable diseases like whooping cough and influenza.
# CONCLUSION
The birth of a baby involves many transitions and adaptations for the woman, the baby, and the family. Parents feel many different things following the birth of their baby-joy, wonder and happiness, as well as anxiety, worry and fatigue. These are all normal feelings. Mothers adapt physically and psychologically following birth as they face lack of sleep, physical discomfort or pain and relationship changes. Caring for a baby is demanding, requiring many adaptations for parents. While the postpartum period is a normal, healthy time of life, it is also challenging for families, even as parents get comfortable with their roles.
Providing family-centred maternity and newborn care to women, their partners, and families during the postpartum period is an essential component of the care offered by all institutions, agencies, and programs. It is important that HCPs focus on the individual needs and values of the mothers, partners, newborns, and families they are working with. As women, their partners, and immediate families develop attachment and confidence in caring for their newborn babies, they will also require support from extended family and friends, in addition to providers and community programs.
# APPENDIX B-LEARNING FROM OTHERS'-POSTPARTUM CARE MODELS AND GUIDANCE
The Netherlands
The Netherlands has a system for postpartum care provided by kraamverzorgenden-maternity home care assistants. Trained caregivers visit the home of new parents and observe the mother and her baby, offer information in baby care and feeding, and even help in household chores, shopping, and if necessary, cooking. The service is popular and, because of a recent shortage of kraamverzorgenden, the average number of hours of maternity home care assistance over the first 8 days after normal childbirth has decreased from 64 to 44 hours. 326 As a result of guidelines developed by government, insurance companies, and professional organizations, maternity care in the Netherlands is considered "remarkable for its degree of cooperation between caregivers at different levels and locations in the system. 326 " Pregnant women can move freely between care settings and caregivers, including midwives, general practitioners, and specialists.
# France
Most babies are born in hospital in France. When families leave the hospital, they are given the telephone number of the nursery nurse in their area and are encouraged to call with any questions or concerns. Newborn babies are issued with a health record book that contains all their medical informationincluding vaccinations-up to age 16 years. The health record book is considered an essential document, and it aids the communication process between HCPs and families. 327 Compulsory medical examinations of children are carried out regularly. The first is within 8 days of birth, another is in month 9 or 10, and the last during month 24 or 25. Mothers and children can access interdisciplinary mother and baby care ("Protection maternelle et infantile") at local maternal and child health clinics. Clinic staff conduct postnatal checks, provide nutritional and health advice, and can administer vaccinations. 327
# Canada
# Nova Scotia-Healthy Babies, Healthy Families: Postpartum & Postnatal Guidelines
The Government of Nova Scotia's Healthy Babies, Healthy Families: Postpartum & Postnatal Guidelines provide guidance for the organization of postpartum services. These guidelines were developed to enhance and support the provision of high quality care to women, their babies, and their families across Nova Scotia in the first 6 weeks postpartum. They contain recommendations that focus on physiological stability, infant feeding or nutrition and growth monitoring, psychosocial/family adjustment, parent-child attachment/parenting, building on capacities and strengths, transition to home and community, family access to community support, healthy lifestyles and environments, collaborative practice, and professional competency. 328
# Ontario-Standards of Postnatal Care
The Standards of Postnatal Care articulate the criteria of postnatal care for mothers and babies in Ontario in immediately postpartum. The Standards identify models, methods, or systems for improving coordination of care along with an evaluation framework to monitor their impact. To support the implementation of the Standards of Postnatal Care, another report was developed: Standards of Postnatal Care for Mothers and Newborns in Ontario (Part II): A focus on implementation and evaluation. This report provides an overview of implementation recommendations to enhance the delivery of postnatal care. It also includes a suggested evaluation framework that identifies priority standards for monitoring across the province. 42
# Ontario-Monarch Centre-Ottawa
The Monarch Centre is a multidisciplinary maternal and newborn health clinic providing evidencebased comprehensive care. Following the birth and discharge from hospital, babies born at the Ottawa Hospital and their mothers can be referred to the Monarch Centre for their first 24-to 48-hour check-up.
The registered nurses, board-certified lactation consultants, and family doctors at the Monarch Centre specialize in maternal and newborn care, and provide all the necessary breastfeeding support, bilirubin checks for jaundice, newborn screening and full postpartum check-ups, services and follow-up for mother and baby.
The Monarch Centre coordinates discharge directly with hospital providers to make sure that mother and baby are discharged when ready-and when it is medically appropriate. Upon coordinated discharge from hospital, Monarch supports the transition home for the new family. 329
# British Columbia-The Nurse-Family Partnership
The Nurse-Family Partnership (NFP) is an intensive home-visiting program designed to help young first-time mothers and their children. A public health nurse visits women enrolled in the program throughout their pregnancy and until their child reaches 2 years of age. The goals are to improve children's health and development while improving mothers' life situations.
McMaster University in Ontario ran a pilot study of the NFP program, and British Columbia is conducting a randomized controlled trial evaluation. In the USA, the program has demonstrated improved parenting, reduced injuries and poisonings, and improved emotional and language development by babies. The mothers have also been found to have benefitted, with greater participation in the workforce and less reliance on social assistance. 330,331
# APPENDIX C-METHODS USED TO DELIVER POSTPARTUM CARE IN THE COMMUNITY
Drop-In Clinics: Usually staffed by nurses, midwives, and lactation consultants, postpartum clinics are geared to mother/baby drop-ins or scheduled visits. The clinic program can be structured for health assessment, health concerns, breastfeeding support, and advice.
Home Visits: A traditional follow-up component of maternal and newborn care is the home visit by either a nurse or midwife. The length and frequency of visits vary according to the needs of the family and the program specifications. Referrals for home visits are made by the hospital or community liaison staff or by the mother herself; often, they are governed by the "urgency" rating of the assessed need.
In some areas, home visiting has been discontinued or replaced with community-based supports that the mother must transit to. Some hospitals have initiated home follow-up by their childbirth staff for mothers in need, as identified by risk criteria or need for additional support. Some home-visiting models use a combination of professional and paraprofessional visitors.
Online: Online resources for postpartum information include social media, websites, and blogs. Online resources enable mothers to engage with other mothers, share experiences, and attain information on caring for themselves and their newborn.
Parenting Courses: As with prenatal classes, some parents benefit from group or individual discussions on parenting during the postpartum period and learn more about their roles as parents through these.
Peer Support: Mother-to-mother support provided in various ways-in person, over the phone, via social media or texts. The supporter is or was in a similar situation to the peer. Some peer-to-peer support deals with specific topics such as breastfeeding or postpartum depression, while others provide general postpartum support.
Phone Lines: Some provinces and communities have initiated phone support and advice for new parents. Parents can ask questions, sometimes day or night, about personal, parenting, and postpartum health concerns. Questions usually relate to breastfeeding, crying, coping at home, and community resources. Phone lines can be connected to general health lines or hospital postpartum wards, or run by public health units or community-based organizations.
Physician/Midwife: Follow-up assessments by the physician, midwife, or other HCP in the community or home. Scheduling/timing of visits depends on general maternal and newborn health; complications of pregnancy, birth, and the postpartum period; and available family/community supports.
Telephone Follow-up: A phone call from public/community health nurses or midwives can ensure that the postpartum plan is in place and working well. Specific outcomes related to feeding and mother and baby well-being can be addressed. The telephone interview may result in a referral to a community agency for service, such as a home visit or other follow-up.
The Canada Prenatal Nutrition Program (CPNP) is a Government of Canada program that provides funding to community groups to help improve the health of pregnant women and new mothers and their babies who face, for example, poverty, teen pregnancy, social and geographical isolation, substance use, or family violence, which put their health at risk. CPNP aims to improve the health of women and their babies by increasing the number of babies born at a healthy weight and promoting and supporting breastfeeding. It ensures culturally sensitive prenatal support for Indigenous women and women who have recently immigrated.
The program provides nutrition counselling, prenatal vitamins, food, food coupons and food preparation training, counselling in prenatal health and lifestyle, breastfeeding education and support, education and support on baby care and child development, and referrals to other agencies and services. 332 The Community Action Program for Children (CAPC) is another Government of Canada program that provides funding to community groups whose focus is the promotion of the healthy development of families (with children from birth to 6 years old) who face challenges that put their health at risk-poverty, teen parenting, social and geographical isolation, substance use, and family violence.
# APPENDIX A-ADDITIONAL RESOURCES
# CLINICAL PRACTICE GUIDELINES RELATING TO POSTPARTUM HEALTH
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# INTRODUCTION
The 2018 update of the Heart and Stroke Foundation of Canada's Canadian Stroke Best Practice Recommendations for Acute Stroke Management, Sixth Edition (CSBPR, 6th Ed.) 1 was developed with input from the Canadian Association of Emergency Physicians (CAEP) Stroke Practice Committee and approved by the CAEP Executive Board. It provides comprehensive, evidenceinformed recommendations for the management of acute ischemic stroke (AIS) and transient ischemic attack (TIA). This article aims to highlight recommendations from the CSBPR, 6th Ed. that are particularly relevant to stroke care in the prehospital and emergency department (ED) settings, including several significant changes for endovascular thrombectomy (EVT) extended treatment time windows 2,3 and revisions for the triage and management of TIA based on recent evidence.
This article is a condensed synthesis of the CSBPR, 6th Ed. reflecting solely the opinions of the authors through a review outside of CSBPR methodology. Readers are encouraged to refer to the primary CSBPR documents, freely available online at www.strokebest practices.ca, for full details of the peer-reviewed recommendations. If specific language from the CSBPR, 6th Ed. is conveyed, it is indicated by quotation marks with the source recommendation location identified by a section number (e.g., Section 3.3.ii). Otherwise, unquoted text represents the commentary of the authors alone in summarizing the CSBPR, 6th Ed. recommendations. All tables taken or modified from the CSBPR, 6th Ed. and presented here are shared with permission from the Heart and Stroke Foundation of Canada, SAGE, and the International Journal of Stroke. (Tables 1 and 3)
Recommendations from the CSBPR, 6th Ed. are organized into the following major sections:
- Stroke awareness, recognition, and response (CSBPR, 6th Ed., Section 1)
- Emergency medical services on-scene response (CSBPR, 6th Ed., Section 3)
- ED evaluation of acute stroke and TIA (CSBPR, 6th Ed., Section 4)
- Treatment of acute stroke (intravenous thrombolysis and endovascular therapy; CSBPR, 6th Ed., Sections 5-7)
- Outpatient management of TIA and non-disabling minor stroke (CSBPR, 6th Ed., Sections 2 and 6)
# PUBLIC STROKE AWARENESS, RECOGNITION, AND RESPONSE
(CSBPR, 6th Edition, Section 1) Emphasis remains on promoting public awareness campaigns to increase early recognition of stroke symptoms and signs by both healthcare providers and members of the public.
- "Public and healthcare provider education should include information that stroke can affect persons of any age, including newborns, children, and adults. Education should also emphasize the benefits of early emergency treatment" (Evidence Level B; Section 1.1.i/v).
- "Public awareness campaigns and education should include use of the FAST 5 (Face, Arms, Speech, Time) acronym to facilitate memory recognition of signs" (Evidence Level B; Section 1.1.iii).
- "Public and healthcare provider education should emphasize the need to respond immediately by calling 9-1-1 or their local emergency number, even if symptoms resolve" (Evidence Level B; Section 1.1.iv).
# EMERGENCY MEDICAL SERVICES ON-SCENE MANAGEMENT
(CSBPR, 6th Edition, Section 3) Stroke systems of care are being reorganized to screen and direct patients potentially eligible for EVT to EVT-capable hospitals. Emergency medical services (EMS) plays a critical role in screening for these patients. New recommendations in the CSBPR, 6th Ed. include a two-stage stroke EMS screening process to identify signs of stroke and further select the subset of patients with severe stroke who are most likely to be eligible for EVT.
- EMS on-scene assessment should include the use of validated out-of-hospital diagnostic tools for a twostage screening process (Evidence Level B; Section 3.2.i):
ο Stage one: screening for signs of stroke with a tool that includes the components of FAST.
ο Stage two: patients who screen positive in stage one then undergo a second screen to assess for stroke severity (which can assist with the identification of EVT candidates for potential large vessel occlusions and inform transport destination decisions).
- "On-scene time with suspected stroke patients should be as short as possible" with a target median on-scene time of "20 minutes or less for patients presenting within 4.5-hours" of symptom onset or last seen normal time (Evidence Level C; Section 3.2.iii).
- "Initial assessment by paramedics on-scene should include capillary blood glucose measurement" (Evidence Level B; Section 3.2.iv).
- Whenever possible prior to transport, the patient's family and/or alternate decision-makers should be directed by EMS to "accompany the patient to hospital or be accessible by phone for
Table 1. Summary of criteria for levels of evidence reported in the CSBPR, 6th Ed., updated 2018 (Adapted from Guyatt et al. 1,4 )
# Level of evidence Criteria
Grade A Desirable effects clearly outweigh undesirable effects, or undesirable effects clearly outweigh desirable effects. Evidence from a meta-analysis of randomized controlled trials or consistent findings from two or more randomized controlled trials. Grade B Desirable effects outweigh or are closely balanced with undesirable effects, or undesirable effects outweigh or are closely balanced with desirable effects. Evidence from a single randomized controlled trial or consistent findings from two or more well-designed nonrandomized and/or noncontrolled trials, and large observational studies. Grade C Desirable effects outweigh or are closely balanced with undesirable effects, or undesirable effects outweigh or are closely balanced with desirable effects, as determined by writing group consensus. Writing group consensus and/or supported by limited research evidence. Recommendations assigned a Level-C evidence may be key system drivers supporting other recommendations, and some may be expert opinion based on common, new, or emerging evidence or practice patterns.
# Clinical consideration
Reasonable practical advice provided by a consensus of the writing group on specific clinical issues that are common and/ or controversial and lack research evidence to guide practice.
decision-making, as well as confirming time last known well, and providing required information about existing health conditions, current medications, and other information as needed" (Evidence Level C; Section 3.2.v).
TRANSPORT FOR SUSPECTED STROKE PATIENTS
- Regional direct transport protocols must be in place to ensure the timely transfer of patients potentially eligible for acute stroke treatment (within 4.5 hours of known or presumed symptom onset for alteplase , 6 hours for EVT, and up to 24 hours for EVT in patients with highly favourable neuroimaging) to treatment-capable stroke centres (Evidence Level C; Section 3.3.i). Optimal protocols remain the subject of ongoing research and are expected to vary across regional stroke systems based on local geographical factors, such as the distribution of primary stroke centres (PSC) and comprehensive stroke centres (CSC), transport times, hospital-specific times from ED arrival to initiating acute stroke reperfusion therapy, and hospital-specific door-in/door-out times for transferred patients. Recommendations for elements of transfer protocols are provided in Section 3.3.ii and include the following:
ο Designation of a PSC and CSC based on criteria summarized in Table 2.
ο Patients potentially eligible for intravenous alteplase (tPA) may be directed to the closest stroke centre (PSC or CSC) (Clinical Consideration; Section 3.1).
ο Patients potentially eligible for EVT may proceed directly to an EVT-enabled CSC or to the nearest PSC first for alteplase (tPA) consideration prior to transfer to an EVT-enabled CSC (Clinical Consideration; Section 3.1).
- "Patients with suspected stroke should be triaged . . . - Patients should remain nil per os (NPO, no oral intake) until a swallowing assessment has been performed, ideally within 24 hours of hospital arrival (Evidence Level B; Section 4.6.ii).
# ACUTE ISCHEMIC STROKE (AIS) TREATMENT
(CSBPR, 6th Edition, Sections 5, 6, and 7)
Rapid delivery of alteplase (tPA) and EVT in eligible patients remains the mainstay of AIS treatment. New extended time windows should not be interpreted to mean that time to treatment can be slowed in any way, because outcomes are optimized with earlier treatment.
# PATIENT SELECTION FOR ACUTE ISCHEMIC STROKE TREATMENTS
- "All ischemic stroke patients not already on an antiplatelet agent and not receiving alteplase (tPA) should be given at least 160 mg of acetylsalicylic acid (ASA) immediately as a one-time loading dose after brain imaging has excluded intracranial hemorrhage" (Evidence Level A; Section 6.i). "ASA (81 to 325 mg daily) should then be continued indefinitely or until an alternative antithrombotic regimen is started" (Evidence Level A; Section 6.i.a.).
- All patients with disabling acute stroke presenting within eligible treatment time windows must be screened without delay through appropriate clinical evaluation and neuroimaging by a physician with stroke expertise (either on-site or by telemedicine/telestroke consultation) (Evidence Level A; Section 5.1.i/ii).
- The following eligibility time windows are based on presentation from time of symptom onset or when last seen normal:
# INTRAVENOUS THROMBOLYSIS WITH ALTEPLASE (tPA)
- "All eligible patients with disabling ischemic stroke should be offered intravenous alteplase (tPA). Eligible patients are those who can receive intravenous alteplase (tPA) within 4.5 hours" of symptom onset time or last seen normal (Evidence Level A; Section 5.3.i).
ο Inclusion and exclusion criteria for alteplase (tPA) eligibility can be reviewed in the CSBPR, 6th Ed. (Box 5B).
ο The decision of the CAEP Stroke Committee to support a 4.5-hour treatment time window for alteplase (tPA) arises from a consensus agreement that the benefits of collaboration, including partnership in improved regional EVT pathways, outweigh the harms of alteplase (tPA) within the 3-to 4.5-hour treatment time window.
- "All eligible patients should receive alteplase (tPA) as soon as possible after hospital arrival" (Evidence Level A; Section 5.3.ii), with a target median doorto-needle time of 30 minutes (Evidence Level B; Section 5.3.ii).
- "Alteplase (tPA) should be administered using a dose of 0.9 mg/kg to a maximum of 90-mg total dose, with 10% (0.09 mg/kg) given as an intravenous bolus over one minute and the remaining 90% (0.81 mg/kg) given as an intravenous infusion over 60 minutes" (Evidence Level A; Section 5.3.iib).
- "In patients treated with intravenous alteplase (tPA), antiplatelets should be delayed until after the 24-hour post-thrombolysis has excluded intracranial hemorrhage" (Evidence Level B; Section 6.iii).
- Alteplase (tPA) should not be routinely administered to patients on anticoagulation therapy presenting with AIS, except when the patient is taking warfarin and the INR is subtherapeutic (less than or equal to 1.7) (Section 5, Box 5B). There is currently no evidence to support routine reversal of anticoagulation to administer alteplase (tPA) (Clinical Consideration; Section 4.6). EVT may be considered in these patients if they are otherwise eligible for treatment (Clinical Consideration; Section 5.3).
# ACUTE ENDOVASCULAR THROMBECTOMY (EVT)
- "EVT should be offered within a coordinated system of care," including EMS, ED, stroke teams, radiology, and local neurointerventional experts. Access to rapid neuroimaging and a stroke unit is critical (Evidence Level A; Section 5.4.i).
- EVT is indicated in eligible patients whether or not they are also eligible to receive or have already received alteplase (tPA) (Evidence Level A; Section 5.4.iii).
ο Whenever possible, patients who are eligible for both alteplase (tPA) and EVT should have alteplase (tPA) administered while simultaneously preparing the angiography suite for EVT (Evidence Level A; Section 5.4.iv).
- Many patients with TIA or non-disabling minor stroke can be safely managed in an outpatient setting. However, the risk of a recurrent stroke is highest within the first 90 days following a TIA or non-disabling minor stroke event (12% to 20%). The goal of outpatient management is to appropriately risk stratify patients and reduce modifiable cardiovascular risk factors. Early recognition, risk factor management, and referral to stroke specialty clinics have been shown to considerably reduce the risk of recurrent stroke. Two randomized controlled trials have now established a role for dual antiplatelet therapy with aspirin and clopidogrel in the first few weeks following a TIA or minor ischemic stroke. 6,7 RISK STRATIFICATION FOR TIA AND NON-DISABLING MINOR STROKE
- The CSBPR, 6th Ed. outlines a risk stratification approach for a suspected TIA or non-disabling minor stroke based on presenting symptoms and the timing of symptom onset.
- Presenting symptoms may be categorized as follows: - Urgency of initial assessment by a healthcare provider with stroke expertise is determined by overall risk stratification, as summarized in Table 3.
# ANTIPLATELET MANAGEMENT FOR TIA AND NON-DISABLING MINOR STROKE
- "All TIA and non-disabling minor stroke patients not already on an antiplatelet agent should be given at least 160 mg of ASA immediately as a one-time loading dose after brain imaging has excluded intracranial hemorrhage" (Evidence Level A; Section 6.i). "ASA (81 to 325 mg daily) should then be continued indefinitely or until an alternative antithrombotic regimen is started" (Evidence Level A; Section 6.ia).
- Patients at very high risk with suspected noncardioembolic origin of stroke should be initiated on a dual-antiplatelet combination of ASA and clopidogrel for a duration of 21 to 30 days followed by antiplatelet monotherapy (such as ASA or clopidogrel alone) 4,5 (Evidence Level B; Section 6.ii).
# CONCLUSION
This CAEP-endorsed summary of the CSBPR, 6th Ed. was developed as a collaboration between Canadian emergency physicians, stroke neurology experts, and the Heart and Stroke Foundation of Canada. It is meant as a tool for knowledge translation to familiarize practicing clinicians with important updates in the management of an acute stroke or TIA. It also serves as a means to promote the importance of partnership between emergency providers, EMS personnel, diagnostic imaging teams, stroke neurology experts, advocacy groups, non-governmental organizations, and system leaders in the management of acute stroke and TIA. 9 Finally, it should be emphasized that an effective interdisciplinary approach to stroke care requires engagement from all stakeholders and must be tailored to meet local needs.
Competing interests: None declared.
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# INTRODUCTION
The 2018 update of the Heart and Stroke Foundation of Canada's Canadian Stroke Best Practice Recommendations for Acute Stroke Management, Sixth Edition (CSBPR, 6th Ed.) 1 was developed with input from the Canadian Association of Emergency Physicians (CAEP) Stroke Practice Committee and approved by the CAEP Executive Board. It provides comprehensive, evidenceinformed recommendations for the management of acute ischemic stroke (AIS) and transient ischemic attack (TIA). This article aims to highlight recommendations from the CSBPR, 6th Ed. that are particularly relevant to stroke care in the prehospital and emergency department (ED) settings, including several significant changes for endovascular thrombectomy (EVT) extended treatment time windows 2,3 and revisions for the triage and management of TIA based on recent evidence.
This article is a condensed synthesis of the CSBPR, 6th Ed. reflecting solely the opinions of the authors through a review outside of CSBPR methodology. Readers are encouraged to refer to the primary CSBPR documents, freely available online at www.strokebest practices.ca, for full details of the peer-reviewed recommendations. If specific language from the CSBPR, 6th Ed. is conveyed, it is indicated by quotation marks with the source recommendation location identified by a section number (e.g., Section 3.3.ii). Otherwise, unquoted text represents the commentary of the authors alone in summarizing the CSBPR, 6th Ed. recommendations. All tables taken or modified from the CSBPR, 6th Ed. and presented here are shared with permission from the Heart and Stroke Foundation of Canada, SAGE, and the International Journal of Stroke. (Tables 1 and 3)
Recommendations from the CSBPR, 6th Ed. are organized into the following major sections:
• Stroke awareness, recognition, and response (CSBPR, 6th Ed., Section 1)
• Emergency medical services on-scene response (CSBPR, 6th Ed., Section 3)
• ED evaluation of acute stroke and TIA (CSBPR, 6th Ed., Section 4)
• Treatment of acute stroke (intravenous thrombolysis and endovascular therapy; CSBPR, 6th Ed., Sections 5-7)
• Outpatient management of TIA and non-disabling minor stroke (CSBPR, 6th Ed., Sections 2 and 6)
# PUBLIC STROKE AWARENESS, RECOGNITION, AND RESPONSE
(CSBPR, 6th Edition, Section 1) Emphasis remains on promoting public awareness campaigns to increase early recognition of stroke symptoms and signs by both healthcare providers and members of the public.
• "Public and healthcare provider education should include information that stroke can affect persons of any age, including newborns, children, and adults. Education should also emphasize the benefits of early emergency treatment" (Evidence Level B; Section 1.1.i/v).
• "Public awareness campaigns and education should include use of the FAST 5 (Face, Arms, Speech, Time) acronym to facilitate memory recognition of [stroke] signs" (Evidence Level B; Section 1.1.iii).
• "Public and healthcare provider education should emphasize the need to respond immediately by calling 9-1-1 or their local emergency number, even if symptoms resolve" (Evidence Level B; Section 1.1.iv).
# EMERGENCY MEDICAL SERVICES ON-SCENE MANAGEMENT
(CSBPR, 6th Edition, Section 3) Stroke systems of care are being reorganized to screen and direct patients potentially eligible for EVT to EVT-capable hospitals. Emergency medical services (EMS) plays a critical role in screening for these patients. New recommendations in the CSBPR, 6th Ed. include a two-stage stroke EMS screening process to identify signs of stroke and further select the subset of patients with severe stroke who are most likely to be eligible for EVT.
• EMS on-scene assessment should include the use of validated out-of-hospital diagnostic tools for a twostage screening process (Evidence Level B; Section 3.2.i):
ο Stage one: screening for signs of stroke with a tool that includes the components of FAST.
ο Stage two: patients who screen positive in stage one then undergo a second screen to assess for stroke severity (which can assist with the identification of EVT candidates for potential large vessel occlusions and inform transport destination decisions).
• "On-scene time with suspected stroke patients should be as short as possible" with a target median on-scene time of "20 minutes or less for patients presenting within 4.5-hours" of symptom onset or last seen normal time (Evidence Level C; Section 3.2.iii).
• "Initial assessment by paramedics on-scene should include capillary blood glucose measurement" (Evidence Level B; Section 3.2.iv).
• Whenever possible prior to transport, the patient's family and/or alternate decision-makers should be directed by EMS to "accompany the patient to hospital or be accessible by phone for [treatment]
Table 1. Summary of criteria for levels of evidence reported in the CSBPR, 6th Ed., updated 2018 (Adapted from Guyatt et al. 1,4 )
# Level of evidence Criteria
Grade A Desirable effects clearly outweigh undesirable effects, or undesirable effects clearly outweigh desirable effects. Evidence from a meta-analysis of randomized controlled trials or consistent findings from two or more randomized controlled trials. Grade B Desirable effects outweigh or are closely balanced with undesirable effects, or undesirable effects outweigh or are closely balanced with desirable effects. Evidence from a single randomized controlled trial or consistent findings from two or more well-designed nonrandomized and/or noncontrolled trials, and large observational studies. Grade C Desirable effects outweigh or are closely balanced with undesirable effects, or undesirable effects outweigh or are closely balanced with desirable effects, as determined by writing group consensus. Writing group consensus and/or supported by limited research evidence. Recommendations assigned a Level-C evidence may be key system drivers supporting other recommendations, and some may be expert opinion based on common, new, or emerging evidence or practice patterns.
# Clinical consideration
Reasonable practical advice provided by a consensus of the writing group on specific clinical issues that are common and/ or controversial and lack research evidence to guide practice.
decision-making, as well as confirming time last known well, and providing required information about existing health conditions, current medications, and other information as needed" (Evidence Level C; Section 3.2.v).
TRANSPORT FOR SUSPECTED STROKE PATIENTS
• Regional direct transport protocols must be in place to ensure the timely transfer of patients potentially eligible for acute stroke treatment (within 4.5 hours of known or presumed symptom onset for alteplase [tPA], 6 hours for EVT, and up to 24 hours for EVT in patients with highly favourable neuroimaging) to treatment-capable stroke centres (Evidence Level C; Section 3.3.i). Optimal protocols remain the subject of ongoing research and are expected to vary across regional stroke systems based on local geographical factors, such as the distribution of primary stroke centres (PSC) and comprehensive stroke centres (CSC), transport times, hospital-specific times from ED arrival to initiating acute stroke reperfusion therapy, and hospital-specific door-in/door-out times for transferred patients. Recommendations for elements of transfer protocols are provided in Section 3.3.ii and include the following:
ο Designation of a PSC and CSC based on criteria summarized in Table 2.
ο Patients potentially eligible for intravenous alteplase (tPA) may be directed to the closest stroke centre (PSC or CSC) (Clinical Consideration; Section 3.1).
ο Patients potentially eligible for EVT may proceed directly to an EVT-enabled CSC or to the nearest PSC first for alteplase (tPA) consideration prior to transfer to an EVT-enabled CSC (Clinical Consideration; Section 3.1).
• "Patients with suspected stroke should be triaged . . . • Patients should remain nil per os (NPO, no oral intake) until a swallowing assessment has been performed, ideally within 24 hours of hospital arrival (Evidence Level B; Section 4.6.ii).
# ACUTE ISCHEMIC STROKE (AIS) TREATMENT
(CSBPR, 6th Edition, Sections 5, 6, and 7)
Rapid delivery of alteplase (tPA) and EVT in eligible patients remains the mainstay of AIS treatment. New extended time windows should not be interpreted to mean that time to treatment can be slowed in any way, because outcomes are optimized with earlier treatment.
# PATIENT SELECTION FOR ACUTE ISCHEMIC STROKE TREATMENTS
• "All ischemic stroke patients not already on an antiplatelet agent and not receiving alteplase (tPA) should be given at least 160 mg of acetylsalicylic acid (ASA) immediately as a one-time loading dose after brain imaging has excluded intracranial hemorrhage" (Evidence Level A; Section 6.i). "ASA (81 to 325 mg daily) should then be continued indefinitely or until an alternative antithrombotic regimen is started" (Evidence Level A; Section 6.i.a.).
• All patients with disabling acute stroke presenting within eligible treatment time windows must be screened without delay through appropriate clinical evaluation and neuroimaging by a physician with stroke expertise (either on-site or by telemedicine/telestroke consultation) (Evidence Level A; Section 5.1.i/ii).
• The following eligibility time windows are based on presentation from time of symptom onset or when last seen normal:
ο < 4.
# INTRAVENOUS THROMBOLYSIS WITH ALTEPLASE (tPA)
• "All eligible patients with disabling ischemic stroke should be offered intravenous alteplase (tPA). Eligible patients are those who can receive intravenous alteplase (tPA) within 4.5 hours" of symptom onset time or last seen normal (Evidence Level A; Section 5.3.i).
ο Inclusion and exclusion criteria for alteplase (tPA) eligibility can be reviewed in the CSBPR, 6th Ed. (Box 5B).
ο The decision of the CAEP Stroke Committee to support a 4.5-hour treatment time window for alteplase (tPA) arises from a consensus agreement that the benefits of collaboration, including partnership in improved regional EVT pathways, outweigh the harms of alteplase (tPA) within the 3-to 4.5-hour treatment time window.
• "All eligible patients should receive alteplase (tPA) as soon as possible after hospital arrival" (Evidence Level A; Section 5.3.ii), with a target median doorto-needle time of 30 minutes (Evidence Level B; Section 5.3.ii).
• "Alteplase (tPA) should be administered using a dose of 0.9 mg/kg to a maximum of 90-mg total dose, with 10% (0.09 mg/kg) given as an intravenous bolus over one minute and the remaining 90% (0.81 mg/kg) given as an intravenous infusion over 60 minutes" (Evidence Level A; Section 5.3.iib).
• "In patients treated with intravenous alteplase (tPA), antiplatelets should be delayed until after the 24-hour post-thrombolysis [neuroimaging] has excluded intracranial hemorrhage" (Evidence Level B; Section 6.iii).
• Alteplase (tPA) should not be routinely administered to patients on anticoagulation therapy presenting with AIS, except when the patient is taking warfarin and the INR is subtherapeutic (less than or equal to 1.7) (Section 5, Box 5B). There is currently no evidence to support routine reversal of anticoagulation to administer alteplase (tPA) (Clinical Consideration; Section 4.6). EVT may be considered in these patients if they are otherwise eligible for treatment (Clinical Consideration; Section 5.3).
# ACUTE ENDOVASCULAR THROMBECTOMY (EVT)
• "EVT should be offered within a coordinated system of care," including EMS, ED, stroke teams, radiology, and local neurointerventional experts. Access to rapid neuroimaging and a stroke unit is critical (Evidence Level A; Section 5.4.i).
• EVT is indicated in eligible patients whether or not they are also eligible to receive or have already received alteplase (tPA) (Evidence Level A; Section 5.4.iii).
ο Whenever possible, patients who are eligible for both alteplase (tPA) and EVT should have alteplase (tPA) administered while simultaneously preparing the angiography suite for EVT (Evidence Level A; Section 5.4.iv).
• Many patients with TIA or non-disabling minor stroke can be safely managed in an outpatient setting. However, the risk of a recurrent stroke is highest within the first 90 days following a TIA or non-disabling minor stroke event (12% to 20%). The goal of outpatient management is to appropriately risk stratify patients and reduce modifiable cardiovascular risk factors. Early recognition, risk factor management, and referral to stroke specialty clinics have been shown to considerably reduce the risk of recurrent stroke. Two randomized controlled trials have now established a role for dual antiplatelet therapy with aspirin and clopidogrel in the first few weeks following a TIA or minor ischemic stroke. 6,7 RISK STRATIFICATION FOR TIA AND NON-DISABLING MINOR STROKE
• The CSBPR, 6th Ed. outlines a risk stratification approach for a suspected TIA or non-disabling minor stroke based on presenting symptoms and the timing of symptom onset.
• Presenting symptoms may be categorized as follows: • Urgency of initial assessment by a healthcare provider with stroke expertise is determined by overall risk stratification, as summarized in Table 3.
# ANTIPLATELET MANAGEMENT FOR TIA AND NON-DISABLING MINOR STROKE
• "All TIA and non-disabling minor stroke patients not already on an antiplatelet agent should be given at least 160 mg of ASA immediately as a one-time loading dose after brain imaging has excluded intracranial hemorrhage" (Evidence Level A; Section 6.i). "ASA (81 to 325 mg daily) should then be continued indefinitely or until an alternative antithrombotic regimen is started" (Evidence Level A; Section 6.ia).
• Patients at very high risk with suspected noncardioembolic origin of stroke should be initiated on a dual-antiplatelet combination of ASA and clopidogrel for a duration of 21 to 30 days followed by antiplatelet monotherapy (such as ASA or clopidogrel alone) 4,5 (Evidence Level B; Section 6.ii).
# CONCLUSION
This CAEP-endorsed summary of the CSBPR, 6th Ed. was developed as a collaboration between Canadian emergency physicians, stroke neurology experts, and the Heart and Stroke Foundation of Canada. It is meant as a tool for knowledge translation to familiarize practicing clinicians with important updates in the management of an acute stroke or TIA. It also serves as a means to promote the importance of partnership between emergency providers, EMS personnel, diagnostic imaging teams, stroke neurology experts, advocacy groups, non-governmental organizations, and system leaders in the management of acute stroke and TIA. 9 Finally, it should be emphasized that an effective interdisciplinary approach to stroke care requires engagement from all stakeholders and must be tailored to meet local needs.
Competing interests: None declared.
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To outline a practical approach for the prevention of venous thromboembolism (VTE) in patients undergoing non-orthopedic surgery.VTE is a common and yet generally preventable cause of post-operative morbidity and mortality. The use of graduated compression stockings (GCS), intermittent pneumatic compression (IPC), low-dose unfractionated heparin (UFH), and low molecular weight heparin (LMWH), combined with early ambulation, have all been shown to reduce post-operative VTE to varying degrees in patients undergoing surgery.# GENERAL PRINCIPLES OF PROPHYLAXIS:
- Thromboprophylaxis decisions rely on a consideration of the balance in the risks of VTE and bleeding, both of which are affected by procedure-specific and patient-specific factors.
- Patients not at low VTE risk without a high bleeding risk should receive pharmacological (anticoagulant) thromboprophylaxis:
- Suggest using LMWH (preferred option in most patients) or UFH (see anticoagulant dosing on page 4) - The use of direct oral anticoagulants (e.g. apixaban, dabigatran, edoxaban, rivaroxaban) has not been well evaluated for thromboprophylaxis in the non-orthopedic surgical setting for thromboprophylaxis 5. For most elective non-orthopedic surgery patients in whom pharmacological thromboprophylaxis is recommended, thromboprophylaxis should be initiated when hemostasis is achieved (for patients without a high risk of bleeding consider starting within 12 hours of surgery). In patients in whom mechanical thromboprophylaxis is recommended, start at the beginning of the procedure. For patients admitted to hospital before surgery, assess for pre-operative pharmacological thromboprophylaxis (see Clinical Guide Thromboprophylaxis: Hospitalized Medical Patients).
- Although the optimal duration of thromboprophylaxis is not well defined, patients with a moderate or high risk for VTE should receive thromboprophylaxis at least until discharge from hospital. Extended duration thromboprophylaxis (up to 30 days) may be considered in select populations.
# THROMBOPROPHYLAXIS APPROACHES IN NON-ORTHOPEDIC SURGERY:
There are three general approaches to thromboprophylaxis in patients undergoing non-orthopedic surgery.
A. Group-based: This approach provides standard thromboprophylaxis to all patients who "belong to" a large group (e.g. abdominal-pelvic surgery, spine surgery, etc.) unless there is a specific patient contraindication. This approach has been adopted by many hospitals in developing their own prophylaxis guidelines.
# B. Individualized:
This strategy is based on individual patient risk assessment using a formal risk assessment model like the Caprini score (/). This score has been validated for general, urologic, and gynecologic surgeries). In general, the estimated VTE risk and thromboprophylaxis recommendations using this approach are similar to the group-based approach.
C. The American Society of Hematology (ASH) 2019 guidelines for management of VTE use a blended approach that incorporates both group-based and individualized recommendations, as summarized in Table 1 below.
Risk of bleeding assessments have not been validated in a formal model for surgical patients.
It is suggested that every institution have a written policy for thromboprophylaxis and, where possible, that thromboprophylaxis protocols be embedded into routinely used electronic or paper order sets.
Evidence is lacking as to whether thromboprophylaxis is needed in neonates and children who have non-orthopedic surgery. However, there may be high-risk cohorts in whom thromboprophylaxis may be considered. Consultation with a pediatrician or hematologist with expertise in pediatric thrombosis is recommended.
# Date of Version: 31January2022
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To outline a practical approach for the prevention of venous thromboembolism (VTE) in patients undergoing non-orthopedic surgery.VTE is a common and yet generally preventable cause of post-operative morbidity and mortality. The use of graduated compression stockings (GCS), intermittent pneumatic compression (IPC), low-dose unfractionated heparin (UFH), and low molecular weight heparin (LMWH), combined with early ambulation, have all been shown to reduce post-operative VTE to varying degrees in patients undergoing surgery.# GENERAL PRINCIPLES OF PROPHYLAXIS:
1. Thromboprophylaxis decisions rely on a consideration of the balance in the risks of VTE and bleeding, both of which are affected by procedure-specific and patient-specific factors.
2. Patients not at low VTE risk without a high bleeding risk should receive pharmacological (anticoagulant) thromboprophylaxis:
• Suggest using LMWH (preferred option in most patients) or UFH (see anticoagulant dosing on page 4) • The use of direct oral anticoagulants (e.g. apixaban, dabigatran, edoxaban, rivaroxaban) has not been well evaluated for thromboprophylaxis in the non-orthopedic surgical setting for thromboprophylaxis 5. For most elective non-orthopedic surgery patients in whom pharmacological thromboprophylaxis is recommended, thromboprophylaxis should be initiated when hemostasis is achieved (for patients without a high risk of bleeding consider starting within 12 hours of surgery). In patients in whom mechanical thromboprophylaxis is recommended, start at the beginning of the procedure. For patients admitted to hospital before surgery, assess for pre-operative pharmacological thromboprophylaxis (see Clinical Guide Thromboprophylaxis: Hospitalized Medical Patients).
6. Although the optimal duration of thromboprophylaxis is not well defined, patients with a moderate or high risk for VTE should receive thromboprophylaxis at least until discharge from hospital. Extended duration thromboprophylaxis (up to 30 days) may be considered in select populations.
# THROMBOPROPHYLAXIS APPROACHES IN NON-ORTHOPEDIC SURGERY:
There are three general approaches to thromboprophylaxis in patients undergoing non-orthopedic surgery.
A. Group-based: This approach provides standard thromboprophylaxis to all patients who "belong to" a large group (e.g. abdominal-pelvic surgery, spine surgery, etc.) unless there is a specific patient contraindication. This approach has been adopted by many hospitals in developing their own prophylaxis guidelines.
# B. Individualized:
This strategy is based on individual patient risk assessment using a formal risk assessment model like the Caprini score (http://thrombosiscanada.ca/resources/prevent/). This score has been validated for general, urologic, and gynecologic surgeries). In general, the estimated VTE risk and thromboprophylaxis recommendations using this approach are similar to the group-based approach.
C. The American Society of Hematology (ASH) 2019 guidelines for management of VTE use a blended approach that incorporates both group-based and individualized recommendations, as summarized in Table 1 below.
Risk of bleeding assessments have not been validated in a formal model for surgical patients.
It is suggested that every institution have a written policy for thromboprophylaxis and, where possible, that thromboprophylaxis protocols be embedded into routinely used electronic or paper order sets.
Evidence is lacking as to whether thromboprophylaxis is needed in neonates and children who have non-orthopedic surgery. However, there may be high-risk cohorts in whom thromboprophylaxis may be considered. Consultation with a pediatrician or hematologist with expertise in pediatric thrombosis is recommended.
# Date of Version: 31January2022
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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# SECTION 1.0: PREAMBLE
Patient Blood Management (PBM) is the timely application of evidence-based medical and surgical concepts designed to maintain hemoglobin concentration, optimize hemostasis and minimize blood loss in an effort to improve patient outcome. 1 Framework for PBM programs may vary whether in a surgical setting (pre-operative, intra-operative, and post-operative) 2 or by goal (stop/minimize blood loss and diagnostic phlebotomy, diagnose and treat coagulopathy, manage anemia, and improve tolerance of anemia) 3 . The aim, regardless of framework, is to improve patient outcomes and make patients the center of care.
PBM programs consistently demonstrate reduced transfusion utilization and cost avoidance 4 ; and they frequently demonstrate reduced hospital length of stay, reduced morbidity, reduced mortality, and overall improved patient outcomes 5 . These benefits are in contrast to the increased recognition that ignoring anemia or utilizing transfusion to treat anemia may increase complications including: infection 6 , thrombosis 7 , stroke/myocardial infarction 8 , transfusion related immunomodulation (which may increase cancer progression and/or recurrence) 9 , 10 , and transfusion reactions such as transfusion associated circulatory overload (TACO) and transfusion associated lung injury (TRALI) 11 .
In many institutions, patient blood management is the standard of care 12 . The World Health Organization issued a resolution in 2010 to improve patient safety by implementing patient blood management programs, 13 and in 2021 issued an updated policy brief calling for an urgent need to implement patient blood management 14 . Specifically, they state, "All Member States should act quickly through their ministry or department of health to adopt their national PBM policy, install the necessary governance, and reallocate resources to improve the population health status and individual patient outcomes while reducing overall health care expenditures." World-wide, there has been country-wide implementation in Austria, the Netherlands 15 , and Western Australia 16 . While there are some references to PBM by Canadian Blood Services 17 , and principles may be found in the NAC blood shortages document 18 , more widespread application across the healthcare spectrum is necessary to improve health care provision and blood utilization in Canada. Many processes need to be aligned, and it is short sighted to attempt to perfect anemia management once a blood shortage occurs. PBM is interdisciplinary and goes beyond transfusion; cooperation and education amongst nursing, physicians, administration, pharmacy, laboratory, and perfusion staff is necessary. PBM should also reflect the patient's medical history, preferences and values.
# SECTION 2.0: COMPONENTS OF A PBM PROGRAM
Successful Patient Blood Management Programs include the following 19 : Education -Many medical practitioners are accustomed to certain practice behaviors that become outdated over time 20 . An example is the transfusion of two units of red blood cells in response to anemia. This has become a focus for Choosing Wisely's, "Why Use Two When One Will Do" campaign 21 . Likewise, transfusion thresholds have steadily decreased over time in response to higher quality evidence advocating for more restrictive thresholds. Unfortunately, implementation of this evidence has been slow and heterogeneous. Finally, while the evidence has supported the use of intravenous iron (IV iron) and erythropoietin stimulating agents (ESA) to reduce transfusion needs 22 , their implementation into practice lags. The reasons for this delay are many, but lack of medical practitioner education on these transfusion alternatives represents a significant barrier to their adoption.
Physician resources -Many programs have a physician director for managing referrals and intervention of complex forms of anemia. A lack of physician education and assigned responsibility for managing anemia results in patients missing opportunities for optimization and better outcomes prior to and during their hospital admission.
Nursing resources -Nursing care forms the backbone of patient blood management programs in terms of direct patient care. A dedicated nursing position ensures continuity of care. Currently in Canada, the Ontario Nurse Transfusion Coordinator (ONTraC) program exemplifies the important role of nursing in patient blood management 23 . Not all sites in Ontario have this program, and most sites outside of Ontario have no formal program. The ONTraC program has one of the best toolkits available for hospital implementation 24 .
Administrative resources -Scheduling patient consultations, interventions, and follow-up is also necessary to maintain patient flow in their care journey. Developing and employing data tracking to ensure quality metrics are achieved is also important.
Physical resources -Some aspects of patient blood management include administration of intravenous and subcutaneous injections, which require patient assessment and monitoring. The best example is intravenous iron. Depending on the IV iron formulation chosen, total chair time to restore iron stores may be as short as 1 hour or up to 10 hours 25 . This requires monitored space to accommodate patients undergoing treatment, as well as nursing and physician resources to staff and supervise administration.
Timing to critical events -A robust system identifies patients well in advance of their surgical or obstetrical delivery date. To utilize low-cost oral iron requires nearly three months on average to restore iron in deficient patients. Most surgical systems do not notify patients or practitioners of upcoming dates with enough time to utilize oral supplements. Peak effect for IV iron and ESA still requires several weeks of planning to optimize anemia and limit transfusion, although there is some evidence that even a single day results in some improvement 26 .
Pharmacy resources -Pharmacy needs to be actively engaged as most budgets are isolated from one another. Labile blood components are funded by a transfusion budget, but adjunctive therapy including IV iron and ESA are funded by a pharmacy budget through exceptional drug status, private insurance, or a patients' own funds. The savings are a result of reduced transfusion costs, activity costs (compatibility testing, inventory management), and reduced hospital costs when the hospital stay is reduced. Conversely, treating anemia without transfusion often increases the pharmaceutical cost. As a net equation, PBM reduces overall system costs. Therefore, pharmacists need to be actively engaged in ensuring appropriate resource management and reimbursement, and to consider the risks and benefits of labile blood components as compared to the risks and benefits of a medication.
Medication funding -Medications specifically shown to reduce transfusion or treat anemia should be considered. Specifically, antifibrinolytics (tranexamic acid) 27 , IV iron (ferric gluconate, iron sucrose, ferric derisomaltose) 28 , and ESAs (Darbopoetin, Epoetin alpha) 29 have a significant transfusion-sparing effect and should be publicly funded.
Laboratory Resources -Laboratory clinicians can often improve diagnostic accuracy and timeliness to assess patient response to therapy. An example would be measuring reticulocyte markers (early red blood cell production) in response to oral iron to assess the need to progress to IV iron or add an ESA. Many laboratories also oversee point of care testing which may reduce the volume of blood lost by patients during diagnosis. Similarly, laboratories can strive to reduce unnecessary diagnostic phlebotomy, duplicate or mislabeled specimens by use of positive patient identification, and use of smaller tubes or those with less vacuum to collect blood samples.
IT support -Data drives decisions and informs future management. A robust system to capture pre and post implementation allows evaluation of value-added patient blood management and helps drive future clinical decisions. Implementing clinical decision support for physician order entry has been shown to reduce unnecessary transfusions 30 .
Perfusion resources -Not every hospital will have perfusion personnel, but where present and in appropriate situations, perfusionists provide cell saver support in massive hemorrhage and high-risk operations. They are an integral part of providing safe cardiovascular surgical care and introducing measures to reduce the risk of transfusion in cardiac surgery.
# SECTION 3.0: RECOMMENDATIONS
# A. Systemic Recommendations
- All hospitals should work with their provincial Ministry of Health and health sector partners to implement PBM as a best practice that improves patient outcomes and system efficacy. A multimodal perioperative PBM program should be instituted in all surgical programs to address preoperative, intra-operative, and postoperative anemia. The resources outlined in Section 2, which are required for successful implementation of patient blood management, should be provided on a site-by-site basis with consideration of clinical need and system resources.
# Provinces should encourage hospitals to participate in initiatives including Choosing Wisely and
Using Blood Wisely which align with patient blood management principles. Providing order sets, and screening for single unit transfusions and restrictive transfusion thresholds (less than 70g/L in all patients except those at risk of ischemia where the threshold is less than 80g/L) reduces blood utilization without adding cost.
- Educational resources should foster the development of local patient blood management leaders and champions. All health care practitioners should be aware that anemia (hemoglobin less than 130g/L in peri-operative patients) increases morbidity and mortality. This is true of preexisting anemia and hospital acquired anemia. Hospitals should recognize that routine or avoidable diagnostic blood draws can result in hospital acquired anemia and prolong patient recovery. Stopping and minimizing blood loss requires interdisciplinary efforts and should be a primary pillar for PBM programs.
# B. Clinical Recommendations
- All patients undergoing surgery or delivery should be screened for anemia at least 6 weeks prior to their anticipated surgical or delivery date.
- Appropriate referral to a specialist for investigation and management of underlying conditions is recommended and may include gastroenterology, gynecology, hematology, nephrology, or others according to the underlying etiology. 6. In anemic patients with ferritin less than 30ucg/L and more than six weeks to an operative or delivery date, oral iron therapy should be instituted.
In anemic patients with ferritin less than 30 ucg/L and less than six weeks to an operative or delivery date, IV iron therapy should be instituted. 8. In patients at risk of anemia and ferritin less than 30ucg/L oral iron therapy should be instituted. 9. In patients with anemia and iron restricted erythropoiesis with ferritin greater than 30ucg/L and TSAT less than 20%, IV iron therapy should be instituted.
- In patients with inadequate response to IV iron or when iron sequestration or inflammation limits the bioavailability of iron, an ESA should be considered on a case-by-case basis.
- In patients with anemia and evidence of inflammation or renal failure where an ESA is indicated, it should be combined with IV iron.
- When an ESA is used, concomitant use of thromboembolic prophylaxis should be considered on a case-by-case basis.
- Anemia should be corrected prior to all elective surgery. Institutions should have guidelines on postponing surgery until anemia is corrected. 14. In patients who develop postoperative or post-hemorrhage related anemia, IV iron is recommended 31 . 15. The risk of surgical bleeding, urgency of surgery, and type of anticoagulation should be addressed to reduce blood loss. For specific recommendations for individual agents, resources such as Thrombosis Canada or a local perioperative thrombosis expert should be consulted. 16. During hemorrhage, permissive hypotension or deliberately induced hypotension should be considered while balancing the risk of blood loss and preservation of vital organ perfusion. 17. When substantial blood loss is anticipated, acute normovolemic hemodilution should be considered. 33,34,35 18. When substantial blood loss is anticipated or encountered, intraoperative cell salvage should be considered. 19. When substantial blood loss is anticipated or encountered, or the patient is involved in trauma or post-partum hemorrhage, antifibrinolytics (tranexamic acid) should be administered. 20. When patients are recovering from anemia, other physiologic parameters should be addressed to reduce oxygen requirements. Hypothermia should be avoided with active warming. Processes that contribute to hospital acquired infections should be minimized, including nasogastric tubes and foley catheters.
Patients must be placed at the center of care. Improving long term outcomes and reducing morbidity and mortality is necessary to improve the quality of care delivered to Canadians. Implementing multidisciplinary strategies as part of a patient blood management program has the potential to improve outcomes and simultaneously reduce system costs. In the interest of improving care to its citizens, every province should develop a patient blood management program (Figure 1).
Current clinical recommendations already exist and examples are offered from ONTraC 24 , the American Society of Hematology, 32 and the Mayo Clinic 2. For visualization purposes, the algorithm from ONTraC is attached.
A cost comparison using a single unit of blood as a cost comparison in managing anemia is attached (Table 1). While transfusion of a single unit of blood may raise hemoglobin levels temporarily, the transfused cells are generally destroyed more rapidly than endogenous cells and contribute to inhibiting production of endogenous cells. Transfused blood is not equivalent to endogenous production of blood.
# SECTION 5.0: REFERENCES
1 Society for the Advancement of Blood Management. accessed January 11, 2021
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# SECTION 1.0: PREAMBLE
Patient Blood Management (PBM) is the timely application of evidence-based medical and surgical concepts designed to maintain hemoglobin concentration, optimize hemostasis and minimize blood loss in an effort to improve patient outcome. 1 Framework for PBM programs may vary whether in a surgical setting (pre-operative, intra-operative, and post-operative) 2 or by goal (stop/minimize blood loss and diagnostic phlebotomy, diagnose and treat coagulopathy, manage anemia, and improve tolerance of anemia) 3 . The aim, regardless of framework, is to improve patient outcomes and make patients the center of care.
PBM programs consistently demonstrate reduced transfusion utilization and cost avoidance 4 ; and they frequently demonstrate reduced hospital length of stay, reduced morbidity, reduced mortality, and overall improved patient outcomes 5 . These benefits are in contrast to the increased recognition that ignoring anemia or utilizing transfusion to treat anemia may increase complications including: infection 6 , thrombosis 7 , stroke/myocardial infarction 8 , transfusion related immunomodulation (which may increase cancer progression and/or recurrence) 9 , 10 , and transfusion reactions such as transfusion associated circulatory overload (TACO) and transfusion associated lung injury (TRALI) 11 .
In many institutions, patient blood management is the standard of care 12 . The World Health Organization issued a resolution in 2010 to improve patient safety by implementing patient blood management programs, 13 and in 2021 issued an updated policy brief calling for an urgent need to implement patient blood management 14 . Specifically, they state, "All Member States should act quickly through their ministry or department of health to adopt their national PBM policy, install the necessary governance, and reallocate resources to improve the population health status and individual patient outcomes while reducing overall health care expenditures." World-wide, there has been country-wide implementation in Austria, the Netherlands 15 , and Western Australia 16 . While there are some references to PBM by Canadian Blood Services 17 , and principles may be found in the NAC blood shortages document 18 , more widespread application across the healthcare spectrum is necessary to improve health care provision and blood utilization in Canada. Many processes need to be aligned, and it is short sighted to attempt to perfect anemia management once a blood shortage occurs. PBM is interdisciplinary and goes beyond transfusion; cooperation and education amongst nursing, physicians, administration, pharmacy, laboratory, and perfusion staff is necessary. PBM should also reflect the patient's medical history, preferences and values.
# SECTION 2.0: COMPONENTS OF A PBM PROGRAM
Successful Patient Blood Management Programs include the following 19 : Education -Many medical practitioners are accustomed to certain practice behaviors that become outdated over time 20 . An example is the transfusion of two units of red blood cells in response to anemia. This has become a focus for Choosing Wisely's, "Why Use Two When One Will Do" campaign 21 . Likewise, transfusion thresholds have steadily decreased over time in response to higher quality evidence advocating for more restrictive thresholds. Unfortunately, implementation of this evidence has been slow and heterogeneous. Finally, while the evidence has supported the use of intravenous iron (IV iron) and erythropoietin stimulating agents (ESA) to reduce transfusion needs 22 , their implementation into practice lags. The reasons for this delay are many, but lack of medical practitioner education on these transfusion alternatives represents a significant barrier to their adoption.
Physician resources -Many programs have a physician director for managing referrals and intervention of complex forms of anemia. A lack of physician education and assigned responsibility for managing anemia results in patients missing opportunities for optimization and better outcomes prior to and during their hospital admission.
Nursing resources -Nursing care forms the backbone of patient blood management programs in terms of direct patient care. A dedicated nursing position ensures continuity of care. Currently in Canada, the Ontario Nurse Transfusion Coordinator (ONTraC) program exemplifies the important role of nursing in patient blood management 23 . Not all sites in Ontario have this program, and most sites outside of Ontario have no formal program. The ONTraC program has one of the best toolkits available for hospital implementation 24 .
Administrative resources -Scheduling patient consultations, interventions, and follow-up is also necessary to maintain patient flow in their care journey. Developing and employing data tracking to ensure quality metrics are achieved is also important.
Physical resources -Some aspects of patient blood management include administration of intravenous and subcutaneous injections, which require patient assessment and monitoring. The best example is intravenous iron. Depending on the IV iron formulation chosen, total chair time to restore iron stores may be as short as 1 hour or up to 10 hours 25 . This requires monitored space to accommodate patients undergoing treatment, as well as nursing and physician resources to staff and supervise administration.
Timing to critical events -A robust system identifies patients well in advance of their surgical or obstetrical delivery date. To utilize low-cost oral iron requires nearly three months on average to restore iron in deficient patients. Most surgical systems do not notify patients or practitioners of upcoming dates with enough time to utilize oral supplements. Peak effect for IV iron and ESA still requires several weeks of planning to optimize anemia and limit transfusion, although there is some evidence that even a single day results in some improvement 26 .
Pharmacy resources -Pharmacy needs to be actively engaged as most budgets are isolated from one another. Labile blood components are funded by a transfusion budget, but adjunctive therapy including IV iron and ESA are funded by a pharmacy budget through exceptional drug status, private insurance, or a patients' own funds. The savings are a result of reduced transfusion costs, activity costs (compatibility testing, inventory management), and reduced hospital costs when the hospital stay is reduced. Conversely, treating anemia without transfusion often increases the pharmaceutical cost. As a net equation, PBM reduces overall system costs. Therefore, pharmacists need to be actively engaged in ensuring appropriate resource management and reimbursement, and to consider the risks and benefits of labile blood components as compared to the risks and benefits of a medication.
Medication funding -Medications specifically shown to reduce transfusion or treat anemia should be considered. Specifically, antifibrinolytics (tranexamic acid) 27 , IV iron (ferric gluconate, iron sucrose, ferric derisomaltose) 28 , and ESAs (Darbopoetin, Epoetin alpha) 29 have a significant transfusion-sparing effect and should be publicly funded.
Laboratory Resources -Laboratory clinicians can often improve diagnostic accuracy and timeliness to assess patient response to therapy. An example would be measuring reticulocyte markers (early red blood cell production) in response to oral iron to assess the need to progress to IV iron or add an ESA. Many laboratories also oversee point of care testing which may reduce the volume of blood lost by patients during diagnosis. Similarly, laboratories can strive to reduce unnecessary diagnostic phlebotomy, duplicate or mislabeled specimens by use of positive patient identification, and use of smaller tubes or those with less vacuum to collect blood samples.
IT support -Data drives decisions and informs future management. A robust system to capture pre and post implementation allows evaluation of value-added patient blood management and helps drive future clinical decisions. Implementing clinical decision support for physician order entry has been shown to reduce unnecessary transfusions 30 .
Perfusion resources -Not every hospital will have perfusion personnel, but where present and in appropriate situations, perfusionists provide cell saver support in massive hemorrhage and high-risk operations. They are an integral part of providing safe cardiovascular surgical care and introducing measures to reduce the risk of transfusion in cardiac surgery.
# SECTION 3.0: RECOMMENDATIONS
# A. Systemic Recommendations
1. All hospitals should work with their provincial Ministry of Health and health sector partners to implement PBM as a best practice that improves patient outcomes and system efficacy. A multimodal perioperative PBM program should be instituted in all surgical programs to address preoperative, intra-operative, and postoperative anemia. The resources outlined in Section 2, which are required for successful implementation of patient blood management, should be provided on a site-by-site basis with consideration of clinical need and system resources.
# Provinces should encourage hospitals to participate in initiatives including Choosing Wisely and
Using Blood Wisely which align with patient blood management principles. Providing order sets, and screening for single unit transfusions and restrictive transfusion thresholds (less than 70g/L in all patients except those at risk of ischemia where the threshold is less than 80g/L) reduces blood utilization without adding cost.
3. Educational resources should foster the development of local patient blood management leaders and champions. All health care practitioners should be aware that anemia (hemoglobin less than 130g/L in peri-operative patients) increases morbidity and mortality. This is true of preexisting anemia and hospital acquired anemia. Hospitals should recognize that routine or avoidable diagnostic blood draws can result in hospital acquired anemia and prolong patient recovery. Stopping and minimizing blood loss requires interdisciplinary efforts and should be a primary pillar for PBM programs.
# B. Clinical Recommendations
4. All patients undergoing surgery or delivery should be screened for anemia at least 6 weeks prior to their anticipated surgical or delivery date.
5. Appropriate referral to a specialist for investigation and management of underlying conditions is recommended and may include gastroenterology, gynecology, hematology, nephrology, or others according to the underlying etiology. 6. In anemic patients with ferritin less than 30ucg/L and more than six weeks to an operative or delivery date, oral iron therapy should be instituted.
# 7.
In anemic patients with ferritin less than 30 ucg/L and less than six weeks to an operative or delivery date, IV iron therapy should be instituted. 8. In patients at risk of anemia and ferritin less than 30ucg/L oral iron therapy should be instituted. 9. In patients with anemia and iron restricted erythropoiesis with ferritin greater than 30ucg/L and TSAT less than 20%, IV iron therapy should be instituted.
10. In patients with inadequate response to IV iron or when iron sequestration or inflammation limits the bioavailability of iron, an ESA should be considered on a case-by-case basis.
11. In patients with anemia and evidence of inflammation or renal failure where an ESA is indicated, it should be combined with IV iron.
12. When an ESA is used, concomitant use of thromboembolic prophylaxis should be considered on a case-by-case basis.
13. Anemia should be corrected prior to all elective surgery. Institutions should have guidelines on postponing surgery until anemia is corrected. 14. In patients who develop postoperative or post-hemorrhage related anemia, IV iron is recommended 31 . 15. The risk of surgical bleeding, urgency of surgery, and type of anticoagulation should be addressed to reduce blood loss. For specific recommendations for individual agents, resources such as Thrombosis Canada or a local perioperative thrombosis expert should be consulted. 16. During hemorrhage, permissive hypotension or deliberately induced hypotension should be considered while balancing the risk of blood loss and preservation of vital organ perfusion. 17. When substantial blood loss is anticipated, acute normovolemic hemodilution should be considered. 33,34,35 18. When substantial blood loss is anticipated or encountered, intraoperative cell salvage should be considered. 19. When substantial blood loss is anticipated or encountered, or the patient is involved in trauma or post-partum hemorrhage, antifibrinolytics (tranexamic acid) should be administered. 20. When patients are recovering from anemia, other physiologic parameters should be addressed to reduce oxygen requirements. Hypothermia should be avoided with active warming. Processes that contribute to hospital acquired infections should be minimized, including nasogastric tubes and foley catheters.
Patients must be placed at the center of care. Improving long term outcomes and reducing morbidity and mortality is necessary to improve the quality of care delivered to Canadians. Implementing multidisciplinary strategies as part of a patient blood management program has the potential to improve outcomes and simultaneously reduce system costs. In the interest of improving care to its citizens, every province should develop a patient blood management program (Figure 1).
Current clinical recommendations already exist and examples are offered from ONTraC 24 , the American Society of Hematology, 32 and the Mayo Clinic 2. For visualization purposes, the algorithm from ONTraC is attached.
A cost comparison using a single unit of blood as a cost comparison in managing anemia is attached (Table 1). While transfusion of a single unit of blood may raise hemoglobin levels temporarily, the transfused cells are generally destroyed more rapidly than endogenous cells and contribute to inhibiting production of endogenous cells. Transfused blood is not equivalent to endogenous production of blood.
# SECTION 5.0: REFERENCES
1 Society for the Advancement of Blood Management. https://sabm.org accessed January 11, 2021
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This guidance is based on known evidence as of May 27, 2021. It is intended for health-care providers caring for newborns born to individuals that: Are a close contact of a person under clinical investigation for COVID-19; Have symptoms suggestive of COVID-19; Are under clinical investigation for COVID-19; or Have a confirmed diagnosis of COVID-19.#
and is waiting to be tested or waiting for the results of a test. A pregnant mother/individual who presents during labour with a temperature above 38 degrees Celsius will be tested for SARS-CoV-2 even in the absence of exposure criteria and/or close contact with a person with a confirmed COVID-19 diagnosis, or a person under clinical investigation for COVID-19.
- Newborn under investigation: A newborn who is symptomatic and/or had close contact with a person with a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19. They can be either waiting to be tested for SARS-CoV-2 or waiting for the results of a test.
- Close contact: A person or newborn who had close physical contact with, or who lived with a person with, a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19.
Maternal critical illness: A pregnant mother/individual with any of the following: 3 Is intubated; SpO2 measures < 94% in room air; Is on supplemental oxygen due to COVID-19; Receives end-organ support; Is significantly immunosuppressed (e.g., HIV with CD4<200); and/or Deemed collectively by members of the delivery team as critically unwell.
Newborn: Infant in the first 28 days after birth. Mother/individual: The term individual is used in this guideline to be inclusive of transgender individuals who gave birth to the newborn and in cases where the caregiver of the newborn is not the mother/individual (e.g., foster parent). Vertical transmission: Transmission of infection directly from mother/individual to embryo, fetus or newborn during the perinatal period through the placenta or human milk. Horizontal transmission: Transmission of infection from one person to another through contact with bodily fluids (respiratory droplets, sputum, blood, etc.).
# General Information
SARS-CoV-2 is a novel coronavirus that causes COVID-19 illness in adults, children and newborns. The incubation period is two to 14 days, with a median of five days. 4 Studies continue to show that COVID-19 infection in newborns is uncommon and most newborns who may become infected are asymptomatic or present with mild to moderate disease.
Overall, pregnancy outcomes among reported cases of COVID-19 infection during pregnancy are mostly good; spontaneous and iatrogenic preterm birth are the most commonly reported adverse outcomes. 5 -7 While there is currently no reported increased risk of congenital anomaly, available data is limited and, at this time, the risk of teratogenicity cannot be excluded. 5,6 While there is no strong evidence of vertical transmission of SARS-CoV-2, the newborn is at risk for postpartum horizontal transmission. 5 -7, 9 -11 The rate of infection in the newborn born to a parent with a confirmed diagnosis of COVID-19, or is a person under clinical investigation, does not vary regardless of mode of delivery, breast/chest feeding or rooming-in practices. 11
# Recommendations
# Personal Protective Equipment (PPE)
Refer to health authority specific guidance and the BCCDC's resources on PPE and aerosol generating medical procedures (AGMP) for the most up-to-date information.
Droplet and contact precautions are recommended for all team members involved in the direct care of a newborn born to a mother/individual who is a confirmed case of, or under clinical investigation for, COVID-19. 5,12 There is no strong evidence of vertical transmission of SARS-CoV-2. Therefore, the risk of transmission during AGMPs employed during newborn resuscitation at birth remains low and additional airborne precautions are not warranted. 5,7,9,10,13,14 Airborne precautions for care teams are only indicated:
- In the case of AGMPs such as intubation and general anesthesia of the mother/individual that has a confirmed COVID-19 diagnosis or who is under clinical investigation for COVID-19. 15 o For maternal/individual critical illness.
# General Preparations Regarding Space and Equipment
While designated space, equipment and number of health-care professionals in attendance during the birth will be different at each site, consider the following when preparing to care for a newborn following delivery: Perform equipment checks prior to the mother/individual with confirmed or suspected COVID-19 entering the labour and delivery area. Commonly used equipment for newborn resuscitation should be readily available at the resuscitation area.
Consider placing the equipment in a plastic bag to minimize the risk of contamination of the equipment. If staff numbers allow, consider removing unnecessary equipment including the newborn resuscitation cart from the delivery room to further limit the potential for contamination. In this case, keep the newborn resuscitation cart outside the delivery room and assign a team member to pass equipment for vascular access, medications and other supplies to the resuscitation team if required.
- Newborn resuscitation can occur in the maternal/individual labour and delivery area if a distance of two metres can be maintained between the newborn resuscitation area and the mother/individual. 5 If a distance of two metres cannot be maintained, assess the risk of exposure and follow PPE recommendations as described in the risk assessment and management of health-care worker exposures to COVID-19. Sites may consider using an adjacent room for newborn resuscitation as it may be difficult to completely protect the newborn from horizontal transmission of SARS-CoV-2 during maternal/individual AGMP or in the case of maternal/individual critical illness. 5 In this case, an assigned team member will bring the newborn to the resuscitation room. This team member will don appropriate PPE as required. This will minimize the need for the newborn resuscitation team to take additional airborne precautions.
# Preparation for Delivery
While most newborns born to COVID-19 confirmed mothers/individuals do not require resuscitation, the team responsible for newborn care should be notified of fetal distress and other risk factors to allow the team to prepare for anticipated resuscitation of the newborn. 5 Team members responsible for newborn resuscitation must perform a huddle to review case specific preparation, including anticipated equipment for newborn resuscitation, PPE needs, delayed cord clamping and team member roles.
Notify the team responsible for newborn resuscitation at the start of second stage of labour or at the time of transfer of the mother/individual to the operating room to ensure there is enough time to don appropriate PPE. Minimize the number of people in the delivery area by limiting access to only those directly involved in the care of the newborn or mother/individual.
General Management Principles (See Figure 1)
# Management of the Newborn at the Time of Birth
Prior to birth, discuss skin-to-skin and the potential risk for horizontal spread of COVID-19 to the newborn with the mother/individual. The decision to allow the newborn to transition while skin-to-skin should be a shared decision between the health-care professional and mother/individual based on current best evidence.
The maternal/individual team will warm, dry and stimulate the newborn. 5,16 Once the newborn is delivered, and mother/individual chooses to do skin-to-skin, they should put on a face mask to limit horizontal spread of COVID-19 to the newborn. Allow newborn to transition while skin-to-skin as per local guidelines.
Continue to practice delayed cord clamping 5,16 unless contraindicated (more information is available on page 6 in the Provincial Perinatal Guidelines Standards for Neonatal Resuscitation). When ready to transfer the newborn to the postpartum unit, transfer newborn in mother/individual's arms following intra-hospital 5 and local infection prevention and control (IPC) transfer guidelines. Newborn can also be transferred to the postpartum unit in a closed incubator preferable (if available) to minimize the possibility of spreading infection. If a closed incubator is not available, clear the pathway to the postpartum unit to minimize potential contamination.
Management of the Newborn that is Unwell or Requires Additional Care at the Time of Birth
If possible, the newborn team should maintain a two metre distance from the mother/individual. 5 The maternal/individual team will warm, dry and stimulate the newborn. 5,16 Delayed cord clamping may be considered 5,16 unless otherwise contraindicated.
If ongoing resuscitation of the newborn is required, newborn care will be transferred to the newborn team for further management either in the delivery suite or in an adjacent area. 5 After completion of newborn resuscitation, prepare the newborn and equipment for transfer to the neonatal intensive care unit (NICU), special care nursery or designated stabilization area.
Transfer the newborn to the transport incubator (closed incubator preferable, if available) to minimize the possibility of spreading infection. If a closed incubator is not available, clear the pathway to NICU, special care nursery or designated stabilization area to minimize potential contamination. Consult local IPC for site-specific intra-hospital patient transfer guidance.
Management Algorithm
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This guidance is based on known evidence as of May 27, 2021. It is intended for health-care providers caring for newborns born to individuals that: Are a close contact of a person under clinical investigation for COVID-19; Have symptoms suggestive of COVID-19; Are under clinical investigation for COVID-19; or Have a confirmed diagnosis of COVID-19.#
and is waiting to be tested or waiting for the results of a test. A pregnant mother/individual who presents during labour with a temperature above 38 degrees Celsius will be tested for SARS-CoV-2 even in the absence of exposure criteria and/or close contact with a person with a confirmed COVID-19 diagnosis, or a person under clinical investigation for COVID-19.
Newborn under investigation: A newborn who is symptomatic and/or had close contact with a person with a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19. They can be either waiting to be tested for SARS-CoV-2 or waiting for the results of a test.
Close contact: A person or newborn who had close physical contact with, or who lived with a person with, a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19.
Maternal critical illness: A pregnant mother/individual with any of the following: 3 Is intubated; SpO2 measures < 94% in room air; Is on supplemental oxygen due to COVID-19; Receives end-organ support; Is significantly immunosuppressed (e.g., HIV with CD4<200); and/or Deemed collectively by members of the delivery team as critically unwell.
Newborn: Infant in the first 28 days after birth. Mother/individual: The term individual is used in this guideline to be inclusive of transgender individuals who gave birth to the newborn and in cases where the caregiver of the newborn is not the mother/individual (e.g., foster parent). Vertical transmission: Transmission of infection directly from mother/individual to embryo, fetus or newborn during the perinatal period through the placenta or human milk. Horizontal transmission: Transmission of infection from one person to another through contact with bodily fluids (respiratory droplets, sputum, blood, etc.).
# General Information
SARS-CoV-2 is a novel coronavirus that causes COVID-19 illness in adults, children and newborns. The incubation period is two to 14 days, with a median of five days. 4 Studies continue to show that COVID-19 infection in newborns is uncommon and most newborns who may become infected are asymptomatic or present with mild to moderate disease.
# 5, 7, 8
Overall, pregnancy outcomes among reported cases of COVID-19 infection during pregnancy are mostly good; spontaneous and iatrogenic preterm birth are the most commonly reported adverse outcomes. 5 -7 While there is currently no reported increased risk of congenital anomaly, available data is limited and, at this time, the risk of teratogenicity cannot be excluded. 5,6 While there is no strong evidence of vertical transmission of SARS-CoV-2, the newborn is at risk for postpartum horizontal transmission. 5 -7, 9 -11 The rate of infection in the newborn born to a parent with a confirmed diagnosis of COVID-19, or is a person under clinical investigation, does not vary regardless of mode of delivery, breast/chest feeding or rooming-in practices. 11
# Recommendations
# Personal Protective Equipment (PPE)
Refer to health authority specific guidance and the BCCDC's resources on PPE and aerosol generating medical procedures (AGMP) for the most up-to-date information.
Droplet and contact precautions are recommended for all team members involved in the direct care of a newborn born to a mother/individual who is a confirmed case of, or under clinical investigation for, COVID-19. 5,12 There is no strong evidence of vertical transmission of SARS-CoV-2. Therefore, the risk of transmission during AGMPs employed during newborn resuscitation at birth remains low and additional airborne precautions are not warranted. 5,7,9,10,13,14 Airborne precautions for care teams are only indicated:
o In the case of AGMPs such as intubation and general anesthesia of the mother/individual that has a confirmed COVID-19 diagnosis or who is under clinical investigation for COVID-19. 15 o For maternal/individual critical illness.
# General Preparations Regarding Space and Equipment
While designated space, equipment and number of health-care professionals in attendance during the birth will be different at each site, consider the following when preparing to care for a newborn following delivery: Perform equipment checks prior to the mother/individual with confirmed or suspected COVID-19 entering the labour and delivery area. Commonly used equipment for newborn resuscitation should be readily available at the resuscitation area.
Consider placing the equipment in a plastic bag to minimize the risk of contamination of the equipment. If staff numbers allow, consider removing unnecessary equipment including the newborn resuscitation cart from the delivery room to further limit the potential for contamination. In this case, keep the newborn resuscitation cart outside the delivery room and assign a team member to pass equipment for vascular access, medications and other supplies to the resuscitation team if required.
Newborn resuscitation can occur in the maternal/individual labour and delivery area if a distance of two metres can be maintained between the newborn resuscitation area and the mother/individual. 5 If a distance of two metres cannot be maintained, assess the risk of exposure and follow PPE recommendations as described in the risk assessment and management of health-care worker exposures to COVID-19. Sites may consider using an adjacent room for newborn resuscitation as it may be difficult to completely protect the newborn from horizontal transmission of SARS-CoV-2 during maternal/individual AGMP or in the case of maternal/individual critical illness. 5 In this case, an assigned team member will bring the newborn to the resuscitation room. This team member will don appropriate PPE as required. This will minimize the need for the newborn resuscitation team to take additional airborne precautions.
# Preparation for Delivery
While most newborns born to COVID-19 confirmed mothers/individuals do not require resuscitation, the team responsible for newborn care should be notified of fetal distress and other risk factors to allow the team to prepare for anticipated resuscitation of the newborn. 5 Team members responsible for newborn resuscitation must perform a huddle to review case specific preparation, including anticipated equipment for newborn resuscitation, PPE needs, delayed cord clamping and team member roles.
Notify the team responsible for newborn resuscitation at the start of second stage of labour or at the time of transfer of the mother/individual to the operating room to ensure there is enough time to don appropriate PPE. Minimize the number of people in the delivery area by limiting access to only those directly involved in the care of the newborn or mother/individual.
General Management Principles (See Figure 1)
# Management of the Newborn at the Time of Birth
Prior to birth, discuss skin-to-skin and the potential risk for horizontal spread of COVID-19 to the newborn with the mother/individual. The decision to allow the newborn to transition while skin-to-skin should be a shared decision between the health-care professional and mother/individual based on current best evidence.
The maternal/individual team will warm, dry and stimulate the newborn. 5,16 Once the newborn is delivered, and mother/individual chooses to do skin-to-skin, they should put on a face mask to limit horizontal spread of COVID-19 to the newborn. Allow newborn to transition while skin-to-skin as per local guidelines.
Continue to practice delayed cord clamping 5,16 unless contraindicated (more information is available on page 6 in the Provincial Perinatal Guidelines Standards for Neonatal Resuscitation). When ready to transfer the newborn to the postpartum unit, transfer newborn in mother/individual's arms following intra-hospital 5 and local infection prevention and control (IPC) transfer guidelines. Newborn can also be transferred to the postpartum unit in a closed incubator preferable (if available) to minimize the possibility of spreading infection. If a closed incubator is not available, clear the pathway to the postpartum unit to minimize potential contamination.
Management of the Newborn that is Unwell or Requires Additional Care at the Time of Birth
If possible, the newborn team should maintain a two metre distance from the mother/individual. 5 The maternal/individual team will warm, dry and stimulate the newborn. 5,16 Delayed cord clamping may be considered 5,16 unless otherwise contraindicated.
If ongoing resuscitation of the newborn is required, newborn care will be transferred to the newborn team for further management either in the delivery suite or in an adjacent area. 5 After completion of newborn resuscitation, prepare the newborn and equipment for transfer to the neonatal intensive care unit (NICU), special care nursery or designated stabilization area.
Transfer the newborn to the transport incubator (closed incubator preferable, if available) to minimize the possibility of spreading infection. If a closed incubator is not available, clear the pathway to NICU, special care nursery or designated stabilization area to minimize potential contamination. Consult local IPC for site-specific intra-hospital patient transfer guidance.
Management Algorithm
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We respectfully acknowledge that the work to complete this rapid guidance document was hosted on Treaty 6 territory, a traditional gathering place for diverse Indigenous peoples including the Cree, Blackfoot, Métis, Nakota Sioux, Iroquois, Dene, Ojibway/Saulteaux/Anishinaabe, Inuit, and many others. We recognize that the ongoing criminalization, institutionalization, and discrimination against people who use substances disproportionately harm Indigenous Peoples, and that continuous efforts are needed to dismantle colonial systems of oppression. We are committed to the process of reconciliation with Indigenous Peoples, and recognize that it requires significant and ongoing changes to the health care system. We hope that this guidance document helps to reduce the harms faced by people who use substances in the COVID-19 pandemic.Funded by the Canadian Institutes of Health Research (CIHR), the Canadian Research Initiative in Substance Misuse (CRISM) is a national research-practice-policy network focused on substance use disorders, comprising four large interdisciplinary regional teams (Nodes) representing British Columbia, the Prairie Provinces, Ontario, and Quebec/Atlantic. Each CRISM node includes regional research scientists, service providers, policy makers, community leaders, and people with lived experience of substance use disorders. CRISM's mission is to translate the best scientific evidence into clinical practice, health services, and policy change. More information about CRISM can be found at: document is one of a series of six national guidance documents, rapidly developed by the CRISM network at the request of the Government of Canada. Collectively, the six documents address urgent needs of people who use substances, service providers, and decision makers in relation to the COVID-19 pandemic. The urgent nature of this work required rapid development and dissemination of this guidance. This, and the continuing evolution of the knowledge base regarding COVID-19, precluded CRISM from conducting a comprehensive review of the relevant literature. However, when available, scientific evidence is cited in support of the expert advice offered herein. The guidance provided in this document is subject to change as new information becomes available. Readers should note that the intent of this document is to provide general guidance rather than detailed procedural and logistical advice. Readers are advised to consult local Public Health and medical authorities for specific input on navigating their own unique regulatory and policy environments, as necessary.#
The CRISM/COVID-19 guidance documents cover the following topics:
- Supporting people who use substances in shelter settings during the COVID-19 pandemic - Telemedicine support for addiction services - Harm reduction worker safety - Recovery environments - Supporting people Who Use Substance in Acute Care Settings (this document)
- Strategies to Help Individuals Self-Isolate for People who use Drugs Completed documents may be accessed at: /. Each document was developed by a core CRISM authorship committee, drawing on expert knowledge, available scientific evidence, and a review of relevant documentation from Public Health authorities. Draft documents produced by each authorship committee were reviewed by pan-Canadian panels of content and clinical experts. People with lived and/or living experience of substance use have participated in the production of the CRISM/COVID-19 guidance document series, either as part of review or authorship committees. A CIHR Directed Operating Grant to CRISM provided funding for this work.
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We respectfully acknowledge that the work to complete this rapid guidance document was hosted on Treaty 6 territory, a traditional gathering place for diverse Indigenous peoples including the Cree, Blackfoot, Métis, Nakota Sioux, Iroquois, Dene, Ojibway/Saulteaux/Anishinaabe, Inuit, and many others. We recognize that the ongoing criminalization, institutionalization, and discrimination against people who use substances disproportionately harm Indigenous Peoples, and that continuous efforts are needed to dismantle colonial systems of oppression. We are committed to the process of reconciliation with Indigenous Peoples, and recognize that it requires significant and ongoing changes to the health care system. We hope that this guidance document helps to reduce the harms faced by people who use substances in the COVID-19 pandemic.Funded by the Canadian Institutes of Health Research (CIHR), the Canadian Research Initiative in Substance Misuse (CRISM) is a national research-practice-policy network focused on substance use disorders, comprising four large interdisciplinary regional teams (Nodes) representing British Columbia, the Prairie Provinces, Ontario, and Quebec/Atlantic. Each CRISM node includes regional research scientists, service providers, policy makers, community leaders, and people with lived experience of substance use disorders. CRISM's mission is to translate the best scientific evidence into clinical practice, health services, and policy change. More information about CRISM can be found at: https://crism.ca.This document is one of a series of six national guidance documents, rapidly developed by the CRISM network at the request of the Government of Canada. Collectively, the six documents address urgent needs of people who use substances, service providers, and decision makers in relation to the COVID-19 pandemic. The urgent nature of this work required rapid development and dissemination of this guidance. This, and the continuing evolution of the knowledge base regarding COVID-19, precluded CRISM from conducting a comprehensive review of the relevant literature. However, when available, scientific evidence is cited in support of the expert advice offered herein. The guidance provided in this document is subject to change as new information becomes available. Readers should note that the intent of this document is to provide general guidance rather than detailed procedural and logistical advice. Readers are advised to consult local Public Health and medical authorities for specific input on navigating their own unique regulatory and policy environments, as necessary.#
The CRISM/COVID-19 guidance documents cover the following topics:
• Supporting people who use substances in shelter settings during the COVID-19 pandemic • Telemedicine support for addiction services • Harm reduction worker safety • Recovery environments • Supporting people Who Use Substance in Acute Care Settings (this document)
• Strategies to Help Individuals Self-Isolate for People who use Drugs Completed documents may be accessed at: https://crism.ca/projects/covid/. Each document was developed by a core CRISM authorship committee, drawing on expert knowledge, available scientific evidence, and a review of relevant documentation from Public Health authorities. Draft documents produced by each authorship committee were reviewed by pan-Canadian panels of content and clinical experts. People with lived and/or living experience of substance use have participated in the production of the CRISM/COVID-19 guidance document series, either as part of review or authorship committees. A CIHR Directed Operating Grant to CRISM provided funding for this work.
# Disclaimer for Health Care Providers
The recommendations in this guidance document represent the view of the National Operational Guidance Document Review Committee, arrived at after careful consideration of the available scientific evidence and external expert peer review. The application of the guidance contained in this document does not override the responsibility of health care professionals to make decisions appropriate to the needs, preferences, and values of an individual patient, in consultation with that patient (and their guardian[s] or family members, when appropriate), and, when appropriate, external experts (e.g. specialty consultation). When exercising clinical judgment in caring for patients, health care professionals may take this guidance document into account while upholding their duties to adhere to the fundamental principles and values of their relevant codes of ethics. Nothing in this guidance document should be interpreted in a way that would be inconsistent with compliance with those duties.
# Legal Disclaimer
While the individuals and groups involved in the production of this document have made every effort to ensure the accuracy of the information contained in this guidance document, please note that the information is provided "as is" and that CIHR and CRISM make no representation or warranty of any kind, either expressed or implied, as to the accuracy of the information or the fitness of the information for any particular use. To the fullest extent possible under applicable law, CIHR and CRISM disclaim and will not be bound by any express, implied, or statutory representation or warranty (including, without limitation, representations or warranties of title or non-infringement). This document is intended to provide guidance to facilitate substance use care. This guidance document is not intended as a substitute for the advice or professional judgment of a health professional, nor is it intended to be the only approach to the management of a clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a local health care professional. In accordance with the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts (i), authorship committee members and external reviewers were asked to disclose all sources and amounts of direct and indirect (i.e., research support) remuneration from industry, for-profit enterprises, and other entities that could potentially introduce real or perceived risk of bias. In addition, authorship committee members and external reviewers were asked to report indirect sources of bias, such as academic advancement, clinical revenue, and professional or public standing that could potentially influence interpretation of research evidence and formulation of recommendations.
Of 30 authorship committee members and external reviewers, 14 acknowledged potential direct conflicts of interest. Of these, 10 acknowledged employment or consulting with organizations including academic institutions, hospitals/health authorities, professional or regulatory associations, HIV/AIDS foundations, community outreach agencies or federal funding agencies. Only one (an external reviewer) disclosed receiving research funding prior to guidance document involvement from a commercial entity (Gilead) that could theoretically benefit from guidance document recommendations. There was one authorship committee member with a commercial interest in the form of partial ownership of a medical clinic that provides treatment to people who use substances including opioid agonist treatment. On review, potential conflicts of interest were not deemed to be of sufficient weight or relevance to warrant exclusion from the guidance committee.
Most (23, 77%) authorship committee members and external reviewers disclosed potential indirect sources of bias (e.g. specialization in addiction medicine, advisory board and committee membership, involvement with acute care programs, provincial substance use treatment programs, previous guideline development, research interests). Of these, 6 acknowledged that they have publicly stated support for acute care treatment of PWUD. i. Schünemann HJ, Al-Ansary LA, Forland F, et al. Guidelines international network: principles for disclosure of interests and management of conflicts in guidelines. Ann Intern Med. 2015;163 (7):548-553.
In order to mitigate the risk of bias while maximizing the contributions of members in their respective areas of expertise, authorship committee members and external reviewers were reminded to consider any influential factors or sources of bias during the review process. Authors and reviewers with indirect potential sources of conflict contributed to review of sections related to their areas of expertise as well as the overarching guideline content to ensure that a broad range of clinical and academic specializations was adequately represented. • People who use substances are at increased risk of negative health outcomes during the COVID-19 pandemic due to coexisting medical and mental health conditions, disruptions in substances supply, and reduced access to addiction treatment, recovery supports, and harm reduction services such as sterile equipment and supervised consumption services.
# TABLE OF CONTENTS
• In order to reduce the risk of patient-initiated discharge in patients under investigation for, or with known, COVID-19, steps should be taken to identify patients with substance use disorders and to swiftly initiate evidence-based treatment, as well as aggressively manage withdrawal and cravings, in hospital settings.
• Despite treatment initiation and other strategies to manage withdrawal and cravings, some patients may continue to use substances during hospital admission. In these cases, patients should be provided with access to sterile equipment, a place to safely dispose of used equipment, education about safer drug use during the COVID-19 pandemic, and an individualized safety plan to minimize the risk to themselves (e.g. unwitnessed overdose) and others.
• People who use substances with life-limiting illness related to COVID-19 should be offered a palliative care approach. A detailed opioid use history should be taken on all patients to guide therapy; for patients on opioid agonist treatment, collaboration should occur between the opioid agonist treatment prescriber and the physician managing end of life symptoms.
• Hospitalization should be viewed as an opportunity to address other patient specific health needs such as: mental health concerns; stabilizing the social determinants of health (e.g. providing or connecting patients to resources around housing, income supports, and medication coverage); providing immunizations; and, screening and treatment initiation for sexually transmitted and blood borne infections.
# Purpose and Scope
The World Health Organization declared the 2019 Novel Coronavirus (COVID-19) viral infection a pandemic on March 11, 2020. Canada has also been experiencing a crisis of opioid-related harm with more than 16,364 apparent opioid-related deaths between January 2016 and March 2020 (1). This is superimposed on endemic high levels of morbidity and mortality from alcohol (2) and significant regional problems with methamphetamines (3). In addition, border closures related to the COVID-19 pandemic have interrupted the supply of illegal drugs potentially worsening a drug market already prone to toxic contaminants (4)(5)(6). The intensity and harms associated with these simultaneously occurring events varies by province, and interventions must be tailored and prioritized to local context. The intersection of these multiple public health emergencies has the potential to magnify the harms already experienced by people who use substances as well as to overwhelm existing acute care resources (6).
In this context, extraordinary measures are required to support people who use substances, minimize the spread of COVID-19 within communities and ensure efficient use of acute care resources. In particular, insufficient and substandard care for people who use substances in acute care settings, while always unacceptable, now poses the additional risk of patient-initiated discharge potentially leading to community transmission of COVID-19.
The purpose of this national rapid guidance document is to support acute care hospital environments in providing evidence-informed care for people who use substances in the context of the COVID-19 pandemic in Canada. The strategies discussed in this document are intended to help hospital based health care providers identify people in need of substance use related support early in their health care encounter, provide care based on best practices, and mitigate the risks of both substance use related harm and COVID-19 transmission during and after hospitalization.
Specifically, this document provides:
• An overview of the combined health risks associated with COVID-19 infection, substance use, and hospitalization
• An overview of general principles for providing care to people who use substances in acute care settings, including COVID-19 specific considerations
• Substance specific management recommendations in the setting of COVID-19
• Strategies for managing ongoing substance use in hospital settings
• Techniques to minimize patient-initiated discharge prior to the completion of medical treatment
• End of life and palliative care considerations for people who use substances dying from COVID-19
• Suggestions for addressing other health and social concerns during hospitalization
• Guidance on seamless discharge to home, inpatient addiction treatment programs, and shelter settings Readers should note that this document does not provide recommendations for medication dosing.
Prescribers are encouraged to consult relevant clinical practice guidelines, specialist colleagues, or other trusted sources if unfamiliar with the indications, contraindications, drug interactions, side effects, and dosing for medications mentioned herein. It also does not provide guidance for patients requiring resuscitation or care in the intensive care unit.
# DEVELOPMENT
This guidance document on supporting people who use substances in acute care settings was developed to provide urgent advice in the context of the COVID-19 pandemic. Members of the authorship committee developed this document based on expert knowledge, scientific evidence, and a review of documentation from health authorities and other relevant organizations. The recently released document entitled, "Management of Substance Use in Acute Care Settings in Alberta: Guidance Document" also informed the development of this work and can be viewed as a complementary resource.
The urgent nature of this work required rapid development and dissemination of this guidance. This timeline and the continuing evolution of the knowledge base regarding COVID-19 precluded a thorough description of extant literature. However, where available, academic studies are cited in support of the expert advice offered herein. Where possible, recommendations were based on the highest level of evidence (a systematic review). While we had intended to assess primary research studies examining clinical care for COVID-19 cases using GRADE, we did not reference any such primary studies, thus making the use of GRADE ratings of limited utility. The evidence base for these recommendations should be considered weak, and implementation of these recommendations is at the clinician's discretion. The guidance in this document is subject to change as new information becomes available.
Readers should note that the intent of this document is to provide general guidance for supporting people who use substances in acute care settings across Canada rather than prescriptive procedural instructions. Hospital policies and procedures may vary by provincial/territorial jurisdiction. Readers should consult provincial/territorial health regulatory authorities for advice on navigating their own unique policy environments, as necessary.
Note that a number of external organizations have produced relevant resources for supporting people who use substances. Where possible, we have linked to external documents or websites which may be useful for readers of this guidance; at the time of publication, all links were confirmed to be active.
# INTENDED AUDIENCE
The target audience for this national rapid guidance document includes both clinical and non-clinical staff caring for people who use substances in acute care hospital settings. The information contained in this document may also be relevant for senior operational and medical leaders, policy makers, public health authorities, those operating shelters for people who use substances, groups representing people who use substances, and people with lived and/or living experience of substance use.
# BACKGROUND
Only a fraction of people who use substances experience substance-related harm or meet diagnostic criteria for a substance use disorder. Yet every day in Canada, more than 400 people are hospitalized because of harm from substance use -more than for heart attacks and strokes combined. Alcohol contributes to more than half of these hospital stays (2). Substance use can result in morbidity and mortality from physical trauma, acute and chronic toxicity, blood borne and pathogenic infections (e.g. HIV, HCV), as well as other health conditions (7,8). Harms can arise from the effect of the substances themselves, or from the circumstances surrounding use such as unsafe injection practices, using alone, and consuming non-beverage alcohol, or contaminated or toxic substances such as fentanyl and other drugs purchased on the illegal market (1,7,8).
# Specific risks related to COVID-19 and substance use
People who use substances may be at increased risk of related harm during the COVID-19 pandemic.
Challenges coping with stress and anxiety caused by threats to both lives and livelihoods, and physical distancing recommendations, may lead to an increase in substance use. Disruptions in access to alcohol among people with alcohol use disorders could lead to serious medical complications, including seizures and death. Disruptions in access to treatment and recovery support for people with substance use disorders may increase the risk of relapse (9). Disruptions in the illegal drug supply may result in increasing levels of contamination and increase the likelihood that people who use substances will experience medical complications associated with withdrawal or toxicity (6). Those who rely on harm reduction programs to obtain sterile equipment, naloxone kits, and supervised consumption services may be unable to access the care they need due to program closures or COVID-19 related capacity constraints (10)(11)(12)(13). Inability to access needed equipment and services may lead to an increased risk of blood borne and other pathogenic infections among people who inject substances through unsafe injection practices such as the reuse of equipment (14,15).
People with substance use disorders are more likely to be structurally vulnerable and to experience comorbid mental health disorders, criminalization, stigma, homelessness, and reduced social and vocational functioning relative to members of the general public (16). Structural vulnerability is "an individual's or a population group's condition of being at risk for negative health outcomes through their interface with socioeconomic, political, and cultural/normative hierarchies" (17, p.17). These factors dramatically increase the risk of negative health outcomes in people with substance use disorders. This is especially true for those who are experiencing vulnerable housing or homelessness and those who rely on higher-risk income generating activities such as sex work, panhandling, dealing, or informal recycling, that require prolonged or close contact with many others (18)(19)(20)(21)(22)(23).
While the effects of structural vulnerability on COVID-19-related health outcomes requires further investigation, it is nevertheless prudent to attempt to reduce health and social inequities in the context of a pandemic. Sleeping in outdoor encampments or shelters makes practicing physical distancing or recommended hygiene practices very challenging (24). A change or reduction in community based services (e.g. loss of shower facilities and safe storage options) also creates challenges. In addition, individuals that choose to comply with Public Health mandated isolation orders in settings such as temporary medical isolation shelters may not have access to the full range of supports available in community settings, such as supervised consumption services. Lastly, for some, the risk of COVID-19 infection may be perceived to be less than the risk of their usual day-to-day activities, and thus compliance with physical distancing may be a lower priority.
# Risks associated with hospitalization for people who use substances
People who use substances, especially those with substance use disorders, are more likely to experience acute health conditions that require immediate medical intervention and, compared to members of the general population, present to acute care settings for treatment more frequently (25,26). Rates of COVID-19 infection and related hospitalization amongst people who use substances are currently unknown, however, substance use disorders commonly occur alongside other comorbid conditions (e.g. chronic respiratory illnesses) that may increase the risk of severe outcomes related to COVID-19 in this patient group (27). People with a mental health disorder and co-existing substance use disorder may have more difficulty adhering to and coping with isolation precautions (28). Some symptoms of COVID-19, such as chills, sweating, rhinorrhea, and muscle aches, may be similar to withdrawal symptoms. Furthermore, consumption of certain substances may increase the user's risk of becoming seriously ill from COVID-19. Effects of opioids, benzodiazepines, and alcohol, all of which reduce the respiratory drive, may be exacerbated by COVID-19 infections. Smoking drugs such as crack cocaine, methamphetamines, and cannabis, may worsen respiratory symptoms (29)(30)(31).
Acute care hospitals can be viewed as a 'risk environment' for people who use substances, and in some cases, hospitalization may actually increase health and social harm experienced by members of this population (32). Substance use may occur in patients who meet DSM-5 criteria for a substance use disorder, or for various reasons, including: relief of inadequately managed pain or withdrawal symptoms, to minimize the symptoms of anxiety or boredom, or out of desire or habit. Substance use may occur anywhere on hospital property, including private patient rooms, public or patient washrooms, and outside; or, patients may leave to use elsewhere and then return (32,33). Acute care staff may attempt to deter ongoing substance use through formal and informal sanctions that include changes to care or increased surveillance (32,34,35). People who use substances have described being less able to practice harm reduction strategies (e.g. using sterile injection equipment) while hospitalized. Thus, due to a combination of factors, people who use substances are more likely than members of the general population to experience poor hospital outcomes including involuntary discharge, leaving against medical advice, and lengthy and costly readmissions (34,36,37). Fostering an environment of open communication where safety concerns related to ongoing drug use can be discussed is important.
3.0 Providing care to people who use substances in acute care settings
# ADDRESSING STIGMA
Stigma is the act of "showing discrimination, judgment and/or isolating and stereotyping others" (38, p. 15) and frequently compounds and intersects with racism and gender bias. Stigma is a major barrier to healthcare access and can contribute to feelings of shame, blame, isolation, and guilt (39). People who use substances often encounter stigma when accessing acute care (40)(41)(42)(43). This can include overt discrimination, such as hurtful or derogatory comments, or negative body language, such as avoiding eye contact. Stigma can also be subtle and may include ignoring requests for care or refusing to make appropriate referrals (39). Eliminating stigmatizing language is one simple way by which stigma can be reduced. This includes avoiding terms like 'addict,' 'junkie,' 'get clean', etc. and adopting neutral and person-centred language like 'people who use substances' or 'patient with a substance use disorder,' 'person in recovery,' instead. Further, healthcare staff should advocate on behalf of people who use substances if they witness them being spoken to or treated in a disrespectful way and educate others about the importance of reducing stigma. Education alone, however, is likely not enough to change stigmatizing practice and should be accompanied by practical experiences and/or opportunities to observe positive role models.
During the COVID-19 pandemic, infection control measures implemented by the hospital may be perceived as stigmatizing and therefore a clear explanation and rationale for all pertinent infection control measures should be provided to the patient upon admission. As changes to hospital policies and procedures occur, these also must be clearly communicated. In addition, patients should be asked if they anticipate any challenges to being able to comply with these measures so that these can be addressed.
# SCREENING AND ASSESSMENT FOR SUBSTANCE USE
Screening acute care patients for substance use is essential to providing appropriate care. The CAGE, AUDIT, and AUDIT-C tools are commonly used to screen for alcohol-use related harms (44,45) and the DAST-10 can be used to screen for substance-use related harms (46). Another option is the NIDA Quick Screen, which asks about past year use of alcohol, tobacco, prescription drugs for non-medical reasons, and illegal drugs (47). When inquiring about substance use, clinical staff may receive more honest and detailed answers if they reassure patients that their goal is to provide them the best care possible, discuss the patient's substance use in private, and emphasize that the information provided by patients is confidential.
# HARM REDUCTION AND RECOVERY
Harm reduction is an umbrella term for both a philosophy of care and a set of interventions that aim to reduce harms associated with consuming substances without making the receipt of care contingent on reducing or stopping substance use. Substance use can occur along a continuum from beneficial to harmful, and people deserve non-judgmental care that supports their rights to autonomy and dignity regardless of where they fall on that continuum. Under a harm reduction approach, modifying risks associated with unsafe drug use practices or settings takes precedence over enforcing abstinence.
Recovery is an active process of ongoing growth, improving quality of life and connectedness (48). People in recovery, or those starting their recovery journey, may need unique supports in the context of the COVID-19 pandemic. Access to addiction treatment and recovery supports, as well as other health and social services are based on each individual's self-defined needs and goals.
# TRAUMA INFORMED CARE
At times, individuals can experience events (e.g. child neglect and abuse, witnessing and experiencing violence) which overwhelm their ability to cope (49,50). These traumatic events can be direct or indirect and can have significant acute and prolonged psychological and physiological impacts, including an increased risk of substance use disorders (50,51).
A trauma-informed approach to acute care recognizes "the need to respond to an individual's intersecting experiences of trauma, mental health, and substance use concerns...in all aspects of service delivery and places priority on the individual's safety, choice, and control" (49, p. 12). Foundational to this approach is ensuring that individuals experience no further trauma and that they make informed choices that feel safe to them (49). In acute care settings, this could mean asking patients with substance use disorders about their priorities regarding their care or asking patients how staff can make their hospital stay more comfortable (52).
# COVID-19 SPECIFIC CONSIDERATIONS
COVID-19 has necessitated the implementation of widespread and sweeping public health efforts across the globe. These efforts are critical to controlling the pandemic and have required individual, municipal, provincial and federal cooperation on a large scale. Given the magnitude of change required, it is not surprising or inappropriate that specific populations may require special consideration in response to urgently implemented practice changes such as physical distancing, restricted visitor access and other measures required to reduce the risk of outbreaks in acute care settings.
COVID-19 related changes to the hospital environment may compound existing challenges people who use substances face while hospitalized. Early involvement of an addiction medicine consult team (if available) or expert consultation via a provincial consultation line is strongly recommended.
Those who test positive for COVID-19, are under investigation for COVID-19, or a close contact of someone with COVID-19, must isolate while in hospital and have visitor restrictions. Due to widespread visitor restrictions at many hospitals, even patients who test negative for COVID-19 or are not admitted with any symptoms of COVID-19 may be unable to have visitors. Enforced isolation may contribute to feelings of stigmatization or trigger memories of historical trauma. A clear explanation of the reasons for isolation and its associated requirements is critical. Any changes to hospital procedures that occur during hospitalization should also be communicated quickly and in a patientcentered manner. Isolation precautions may also disrupt access to alcohol or drugs (32,33). As a result, patients who use substances may be at risk of experiencing potentially serious withdrawal symptoms, or acute toxicity if using alone in their rooms. Withdrawal symptoms may confound monitoring for COVID-19 related symptoms. Additionally, those who experience a period of abstinence while hospitalized may develop reduced tolerance and be at increased risk of overdose and death if they return to substance use post-discharge (53)(54)(55). Evidence-based treatment for those with substance use disorders should be initiated and continued after discharge whenever possible. People who use substances may also struggle to communicate with their friends and family while in hospital and those who are structurally vulnerable may lack access to a cell phone for communication. Patients who earn their income through informal means may require income support or income replacement, particularly if they are supporting a loved one as well. In these cases, consideration could be given to providing financial compensation for treatment adherence (56,57).
Due to a combination of factors, some patients may experience increased emotional and physical distress while hospitalized, further exacerbating ongoing substance use as well as precipitating patient-initiated discharge. People with substance use disorders are also more likely to have an acute mental health condition (e.g. psychosis or suicidality). It is important to perform a mental health assessment so as not to erroneously attribute symptoms to another cause thus resulting in missed or undertreated mental health concerns.
# Substance Specific Recommendations
# GENERAL CONSIDERATIONS
While each treatment plan must be individualized to patient and provider circumstances, some general considerations include the following:
• Coordination of medication dosing times and other patient care activities to reduce the frequency of patient-facing contact and personal protective equipment (PPE) usage in patients tested positive for COVID-19 or under investigation for COVID-19
• When initiating new treatments in hospital, consider the availability of ongoing treatment in the patient's local community
• All patients at risk of having an unintentional opioid overdose should have an as needed naloxone order on their chart as well as be provided with a naloxone kit upon admission
• All patients should be provided with tailored education about safer substance use in the setting of COVID-19 (more information can be found in the CRISM National Rapid Guidance Document 'Supporting people who use substances in shelter settings during the COVID-19 pandemic')
# TOBACCO USE
Smoking cessation should be encouraged for all patients admitted with a respiratory illness, including COVID-19. Smoking has been associated with COVID-19 progression (58,59). Nicotine replacement therapy (NRT) products (including transdermal patches, lozenges, gum, inhalers, and oral sprays) are generally safe and increase smoking cessation rates. Choice of product depends on availability and patient preference although combining two forms of NRT is associated with higher rates of smoking cessation (60). First line medication options include varenicline and bupropion SR, both of which increase rates of smoking cessation during hospitalization. Regardless of whether medication is initiated, patients may still benefit from NRT -which is safe to combine with pharmacotherapy (61) -to help them cut down on their use, or to help manage cravings and withdrawal symptoms if they are unable to smoke as frequently as they would like due to isolation precautions. Ideally, patients on isolation precautions should always have at least two forms of NRT available at the bedside.
# ALCOHOL
Alcohol use disorder is a risk factor for leaving hospital against medical advice and readmission within 15 days (36,62). In order to decrease this risk, both alcohol withdrawal and ongoing cravings to consume alcohol need to be appropriately managed in hospitalized patients.
Alcohol withdrawal is a life-threatening medical condition requiring urgent management to prevent sequelae such as cardiac arrhythmias, seizures, and delirium. Withdrawal typically presents within 6-72 hours after a patient's last drink and can be present when alcohol levels are still elevated. The Prediction of Alcohol Withdrawal Severity Scale (PAWSS) can be used to help identify which patients may be most at risk of developing severe symptoms (63). Benzodiazepines are the standard of care for managing withdrawal and a symptom-triggered approach using the Clinical Institute Withdrawal Assessment for Alcohol Withdrawal (CIWA-Ar) ( 64) can be used to guide when benzodiazepines are indicated. However, in the context of COVID-19, use of regularly scheduled benzodiazepines or use of other medication adjuncts could be considered in order to minimize healthcare worker contact and conserve PPE in patients tested positive for COVID-19 or those under investigation for COVID-19. Care must also be taken to avoid the harms associated with benzodiazepine toxicity, particularly in patients with an overlapping acute medical illness such as COVID-19 (65). Intravenous thiamine replacement should also be provided.
Even if alcohol withdrawal has been appropriately treated and resolved, cravings may persist. First line medication options such as naltrexone and acamprosate have been found to assist those with alcohol use disorder to reduce intake, support abstinence, and delay time to first relapse. Second line, off-label medications include gabapentin, topiramate, valproic acid and others (66,67).
In situations where an abstinence-based management plan is declined, or when a patient continues to use alcohol while in hospital (or is likely to continue to use alcohol), and/or when ongoing alcohol use has previously interfered with an individual's ability to address their health concerns, the provision of alcohol via a managed alcohol program should be considered. This is particularly important in patients who tested positive for COVID-19 where patient-initiated discharge is likely to put the patient and others in the community at risk. In addition, patients with confirmed, or under investigation for, COVID-19 who have a history of severe withdrawal requiring previous intensive care unit admission should also be considered for an inpatient managed alcohol program so as to avoid the potential need for intubation due to severe withdrawal. The amount and frequency of alcohol required will need to be determined based on the patient's reported use and a dosing schedule determined. When determining dosing frequency, a balance must be found between frequent dosing requiring patientfacing contact and use of PPE, and management of withdrawal and cravings. An assessment should be done prior to administration to prevent over-intoxication and doses are typically consumed under supervision [see 38, Appendix B -Sample Alcohol Order] (38,68). A managed alcohol program may reduce the daily amount of alcohol the patient consumes and assist with stabilization. At the time of discharge and following completion of isolation requirements, patients should be offered various options for ongoing treatment including managed alcohol programs in the community (if available), detoxification programs, and/or other recovery supports.
# CANNABIS
First-line treatment for cannabis use disorder includes psychosocial interventions such as cognitive-behavioral therapy (CBT), motivational enhancement therapy (MET), or contingency management (69); if available, consideration should be given to offering these via virtual platforms in hospital, if appropriate. There is currently no evidence to support using other cannabinoid preparations for the treatment of cannabis use disorder. For patients with cannabis use disorder who wish to attempt cessation while admitted to hospital, a trial of gabapentin, nabiximols (if available), or nabilone may be warranted. A small research study showed that gabapentin in doses of 1200 mg daily, in addition to psychosocial support, was associated with reduced cannabis use (70); however, gabapentin should be used with caution in patients at risk for respiratory depression or taking other sedating medications. Evidence on the use of nabiximols, a cannabis whole-plant extract, is mixed (71,72) though it may be better tolerated than gabapentin. A small study using nabilone to treat withdrawal and reduce cannabis use showed some encouraging results (73). The use of gabapentin, nabiximols, or nabilone is considered off-label use.
Patients with cannabis use disorder on isolation precautions, or those without a steady supply of cannabis, may be at risk of withdrawal symptoms which can include irritability, anxiety, and sleep disturbances. In some settings, patients may be able to use their own (or hospital provided) edible cannabis products. Most symptoms are mild and, if needed, treatment can be provided to target specific symptoms (e.g. using trazodone at night for insomnia). More severe symptoms could warrant treatment with off-label options such as gabapentin, nabilone, or nabiximols (if available) (74).
# OPIOIDS
Opioid agonist treatment (OAT) is considered the standard of care for people with opioid use disorders (75). Buprenorphine/naloxone is the preferred first-line treatment and methadone is considered an alternative first-line treatment. Ideally, patients with untreated opioid use disorder admitted to acute care environments would have rapid access to health care providers able to initiate and titrate these medications. Buprenorphine/naloxone microinductions can be used in patients requiring opioids for acute pain management, or those where the requirement of withdrawal for traditional induction is not tolerable or medically safe (e.g. pregnancy) (76). Other buprenrophine formulations, such as Sublocade (R) or implantable buprenorphine, should also be considered for in-hospital use. A patient-centered approach to titration (i.e. consideration of the patient's perception of adequacy of OAT dose) is critical to achieving the expected health benefits (77). Immediate treatment initiation, along with withdrawal management, is critical for preventing premature discharge of patients under investigation for, or with confirmed, COVID-19.
Other expert-led treatments for opioid use disorder include slow release oral morphine (SROM) and injectable opioid agonist treatment (iOAT). SROM involves oral administration of opened, witnessed capsules of 24-hour extended-release morphine (78). iOAT involves patient self-administration of prescribed diacetylmorphine or hydromorphone intravenously (or intramuscularly) multiple times per day under health care provider supervision (79). For patients unable to stabilize on first-line treatments, these alternative treatment options should be considered and initiated whenever possible (79,80). Health care providers working in hospitals without addiction medicine consult teams may be able to access advice through provincial consult lines or by consulting addiction medicine specialists in the community.
When evidence-based treatments are being titrated, or are not effective, not available, or declined by the patient, an alternative harm reduction approach should be employed. This involves titrating full-agonist opioids (typically observed doses of liquid oral solution morphine or hydromorphone) to manage withdrawal and cravings. If liquid medications are not effective, consideration should be given to nursing administered subcutaneous, intravenous, or transdermal opioids as a next step (38). Under no circumstances should patients be forcibly detoxified from opioids as this is considered harmful and increases the risk of death post-discharge (75). Before initiating opioids for this purpose, discharge planning should be considered including whether referral to another provider will occur, the medication will be tapered, or a short-term supply provided.
Despite all the above measures, some patients may continue to leave hospital for periods of time to procure and/or consume illegal opioids. For patients who tested positive for COVID-19, or under investigation for COVID-19, this places the patient and others in the community at risk. In these exceptional situations, provision of a prescribed supply of opioids for patients to self-administer under nursing supervision with sterile equipment (e.g. parenteral hydromorphone administered by the patient intravenously or intramuscularly, or hydromorphone 8 mg tablets which can be crushed for intranasal use) may be considered (38). In these cases, consultation with an addiction medicine specialist is advised. In some provinces, there may be recommendations to provide medications for unsupervised use as well (81). Please see Appendix 4: Health Canada Tool Kit on page 51 for more information. Patients should continue to be offered all forms of OAT throughout their admission and, although this type of prescribing may not be possible after discharge, patients should be connected to a prescriber for follow up. An informed consent discussion with the patient outlining the risks, benefits, and alternative treatments that have been discussed should be documented on the chart.
# STIMULANTS
There are currently no pharmacotherapies that have been shown to be effective for the treatment of stimulant use disorders, however research is ongoing (82). Stimulant induced psychosis may require administration of benzodiazepines and/or anti-psychotics. Stimulant withdrawal can present as hypersomnolence, anxiety, difficulty concentrating, and irritability. Withdrawal is typically mild and medications can be offered to address specific symptoms. Where available, connection to contingency management programs and addiction counselling should be considered (83).
For patients with ongoing harms related to stimulant use during hospital admission, a prescribed supply of stimulants can be considered. Prescribing stimulants may help to reduce the risk to the patient and the community from the risks associated with the illegal drug market (including contamination of stimulants with high potency synthetic opioids), as well as the activities required to procure substances which facilitate the spread of COVID-19. Medications such as dextroamphetamine SR, methylphenidate IR, or methylphenidate SR (all off-label use) could be considered for this purpose, but remain unstudied and should be considered strictly a harm reduction measure (81,84,85). For patients with a history of a mental health disorder, especially psychosis or mania, or those who are hospitalized for mental health reasons, the risks and benefits of this type of approach should be carefully considered before prescribing a psychostimulant medication. An informed consent discussion with the patient outlining the risks, benefits, contraindications, and alternative treatments that have been discussed should be documented on the chart.
# ADDRESSING ONGOING SUBSTANCE USE IN HOSPITAL SETTINGS
Despite offering a full spectrum of evidence-based treatments as well as other prescribed medication options, some patients may still continue to use substances during their hospital admission. In these situations, concerted efforts should be made to ensure that the risks of infection (e.g. from the use of contaminated or reused injection equipment), death, and COVID-19 transmission are minimized. At a minimum and throughout their hospitalization, all patients should have access to safer use equipment, a way to safely dispose of used equipment, and a naloxone kit. A harm reduction and trauma informed approach should be used to inform the delivery of care. Creating an environment where patients feel comfortable disclosing ongoing injection drug use to their health care team may help to identify the patients at highest risk of unintentional overdose and those most in need of substance use related support. All patients, whether or not they can abstain from substance use, deserve respect, compassion, and treatment for their medical condition(s).
Overdose events are expected to increase as COVID-19 related disruptions in the drug supply chain lead to increased toxicity in the illegal drug market (4)(5)(6). Hospitals should prepare to experience an increase in unintentional opioid poisoning events on hospital campuses. These may involve patients, visitors, and/or staff. Strategies to consider include: performing overdose simulations in patient care and public areas; ensuring availability of naloxone and appropriate PPE across the site and across disciplines (including protective services team members); and, reviewing safety of single use washrooms available for public use. Those likely to respond to overdoses on hospital property should be updated on changes to local resuscitation guidelines designed to reduce the risk of COVID-19 transmission (e.g. the use of N95 respirators for procedures involving airway manipulation).
# Safer use equipment distribution in acute care settings
Harm reduction programs which provide sterile syringes and other equipment substantially reduce rates of HIV transmission, have no significant unintended consequences, and are cost effective (86)(87)(88). These programs are based on the fundamental principles of harm reduction and have been shown to engage individuals in primary care and substance use treatment programs as well as reduce the frequency of injection drug use and other complications (e.g. abscesses). Patients who are admitted to hospital should have easy access to sterile injection equipment, including syringes, alcohol swabs, tourniquets, filters, cookers, sterile water, and vitamin C (to break down any tablets). This equipment can be ordered from specialized distributors or possibly obtained from local community-based harm reduction service providers. Harm reduction education about safer drug use, including avoidance of groin and neck veins, and any peripherally or centrally inserted catheters, should also be provided. It is important to provide ready access to sharps containers and instruction on how to safely dispose of used equipment (87).
For more information on equipment distribution refer to:
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# Supervised consumption services in acute care settings
Embedded supervised consumption services in acute care hospitals have the potential to improve safety and engage patients in addiction treatment (89). Hospitals responding to opioid poisoning events on their campus should consider opening an Urgent Public Health Need Site (UPHNS) or offering a bedside supervision model. A legal exemption is only required for the supervision of illegal (non-prescribed) substances. Information on how to obtain an exemption and set up supervised consumption services can be found in a companion document in CRISM's national rapid guidance series, Supporting people who use substances in shelter settings during the COVID-19 pandemic. Information about how to operate these sites safely during the COVID-19 pandemic can also be found in this companion document. Reduced access to community-based supervised consumption services due to the physical distancing requirements of COVID-19 may also prompt consideration of expanding any hospital-based UPHNS or supervised consumption sites to include access for the general public.
If supervised use is not possible, steps should be taken to identify patients at risk of unintentional overdose. Developing an individualized safety plan to minimize the risk of unwitnessed overdose during admission is warranted especially for patients with visitor restrictions who will be more likely to consume substances alone. Education on safer use practices during the COVID-19 pandemic should be provided to all patients and could include information such as virtual supervision methods, strategies to minimize contact with others, and recommended hygiene practices (not sharing equipment, preparing drugs yourself, washing hands) (please see Appendix 3: Online Substance Use Resource Listing on page 48).
# Preventing Patient-Initiated Discharges in COVID-19 Positive Patients
# GENERAL PRINCIPLES
People who use substances are more likely to leave hospital against medical advice (90). Patientinitiated discharges increase morbidity, mortality, and health care system costs. In addition, in the context of communicable diseases such as COVID-19, premature discharge against medical advice of a patient with confirmed or suspected COVID-19 has the potential to further exacerbate community spread of the virus during an outbreak. It is therefore critical to pre-empt with measures that reduce premature discharge. Immediately upon admission, efforts should be made to identify what would be helpful to support treatment completion, as well as patient-identified barriers. This may include things like the need to take care of a loved one or pet, concerns around unattended belongings, the need to maintain or secure housing, court or custody proceedings, and unmanaged withdrawal and/ or cravings. Working together to identify the goals of the admission, and expectations on both sides, may help to create an open and collaborative relationship from the start.
# COMFORT AND ENTERTAINMENT RESOURCES
Patients on isolation precautions for COVID-19 or other infections may be asked or required to remain in their rooms for long periods of time. This can be difficult for anyone, particularly those with comorbid anxiety, depression, post-traumatic stress disorder or attention deficit hyperactivity disorder. In addition, some people who use substances may have a history of incarceration and/or past traumatic experiences involving coercive admissions and confinement. Isolation requirements for COVID-19 should be considered in this context and implemented via the least restrictive means and in a way that provides the most comfort. If possible, patients should have access to entertainment resources; for those unable to access through other means, the hospital can consider supplying as a way to facilitate engagement in care. Some examples include free television, access to tablets, music, reading materials, and art supplies. Some individuals may desire extra food portions, or have specific dietary requests, which, if accommodated, may increase overall comfort in hospital. Working with the Infection Prevention and Control Team to ensure compliance with local guidelines is important.
# CONNECTION TO SUPPORTS
During the COVID-19 pandemic, visitor access at most hospitals is severely limited. This makes it difficult for patients to connect to family, friends, and existing community supports (e.g. an Alcoholics Anonymous sponsor, housing worker, addiction counsellor etc.) during an extremely stressful time.
In addition, some patients may not have a phone and access to shared phones in the hospital unit may be limited due to infection prevention and control measures. In these situations, the provision of tablets and/or cell phones for patient use during hospitalization has the potential to reduce isolation, improve well-being, and facilitate ongoing connection to existing supports. For example, many community-based peer support programs have moved to a virtual format so with access to the appropriate technology, some patients may be able to participate in their usual recovery activities even while in hospital or on isolation precautions.
In addition to permitting ongoing connection to existing supports, technology may also be used to connect patients to new health care providers and community supports. With many services moving to virtual care delivery models, patients could now potentially use hospital provided technology to meet a new primary care provider, addiction counsellor, or recovery coach virtually prior to hospital discharge. These platforms may also be used to connect patients to online cognitive behavioural therapy and mental health resources during and after admission.
# PEER SUPPORT SERVICES
Emotional support can be provided by a trained peer support worker to a patient, where a shared common experience of addiction exists. Provision of peer support may be particularly important in stressful times and when access to visitors is restricted. Hospital employed peer support workers who can provide in-person support or virtual access to peer support workers in the community may be helpful for patients coping with the combined stresses of a substance use disorder and COVID-19. More information about peer support can be found at Peer Support Canada (https:// peersupportcanada.ca/).
# CONNECTION TO SUBSTANCE USE SUPPORTS AND RECOVERY RESOURCES
Where possible, patients should have access to substance use supports and recovery resources. These can either be in person (such as hospital employed addiction counsellors), via virtual connection to community-based programs, or via hospital-community partnerships that offer a hybrid model.
Emergency department visits and hospital admissions have been identified as a key point of contact with the health care system for individuals who use substances and an overlooked opportunity to initiate addiction treatment (91-93).
# USE OF NURSING ASSISTANTS AND OTHER SUPPORT STAFF
Some patients may have difficulty complying with infection prevention and control guidelines. This may be due to a number of factors, including but not limited to: untreated and/or unidentified substance use concerns; cognitive impairment; and, mental health concerns. Early identification and mitigation of specific issues should be a top priority for health care providers in the acute care setting. This is particularly important in the context of a pandemic to facilitate maintenance of isolation and prevention of disease transmission. In some cases, and if within scope of practice and utilizing recommended PPE, a nursing assistant or other team member who can remain with the patient may be helpful, particularly if patients require frequent reminding, redirection, or accompaniment off unit.
# USE OF THE PUBLIC HEALTH ACT
In extreme cases, patients who are confirmed to have tested positive for COVID-19 positive and are unable to comply with isolation requirements may require apprehension under the relevant provincial, territorial or federal Public Health Act. This will require collaboration and consultation with the local Medical Officer of Health. Each case will require a balance between respecting individual rights and maintaining public health and safety. When these patients also require admission to acute care, every effort should be made to ensure that substance use related concerns are identified and managed.
Patients tested positive for COVID-19 who are unable to comply with isolation requirements in shelter settings may require transfer to acute care or another facility where more supports are available. Proactively developing transfer of care procedures and identifying vehicles suitable for the medical transport of people with COVID-19 will minimize the risk of community transmission.
6.0 End of life and palliative care considerations
# DEFINITION OF PALLIATIVE CARE
Palliative care involves the relief of suffering (physical, emotional, spiritual and existential), and focuses on quality of life in the setting of life-limiting illness (94). The intent is to provide 'whole person' care in alignment with the patient's goals and values. Palliative care is not the domain of any specific team but rather an approach that can be employed by all healthcare professionals. Specialist palliative consult teams remain ready to help provide assistance and advice for refractory symptoms and for those that require more specialized care. Advocates believe that palliative care should be a human right, but there is evidence that facing a life-limiting illness can actually increase inequities particularly for those that are structurally vulnerable (95). A multidisciplinary and collaborative approach to care is essential for equitable delivery of palliative care.
# CONVERSATIONS AND PLANNING
Goals of care conversations should occur in an iterative manner and, if possible, with a healthcare provider with whom the patient already has a trusting relationship. Patients focused on surviving and living in the present moment may be more reluctant to discuss these topics. Evidence has shown that with appropriate intervention a high rate of advanced care directives can be completed for those who are chronically homeless (96).
In the setting of a more acute illness and presentation to acute care, conversations about goals of care may need to be readdressed. Again, having healthcare teams with whom the patient has a relationship present, even virtually, can be very helpful. Both collaborative and trauma informed approaches are needed. Tools such as the Serious Illness Conversation Guide (97) may be helpful and provide patient-tested language to help guide such conversations.
Substitute decision-makers (SDM) are consulted if the patient is not able to participate in discussions regarding goals of care. If a SDM has not been designated and there is no clear family contact, the office of the Public Guardian (or provincial/territorial equivalent) may need to be involved, but this process takes time. If time will not allow for the involvement of a Public Guardian's office, it may be helpful to involve another team (such as palliative care) or a second physician to review the case and assist in making decisions regarding appropriate medical intervention.
Past experiences, including lived experience, systemic discrimination and loss of loved ones, may cause reluctance to discuss end of life and acceptance of a palliative care approach. Patient-centered care with provision of best possible care will help mitigate fears of abandonment or receiving substandard care. If comfort care is desired, the patient's goals and values are central to guide care.
# SYMPTOM MANAGEMENT
Symptoms anticipated for patients tested positive for COVID-19 include dyspnea (along with associated anxiety), cough, upper respiratory secretions, fever, pain and delirium. Whenever possible, treatment for the underlying cause should be optimized if it is within the patient's goals of care. Collaboration should occur with allied care providers including Nursing, Spiritual Care, Cultural Liaison departments, Psychology, Social Work, Infection Prevention and Control, and others. No one person or role can address and alleviate all the aspects of suffering experienced by patients. Nearing the end of life brings a desire to reconnect with spiritual and/or cultural roots for some patients; for others this may not be the case (98,99). Many symptoms are subjective in nature, so assessment tools such as the Edmonton Symptom Assessment System Revised (ESAS-r) are helpful to follow symptoms over time and monitor effectiveness of treatments (100). A detailed opioid history should be taken on all patients prior to initiation of opioid medications to assess for tolerance, efficacy and to guide initial dosing.
# Dyspnea
Dyspnea is a common symptom and can be severe at the end of life in COVID-19. Re-positioning can be used including sitting upright to increase peak ventilation and reduce airway obstruction (101). Therapy that is considered higher risk of transmitting COVID-19 to health care workers and family include: a fan, oxygen flow greater than 6L/min, continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP) and nebulized medication treatments (102). Appropriate PPE must be utilized as per hospital policy if these interventions are used. If a patient is intubated and withdrawal of therapy is appropriate it is best to do this as per hospital protocol to reduce the risk of COVID-19 transmission to others.
Pharmacologic agents, including opioids, are the mainstay treatment for the relief of severe dyspnea. For patients on OAT, collaboration between the addiction medicine team or OAT prescriber will be key to determining whether OAT can be modified to be dosed more frequently, additional agents should be added, or medications should be changed to a different opioid entirely. If dyspnea is present the majority of the time, opioids should be dosed around-the-clock and consideration should be given to providing as needed opioids for breakthrough dyspnea. When initiating or titrating opioids, consider prescribing medications for the management of common side effects such as anti-emetic and laxative medications.
Dyspnea is often associated with increased anxiety and many patients benefit from specific anxiety management. If there is a history of seizure (e.g. alcohol withdrawal seizures) or the patient is at increased risk of extrapyramidal side-effects (e.g. Parkinson's), benzodiazepines are recommended. However, given their risk of delirium, neuroleptics at low dose are often preferred. Commonly prescribed neuroleptics are haloperidol, olanzapine, and methotrimeprazine as all can be administered orally or parenterally including subcutaneously. As with opioids, with severe symptoms, dose titration should occur and the patient will likely need around the clock dosing or an infusion if symptoms are refractory. Additionally, relief of severe dyspnea may require use of medications that are sedating (e.g. methotrimeprazine) and/or have quick onset of action (e.g. midazolam).
Medications used to control symptoms, such as opioids and benzodiazepines, may be a trigger for individuals who use substances (103). The use of these medications should be reviewed with the patient if they are well enough to engage in a conversation. However, if indicated for symptom management, these medications should never be withheld in those at the end of life because of past or current substance use.
# Cough
Significant overlap exists between the treatments for cough and dyspnea. Non-pharmacological treatment such as repositioning can be initiated. For distressing symptoms of cough, opioids can be initiated if the patient is not already on opioids or OAT.
# Upper respiratory secretions
At end of life, noisy upper airway secretions may develop due to an inability to clear secretions. Re-positioning can improve symptoms. Parenteral fluids should be reassessed as they may be contributing to the amount of secretions. In the last days or hours, fluids do not change prognosis and do not need to be routinely offered if there are no symptoms of opioid neurotoxicity (e.g. myoclonus, hallucinations). Glycopyrrolate can be useful in managing symptoms; if ineffective, scopolamine can be used instead, however it can be more sedating. In addition to thickening secretions, these medications also have anticholinergic side effects which can be bothersome if initiated too early.
Deep tracheal suctioning and open airway suctioning should be avoided in patients tested positive for COVID-19 due to the risk of aerosolization of the virus (102).
# Fever
If the patient has discomfort from fever, acetaminophen can be given orally or rectally. If goals of care are comfort and treatment for fever is symptom focused, then acetaminophen can be considered in those with elevated liver function testing without further monitoring.
# Pain
Pain can be multifaceted in nature and is termed 'total pain' in the setting of significant psychological, emotional, and spiritual suffering along with physical pain. Titration and changes in opioids should be managed in a collaborative approach for patients on OAT. Similar to management of dyspnea, if pain is present the majority of the time, opioids should be dosed around the clock and consideration should be given to providing as needed opioids for breakthrough pain. When initiating or titrating opioids, consider prescribing medications for the common side effects such as anti-emetic and laxative medications.
# Delirium
Delirium is common at the end of life and often multifactorial in nature. Delirium or altered mental status can interfere with a thorough symptom and risk factor assessment for COVID-19. Investigations and treatment of reversible causes should be aligned with goals of care. Commonly advised non-pharmacologic options, such as the presence of family or friends, are more challenging in the context of COVID-19. If the delirium is episodic and mild in intensity, then the neuroleptics should be initially prescribed on an as needed basis to manage the agitation, distress, and confusion. For delirium that is irreversible and due to underlying disease progression, neuroleptics may be needed around the clock to manage ongoing agitation and anxiety. If haloperidol around the clock is no longer effective another agent can be trialed such as loxapine or methotrimeprazine. Methotrimeprazine is often more effective for hyperactive delirium leading to increased agitation; however, is more sedating. Irreversible delirium, progressing rapidly over days or even hours, is a poor prognostic indicator, so this should be conveyed to friends and family. Education should be provided to family and/or friends including the challenges of assessing other symptoms in the setting of delirium. It is not uncommon for family supports to misconstrue periods of somnolence and hypoactivity as being depression or overuse of medications, and periods of agitation or hyperactivity as pain, so education and reassurance is important. When delirium occurs at the end of life, it is a time to advocate that visits by family, friends and spiritual leaders, be facilitated, if at all possible.
6.4 OTHER CONSIDERATIONS
# Palliative Care Consultation
If symptoms are persisting or additional advice around conversations and direction of care are needed, consider consulting your local palliative care team.
# Palliative care in other settings
Palliative care should be available in all settings including home, hospital, hospice, long term care, and shelters. The Canadian government has released information on how to care for a person with COVID-19 at home which should be applied to any location that a patient identifies as home (104).
Requests for Medical Assistance in Dying (MAID) do not change the course of palliative care and MAID referrals are region specific.
# Psychological and grief support
Those affected by COVID-19 and their supports can have a psychological burden that is complicated by factors such as isolation and financial strain (105). Family and friends that experience death of a loved one will experience grief, a universal human process. Referral for grief services should be considered for friends and family of those affected. Family units should not be assumed, and contact information should be gathered by the attending health care team.
# Addressing other health needs
In addition to identifying and initiating treatment and referral for substance use disorders, a period of hospitalization can also be an opportunity to address other unmet health and social needs. Four areas of particular relevance during the COVID-19 pandemic include addressing mental health concerns, ensuring the social determinants of health are assessed, preventing future infections via immunization, and identifying any other untreated infections. Others areas of intervention that could be considered if feasible and appropriate include addressing sexual health and contraception needs.
# MENTAL HEALTH CONCERNS
People with mental health disorders may be more susceptible to COVID-19, more substantially influenced by the emotional responses brought on by the COVID-19 pandemic, and/or unable to access their usual mental health supports (106). Patients should be screened for mental health concerns and referred to treatment or local supports as clinically indicated.
# SOCIAL DETERMINANTS OF HEALTH
Effective medical treatment also involves understanding and appreciating a patient's social determinants of health. All patients should be asked about the availability and safety of housing, screened for poverty or inadequate legal income, and assessed for active medication coverage. Early involvement of social workers can be critical in addressing unmet social needs and ensuring that patients can comply with any isolation requirements after hospital discharge (107).
# IMMUNIZATIONS
Some patients who use substances are at risk of developing vaccine preventable infections. In particular, patients who are immunocompromised, have liver failure or cirrhosis, or live in shelters are eligible for extended adult vaccination regimens. Where possible, consider offering immunizations during a period of hospitalization as a highly cost effective way to reduce future morbidity and mortality (108).
# SCREENING FOR SEXUALLY TRANSMITTED AND BLOOD BORNE INFECTIONS
Some patients who use substances may also be at risk of sexually transmitted and blood borne infections. If a patient consents, screening should be performed in hospital so that treatment and any appropriate referrals can be initiated (109).
8.0 Transfer of care to community providers at discharge
# GENERAL CONSIDERATIONS
A discharge checklist can be found in Appendix 2: Discharge Checklist on page 46. At the time of discharge, any active infection prevention and control issues need to be clarified. If appropriate, providing patients with a discharge letter stating that the individual has completed the legal/medical requirements of isolation and is safe to return to the community can reduce the risk of unfounded discrimination or refused re-entry into congregate living environments. Additionally, if clinically indicated, ensure the patient still has the take home naloxone kit provided earlier in the admission as well as up to a two week supply of sterile drug use equipment.
# DISCHARGE TO HOME
If a patient is discharging home, ensure this remains a safe disposition plan. If the patient requires ongoing isolation, ensure that this will be possible within their home, that there is support for basic necessities (e.g. someone able to deliver them food, medication, cleaning supplies), and that the patient understands how to safely self-isolate. Patients on self-isolation will also need medications delivered and virtual follow-up appointments arranged until the requirement for self-isolation ends. If the patient is required to leave their home, then they must wear a mask. Confirmation of active medication coverage and income support is important to ensure a seamless discharge back to the community.
Even if the patient is not required to self-isolate, community providers may be following up with their patients via telehealth or other virtual care platforms. When able, coordinate virtual and/ or phone follow ups to support patients to adhere to physical distancing recommendations in the community. Confirm whether the patient has access to a telephone or technology and, with consent, provide this contact information to the ongoing community provider and pharmacist.
# TRANSFER TO AN INPATIENT ADDICTION TREATMENT PROGRAM
Even during the COVID-19 pandemic, some inpatient addiction treatment programs may still be accepting patients. When possible, and if desired by the patient, transfer from an acute care setting directly to a specialized addiction treatment program should be facilitated whenever possible.
Patients admitted to an acute care setting who have stopped using substances and had their withdrawal managed will likely meet program requirements (if any) of a period of abstinence from substance use prior to admission. Direct transfer from acute care minimizes the risk of relapse which would then require another period of detoxification prior to program admission.
Prior to transfer it will be important to confirm program admission requirements (including COVID-19 specific changes) and whether the program can accommodate isolation requirements (if still needed).
A plan for any ongoing prescribing should be coordinated with the program's medical team or the patient's primary care provider. In addition, some programs require that prescriptions be sent to a specific pharmacy for the duration of the treatment program.
# TRANSFER TO AN EMERGENCY SHELTER
In response to the pandemic, many jurisdictions have adapted their existing shelters to comply with physical distancing requirements or moved to new settings (e.g. hotels, convention centres) to establish medical isolation shelters. As the pandemic evolves, many shelter settings are fluid and are adapting to the needs of the clients accessing their site(s). It is important to be aware of what services are offered on site and, for those services that are not, how patients can be supported to access the services they need. Prior to discharge, the acute care team should confirm with the site Infection Prevention and Control team (or Public Health, depending on hospital procedure) whether the isolation period has ended, and if not, that appropriate isolation facilities are available at the discharging facility.
# Adapted shelter (a shelter setting where patients are not required to self-isolate)
Prior to discharging to shelter, the acute care team should confirm that the patient is agreeable to stay at the shelter and whether there is current availability.
In an adapted shelter setting, the patient may still be able to present to their pharmacy for witnessed ingestion and/or medication pick up. Carries and/or decreased frequency of dispensing may be appropriate to promote physical distancing based on a shared decision making process between patient and provider. Decisions regarding carries should be made in collaboration with the patient's community prescriber. If carries are not appropriate and/or the patient is unable to present to the pharmacy, other options for ongoing medication access may include having the patient's community pharmacy deliver daily to the shelter or deliver several days of medications if safe to do so and there is access to a secure storage space. Confirmation of access to secure storage space at the shelter should be confirmed prior to discharge.
# Medical Isolation Shelter (shelter setting where patients are required to self-isolate)
Each acute care setting should establish a seamless care pathway to the medical isolation shelter (if available). It is necessary to have clear communication and an understanding of the requirements, expectations, and services available at the shelter to ensure patients are supported in their transition between settings. Acute care providers should be well informed of both admission and exclusion criteria for the medical isolation shelter.
Prior to coordinating transfer to a medical isolation shelter, it is essential that the patient be informed of this plan. Patients should be supported to understand why discharge to a medical isolation shelter is required and what supports are available on site.
Acute care settings should consider the most appropriate and safest mode of transport to the medical isolation shelter. Transport must abide by local recommendations for infection prevention and control for both the patient and staff. This may vary by jurisdiction and availability of resources. In the event a patient does not successfully arrive at the medical isolation shelter, there should be a clear plan for next actions including connecting with Public Health to determine appropriate measures to locate the patient (which may be dependent on whether the patient was known to have tested positive for COVID-19 or under investigation) and, as appropriate, re-activating the patient's previous community connections and prescriptions for ongoing care.
On discharge from the shelter, the shelter medical team should reconnect patients to their existing community connections or, as required, refer them to new providers for ongoing care.
# DISCHARGE PRESCRIBING
The acute care team must collaborate with the patient's community providers to coordinate seamless care and ongoing prescribing. Furthermore, early collaboration between the acute care team with a hospital or community pharmacist is important to proactively identify any barriers to seamless care planning including drug shortages and ability to continue therapy. Prior to discharge, it is essential to confirm that medication coverage is active. For those without coverage, collaborate with a social worker to ensure coverage is in place before discharge.
Community providers may be following up with their patients via telehealth or other virtual care platforms. Consider providing a lengthier discharge prescription than usual to accommodate for the time it may take for the patient to reconnect with their prescriber in this new climate. For all prescriptions, ensure it does not lapse on a Friday, weekend, or statutory holiday. For OAT bridge prescriptions, include documentation of the milligram dose and date last received in hospital, dispensing frequency (i.e. daily versus carries), who will be taking over prescribing as well as follow up appointment details, instruction on when doses are to be held, instruction for missed dose management, who to notify of missed doses, and whether medications can be released to an authorized individual if the patient is unavailable to receive their delivery directly. If carries are authorized, clearly document the quantity of carries approved and confirm that the patient is able to securely store the carries (at minimum, a bag that can close with two zippers along with a lock to secure the two zippers together). Patients may not be required to keep or return their empty carry containers due to the risk of COVID-19 transmission however alternate arrangements, as required, can be explored between the patient, pharmacist, and OAT prescriber.
As part of the COVID-19 pandemic response and in an effort to support seamless care, Health Canada has issued certain exemptions for prescriptions of controlled substances under the Controlled Drugs and Substances Act (CDSA) and its Regulations. These exemptions permit the extension and transfer of prescriptions of controlled substances by pharmacists, the delivery of controlled substances by pharmacy employees to patient's homes or other locations they are staying, as well as permitting prescribers to issue verbal orders to extend or refill prescriptions for controlled substances. Please refer to the Health Canada Subsection 56(1) Class Exemption for Patients, Practitioners, and Pharmacists Prescribing and Providing Controlled Substances in Canada during the Coronavirus Pandemic for further details regarding the exemptions and their application to specific provincial/ territorial scopes of practice.
Discharge planning to a medical isolation shelter should be tailored based on the services offered at the shelter. If there are medical supports available, a bridge prescription for OAT or other medications may not be required as long as clear and direct communication occurs regarding the need for isolation shelter medical staff to manage ongoing prescribing. If pharmacy services are available at the isolation shelter, it is essential that the discharge prescription be sent to the isolation shelter pharmacy, if different than their usual pharmacy, for continuity of care. Patients may be required to present with a 24-hour supply of their discharge medications. Not all medications may be appropriate to provide as a bridge supply. For those medications, it is best to administer the medication in the acute care setting prior to discharge. This can be communicated to isolation shelter medical staff in the discharge process and/or by faxing a copy of the medication administration record from the hospital.
from a commercial entity (Gilead) that could theoretically benefit from guidance document recommendations. There was one authorship committee member with a commercial interest in the form of partial ownership of a medical clinic that provides treatment to PWUD. On review, potential conflicts of interest were not deemed to be of sufficient weight or relevance to warrant exclusion from the guidance committee.
Most (23, 77%) authorship committee members and external reviewers disclosed potential indirect sources of bias (e.g. specialization in addiction medicine, advisory board and committee membership, involvement with acute care programs, provincial substance use treatment programs, previous guideline development, research interests). Of these, 6 acknowledged that they have publicly stated support for acute care treatment of PWUD. In order to mitigate the risk of bias while maximizing the contributions of members in their respective areas of expertise, authorship committee members and external reviewers were reminded to consider any influential factors or sources of bias during the review process. Authors and reviewers with indirect potential sources of conflict contributed to review of sections related to their areas of expertise as well as the overarching guideline content to ensure that a broad range of clinical and academic specializations was adequately represented. Individual author conflicts of interest are available by contacting CRISM.
# Acknowledgments
The committee acknowledges the assistance of the CRISM Node managers: Denise Adams (Prairies), Farihah Ali (Ontario), Nirupa Goel (BC), and Aissata Sako (Quebec/Atlantic). This work was undertaken, in part, thanks to funding from the CIHR CRISM Urgent Guideline Activities Related to COVID-19.
# Appendix 1 Conflict of Interest Policy
Conflicts of interest were assessed using the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts (i). For this Guidance document, authorship committee members and external reviewers were required to disclose all sources and amounts of direct and indirect remuneration received in the past five years from industry, for-profit enterprises, and other entities (e.g. direct financial conflicts) that could introduce real, potential, or perceived risk of bias. In addition, authorship committee members and external reviewers were asked to disclose possible indirect conflicts of interest, such as academic advancement, clinical revenue, and professional or public standing that could potentially influence interpretation of evidence and formulation of recommendations.
Before the draft guidance document was circulated for review, two CRISM staff members independently reviewed the disclosure forms to screen potential authorship committee members and external reviewers who should be precluded from participation due to ongoing or current financial relationships (e.g. employment, paid consultancy or advisory board membership, stock ownership, intellectual property) with industry or commercial entities that could theoretically benefit from the guidance document recommendations. Consistent with the Institute of Medicine Standards for Developing Trustworthy Clinical Practice Guidelines, any individual with a current, ongoing relationship with industry, who had received any remuneration or non-monetary support from industry within the past 12 months, or with a history of significant remuneration or non-monetary support from industry (defined for our purposes as cumulative receipt of more than $10,000 or equivalent value within the past five years), was excluded from participation on the guidance document prior to the review process. No authors nor contributors were excluded during initial screening as none met these criteria for exclusion.
# Summary of disclosures
Of 30 authorship committee members and external reviewers, 14 acknowledged potential direct conflicts of interest. Of these, 10 acknowledged employment or consulting with organizations including academic institutions, hospitals/health authorities, professional or regulatory associations, HIV/AIDS foundations, community outreach agencies or federal funding agencies. Only one (an external reviewer) disclosed receiving research funding prior to guidance document involvement i. Schünemann HJ, Al-Ansary LA, Forland F, et al. Guidelines international network: principles for disclosure of interests and management of conflicts in guidelines. Ann Intern Med. 2015;163(7):548-553.
# Government of Canada Coronavirus disease (COVID-19) resources for health professionals.
# Health Canada Subsection 56(1) Class Exemption for Patients, Practitioners and Pharmacists Prescribing and Providing Controlled Substances in Canada during the Coronavirus Pandemic
In response to the evolving health risk due to COVID-19, to maintain Canadians' access to controlled substances for medical treatments (e.g. treatment of substance use disorders and chronic pain), while they adhere to social distancing guidance from public health officials or if they need to selfisolate, Health Canada has issued exemptions for prescriptions of controlled substances under the Controlled Drugs and Substances Act (CDSA) and its Regulations.
# Mental Health First Aid Canada
Resource hub which provides credible information and resources for mental health for the Healthcare professionals "Resources for Healthcare Sector"
# Appendix 4: Health Canada Tool Kit
Health Canada has compiled a number of resources in an effort to provide clarity regarding the rules that apply for substance use disorder treatment or providing a pharmaceutical grade alternative to the toxic street supply in Canada, in the context of COVID-19. This includes:
• A regulatory pathways graphic;
• Frequently asked questions and answers related to the legislative and regulatory requirements for substance use disorder treatment/safer supply;
• A list of all relevant exemptions that have been issued under the Controlled Drugs and Substances Act;
• Formulary coverage under drug plans of medications used in substance use disorder treatment and as pharmaceutical grade alternatives to the illegal supply; and,
• Resources related to substance use disorder treatment and providing safer supply, both in general and during the COVID-19 pandemic.
https://www.dropbox.com/sh/x622qndzvmydsvm/AABi888G_Ase6T0-N1Pd3uboa?dl=0
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What is Multisystem Inflammatory Syndrome in Children (MIS-C)?
Multisystem inflammatory syndrome in children (MIS-C) is a rare condition associated with COVID-19. Evidence supports that MIS-C is a post-infectious illness, occurring between two to six weeks following SARS-CoV-2 infection. A child can develop MIS-C regardless if their acute infection was asymptomatic or symptomatic.
# What are the Features of MIS-C?
The case definition of a person under investigation or a confirmed case of MIS-C used in B.C. is adapted from the case definition developed by the World Health Organization (see appendix A).
There is likely a spectrum of disease severity and phenotypes in children affected by MIS-C. However, the majority of children with MIS-C are usually sick enough to require hospitalization and, often, intensive care. Children with MIS-C may initially present with mild symptoms, which can progress quickly. Presenting symptoms usually reflect systemic inflammation and often have similarities to Kawasaki disease (KD), toxic shock syndrome (TSS) and macrophage activation syndrome. Prominent features include:
# When to Consider MIS-C?
There should be a low threshold to consider and evaluate for MIS-C in children who present with unexplained fever for three days or more, even if they are well-appearing on initial presentation and especially within two months following a known COVID-19 infection or exposure. The initial infection with SARS-CoV2 may have been asymptomatic, therefore, MIS-C should still be considered in children without a previous history of infectious symptoms.
# Treatment
The management of MIS-C differs from that of severe acute COVID-19. Severe acute COVID-19 infection remains rare in pediatrics and any suspected cases of COVID-19 should be discussed with specialists at BCCH as this is a separate entity from MIS-C but may require active therapy.
Evidence for the optimal management of MIS-C should be guided by these specialists. The majority of children require early fluid resuscitation. The mainstay of treatment has been early use of intravenous immunoglobulin (IVIg) with or without intravenous steroids. Some children have required immunomodulatory therapy (biologic treatments) for refractory symptoms as guided by a rheumatologist. Low dose aspirin is recommended in children with MIS-C who have features of KD or coronary aneurysms seen on echocardiogram, in consultation with rheumatology. Even with treatment, children with MIS-C require serial monitoring of clinical and laboratory parameters, cardiac imaging and close follow up post-discharge (see disposition section).
# Disposition
All follow up appointments should be made and clearly communicated to families prior to discharge. Discharge documentations should be sent to all relevant specialist involved in the patient's care. The longterm sequalae of MIS-C is still unknown but being studied.
- Primary care provider: All patients evaluated for MIS-C should be seen by their primary care provider within one week of discharge, regardless if they were a confirmed case or not. Pediatrics: Children hospitalized with MIS-C should be referred to a pediatrician on discharge for follow up. For those with abnormal inflammatory markers or laboratory findings at discharge, repeat bloodwork should be considered prior to this visit. Cardiology: Confirmed cases of MIS-C will require a repeat echocardiogram, typically four to six weeks after discharge, as guided by cardiology. Rheumatology: Follow up will depend on the severity of illness and discharge medications, as guided by rheumatology.
- Haematology: For children who were started on prophylactic/therapeutic anticoagulation in hospital, the dose and duration of therapy should be clearly communicated to the family prior to discharge, if applicable. Follow up will be guided by haematology. Mental health: Families with children who were hospitalized for MIS-C should be offered mental health support in the community as needed. Others: Follow up with other specialties (e.g., neurology, immunology) will depend on their clinical features and course in hospital. Return to emergency department: Families should be counselled on when to bring their child back to the emergency department. Reasons to return include: o Persisting fever > 38 degrees Celsius. o Recurrence of presenting symptoms or child becomes unwell with other symptoms. o New appearance of respiratory distress or shortness of breath.
Appendix A: Case Definition for MIS-C
# Confirmed case
Children 0-19 years of age requiring hospitalization with fever for three days or more and two of the following: a) Acute gastrointestinal symptoms (abdominal pain, vomiting, diarrhea); b) Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet); c) Hypotension or shock; d) Features of myocardial dysfunction or pericarditis or valvulitis or coronary abnormalities: ECHO findings or elevated troponin/ brain natriuretic peptide (BNP)/ natriuretic peptide tests (NT-proBNP); e) Evidence of coagulopathy: Abnormal prothrombin time/ partial thromboplastin time (PT/PTT), elevated d-dimer;
# And
Elevated markers of inflammation such as erythrocyte sedimentation rate, C-reactive protein, or procalcitonin;
# And
No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, and no alternative plausible obvious diagnosis;
# And
Evidence of SARS-CoV-2 infection (positive NAAT test, antigen test and/or serology) or close contact 1 with a confirmed or probable (lab-probable or epi-link probable) COVID-19 case. 2
# Appendix B: Full MIS-C Evaluation
To be performed in addition to workup of alternative diagnosis, including sepsis.
- Complete blood count (CBC) with differential.
- Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP).
- Electrolytes, blood urea nitrogen (BUN), creatinine.
- Liver function tests (LFTs), lactate dehydrogenase (LDH), albumin.
- Ferritin, d-dimer, prothrombin time/ partial thromboplastin time (PT/PTT).
- Troponin, brain natriuretic peptide (BNP).
- Urinalysis.
- SARS-CoV-2 testing: o SARS CoV-2 polymerase chain reaction (PCR): Respiratory (nasopharyngeal swab/saline gargle/ sputum/ bronchoalveolar lavage); o SARS CoV2 antigen o SARS CoV-2 serology: Contact local medical microbiology on call for approval and fill out serology request form. Obtain serology pre-IVIG whenever possible. - Type and Screen (for those receiving IVIG).
- Electrocardiogram (EKG).
- Chest X-ray (CXR).
- Echocardiogram.
- Consider all usual bacterial or viral illnesses and alternative diagnoses and test as appropriate (e.g., cultures, other infectious studies).
For further clinical guidance on COVID-19 in children, see Clinical Reference Group Recommendation: Pediatric Clinical Guidance for COVID-19.
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#
What is Multisystem Inflammatory Syndrome in Children (MIS-C)?
Multisystem inflammatory syndrome in children (MIS-C) is a rare condition associated with COVID-19. Evidence supports that MIS-C is a post-infectious illness, occurring between two to six weeks following SARS-CoV-2 infection. A child can develop MIS-C regardless if their acute infection was asymptomatic or symptomatic.
# What are the Features of MIS-C?
The case definition of a person under investigation or a confirmed case of MIS-C used in B.C. is adapted from the case definition developed by the World Health Organization (see appendix A).
There is likely a spectrum of disease severity and phenotypes in children affected by MIS-C. However, the majority of children with MIS-C are usually sick enough to require hospitalization and, often, intensive care. Children with MIS-C may initially present with mild symptoms, which can progress quickly. Presenting symptoms usually reflect systemic inflammation and often have similarities to Kawasaki disease (KD), toxic shock syndrome (TSS) and macrophage activation syndrome. Prominent features include:
# When to Consider MIS-C?
There should be a low threshold to consider and evaluate for MIS-C in children who present with unexplained fever for three days or more, even if they are well-appearing on initial presentation and especially within two months following a known COVID-19 infection or exposure. The initial infection with SARS-CoV2 may have been asymptomatic, therefore, MIS-C should still be considered in children without a previous history of infectious symptoms.
# Treatment
The management of MIS-C differs from that of severe acute COVID-19. Severe acute COVID-19 infection remains rare in pediatrics and any suspected cases of COVID-19 should be discussed with specialists at BCCH as this is a separate entity from MIS-C but may require active therapy.
Evidence for the optimal management of MIS-C should be guided by these specialists. The majority of children require early fluid resuscitation. The mainstay of treatment has been early use of intravenous immunoglobulin (IVIg) with or without intravenous steroids. Some children have required immunomodulatory therapy (biologic treatments) for refractory symptoms as guided by a rheumatologist. Low dose aspirin is recommended in children with MIS-C who have features of KD or coronary aneurysms seen on echocardiogram, in consultation with rheumatology. Even with treatment, children with MIS-C require serial monitoring of clinical and laboratory parameters, cardiac imaging and close follow up post-discharge (see disposition section).
# Disposition
All follow up appointments should be made and clearly communicated to families prior to discharge. Discharge documentations should be sent to all relevant specialist involved in the patient's care. The longterm sequalae of MIS-C is still unknown but being studied.
Primary care provider: All patients evaluated for MIS-C should be seen by their primary care provider within one week of discharge, regardless if they were a confirmed case or not. Pediatrics: Children hospitalized with MIS-C should be referred to a pediatrician on discharge for follow up. For those with abnormal inflammatory markers or laboratory findings at discharge, repeat bloodwork should be considered prior to this visit. Cardiology: Confirmed cases of MIS-C will require a repeat echocardiogram, typically four to six weeks after discharge, as guided by cardiology. Rheumatology: Follow up will depend on the severity of illness and discharge medications, as guided by rheumatology.
Haematology: For children who were started on prophylactic/therapeutic anticoagulation in hospital, the dose and duration of therapy should be clearly communicated to the family prior to discharge, if applicable. Follow up will be guided by haematology. Mental health: Families with children who were hospitalized for MIS-C should be offered mental health support in the community as needed. Others: Follow up with other specialties (e.g., neurology, immunology) will depend on their clinical features and course in hospital. Return to emergency department: Families should be counselled on when to bring their child back to the emergency department. Reasons to return include: o Persisting fever > 38 degrees Celsius. o Recurrence of presenting symptoms or child becomes unwell with other symptoms. o New appearance of respiratory distress or shortness of breath.
#
Appendix A: Case Definition for MIS-C
# Confirmed case
Children 0-19 years of age requiring hospitalization with fever for three days or more and two of the following: a) Acute gastrointestinal symptoms (abdominal pain, vomiting, diarrhea); b) Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet); c) Hypotension or shock; d) Features of myocardial dysfunction or pericarditis or valvulitis or coronary abnormalities: ECHO findings or elevated troponin/ brain natriuretic peptide (BNP)/ natriuretic peptide tests (NT-proBNP); e) Evidence of coagulopathy: Abnormal prothrombin time/ partial thromboplastin time (PT/PTT), elevated d-dimer;
# And
Elevated markers of inflammation such as erythrocyte sedimentation rate, C-reactive protein, or procalcitonin;
# And
No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, and no alternative plausible obvious diagnosis;
# And
Evidence of SARS-CoV-2 infection (positive NAAT test, antigen test and/or serology) or close contact 1 with a confirmed or probable (lab-probable or epi-link probable) COVID-19 case. 2
# Appendix B: Full MIS-C Evaluation
To be performed in addition to workup of alternative diagnosis, including sepsis.
• Complete blood count (CBC) with differential.
• Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP).
• Electrolytes, blood urea nitrogen (BUN), creatinine.
• Liver function tests (LFTs), lactate dehydrogenase (LDH), albumin.
• Ferritin, d-dimer, prothrombin time/ partial thromboplastin time (PT/PTT).
• Troponin, brain natriuretic peptide (BNP).
• Urinalysis.
• SARS-CoV-2 testing: o SARS CoV-2 polymerase chain reaction (PCR): Respiratory (nasopharyngeal swab/saline gargle/ sputum/ bronchoalveolar lavage); o SARS CoV2 antigen o SARS CoV-2 serology: Contact local medical microbiology on call for approval and fill out serology request form. Obtain serology pre-IVIG whenever possible. • Type and Screen (for those receiving IVIG).
• Electrocardiogram (EKG).
• Chest X-ray (CXR).
• Echocardiogram.
• Consider all usual bacterial or viral illnesses and alternative diagnoses and test as appropriate (e.g., cultures, other infectious studies).
For further clinical guidance on COVID-19 in children, see Clinical Reference Group Recommendation: Pediatric Clinical Guidance for COVID-19.
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6bf283e3cb7a4966f731d4eac00c5c750751f941
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Sudden cardiac death (SCD), especially in a young seemingly healthy individual, is a tragic and highly publicized event, which is often followed by a strong emotional reaction from the public and medical community." Although rare, SCD in the young is devastating to families and communities, underpinning our society's desire to avoid anyLa mort subite d'origine cardiaque (MSOC), en particulier chez une personne jeune et qui semblait être en bonne sant e, est un ev enement tragique et hautement m ediatis e qui engendre souvent de la part du public ou du milieu m edical un « appel à l'action ». La MSOC chez les jeunes, si elle est rare, n'en a pas moins des cons equences The Canadian Cardiovascular Society (CCS) Guidelines Committee identified the need for a Position Statement addressing cardiovascular (CV) screening of competitive athletes with particular attention to the 12-lead electrocardiogram (ECG). Currently, European and American recommendations exist, however the lack of a national position has led to tremendous variation of practice in Canada. 1 This statement provides appropriate, evidence-based recommendations for Canadian sporting organizations and institutions with a focus on the role of routine ECG screening in preventing sudden cardiac death (SCD).The CCS Guidelines Committee appointed co-chairs, and a primary and secondary panel to develop this document. The primary panel established its scope, identified topics, reviewed literature, prepared and voted on the recommendations on the#
basis of the Grading of Recommendations Assessment, Development and Evaluation system. In this system, the panel must consider not only the quality of the scientific evidence but also values, preferences, and practicality in forming recommendations. These factors included the current Canadian health care model, good clinical practice, cost, infrastructure, and the feasibility of screening components. The secondary panel peer-reviewed the manuscript; the final document was submitted to the CCS Council for approval.
The competitive athlete is defined as "one who participates in an organized team or individual sport; is engaged in regular, systematic, and often intense training with high CV demands; participates in competition against others; and places a premium on excellence and achievement." 2 The distinction between competitive and recreational athletes often lies in the ability and freedom afforded by the participant to judge when it is prudent to reduce or stop exertion. 3,4 Competitive athletes may also be defined as those engaged in training and competition on a regular basis; 10 hours weekly. 5 We acknowledge that our scope neglects younger, less competitive, or older athletes who collectively represent a population in which a much larger number of CV events can occur. 6 "Red flags" refer to a symptom, sign, history, or abnormality for which further investigation is strongly recommended by existing contemporary guidelines. In this statement, we refer to and contextualize the utility of these tools rather than list each possible "red flag." Potential or emerging bedside screening tools (ie, ultrasound and molecular diagnostics) were not considered in the present scope. CV screening is usually undertaken specifically to assess the risk of SCD during or related to sport. The reported incidence of SCD in athletes varies greatly according to age, geography, level of competition, method of case ascertainment (numerator), and the defined number of athletes at risk (the denominator). In one region of Canada (Toronto, Ontario), the risk of death during competitive sport in a sample aged 12-45 years, derived from 5 years of Emergency Medical System registry data, was 0.76 cases per 100,000 athlete-years 7 which is consistent with the estimate from a meta-analysis of a diverse population and geography (0.72 cases per 100,000). 7,8 "CV screening" is used throughout this document in place of "preparticipation screening" (PPS) because most Canadian collegiate and other competitive athletes have typically been previously participating in high volume/intensity training and competition. Screening in this context is defined as a systematic evaluation of all participants in a defined subset of athletes; it is differentiated from "case finding"; the appropriate investigation of a disease serendipitously identified by other means (eg, as part of routine clinical care). Recommendations were formed after consideration of: (1) frequency and nature of the disease identified; (2) "lives expected to be saved" as a result of screening; and (3) risks associated with false-positive testing. In addition to these factors, recommendations reflect sensitivity to resource limitations and a nonpaternalistic approach. Finally, it is critical to note that these recommendations occur in context of a universal health care system (Canada Health Act, 1984). Most athletes (and nonathletes) have had medical contact or "well-checks" within a system underpinned by family physicians or primary care providers before, during, and after entering competition.
circumstances predisposing to the loss of human life during exertion. The Canadian Cardiovascular Society Position Statement on the cardiovascular screening of athletes provides evidence-based recommendations for Canadian sporting organizations and institutions with a focus on the role of routine electrocardiogram (ECG) screening in preventing SCD. We recommend that the cardiac screening and care of athletes within the Canadian health care model comprise a sequential (tiered) approach to the identification of cardiac risk, emphasizing the limitations of screening, the importance of shared decision-making when cardiac conditions are diagnosed, and the creation of policies and procedures for the management of emergencies in sport settings. Thus, we recommend against the routine (first-line or blanket mass performance of ECG) performance of a 12-lead ECG for the initial cardiovascular screening of competitive athletes. Organization/athletecentred cardiovascular screening and care of athletes program is recommended. Such screening should occur in the context of a consistent, systematic approach to cardiovascular screening and care that provides: assessment, appropriate investigations, interpretation, management, counselling, and follow-up. The recommendations presented comprise a tiered framework that allows institutions some choice as to program creation. evaluation, examens appropri es, interpr etation, prise en charge, counseling et suivi. Les recommandations pr esent ees incluent un cadre à plusieurs paliers qui donne aux institutions une certaine latitude pour l' elaboration du programme.
# Elements of CV Screening
The history and physical examination PPS, with a standardized questionnaire, a medical history, and physical examination has been recommended in all major guidelines. However, high quality, outcomes-based evidence supporting the use of mass PPS with history and physical examination is limited. Presently within Canada, there is no widely accepted systematic screening process to identify athletes at risk. A PPS medical questionnaire may be administered by an athlete's organization. Questionnaires are ideally standardized, performed and interpreted by a physician, or other qualified health professional with relevant expertise. Preferably, questionnaires are followed by a physical examination, permitting an opportunity to review responses of concern. The diagnostic yield of a questionnaire or medical history used for mass CV screening of athletes is poor. 12,13 Several prospective, observational studies have compared the results of a medical history and physical examination. A meta-analysis of 15 studies reported a pooled sensitivity of 20% for history and 9% for physical examination in identifying disease 13 and subsequent studies have reported similar results. However, these studies did not have a "gold standard" comparator, because denominators were created from total positive screening results. 13 Therefore, false-negative rates and negative predictive values cannot be accurately assessed, supporting the view that such approaches should be considered poor for identifying disease but might assist in identifying athletes at risk of a CV event. It has been reported that 72% of SCD victims were described by their parents to have at least 1 CV symptom before SCD 17 in contrast to a larger autopsy study in which most of the athletes were deemed asymptomatic. 18 Several studies have included athletes who screened "positive" for conditions associated with no additional risk of SCD (ie, isolated bicuspid aortic valve) and were subsequently cleared for participation. 15,19,20 The reported low sensitivity of history/questionnaire is not surprising because 70%-80% of SCD occurs as the first manifestation of an underlying cardiac disease. 18,21,22 Furthermore, although an important small percentage of the causes of SCD in young athletes are heritable, a positive family history is reported in some cases (8%-40%). 17,18 Thus, the low positive predictive value of history and physical examination in 47,137 athletes (a total of 160 potentially lethal CV conditions detectable using ECG; a rate of 0.3%), means that a positive result translates to only a small increase in the likelihood of disease. 13 Nonspecific symptoms, such as fatigue might be common; however, the diagnostic utility of this symptom, although uncertain, 16 might not be trivial because fatigue (44%) and nearsyncope/light-headedness (30%) have been reported to be the 2 most common symptoms before sudden cardiac arrest (SCA). 17 An athlete's interpretation of what entails a positive response to personal and family history on medical questionnaires is variable. High rates of "positive" responses (up to 68%) have been reported to occur, before review by a physician or health care professional. 15,23 The high falsepositive rate, low level of sensitivity, and the presence of nonspecific symptoms, in populations at varying risk, combine to limit the diagnostic accuracy of questionnaires.
Further compromising diagnostic accuracy is the marked variability of the guideline-recommended questionnaires used by institutions. An analysis of the questionnaires used by U-SPORTS institutions in Canada revealed that only 10% strictly follow guideline-endorsed questions and less than half (43%) contain at least 75% of the recommended items. 1 The 12-lead ECG International guidelines differ in their recommendations addressing ECG screening of competitive athletes. 24 The resting 12-lead ECG is superior to the history and physical examination in the detection of disease associated with SCD. 13 Factors considered in recommending ECGs are: (1) detection of subclinical asymptomatic electrophysiological disease such as Wolff-Parkinson-White, some channelopathies, and occult cardiomyopathies such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (ARVC) 24 ; (2) the fact that most athletes who succumb to SCD are asymptomatic; and (3) the low percentage of deaths that are readily identifiable using physical examination. 13,18 The utility of an ECG to improve detection is influenced by the underlying prevalence of disease predisposing to SCD specifically during sport (which is very challenging to determine), the sensitivity of the ECG in young athletes, and the experience of its reader. Indeed, the ECG as a tool is not without limitations, including: (1) low positive likelihood to predict SCD; (2) high costs of secondary evaluations required to evaluate an "abnormal" ECG; (3) variability of accurate athlete-specific ECG interpretation; (4) logistics of implementing screening programs; and (5) false reassurance of a normal ECG in athletes with disease. Continued study of what is "normal" for an athlete, and refinement of ECG interpretation criteria for young athletes, has led to a marked decrease in the number of false-positive results from 21.8% with the 2010 European Society of Cardiology criteria to 3% 25,26 with the 2017 international recommendations. 27 Whether ECG-inclusive PPS significantly reduces SCD in competitive athletes remains uncertain. However, it is clear that the risk of SCD during sport is low. 8 To date, only the Italian ECG-inclusive PPS experience in Veneto, Italy (where there is a pronounced increase in the prevalence of ARVC) has suggested a reduction in the incidence of death after introducing mandatory ECG screening. 28 The low incidence of SCD in athletes, and the major limitations of historical controls as a standard for assessing effectiveness of screening, are cited as reasons against including ECG as part of PPS; as is the small absolute reduction in SCD that might be gained by consequent restriction of sport. On the basis of the Italian data, an argument has been made that the restriction of activity might reduce disease progression and death; however, most presumed cardiac deaths in young participants occur during sleep or at rest. 18,29,30 One might argue that PPS might lead to a diagnosis of heart disease, and the provision of advice regarding vigorous physical activity that might reduce the future risk of SCD. Nevertheless, there is a paucity of evidence that such an approach will protect an individual from cardiac events.
Because of the weak evidence for the benefit of ECG screening to reduce SCD weighed against potential harms including inappropriate restriction, psychologic and career impact, the potential for unnecessary testing, and real-world limitations in resources depending on the environment of the organization, we have recommended an institution-centred or regionalized approach to CV screening of athletes. In the "tiered" approach, we define minimal requirements before beginning a screening program, and then describe which components of screening should be considered next in a stepwise or incremental fashion. The ordering of the tiers is not only on the basis of the test characteristics of each action; in other words, the Panel does not believe that the history and physical examination are superior to ECG as components of screening, but because they are part of good clinical practice, and achievable, should be performed before contemplation of adding ECG testing to screening. This expert-derived consensus upon the ordering of tiers considers the Canadian health care model, where virtually all athletes have had some contact with primary care networks before collegiate-level sports participation. The tiered approach allows institutions some choice as to how to build up to a cardiovascular screening and care of athletes program (CSCAP), which could include qualified ECG performance, on the basis of their environment and resources. The tiers in this approach are ordered on the basis of the recommendation intensity, which considers not only evidence, but also achievability, values, and good clinical practices. The starting foundational component related to automated external defibrillator (AED) and emergency protocol has the greatest recommendation intensity, and ECG for routine screening has the lowest recommendation intensity (visually depicted in Fig. 1).
In summary, the history and physical examination components are a reasonable initial aspect of screening in a stepwise program or incremental approach (tier 1 and 2). Abnormal findings on history and physical exam require further investigation, such as with ECG (tier 3) to ascertain diagnosis as per standard of care. Standard follow-up investigations of abnormal history, physical examination, and ECG findings are well described. Certain initial abnormal ECG findings require further cardiac evaluation (Table 1). Interdisciplinary collaboration to appropriately guide followup investigations becomes important to prevent falsepositive interpretations, unnecessary investigations, and inappropriate sport restriction. Abnormal screening findings Figure 1. Cardiovascular screening and care of the athlete program (CSCAP): the tiered approach. The illustration suggests an evidence-based approach encouraging organizations to direct resources to ensure a stepwise approach to the performance of processes and resource utilization. This program operates within a broader health care model supported by family physicians and primary care providers. Each organization should consider linking to other centres to allow a national approach to gathering and enhancing the quality of evidence as part of a proposed network. It is critical to note that the ordering of tiers is not on the basis of test characteristics alone (sensitivity for detecting sudden cardiac death). It is recognized that tier 1 and 2 have poorer test characteristics for detecting sudden cardiac death compared with electrocardiogram (ECG; tier 3) but represent good clinical practice and reflect achievability as defined by expert consensus. AED, automated external defibrillator; CPR, cardiopulmonary resuscitation.
require a shared decision-making (SDM) approach to guide next steps.
# SDM
"Red flags" or abnormalities during the screening process necessitate an SDM approach toward further management. This process of deliberation and exchange between clinicians and patients ensures decisions are informed by the best available evidence. 27 SDM is highly appropriate for the CV care of athletes because it acknowledges the uncertainties surrounding screening, diagnosis, and the risk of CV events during sport. SDM involves ensuring that all involved become fully informed of: (1) degree of uncertainty surrounding the association of a particular diagnosis and actual SCD risk; (2) harms and benefits of the diagnostic cascade and intervention (restriction of competition); and (3) alternative approaches, if any, to management. 31 Practically, SDM should consist of 3 steps: (1) choice awareness; (2) an options dialogue; and (3) a decision discussion 27 (Fig. 2).
# Choice awareness
Athletes, physicians, and sport organizations should understand the limitations and implications of a CV screening program and the need for careful, informed interpretation of 'abnormal' findings potentially suggestive of CV disease. Athletes should be provided a choice to participate in screening and provide informed consent. There are understandable expectations that a sport organization will act to safeguard the health and well-being of participants and other competitors, and show specific self-interest in seeking to reduce the possibility of tragic deaths in their programs. Thus, it is RECOMMENDATION 1. We recommend an incremental (tiered) approach to CV screening of competitive athletes as part of a broad, organization/athlete-centred CSCAP. Such screening should occur in the context of a consistent, systematic approach to CV screening and care that provides assessment, appropriate investigations, interpretation, management, counselling, follow-up.
Strong Recommendation, Low-Quality Evidence 2. We recommend that a history/questionnaire should constitute the initial CV screening (tier 1), provided it is: i. Standardized according to at least 1 of the American Heart Association, European Society of Cardiology, fourth-edition Preparticipation Physical Evaluation, or SportsCardiologyBC tools or equivalent; ii. Accurately interpreted by an appropriately qualified professional experienced in the care of athletes; and iii. Is followed with appropriate investigations as "clinically warranted." "Clinically warranted" findings are those deemed by the interpreter as requiring further assessment, for example using: physical examination; investigations such as ECG testing, imaging, or stress testing; and/or consultation with a specialist.
Strong Recommendation, Low-Quality Evidence 3. We recommend that a physical examination should be considered as an adjunct component of CV screening of competitive athletes (tier 2) provided it is: i. Performed by an appropriately qualified professional involved in the care of athletes; and ii. Followed-up as clinically warranted.
Strong Recommendation, Low-Quality Evidence 4. We recommend against the "routine" performance of a 12-lead ECG for the initial CV screening of competitive athletes. "Routine" in this context is defined as "first-line" or blanket mass performance of ECG not occurring in context of an integrated program as described in Recommendation 5.
Strong Recommendation, Low-Quality Evidence 5. We recommend that a 12-lead ECG should be performed for screening of competitive athletes only when indicated according to history/questionnaire and/or physical examination (targeted screening, tier 3) and provided it is: i. Of "adequate" quality. In this context "adequate" is defined as technically sufficient and of the highest possible quality; ii. Interpreted by those with "appropriate expertise"
("appropriate expertise" is defined as training and skills in ECG interpretation specific to athletes and persons with disorders associated with arrhythmias) and with consideration of sport history, sex, ethnicity, age, family history, relevant clinical findings, "regional" ("regional" refers to geographic areas with a relatively high incidence of certain relevant cardiac conditions) occurrence of disease; and iii. Accompanied by appropriate investigations and expert referral if clinically warranted.
# Strong Recommendation, Low-Quality Evidence
Values and preferences. We disclose that there was an important disagreement between the primary writing panel (composed of Canadian experts) and the secondary international review panel (composed of American and European experts) with respect to Recommendations 4 and 5. The international experts on the secondary panel emphasize that SCD in athletes occurs in the absence of warning symptoms. Performance of targeted screening will miss these occurrences. In rebuttal, the primary panel clarified our position that these recommendations do not prohibit organizations from performing ECG screening, but suggest a tiered approach that can be tailored to regional needs, resources, and values. The benefit of mass ECG screening to prevent SCD in asymptomatic athletes is challenging to assess. As further detailed, our current position is that any ECG performance, whether it is targeted or not, occur in context of an expert-led, integrated program to ensure accuracy, minimization of false-positive results, prioritization of safety protocols in the case of SCA, and follow-up of abnormal findings.
recognized that a sports organization might wish to restrict certain athletes from training and competing, for example, if they do not participate in a screening process (Fig. 2).
# Options dialogue
The second stage in the SDM approach is to convey the meaning of positive findings on the questionnaire/history, physical examination, or ECG. Conveying the concept of false-positive results and their rate allows the athlete to make an informed decision. If disease is identified, consideration of the specific disorder, and the probability of SCD or disease progression as a consequence of continued athletic activity, should be weighed against the risks associated with a more sedentary or restricted lifestyle. The SDM process might require more than 1 clinical contact and involve discussions pertaining to further diagnostic testing, and the potential benefits or harms during the options dialogue (Fig. 2). For athletes with CV findings, further dialogue, with other experts might be appropriate. Patient athletes or relatives are supported to explore "what matters most to them," so that they can participate in the selection of the best course of action. 35
# The decision discussion and participation restriction
There is a lack of data to suggest that restricting athletes from sport results in a reduction of SCD from most of the predisposing conditions that can be identified, except for ARVC, when genotypic or phenotypic ARVC has been diagnosed as per established criteria. 36 Furthermore, there is a marked disparity between the prevalence of disease and the incidence of SCD; most athletes with underlying CV disease will never experience SCD during exercise. 7,18,29 Conversely, SCD might occur in the absence of abnormal findings during screening and most cases do not occur during vigorous exercise. 18,29,30 Although it is believed that vigorous exercise is a potential trigger for SCD, an examination of deaths of young persons in the United Kingdom and Australia/New Zealand showed that most deaths occurred at rest 18,29,30 ; which brings into question the efficacy of restriction. Even among high-risk athletes with implantable cardioverter-defibrillators who continued to participate in sport, registry data showed no tachyarrhythmic deaths nor externally resuscitated tachyarrhythmia during or after sport. 4 Athletes in this population experienced appropriate implantable cardioverter-defibrillator shocks (for ventricular tachycardia/fibrillation) during competition or practice at a rate of 3 per 100 person-years but this should clearly be individualized. 37,38 Offsetting a possible benefit of reducing SCD by restricting an athlete is the potential harm of denying a young person the benefits of physical activity such as: improved physical and psychological well-being, and decreased depression, obesity, and illicit drug use, 39 as well as implications for scholarship and career opportunities. It is recognized that there are situations (such as a high-risk case of hypertrophic cardiomyopathy 40 ) in which there is a higher risk of SCD with competition and the physician might strongly advise against participation. It is also recognized that some individuals might decide not to follow such advice and attempt to continue to participate irrespective of the personal risk communicated to them. 41,42 In this setting, an array of legal, financial, and ethical issues might emerge as a consequence of a physician's advice to restrict further opportunity for sport participation. 43
# Secondary Prevention of SCD and CV Emergencies
# Basic requirements
Sport organizations must recognize the need to ensure that appropriate approaches and equipment are available to address emergencies involving spectators, officials, staff, and competitors. Training in cardiopulmonary resuscitation (CPR), the availability of AEDs in key activity (competition and training) spaces, and the creation of emergency management protocols should be standard. 47,48 These are the bedrock of a CSCAP; Fig. 1).
# AEDs
Increased public awareness and advocacy has led to a wide availability of AEDs in public and private sporting venues. They provide a means of early defibrillation not only for athletes, but for spectators and other attendees in the rare event of SCD. 46,47,49,50 Recent data 51 suggest that AED use has improved the SCA resuscitation success rates among athletes, thereby conferring a survival benefit. Limited data from the United States National Registry for AED use in sports suggests that AEDs in high schools, although more commonly used on nonathlete adults, have yielded a high success rate (to hospital discharge) between 50% and exceeding 85% in young athletes. 7,51 Most college and high schools in the United States do in fact have AEDs in place, 44, yet the provision of AEDs in some settings might be limited by financial resources. 45 European and American authorities recommend AEDs be placed at high school and college sporting venues. 54,55 Regarding older individuals practicing sport, a recent report showed that the presence of on-site AEDs in amateur sports centres was associated with neurologically intact survival after an exercise-related SCA. Indeed, neurologically intact survival rates were 93% in centres with onsite AEDs and 9% in centres without (P < 0.001). 56
# Education of personnel and medical action plans
The regular rehearsal of an effective medical action plan (MAP) is as critical as the provision of AEDs. 51 Key components of an effective MAP include: (1) knowledge of AED location; (2) protocols to alert first responders and AED retrieval; and (3) training of personnel in CPR and AED use. Current American and European guidelines recommend that a time-to-shock using an AED should be < 3 minutes 52 ; each minute of delay reduces SCA survival by 7%-10%. 57 This is particularly important in rural communities, where in the absence of AEDs, the Emergency Medical System-dependent time-to-shock might be prolonged. Training in contemporary approaches to CPR is fundamental. 57 Current American guidelines call for CPR training of all team members, staff, and referees. 58 The Enhanced Environment of a Sports Cardiology Centre
Organizations offering a comprehensive CV screening program in an attempt to identify risk of SCD require an integrated array of resources and personnel. 52,59,60 This writing panel recommended against the routine performance of a 12-lead ECG, meaning that it should not be the sole or first-line screening procedure without adequate good clinical practice in place (history and physical) and without adequate interpretation and follow-up. However, if a given institution/ organization decides to administer a routine 12-lead ECG as part of the screening process towards tier 3 after achieving all previous steps, it must be accompanied by an interpretation by clinicians experienced in the assessment of an athlete's RECOMMENDATION 6. We recommend that after the identification and confirmation of any predisposing condition using screening, the probability of "SCD" ("SCD" in this context includes the probability of SCA; it is recognized that for some conditions it might be very difficult to define such probability) be estimated to facilitate a SDM process regarding sport participation involving the athlete (and parent/guardian if appropriate), caregiver, and sport organization.
Strong Recommendation, Low-Quality Evidence 7. We recommend that sport restriction be considered and discussed in the following conditions: ARVC, exerciseinduced significant ventricular arrhythmias (if arrhythmogenic risk cannot be mitigated), catecholaminergic polymorphic ventricular tachycardia, exercise-induced heart block, hypertrophic cardiomyopathy with sustained ventricular tachycardia or multiple risk factors, dilated cardiomyopathy unrelated to an athlete's heart, left ventricular noncompaction with left ventricular dysfunction and or ventricular arrhythmia, Marfan syndrome with aortic dilatation, significant aortic dilatation, coronary artery aneurysm with ischemia, oral anticoagulation treatment in an athlete competing in sports with a high risk of injury causing bleeding, pulmonary hypertension, and cyanotic congenital heart disease.
Strong Recommendation, Low-Quality Evidence RECOMMENDATION 8. We recommend the creation of specific policies and protocols for the delivery of MAPs specific to cardiac emergencies in all competitive sport settings and as the foundation of a CSCAP.
Strong Recommendation, High-Quality Evidence 9. We recommend that all educational and recreational facilities with athletic or sports programs must have AEDs located to ensure rapid access and initiation of defibrillation in < 3 minutes. These should be placed within close proximity to, if not within, all physical activity spaces used by athletes.
Strong Recommendation, Moderate-Quality Evidence 10. We recommend that because athletes, team staff, and referees are mostly likely to initially witness and attend a collapsed athlete, that at a minimum, team staff and referees be trained in CPR and be familiar with the use of AEDs, rehearse the MAP at their own facility, and be familiar with MAPs at other sporting facilities.
Despite the low incidence of SCD in athletes, it is recommended that SCA be considered the likely cause of an athlete's nontraumatic collapse during sport.
Strong Recommendation, Moderate-Quality Evidence ECG. 13, The limitations of such programs must be appreciated. 19, The capacity to provide expeditious access to further cardiac investigations must be in place. 52 In the Canadian context, this will typically involve the participation of an experienced sports medicine physician and a clearly identified cardiologist. 52,60 It is important to ensure that oversight of screening programs is assumed by trained physicians and specialists (which includes available general cardiologists). The development of sport cardiology centres (or centres of excellence) in certain regional settings will greatly assist those with limited access to specialty services. 59 Such networks might also facilitate research into the utility of emerging bedside screening tools and consensus-building related to defining "red flags" and sport participation.
# Limitations
With consideration of the assigned scope of this position statement, the writing committee was not able to comprehensively evaluate important topic areas related to CV screening in Canadian athletes. Further discussion of these topics is of paramount importance and will be eventually presented in a series of companion articles contextualized by this position statement by the CCS Sport Group. These topic areas currently in development include: prevalence of disease related to SCD in Canadian athletes, the role of imaging and point of care ultrasound in CV screening, and medico-legal aspects and the participation decision. The CCS group is proposing the creation of a network of centres of excellence to study these topic areas further because of the paucity of Canadian data. The cardiovascular screening and care of athletes program infers a shared decision-making approach to contextualize the screening process, understand options during recommended investigations and treatment, and ensures an informed discussion when deciding between continued participation or restriction (Recommendations 5-9). The "tiered approach" to screening is described in the text, by Recommendations 1-4, and further summarized in Figure 1
# Summary
The hallmarks of a high-quality approach to the initial cardiac screening and care of athletes within the Canadian health care model comprises a sequential (tiered) approach to the identification of cardiac risk, an appreciation of the limitations of screening, the importance of SDM when cardiac conditions are diagnosed, and the creation of policies and procedures for the management of emergencies in sport settings. The recommendations presented in this position statement comprise a tiered framework that allows institutions some choice as to program creation. The creation of a network of such regions of excellence, with the goal of further implementation, research, and standardization will enhance the safety of our athletes.
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Sudden cardiac death (SCD), especially in a young seemingly healthy individual, is a tragic and highly publicized event, which is often followed by a strong emotional reaction from the public and medical community." Although rare, SCD in the young is devastating to families and communities, underpinning our society's desire to avoid anyLa mort subite d'origine cardiaque (MSOC), en particulier chez une personne jeune et qui semblait être en bonne sant e, est un ev enement tragique et hautement m ediatis e qui engendre souvent de la part du public ou du milieu m edical un « appel à l'action ». La MSOC chez les jeunes, si elle est rare, n'en a pas moins des cons equences The Canadian Cardiovascular Society (CCS) Guidelines Committee identified the need for a Position Statement addressing cardiovascular (CV) screening of competitive athletes with particular attention to the 12-lead electrocardiogram (ECG). Currently, European and American recommendations exist, however the lack of a national position has led to tremendous variation of practice in Canada. 1 This statement provides appropriate, evidence-based recommendations for Canadian sporting organizations and institutions with a focus on the role of routine ECG screening in preventing sudden cardiac death (SCD).The CCS Guidelines Committee appointed co-chairs, and a primary and secondary panel to develop this document. The primary panel established its scope, identified topics, reviewed literature, prepared and voted on the recommendations on the#
basis of the Grading of Recommendations Assessment, Development and Evaluation system. In this system, the panel must consider not only the quality of the scientific evidence but also values, preferences, and practicality in forming recommendations. These factors included the current Canadian health care model, good clinical practice, cost, infrastructure, and the feasibility of screening components. The secondary panel peer-reviewed the manuscript; the final document was submitted to the CCS Council for approval.
The competitive athlete is defined as "one who participates in an organized team or individual sport; is engaged in regular, systematic, and often intense training with high CV demands; participates in competition against others; and places a premium on excellence and achievement." 2 The distinction between competitive and recreational athletes often lies in the ability and freedom afforded by the participant to judge when it is prudent to reduce or stop exertion. 3,4 Competitive athletes may also be defined as those engaged in training and competition on a regular basis; 10 hours weekly. 5 We acknowledge that our scope neglects younger, less competitive, or older athletes who collectively represent a population in which a much larger number of CV events can occur. 6 "Red flags" refer to a symptom, sign, history, or abnormality for which further investigation is strongly recommended by existing contemporary guidelines. In this statement, we refer to and contextualize the utility of these tools rather than list each possible "red flag." Potential or emerging bedside screening tools (ie, ultrasound and molecular diagnostics) were not considered in the present scope. CV screening is usually undertaken specifically to assess the risk of SCD during or related to sport. The reported incidence of SCD in athletes varies greatly according to age, geography, level of competition, method of case ascertainment (numerator), and the defined number of athletes at risk (the denominator). In one region of Canada (Toronto, Ontario), the risk of death during competitive sport in a sample aged 12-45 years, derived from 5 years of Emergency Medical System registry data, was 0.76 cases per 100,000 athlete-years 7 which is consistent with the estimate from a meta-analysis of a diverse population and geography (0.72 cases per 100,000). 7,8 "CV screening" is used throughout this document in place of "preparticipation screening" (PPS) because most Canadian collegiate and other competitive athletes have typically been previously participating in high volume/intensity training and competition. Screening in this context is defined as a systematic evaluation of all participants in a defined subset of athletes; it is differentiated from "case finding"; the appropriate investigation of a disease serendipitously identified by other means (eg, as part of routine clinical care). Recommendations were formed after consideration of: (1) frequency and nature of the disease identified; (2) "lives expected to be saved" as a result of screening; and (3) risks associated with false-positive testing. In addition to these factors, recommendations reflect sensitivity to resource limitations and a nonpaternalistic approach. Finally, it is critical to note that these recommendations occur in context of a universal health care system (Canada Health Act, 1984). Most athletes (and nonathletes) have had medical contact or "well-checks" within a system underpinned by family physicians or primary care providers before, during, and after entering competition.
circumstances predisposing to the loss of human life during exertion. The Canadian Cardiovascular Society Position Statement on the cardiovascular screening of athletes provides evidence-based recommendations for Canadian sporting organizations and institutions with a focus on the role of routine electrocardiogram (ECG) screening in preventing SCD. We recommend that the cardiac screening and care of athletes within the Canadian health care model comprise a sequential (tiered) approach to the identification of cardiac risk, emphasizing the limitations of screening, the importance of shared decision-making when cardiac conditions are diagnosed, and the creation of policies and procedures for the management of emergencies in sport settings. Thus, we recommend against the routine (first-line or blanket mass performance of ECG) performance of a 12-lead ECG for the initial cardiovascular screening of competitive athletes. Organization/athletecentred cardiovascular screening and care of athletes program is recommended. Such screening should occur in the context of a consistent, systematic approach to cardiovascular screening and care that provides: assessment, appropriate investigations, interpretation, management, counselling, and follow-up. The recommendations presented comprise a tiered framework that allows institutions some choice as to program creation. evaluation, examens appropri es, interpr etation, prise en charge, counseling et suivi. Les recommandations pr esent ees incluent un cadre à plusieurs paliers qui donne aux institutions une certaine latitude pour l' elaboration du programme.
# Elements of CV Screening
The history and physical examination PPS, with a standardized questionnaire, a medical history, and physical examination has been recommended in all major guidelines. [9][10][11] However, high quality, outcomes-based evidence supporting the use of mass PPS with history and physical examination is limited. Presently within Canada, there is no widely accepted systematic screening process to identify athletes at risk. A PPS medical questionnaire may be administered by an athlete's organization. Questionnaires are ideally standardized, performed and interpreted by a physician, or other qualified health professional with relevant expertise. Preferably, questionnaires are followed by a physical examination, permitting an opportunity to review responses of concern. The diagnostic yield of a questionnaire or medical history used for mass CV screening of athletes is poor. 12,13 Several prospective, observational studies have compared the results of a medical history and physical examination. [13][14][15] A meta-analysis of 15 studies reported a pooled sensitivity of 20% for history and 9% for physical examination in identifying disease 13 and subsequent studies have reported similar results. [14][15][16] However, these studies did not have a "gold standard" comparator, because denominators were created from total positive screening results. 13 Therefore, false-negative rates and negative predictive values cannot be accurately assessed, supporting the view that such approaches should be considered poor for identifying disease but might assist in identifying athletes at risk of a CV event. It has been reported that 72% of SCD victims were described by their parents to have at least 1 CV symptom before SCD 17 in contrast to a larger autopsy study in which most of the athletes were deemed asymptomatic. 18 Several studies have included athletes who screened "positive" for conditions associated with no additional risk of SCD (ie, isolated bicuspid aortic valve) and were subsequently cleared for participation. 15,19,20 The reported low sensitivity of history/questionnaire is not surprising because 70%-80% of SCD occurs as the first manifestation of an underlying cardiac disease. 18,21,22 Furthermore, although an important small percentage of the causes of SCD in young athletes are heritable, a positive family history is reported in some cases (8%-40%). 17,18 Thus, the low positive predictive value of history and physical examination in 47,137 athletes (a total of 160 potentially lethal CV conditions detectable using ECG; a rate of 0.3%), means that a positive result translates to only a small increase in the likelihood of disease. 13 Nonspecific symptoms, such as fatigue might be common; however, the diagnostic utility of this symptom, although uncertain, 16 might not be trivial because fatigue (44%) and nearsyncope/light-headedness (30%) have been reported to be the 2 most common symptoms before sudden cardiac arrest (SCA). 17 An athlete's interpretation of what entails a positive response to personal and family history on medical questionnaires is variable. High rates of "positive" responses (up to 68%) have been reported to occur, before review by a physician or health care professional. 15,23 The high falsepositive rate, low level of sensitivity, and the presence of nonspecific symptoms, in populations at varying risk, combine to limit the diagnostic accuracy of questionnaires.
Further compromising diagnostic accuracy is the marked variability of the guideline-recommended questionnaires used by institutions. An analysis of the questionnaires used by U-SPORTS institutions in Canada revealed that only 10% strictly follow guideline-endorsed questions and less than half (43%) contain at least 75% of the recommended items. 1 The 12-lead ECG International guidelines differ in their recommendations addressing ECG screening of competitive athletes. 24 The resting 12-lead ECG is superior to the history and physical examination in the detection of disease associated with SCD. 13 Factors considered in recommending ECGs are: (1) detection of subclinical asymptomatic electrophysiological disease such as Wolff-Parkinson-White, some channelopathies, and occult cardiomyopathies such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (ARVC) 24 ; (2) the fact that most athletes who succumb to SCD are asymptomatic; and (3) the low percentage of deaths that are readily identifiable using physical examination. 13,18 The utility of an ECG to improve detection is influenced by the underlying prevalence of disease predisposing to SCD specifically during sport (which is very challenging to determine), the sensitivity of the ECG in young athletes, and the experience of its reader. Indeed, the ECG as a tool is not without limitations, including: (1) low positive likelihood to predict SCD; (2) high costs of secondary evaluations required to evaluate an "abnormal" ECG; (3) variability of accurate athlete-specific ECG interpretation; (4) logistics of implementing screening programs; and (5) false reassurance of a normal ECG in athletes with disease. Continued study of what is "normal" for an athlete, and refinement of ECG interpretation criteria for young athletes, has led to a marked decrease in the number of false-positive results from 21.8% with the 2010 European Society of Cardiology criteria to 3% 25,26 with the 2017 international recommendations. 27 Whether ECG-inclusive PPS significantly reduces SCD in competitive athletes remains uncertain. However, it is clear that the risk of SCD during sport is low. 8 To date, only the Italian ECG-inclusive PPS experience in Veneto, Italy (where there is a pronounced increase in the prevalence of ARVC) has suggested a reduction in the incidence of death after introducing mandatory ECG screening. 28 The low incidence of SCD in athletes, and the major limitations of historical controls as a standard for assessing effectiveness of screening, are cited as reasons against including ECG as part of PPS; as is the small absolute reduction in SCD that might be gained by consequent restriction of sport. On the basis of the Italian data, an argument has been made that the restriction of activity might reduce disease progression and death; however, most presumed cardiac deaths in young participants occur during sleep or at rest. 18,29,30 One might argue that PPS might lead to a diagnosis of heart disease, and the provision of advice regarding vigorous physical activity that might reduce the future risk of SCD. Nevertheless, there is a paucity of evidence that such an approach will protect an individual from cardiac events.
Because of the weak evidence for the benefit of ECG screening to reduce SCD weighed against potential harms including inappropriate restriction, psychologic and career impact, the potential for unnecessary testing, and real-world limitations in resources depending on the environment of the organization, we have recommended an institution-centred or regionalized approach to CV screening of athletes. In the "tiered" approach, we define minimal requirements before beginning a screening program, and then describe which components of screening should be considered next in a stepwise or incremental fashion. The ordering of the tiers is not only on the basis of the test characteristics of each action; in other words, the Panel does not believe that the history and physical examination are superior to ECG as components of screening, but because they are part of good clinical practice, and achievable, should be performed before contemplation of adding ECG testing to screening. This expert-derived consensus upon the ordering of tiers considers the Canadian health care model, where virtually all athletes have had some contact with primary care networks before collegiate-level sports participation. The tiered approach allows institutions some choice as to how to build up to a cardiovascular screening and care of athletes program (CSCAP), which could include qualified ECG performance, on the basis of their environment and resources. The tiers in this approach are ordered on the basis of the recommendation intensity, which considers not only evidence, but also achievability, values, and good clinical practices. The starting foundational component related to automated external defibrillator (AED) and emergency protocol has the greatest recommendation intensity, and ECG for routine screening has the lowest recommendation intensity (visually depicted in Fig. 1).
In summary, the history and physical examination components are a reasonable initial aspect of screening in a stepwise program or incremental approach (tier 1 and 2). Abnormal findings on history and physical exam require further investigation, such as with ECG (tier 3) to ascertain diagnosis as per standard of care. Standard follow-up investigations of abnormal history, physical examination, and ECG findings are well described. Certain initial abnormal ECG findings require further cardiac evaluation (Table 1). Interdisciplinary collaboration to appropriately guide followup investigations becomes important to prevent falsepositive interpretations, unnecessary investigations, and inappropriate sport restriction. Abnormal screening findings Figure 1. Cardiovascular screening and care of the athlete program (CSCAP): the tiered approach. The illustration suggests an evidence-based approach encouraging organizations to direct resources to ensure a stepwise approach to the performance of processes and resource utilization. This program operates within a broader health care model supported by family physicians and primary care providers. Each organization should consider linking to other centres to allow a national approach to gathering and enhancing the quality of evidence as part of a proposed network. It is critical to note that the ordering of tiers is not on the basis of test characteristics alone (sensitivity for detecting sudden cardiac death). It is recognized that tier 1 and 2 have poorer test characteristics for detecting sudden cardiac death compared with electrocardiogram (ECG; tier 3) but represent good clinical practice and reflect achievability as defined by expert consensus. AED, automated external defibrillator; CPR, cardiopulmonary resuscitation.
require a shared decision-making (SDM) approach to guide next steps.
# SDM
"Red flags" or abnormalities during the screening process necessitate an SDM approach toward further management. This process of deliberation and exchange between clinicians and patients ensures decisions are informed by the best available evidence. 27 SDM is highly appropriate for the CV care of athletes because it acknowledges the uncertainties surrounding screening, diagnosis, and the risk of CV events during sport. SDM involves ensuring that all involved become fully informed of: (1) degree of uncertainty surrounding the association of a particular diagnosis and actual SCD risk; (2) harms and benefits of the diagnostic cascade and intervention (restriction of competition); and (3) alternative approaches, if any, to management. 31 Practically, SDM should consist of 3 steps: (1) choice awareness; (2) an options dialogue; and (3) a decision discussion 27 (Fig. 2).
# Choice awareness
Athletes, physicians, and sport organizations should understand the limitations and implications of a CV screening program and the need for careful, informed interpretation of 'abnormal' findings potentially suggestive of CV disease. [32][33][34] Athletes should be provided a choice to participate in screening and provide informed consent. There are understandable expectations that a sport organization will act to safeguard the health and well-being of participants and other competitors, and show specific self-interest in seeking to reduce the possibility of tragic deaths in their programs. Thus, it is RECOMMENDATION 1. We recommend an incremental (tiered) approach to CV screening of competitive athletes as part of a broad, organization/athlete-centred CSCAP. Such screening should occur in the context of a consistent, systematic approach to CV screening and care that provides assessment, appropriate investigations, interpretation, management, counselling, follow-up.
Strong Recommendation, Low-Quality Evidence 2. We recommend that a history/questionnaire should constitute the initial CV screening (tier 1), provided it is: i. Standardized according to at least 1 of the American Heart Association, European Society of Cardiology, fourth-edition Preparticipation Physical Evaluation, or SportsCardiologyBC tools or equivalent; ii. Accurately interpreted by an appropriately qualified professional experienced in the care of athletes; and iii. Is followed with appropriate investigations as "clinically warranted." "Clinically warranted" findings are those deemed by the interpreter as requiring further assessment, for example using: physical examination; investigations such as ECG testing, imaging, or stress testing; and/or consultation with a specialist.
Strong Recommendation, Low-Quality Evidence 3. We recommend that a physical examination should be considered as an adjunct component of CV screening of competitive athletes (tier 2) provided it is: i. Performed by an appropriately qualified professional involved in the care of athletes; and ii. Followed-up as clinically warranted.
Strong Recommendation, Low-Quality Evidence 4. We recommend against the "routine" performance of a 12-lead ECG for the initial CV screening of competitive athletes. "Routine" in this context is defined as "first-line" or blanket mass performance of ECG not occurring in context of an integrated program as described in Recommendation 5.
Strong Recommendation, Low-Quality Evidence 5. We recommend that a 12-lead ECG should be performed for screening of competitive athletes only when indicated according to history/questionnaire and/or physical examination (targeted screening, tier 3) and provided it is: i. Of "adequate" quality. In this context "adequate" is defined as technically sufficient and of the highest possible quality; ii. Interpreted by those with "appropriate expertise"
("appropriate expertise" is defined as training and skills in ECG interpretation specific to athletes and persons with disorders associated with arrhythmias) and with consideration of sport history, sex, ethnicity, age, family history, relevant clinical findings, "regional" ("regional" refers to geographic areas with a relatively high incidence of certain relevant cardiac conditions) occurrence of disease; and iii. Accompanied by appropriate investigations and expert referral if clinically warranted.
# Strong Recommendation, Low-Quality Evidence
Values and preferences. We disclose that there was an important disagreement between the primary writing panel (composed of Canadian experts) and the secondary international review panel (composed of American and European experts) with respect to Recommendations 4 and 5. The international experts on the secondary panel emphasize that SCD in athletes occurs in the absence of warning symptoms. Performance of targeted screening will miss these occurrences. In rebuttal, the primary panel clarified our position that these recommendations do not prohibit organizations from performing ECG screening, but suggest a tiered approach that can be tailored to regional needs, resources, and values. The benefit of mass ECG screening to prevent SCD in asymptomatic athletes is challenging to assess. As further detailed, our current position is that any ECG performance, whether it is targeted or not, occur in context of an expert-led, integrated program to ensure accuracy, minimization of false-positive results, prioritization of safety protocols in the case of SCA, and follow-up of abnormal findings.
recognized that a sports organization might wish to restrict certain athletes from training and competing, for example, if they do not participate in a screening process (Fig. 2).
# Options dialogue
The second stage in the SDM approach is to convey the meaning of positive findings on the questionnaire/history, physical examination, or ECG. Conveying the concept of false-positive results and their rate allows the athlete to make an informed decision. If disease is identified, consideration of the specific disorder, and the probability of SCD or disease progression as a consequence of continued athletic activity, should be weighed against the risks associated with a more sedentary or restricted lifestyle. The SDM process might require more than 1 clinical contact and involve discussions pertaining to further diagnostic testing, and the potential benefits or harms during the options dialogue (Fig. 2). For athletes with CV findings, further dialogue, with other experts might be appropriate. Patient athletes or relatives are supported to explore "what matters most to them," so that they can participate in the selection of the best course of action. 35
# The decision discussion and participation restriction
There is a lack of data to suggest that restricting athletes from sport results in a reduction of SCD from most of the predisposing conditions that can be identified, except for ARVC, when genotypic or phenotypic ARVC has been diagnosed as per established criteria. 36 Furthermore, there is a marked disparity between the prevalence of disease and the incidence of SCD; most athletes with underlying CV disease will never experience SCD during exercise. 7,18,29 Conversely, SCD might occur in the absence of abnormal findings during screening and most cases do not occur during vigorous exercise. 18,29,30 Although it is believed that vigorous exercise is a potential trigger for SCD, an examination of deaths of young persons in the United Kingdom and Australia/New Zealand showed that most deaths occurred at rest 18,29,30 ; which brings into question the efficacy of restriction. Even among high-risk athletes with implantable cardioverter-defibrillators who continued to participate in sport, registry data showed no tachyarrhythmic deaths nor externally resuscitated tachyarrhythmia during or after sport. 4 Athletes in this population experienced appropriate implantable cardioverter-defibrillator shocks (for ventricular tachycardia/fibrillation) during competition or practice at a rate of 3 per 100 person-years but this should clearly be individualized. 37,38 Offsetting a possible benefit of reducing SCD by restricting an athlete is the potential harm of denying a young person the benefits of physical activity such as: improved physical and psychological well-being, and decreased depression, obesity, and illicit drug use, 39 as well as implications for scholarship and career opportunities. It is recognized that there are situations (such as a high-risk case of hypertrophic cardiomyopathy 40 ) in which there is a higher risk of SCD with competition and the physician might strongly advise against participation. It is also recognized that some individuals might decide not to follow such advice and attempt to continue to participate irrespective of the personal risk communicated to them. 41,42 In this setting, an array of legal, financial, and ethical issues might emerge as a consequence of a physician's advice to restrict further opportunity for sport participation. 43
# Secondary Prevention of SCD and CV Emergencies
# Basic requirements
Sport organizations must recognize the need to ensure that appropriate approaches and equipment are available to address emergencies involving spectators, officials, staff, and competitors. [44][45][46] Training in cardiopulmonary resuscitation (CPR), the availability of AEDs in key activity (competition and training) spaces, and the creation of emergency management protocols should be standard. 47,48 These are the bedrock of a CSCAP; Fig. 1).
# AEDs
Increased public awareness and advocacy has led to a wide availability of AEDs in public and private sporting venues. They provide a means of early defibrillation not only for athletes, but for spectators and other attendees in the rare event of SCD. 46,47,49,50 Recent data 51 suggest that AED use has improved the SCA resuscitation success rates among athletes, thereby conferring a survival benefit. Limited data from the United States National Registry for AED use in sports suggests that AEDs in high schools, although more commonly used on nonathlete adults, have yielded a high success rate (to hospital discharge) between 50% and exceeding 85% in young athletes. 7,51 Most college and high schools in the United States do in fact have AEDs in place, 44,[51][52][53] yet the provision of AEDs in some settings might be limited by financial resources. 45 European and American authorities recommend AEDs be placed at high school and college sporting venues. 54,55 Regarding older individuals practicing sport, a recent report showed that the presence of on-site AEDs in amateur sports centres was associated with neurologically intact survival after an exercise-related SCA. Indeed, neurologically intact survival rates were 93% in centres with onsite AEDs and 9% in centres without (P < 0.001). 56
# Education of personnel and medical action plans
The regular rehearsal of an effective medical action plan (MAP) is as critical as the provision of AEDs. 51 Key components of an effective MAP include: (1) knowledge of AED location; (2) protocols to alert first responders and AED retrieval; and (3) training of personnel in CPR and AED use. Current American and European guidelines recommend that a time-to-shock using an AED should be < 3 minutes 52 ; each minute of delay reduces SCA survival by 7%-10%. 57 This is particularly important in rural communities, where in the absence of AEDs, the Emergency Medical System-dependent time-to-shock might be prolonged. Training in contemporary approaches to CPR is fundamental. 57 Current American guidelines call for CPR training of all team members, staff, and referees. 58 The Enhanced Environment of a Sports Cardiology Centre
Organizations offering a comprehensive CV screening program in an attempt to identify risk of SCD require an integrated array of resources and personnel. 52,59,60 This writing panel recommended against the routine performance of a 12-lead ECG, meaning that it should not be the sole or first-line screening procedure without adequate good clinical practice in place (history and physical) and without adequate interpretation and follow-up. However, if a given institution/ organization decides to administer a routine 12-lead ECG as part of the screening process towards tier 3 after achieving all previous steps, it must be accompanied by an interpretation by clinicians experienced in the assessment of an athlete's RECOMMENDATION 6. We recommend that after the identification and confirmation of any predisposing condition using screening, the probability of "SCD" ("SCD" in this context includes the probability of SCA; it is recognized that for some conditions it might be very difficult to define such probability) be estimated to facilitate a SDM process regarding sport participation involving the athlete (and parent/guardian if appropriate), caregiver, and sport organization.
Strong Recommendation, Low-Quality Evidence 7. We recommend that sport restriction be considered and discussed in the following conditions: ARVC, exerciseinduced significant ventricular arrhythmias (if arrhythmogenic risk cannot be mitigated), catecholaminergic polymorphic ventricular tachycardia, exercise-induced heart block, hypertrophic cardiomyopathy with sustained ventricular tachycardia or multiple risk factors, dilated cardiomyopathy unrelated to an athlete's heart, left ventricular noncompaction with left ventricular dysfunction and or ventricular arrhythmia, Marfan syndrome with aortic dilatation, significant aortic dilatation, coronary artery aneurysm with ischemia, oral anticoagulation treatment in an athlete competing in sports with a high risk of injury causing bleeding, pulmonary hypertension, and cyanotic congenital heart disease.
Strong Recommendation, Low-Quality Evidence RECOMMENDATION 8. We recommend the creation of specific policies and protocols for the delivery of MAPs specific to cardiac emergencies in all competitive sport settings and as the foundation of a CSCAP.
Strong Recommendation, High-Quality Evidence 9. We recommend that all educational and recreational facilities with athletic or sports programs must have AEDs located to ensure rapid access and initiation of defibrillation in < 3 minutes. These should be placed within close proximity to, if not within, all physical activity spaces used by athletes.
Strong Recommendation, Moderate-Quality Evidence 10. We recommend that because athletes, team staff, and referees are mostly likely to initially witness and attend a collapsed athlete, that at a minimum, team staff and referees be trained in CPR and be familiar with the use of AEDs, rehearse the MAP at their own facility, and be familiar with MAPs at other sporting facilities.
Despite the low incidence of SCD in athletes, it is recommended that SCA be considered the likely cause of an athlete's nontraumatic collapse during sport.
Strong Recommendation, Moderate-Quality Evidence ECG. 13,[61][62][63] The limitations of such programs must be appreciated. 19,[64][65][66][67][68][69][70] The capacity to provide expeditious access to further cardiac investigations must be in place. 52 In the Canadian context, this will typically involve the participation of an experienced sports medicine physician and a clearly identified cardiologist. 52,60 It is important to ensure that oversight of screening programs is assumed by trained physicians and specialists (which includes available general cardiologists). The development of sport cardiology centres (or centres of excellence) in certain regional settings will greatly assist those with limited access to specialty services. 59 Such networks might also facilitate research into the utility of emerging bedside screening tools and consensus-building related to defining "red flags" and sport participation.
# Limitations
With consideration of the assigned scope of this position statement, the writing committee was not able to comprehensively evaluate important topic areas related to CV screening in Canadian athletes. Further discussion of these topics is of paramount importance and will be eventually presented in a series of companion articles contextualized by this position statement by the CCS Sport Group. These topic areas currently in development include: prevalence of disease related to SCD in Canadian athletes, the role of imaging and point of care ultrasound in CV screening, and medico-legal aspects and the participation decision. The CCS group is proposing the creation of a network of centres of excellence to study these topic areas further because of the paucity of Canadian data. The cardiovascular screening and care of athletes program infers a shared decision-making approach to contextualize the screening process, understand options during recommended investigations and treatment, and ensures an informed discussion when deciding between continued participation or restriction (Recommendations 5-9). The "tiered approach" to screening is described in the text, by Recommendations 1-4, and further summarized in Figure 1
# Summary
The hallmarks of a high-quality approach to the initial cardiac screening and care of athletes within the Canadian health care model comprises a sequential (tiered) approach to the identification of cardiac risk, an appreciation of the limitations of screening, the importance of SDM when cardiac conditions are diagnosed, and the creation of policies and procedures for the management of emergencies in sport settings. The recommendations presented in this position statement comprise a tiered framework that allows institutions some choice as to program creation. The creation of a network of such regions of excellence, with the goal of further implementation, research, and standardization will enhance the safety of our athletes.
# Acknowledgements
Figures designed by Julia Herr at CINQLab.com.
Funding Sources Dr A.M. Johri is funded by a Heart and Stroke Foundation of Canada (Phase I Career Award), Kingston, Ontario, Canada and the Southeastern Ontario Academic Medical Organization.
# Supplementary Material
To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at https://doi.org/10. 1016/j.cjca.2018.10.016.
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# Limitations of Scope
Iatrogenic opioid withdrawal: Infants recovering from serious illness who received opioids and sedatives in the hospital may experience symptoms of withdrawal once the drug is discontinued or tapered too quickly. While these infants may benefit from the management strategies discussed in this module, the ESC Care Tool is intended for newborns with prenatal substance exposure.
# Language
A note about gender and sexual orientation terminology: In this module, the terms pregnant women and pregnant individual are used. This is to acknowledge and be inclusive of transgender individuals who are pregnant, and to respect those who wish to continue to be identified as pregnant women or mothers. We encourage all providers to not assume the gender identity or sexual orientation of the pregnant person (or their partner) and to respectfully and non-judgmentally ask all pregnant people about their preference for how they wish to be addressed.
# INTRODUCTION Terminology
Reviewing the literature on substance exposed newborns several terms and/or diagnoses are used such as:
Neonatal Abstinence Syndrome 1,2 Clinical diagnosis of neurologic, gastrointestinal, and musculoskeletal disturbances associated with withdrawal when substance source(s) are interrupted at birth. Withdrawal from opioids and other psychoactive substances. - This is the term that will be used in the manual.
Neonatal Opioid Withdrawal Syndrome 1,3 Clinical features specific to withdrawal from opioids.
Poor Neonatal Adaptation Syndrome 4,5,6 Clinical features specific to prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Includes features observed in NAS and NOWS, but also characterized by respiratory distress syndrome (RDS). Also called SSRI neonatal behavioural syndrome (SNBS) but restricted to SSRI.
Substance Exposed Newborn 1,7 Newborn exposed to substances during pregnancy that may cause symptoms of withdrawal postnatally.
# Epidemiology Incidence
Canadian incidence of NAS tripled between 2003 -2014. 8 Incidence rates in BC have risen from 2.6 to 4.7/1000 livebirths between 2010 -2018 9 (see Figure 1). Newborns diagnosed with NAS have longer and more costly length of stay in hospital (Figure 2), especially when treated with morphine. 8,9,10 This has imposed an increasing economic burden on the BC health care system, with total NAS-related hospital expenditure in 2014 reported to be 1.7 times higher than in 2010. 8
# Hospital Beds Occupied Per Day by Newborns with NAS in BC
Trends in incidence of neonatal abstinence syndrome in Canada and associated healthcare resource utilization. Jacqueline Filteaua, Helen Cooa, Kimberly Dowa
# Hospital beds occupied per day
# NEWBORN CARE GUIDING PRINCIPLES Trauma Informed Age Appropriate Care (TIAAC)
The period following birth is a sensitive period and a critical phase in human development. 11 Trauma suffered during the first few years of life can lead to toxic stress and adversely influence normal development.
Toxic stress is defined as strong, prolonged, and/or frequent adverse experiences that activate the stress response in the newborn in the absence of protective relationships. Potential stressors include:
⦁ ⦁ maternal separation ⦁ ⦁
unresponsive and/or inconsistent care ⦁ ⦁ an overwhelming sensory environment Toxic stress can result in epigenetic modification in which changes occur in DNA transcription affecting the development of major organs, especially the heart, brain, and kidneys, with lifelong health consequences. Providing appropriate care for the newborn during periods of acute withdrawal should focus on mitigating the effects of toxic stress. This involves providing effective social emotional buffering by adhering to age appropriate, trauma-informed care principles. Social buffering confers protective effects against toxic stress. 15 Quality of parenting where the parent actively engages and responds to the needs of the newborn can have a profound positive influence on the effectiveness of social buffering during stressful situations. 18 Examples of trauma informed age appropriate care include:
# Modified gene expression can influence the development of major organs
# How Early Experiences Alters Gene Expression and Shape Development
Newborn Responsive and Family-Centered Care Newborn responsive and family-centered care focus on the newborn and family and: ⦁ ⦁ is optimal, evidence-based, and applies to all care environments; ⦁ ⦁ enhances bonding and attachment and promotes healthy physical and emotional development of the newborn; ⦁ ⦁ requires collaboration between healthcare providers and the mother, recognizing that the mother plays an integral role in the care of her newborn; ⦁ ⦁ needs to be holistic, culturally appropriate, and delivered as close to home as possible; ⦁ ⦁ systems of care must be prioritized to meet the needs of the newborn and the family. Honest consistent communication, and support, will empower the mother to build care capacity that will ensure ongoing competent care; ⦁ ⦁ promotes mother and baby togetherness, skin-to-skin care, breastfeeding (unless contraindicated), and maternal emotional support to manage the stress related to the symptoms of substance withdrawal in her newborn; ⦁ ⦁ promotes an appropriate care environment for the newborn exposed to substances that will allow for the control of light and noise as tolerated; ⦁ ⦁ is sleep protective. The newborn exposed to substances should not be awakened unnecessarily for assessments and/or procedures;
⦁ ⦁ decreases length of hospital stay; ⦁ ⦁ is neuroprotective; ⦁ ⦁
allows for better allocation of resources.
# CLINICAL PRESENTATION OF NEONATAL ABSTINENCE SYNDROME Pathophysiology
While the pathophysiology of NAS is unclear, exposure and abrupt discontinuation of substances during pregnancy alters neurotransmitter activity in the brain of the newborn.
Withdrawal symptoms may present similar to drug toxicity syndrome (effect of too much of the substance). However, symptoms of drug toxicity decrease as the drug is eliminated where symptoms of withdrawal increase due to interruption of the drug supply. Prenatal exposure to substances such as cocaine and SSRIs can result in symptoms of withdrawal, drug toxicity, or a combination of both. Antenatal exposure to habit forming substances Substances with molecular weight < 600da, that is lipid solubilize, non-ionized and not bound to protein, readily crosses the placenta by passive diffusion
# In the fetus drug molecules attach to biochemical receptors in the CNS, blocking the action of neurotransmitters
As gestation increases more substances will cross the placental barrier due to a larger surface area, decreased diffusion distance, and increased placental blood flow
# Cord clamping at birth interrupts drug supply
Newborn continues to metabolize and excrete remaining metabolites of substances until depleted / excreted Absence of substance(s) at chronically stimulated receptors Altered neurotransmitter release (too much or too little) at the synapses
# Onset of withdrawal symptoms
Substance Effects on Neurotransmitters Cord clamping and cutting at birth interrupts the drug supply. The newborn will continue to metabolize and excrete the remaining metabolites of substances until depleted and once depleted the absence of substances alter neurotransmitter release resulting in signs of substance withdrawal. Presentation of withdrawal signs and symptoms will depend on the type of substance and the type of neurotransmitter that is affected.
TCA = Tricyclic antidepressant SSRI = Selective serotonin reuptake inhibitor SNRI = Serotonin norepinephrine reuptake inhibitor GABA = Gamma aminobutyric acid (naturally occurring amino acid that works as a neurotransmitter in the brain For interactive content, please access module 3: Care of the newborn exposed to substances during pregnancy (lesson 3) via
# Signs and Symptoms
NAS consists of neurologic, gastrointestinal, and musculoskeletal disturbances associated with withdrawal once the source of the substance(s) is interrupted at birth. However, these disturbances are highly variable and there is currently no reliable way to predict presence or severity of withdrawal symptoms.
# SYSTEM SIGNS AND SYMPTOMS Central Nervous System
Irritability, high pitched cry, tremors, hypertonic, sleep disturbances
# Gastrointestinal System
Loose stools, vomiting, dysrhythmic sucking and swallowing, poor intake with weight loss
# Respiratory System
Excessive secretions, nasal stuffiness, tachypnea
# Autonomic Nervous System
Sweating, sneezing, yawning, hyperthermia
# Variation in Expression and Severity of Withdrawal Symptoms
The incidence, timing of onset, presentation, and severity of NAS varies significantly among the population of newborns exposed to substances. 10,23,33,34 Variation can be attributed to a variety of factors such as:
type of maternal opioid replacement therapy 35,37 ⦁ ⦁ maternal polysubstance use and patterns of substance use 38,39 ⦁ ⦁ period of substance exposure and total accumulation of substance/s
# Comorbidities (HIV, HepB)
Not all newborns exposed to substances are at risk of HIV and Hepatitis B transmission. Review the maternal history to determine risk and need for prophylaxis.
Mother to child transmission of HIV can occur during pregnancy, at the time of delivery, or via breastmilk. For more information on screening for risk factors and management of the newborn visit the BC Women's Hospital and Health Centre HIV/AIDS Resource webpage at .
Mother to child transmission of Hepatitis B can occur during pregnancy. 47 Consult the BC Centre for Disease Control website at for most current information on screening the newborn at risk for Hepatitis B, prophylaxis indications and interventions.
# Diagnostic Testing for Prenatal Drug Exposure
Although neonatal drug testing is often performed to inform treatment planning, the decision to screen a newborn can be stigmatizing. 48 Routine testing for suspected prenatal substance use is not advisable, 49 as it can adversely affect the therapeutic relationship between the mother and health providers and can affect child welfare services. 50 A positive screen does not necessarily indicate the need for child protection nor influence the type of support required. Informed consent must be obtained prior to testing. However, tests may still be ordered by the primary care provider in the absence of maternal consent if deemed medically necessary.
# Issues with diagnostic testing for substance exposure ⦁ ⦁
Pharmacokinetics of drugs through the maternal-placental-fetal unit and in the newborn are not well understood. 48
Variation in specimen collection methods, storage, and transport of the specimen to the laboratory can influence test accuracy. 51,52
Poor sensitivity and specificity may generate false positive or negative results. 53,54 ⦁ ⦁ Local laboratories may lack the ability to further analyze positive screens required to inform clinical management, or the resources to process them in a timely manner. 55,56 Newborn Drug Testing Information
# SPECIMEN EASE OF COLLECTION WINDOW OF DETECTION
# SENSITIVITY AND SPECIFICTY
# ASSESSMENT OF WITHDRAWAL SYMPTOMS Tools for Assessment
Several neonatal withdrawal assessment tools have been developed over the years. 67 The Finnegan Neonatal Abstinence Scoring Tool (FNAST) is the most commonly used tool to assess the severity of withdrawal and inform clinical management. However, with the increased understanding of neonatal substance withdrawal the usefulness of the FNSAT is being questioned.
Limitations of the FNSAT:
Modified and unvalidated versions are often used due to its intimidating length and complexity 67,73,74 ⦁ ⦁
To minimize subjectivity and maximize inter-rater reliability, extensive and continuous training is required ⦁ ⦁
Assessment of some criteria (e.g., Moro reflex) requires the newborn to be disturbed, which may artificially inflate scores
Validated for use in full term newborns only 72
Likely to prompt earlier initiation and greater intensity of pharmacological management 48
# The Eat, Sleep and Console (ESC) Care Tool
In 2008, a quality improvement initiative was launched at Yale New Haven Children's Hospital, Connecticut, USA to improve inpatient outcomes for Neonatal Abstinence Syndrome. 78 The objective was to decrease the average length of hospital stay by 50% for newborns exposed to substances in utero. One of the key interventions of the Yale New Haven quality improvement project was the development and implementation of a novel assessment tool; the Eat, Sleep and Console (ESC) Care Tool. This work was influenced by the innovative work done by Dr Ron Abrahams, Dr Paul Thiessen and Sarah Payne on Fir Square, BC Women's Hospital where mothers and babies were kept together, and functional assessments and weight gain were used to assess withdrawal in the newborn. The ESC Care Tool, developed in 2017, is a function-based assessment tool that assesses how the newborn eats, sleeps, and consoles. The ESC Care Tool was adapted by BC with permission from the developers of the original ESC Care Tool and:
Is best practice evidence-based care. 86
Aligns with trauma informed, culturally safe care and newborn responsive care
# Promotes mother and baby togetherness ⦁ ⦁
Promotes the use of non-pharmacological strategies to support the newborn during the acute phase of substance withdrawal
Allows for easy adoption and implementation across all care settings in BC.
Is an objective assessment tool with high inter-rater reliability. 84
Promotes standardized documentation and care.
Is low cost, simple and achievable. 85
# Principles of the ESC Approach
Aims to support the newborn exposed to substances to achieve developmentally normal eating, sleeping, consoling, and weight gain milestones.
Mother/caregiver is the primary provider of responsive, newborn-centered care and integral to managing NAS.
Encourage the mother and health care professional to consider reasons other than withdrawal that may affect how the baby is eating, sleeping, consoling, and/or gaining weight.
# Recommendations
ESC Care Tool is developed to track the newborns ESC behaviours and interventions over a 24-hour period:
Initiate ESC assessments and non-pharmacological strategies within 4 -6 hours of birth.
Perform ESC assessment every 2 -4 hours after feeding in collaboration with parent/ caregiver. 84
Continue for at minimum of 4 -7 days for the newborn exposed to long-acting opioids such as methadone, and a minimum of 48 hours for shorter acting opioids (e.g., oxycodone, codeine). 84,87,88 ⦁ ⦁
For newborns that required pharmacological management, ESC assessments should continue for at least 24 hours after administration of the last dose of morphine. 89,90 ⦁ ⦁
Gestational age at birth and actual postnatal age needs to be considered when assessing ESC behaviours. Some of these behaviours may be normal age appropriate behaviour such as cluster feeding and natural fluctuations in sleep-wake patterns.
Assessments include all ESC behaviours that occurred since the newborn's last assessment as well as all non-pharmacological care interventions implemented. Incorporate input from all caregivers who interacted with the newborn during this period. Monitor excessive weight loss and slow weight gain due to higher energy requirements, poor feeding, loose stools, and vomiting.
Weight loss more than 10% requires a full care team huddle regardless of ESC assessment.
# ESC Assessment Eating
Assess eating behaviour.
Poor eating is defined as follows:
⦁ ⦁ Newborn is unable to coordinate feeding within 10 minutes of showing hunger cues AND/OR ⦁ ⦁ Newborn is unable to sustain feeding for age appropriate duration at breast OR
Newborn is unable to take in age and weight appropriate volume by alternative feeding method
If the newborn is eating well answer NO and move to section that assess sleeping.
If the newborn is eating poorly answer YES and answer the next question to determine if poor eating is due to substance withdrawal or not.
Substance withdrawal symptoms such as fussiness, tremors, uncoordinated suck, and excessive rooting can affect the newborn's ability to eat and gain weight effectively. If poor eating is due to symptoms of substance withdrawal answer YES.
If poor eating is clearly due to reasons other than symptoms of withdrawal such as prematurity, transitional sleepiness, excess mucus in the first 24 hours, and inability to latch due to infant / maternal anatomical factors, answer NO. Implement appropriate management strategies (e.g., NG feeds for preterm infants), optimize nonpharmacological interventions, and monitor closely.
If it is unclear whether substance withdrawal symptoms are responsible for poor eating, answer YES and continue to monitor closely as this may be an indication of escalating withdrawal symptoms.
Review optimal feeding recommendations with the parent/caregiver and continue to optimize nonpharmacological strategies.
If the newborn is eating poorly a Parent/caregiver-RN huddle is recommended to review optimal feeding recommendations with parent/caregiver. If eating has not improved on subsequent assessment, despite interventions, a full care team huddle is indicated.
# Sleeping
Assess sleeping behaviour.
If the newborn sleeps for more than one hour after feeding answer NO and move to the section that assess consoling.
If the newborn is unable to sleep for at least one hour after feeding answer YES for poor sleeping and answer the next question to determine if poor sleeping is due to substance withdrawal or not.
Substance withdrawal symptoms such as fussiness, restlessness, increased startle, and tremors can affect sleeping behaviour. If the newborn is unable to sleep for at least one hour after feeding due to substance withdrawal symptoms answer YES.
If the baby sleep less than 1 hour due to reasons other than substance withdrawal such as physiologic cluster feeding in first few days of life, interruptions in sleep due to external noise and ambient light, and interruption of sleep due to clinical care answer NO.
If it is unclear whether substance withdrawal symptoms are responsible for poor sleeping or not answer YES and continue to monitor.
A Parent/caregiver-RN huddle is recommended to review nonpharmacological strategies to promote sleeping. If, on subsequent assessment, baby is still sleeping less than one hour after feeding due to symptoms of withdrawal, despite interventions, a full care team huddle is indicated.
# Console
Assess consoling behaviour.
If the newborn consoles easily within 10 minutes and remains consoled for longer than 10 minutes answer NO to indicated that the newborn does not experience any difficulty in consoling and move to the section that assess parental/caregiver presence.
If the newborn is unable to console within 10 minutes or remain consoled for longer than 10 minutes answer YES for difficulty in consoling and answer the next question to determine if difficulty in consoling is due to substance withdrawal or not.
Altered neurotransmitter release due to substance withdrawal increase agitation and difficulty in consoling. If the newborn is unable to console easily within 10 minutes and remains consoled for longer than 10 minutes due to substance withdrawal symptoms answer YES.
Answer NO if the newborn's inconsolability is clearly due to other factors such as caregiver non-responsiveness to infant hunger cues.
If it is unclear whether substance withdrawal symptoms are responsible for inconsolability or not answer YES and continue to monitor.
If newborn has difficulty in consoling regardless of reason a Parent/caregiver-RN Huddle is recommended to review appropriate care interventions and Consoling Support Interventions.
Monitor the newborn closely and continue to optimize non-pharmacological strategies. If newborn is still unable to console at subsequent assessment, despite effective implementation of all levels of consoling support, a full care team huddle is indicated.
Document consoling support needed using the numerical codes 1, 2 or 3:
- Newborn is able to self-console 2. Newborn can console (and stay consoled) with caregiver support within 10 min 3. Newborn is unable to console with caregiver support within, or cannot stay consoled for 10 minutes Please note the numbers are NOT intended as a "score" but to indicate an escalation of withdrawal symptoms and identify a need for increased intervention.
# Parent/Caregiver Section
Parent/Caregiver Presence and Involvement in Care of the Newborn ⦁ ⦁ Document the time, since last assessment, that the parent/s, or another caregiver, spent with the infant.
Caregiver can be a parent, other family member, designated visitor, cuddler, or healthcare worker that can deliver responsive care in a timely manner.
Document the caregiver who provided the most care.
Numbers above are NOT intended as a "score" but used for ease of documentation and to identify parental/caregiver involvement in the care of the baby. A Parent/caregiver-RN huddle is recommended if parent/caregiver is not spending enough time at the bedside, and/or not delivering newborn care in a responsive and timely manner. During the huddle the parent/ bedside RN will review options to assist the parent/caregiver to provide responsive and timely care.
# Plan of Care
Parent/Caregiver and Bedside RN huddle
Parent/caregiver and Bedside RN should meet if infant receives a YES for any ESC item, to determine if non-pharmacological care interventions can be optimized further.
During the huddle, the parent/caregiver and RN review and discuss how to optimize non-pharmacological care interventions to improve feeding, sleeping and consoling behaviour.
# Full Care Team Huddle
Bedside meeting of entire team (parents/caregiver, bedside RN, nurse leadership if applicable, and provider) is indicated if the newborn:
Has more than 10% weight loss
Continued YES for any ESC items despite optimal non-pharmacological care
Is unable to console despite effective implementation of all levels of consoling support
Has any other significant concerns
The full care team will:
Review non-pharmacological strategies and parental presence
If non-pharmacological care interventions are maximized to the fullest and the newborn continues to have poor eating, sleeping, or consoling behaviour (or other significant concerns are present) and symptoms are felt to be due to substance withdrawal, pharmacological management may be indicated.
# Continue to follow the infant closely, optimizing all non-pharmacological interventions regardless of management decision
# Non-Pharmacological Care Interventions
The ESC Care Tool promotes the use of non-pharmacological strategies to support the newborn during the acute phase of substance withdrawal. Use this section to indicate the use of these strategies using the following codes:
# NON-PHARMACOLOGICAL MANAGEMENT
Withdrawal from substances after birth results in physiological and physical dysregulation. This may impact sensory stimulation integration, state regulation, motor and tone control, and the autonomic nervous system. 91 The objective of non-pharmacological care interventions are to provide the infant with an environment that supports their ability to self-regulate. Although these strategies are commonly used to comfort and support infants, high quality research to determine their effectiveness is lacking. Despite the current shortcomings in research methodology, data suggests that non-pharmacological interventions may decrease the severity of withdrawal, the need for medical intervention, and duration of hospitalization. 34,92
# Sensory Stimulation Integration
The following strategies may be helpful to support the infant and prevent sensory overload during the active period of withdrawal: approach the bedside using a gentle voice prior to touching the infant 96 ⦁ ⦁ slow, gentle handling 91,96 ⦁ ⦁ hold infant closely when transferring infant from one space to another to prevent startling 91 ⦁ ⦁ swaddling contains and prevents erratic movements and startling 91,95 ⦁ ⦁ tactile stimulation should be gentle and firm; avoid stroking 80 ⦁ ⦁ apply gentle pressure over the infant's head or body 91,94 ⦁ ⦁ bringing arms/hands midline and positioning infants in a fetal position 91,96,97
# Swaddling
In the newborn exposed to substances swaddling has been shown to:
reduce crying, startles, and physiological stress 98,99 ⦁ ⦁ improve sleep, motor organization and self-regulation 98,99
# Safety
Combination of swaddling with prone position increases the risk of sudden infant death syndrome. Discontinue use of swaddling prior to discharge, as soon as withdrawal symptoms have resolved. See .
# State Regulation
Sleep-wake regulation is an indication of how effectively the infant can regulate his/her internal processes and the influence of external stimulations. Full-term infants will transition between quiet sleep, active sleep, drowsy, quiet awake, and crying.
The infant exposed to substances may:
# Skin-to-Skin
Encourage skin-to-skin contact as much as possible to help calm the baby, promote neurobehavioural organization, bonding and attachment, and increase breastmilk supply (if breastfeeding). Skin-to-skin care is associated with improved sleep patterns, 102 a reduction in excessive crying and motor agitation associated with NAS, and a decreased need for pharmacological management. 103 Parent/caregiver should sit in a comfortable chair and be fully awake and focused on the infant.
Distractions such as cell phones should be avoided. Infant should be naked except for diaper and placed directly on mother's/parent/caregiver's chest with a blanket placed over both for warmth.
A wrap can also be used to secure infant.
# Ensure infant's:
head is turned to one side
head is in the sniffing position and neck straight to maintain airway
⦁ ⦁ face is visible ⦁ ⦁
nose and mouth are not covered by the blanket or wrap
legs are flexed and is lying chest to chest with mother/parent
# Vertical Rocking
Vertical rocking has been shown to decrease neurological hyperactivity and promote selfregulation. 191,104,105 The Hold 106
See .
Infant can be swaddled. If not, fold infant's arms snugly across his/her chest.
Pick up infant and hold in a vertical, flexed position.
Gently but securely hold infant's bottom with the dominant hand.
Maintain airway by supporting infant's chin with the other hand.
Bring infant's head a bit forward to position infant at a 45-degree angle, as it will be easier to control the infant.
Slowly and rhythmically rock infant up and down.
# Rhythmic movement using swings, chairs or beds ⦁ ⦁
Swings or vibrating bouncy seats can also be used to provide rhythmical rocking.
Adhere to manufacturer's safety recommendations and site-specific protocols when using. 107
# Motor and Tone Control
The newborn exposed to substances may display: dysmature pattern of swallow-breath interaction 111 These feeding difficulties and the hypermetabolic state due to withdrawal may result in difficulties with weight gain.
# Feeding
Mothers are encouraged to breastfeed unless there is concern related to continued substance use or other medical contraindication is present such as HIV.
Despite the documented benefits of human milk, breastfeeding rates are low in women with substance use disorder. ⦁ ⦁
The risk-benefits of breastfeeding should be carefully considered, and attempts should be made to minimize barriers and promote breastfeeding.
In the infant exposed to substances, breastfeeding is associated with:
⦁ ⦁ delayed onset of withdrawal symptoms 96,115 ⦁ ⦁ decreased severity of withdrawal symptoms 82,112,115,116 ⦁ ⦁ decreased need for pharmacological management 115,11,12 ⦁ ⦁ decreased length of pharmacological management 96,112 ⦁ ⦁ shorter length of hospital stay 7,13,14 The Following General Strategies May Be Helpful to Support Optimal Feeding ⦁ ⦁ optimal feeding at early hunger cues without any limits placed in duration or volume of feeding If newborn is breastfeeding, ensure the newborn is latching deeply, with a comfortable latch for mother, and with sustained active suckling with only brief pauses noted. If necessary, assist the mother to achieve more optimal latch/position. To organize suck prior to latching, use expressed breastmilk and have the infant suck on an adult finger. Withhold pacifier use if possible.
To organize suck prior to latching, use expressed breastmilk and have the infant suck on an adult finger. Withhold pacifier use if possible.
Consider fortifying breastmilk or supplementation with a high-calorie breast milk substitute for poor weight gain. 15,16,17 Bottle Feeding
If newborn is bottle feeding:
Reduce GI discomfort by using mother's expressed breast milk, donor breast milk or breastmilk substitute with a low osmolality. 117
Mimic breastfeeding by letting baby pause and rest periodically.
# Skin Care
Newborns are at risk for skin injuries as adaptation to the extrauterine environment is still ongoing. The functionally immature epidermal barrier and acid-mantle increases the risk of chemical, microbial, or friction skin injuries. 119,120 Due to irritability, uncontrolled movements, and diarrhea related to withdrawal, the newborn exposed to substances is at risk for excoriations and diaper dermatitis. 121
# Types of skin injuries Excoriation/abrasions
Redness of the skin or broken/bleeding skin often found on chin, ankles and face.
Cause: Rubbing of an extremity or face on a linen covered surface/blankets due to excessive and uncontrolled movements of the extremities and/or head.
# PHARMACOLOGICAL MANAGEMENT Current Status
The current evidence as to when to initiate medication, treatment regimens, dosing, weaning protocols and use of adjunctive management is limited. 124,125,126 Evidence does show that a standardized pharmacological management protocol with clear weaning guidelines decreases the length of pharmacological intervention and hospital stay. 116,124,127,128 While suboxone and methadone can be used to manage substance withdrawal symptoms in the newborn, morphine is the most commonly used drug to manage newborn opioid withdrawal. 10,23,129 Morphine is a full mu-opioid receptor agonist with well-established pharmacokinetic features and a short half-life.
# General Principles ⦁ ⦁
Rooming-in and implementing non-pharmacological is paramount. Pharmacological intervention should be employed as an adjunct.
Use ESC Care Tool to guide management.
Minimize opiate replacement exposure in the newborn.
The need for pharmacological management alone is not an indication for admission to the NICU. Transfer to the NICU only if there is a medical indication.
Treatment Algorithm for the Newborn Exposed to Substance(s) in Pregnancy
# APPENDIX: CONSOLING SUPPORT INTERVENTIONS CONSOLING SUPPORT INTERVENTIONS THAT CAN BE USED WHEN BABY IS DIFFICULT TO CONSOLE
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# Limitations of Scope
Iatrogenic opioid withdrawal: Infants recovering from serious illness who received opioids and sedatives in the hospital may experience symptoms of withdrawal once the drug is discontinued or tapered too quickly. While these infants may benefit from the management strategies discussed in this module, the ESC Care Tool is intended for newborns with prenatal substance exposure.
# Language
A note about gender and sexual orientation terminology: In this module, the terms pregnant women and pregnant individual are used. This is to acknowledge and be inclusive of transgender individuals who are pregnant, and to respect those who wish to continue to be identified as pregnant women or mothers. We encourage all providers to not assume the gender identity or sexual orientation of the pregnant person (or their partner) and to respectfully and non-judgmentally ask all pregnant people about their preference for how they wish to be addressed.
# INTRODUCTION Terminology
Reviewing the literature on substance exposed newborns several terms and/or diagnoses are used such as:
⦁ ⦁
Neonatal Abstinence Syndrome 1,2 Clinical diagnosis of neurologic, gastrointestinal, and musculoskeletal disturbances associated with withdrawal when substance source(s) are interrupted at birth. Withdrawal from opioids and other psychoactive substances. * This is the term that will be used in the manual.
# ⦁ ⦁
Neonatal Opioid Withdrawal Syndrome 1,3 Clinical features specific to withdrawal from opioids.
# ⦁ ⦁
Poor Neonatal Adaptation Syndrome 4,5,6 Clinical features specific to prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Includes features observed in NAS and NOWS, but also characterized by respiratory distress syndrome (RDS). Also called SSRI neonatal behavioural syndrome (SNBS) but restricted to SSRI.
# ⦁ ⦁
Substance Exposed Newborn 1,7 Newborn exposed to substances during pregnancy that may cause symptoms of withdrawal postnatally.
# Epidemiology Incidence
Canadian incidence of NAS tripled between 2003 -2014. 8 Incidence rates in BC have risen from 2.6 to 4.7/1000 livebirths between 2010 -2018 9 (see Figure 1). Newborns diagnosed with NAS have longer and more costly length of stay in hospital (Figure 2), especially when treated with morphine. 8,9,10 This has imposed an increasing economic burden on the BC health care system, with total NAS-related hospital expenditure in 2014 reported to be 1.7 times higher than in 2010. 8
# Hospital Beds Occupied Per Day by Newborns with NAS in BC
Trends in incidence of neonatal abstinence syndrome in Canada and associated healthcare resource utilization. Jacqueline Filteaua, Helen Cooa, Kimberly Dowa
# Hospital beds occupied per day
# NEWBORN CARE GUIDING PRINCIPLES Trauma Informed Age Appropriate Care (TIAAC)
The period following birth is a sensitive period and a critical phase in human development. 11 Trauma suffered during the first few years of life can lead to toxic stress and adversely influence normal development.
Toxic stress is defined as strong, prolonged, and/or frequent adverse experiences that activate the stress response in the newborn in the absence of protective relationships. Potential stressors include:
⦁ ⦁ maternal separation ⦁ ⦁
unresponsive and/or inconsistent care ⦁ ⦁ an overwhelming sensory environment [11][12][13][14][15] Toxic stress can result in epigenetic modification in which changes occur in DNA transcription affecting the development of major organs, especially the heart, brain, and kidneys, with lifelong health consequences. [15][16][17] Providing appropriate care for the newborn during periods of acute withdrawal should focus on mitigating the effects of toxic stress. This involves providing effective social emotional buffering by adhering to age appropriate, trauma-informed care principles. Social buffering confers protective effects against toxic stress. 15 Quality of parenting where the parent actively engages and responds to the needs of the newborn can have a profound positive influence on the effectiveness of social buffering during stressful situations. 18 Examples of trauma informed age appropriate care include:
# Modified gene expression can influence the development of major organs
# How Early Experiences Alters Gene Expression and Shape Development
Newborn Responsive and Family-Centered Care Newborn responsive and family-centered care [19][20][21][22] focus on the newborn and family and: ⦁ ⦁ is optimal, evidence-based, and applies to all care environments; ⦁ ⦁ enhances bonding and attachment and promotes healthy physical and emotional development of the newborn; ⦁ ⦁ requires collaboration between healthcare providers and the mother, recognizing that the mother plays an integral role in the care of her newborn; ⦁ ⦁ needs to be holistic, culturally appropriate, and delivered as close to home as possible; ⦁ ⦁ systems of care must be prioritized to meet the needs of the newborn and the family. Honest consistent communication, and support, will empower the mother to build care capacity that will ensure ongoing competent care; ⦁ ⦁ promotes mother and baby togetherness, skin-to-skin care, breastfeeding (unless contraindicated), and maternal emotional support to manage the stress related to the symptoms of substance withdrawal in her newborn; ⦁ ⦁ promotes an appropriate care environment for the newborn exposed to substances that will allow for the control of light and noise as tolerated; ⦁ ⦁ is sleep protective. The newborn exposed to substances should not be awakened unnecessarily for assessments and/or procedures;
⦁ ⦁ decreases length of hospital stay; ⦁ ⦁ is neuroprotective; ⦁ ⦁
allows for better allocation of resources.
# CLINICAL PRESENTATION OF NEONATAL ABSTINENCE SYNDROME Pathophysiology
While the pathophysiology of NAS is unclear, exposure and abrupt discontinuation of substances during pregnancy alters neurotransmitter activity in the brain of the newborn.
Withdrawal symptoms may present similar to drug toxicity syndrome (effect of too much of the substance). However, symptoms of drug toxicity decrease as the drug is eliminated where symptoms of withdrawal increase due to interruption of the drug supply. Prenatal exposure to substances such as cocaine and SSRIs can result in symptoms of withdrawal, drug toxicity, or a combination of both. [23][24][25][26][27] Antenatal exposure to habit forming substances Substances with molecular weight < 600da, that is lipid solubilize, non-ionized and not bound to protein, readily crosses the placenta by passive diffusion
# In the fetus drug molecules attach to biochemical receptors in the CNS, blocking the action of neurotransmitters
As gestation increases more substances will cross the placental barrier due to a larger surface area, decreased diffusion distance, and increased placental blood flow
# Cord clamping at birth interrupts drug supply
Newborn continues to metabolize and excrete remaining metabolites of substances until depleted / excreted Absence of substance(s) at chronically stimulated receptors Altered neurotransmitter release (too much or too little) at the synapses
# Onset of withdrawal symptoms
Substance Effects on Neurotransmitters [28][29][30][31][32] Cord clamping and cutting at birth interrupts the drug supply. The newborn will continue to metabolize and excrete the remaining metabolites of substances until depleted and once depleted the absence of substances alter neurotransmitter release resulting in signs of substance withdrawal. Presentation of withdrawal signs and symptoms will depend on the type of substance and the type of neurotransmitter that is affected.
TCA = Tricyclic antidepressant SSRI = Selective serotonin reuptake inhibitor SNRI = Serotonin norepinephrine reuptake inhibitor GABA = Gamma aminobutyric acid (naturally occurring amino acid that works as a neurotransmitter in the brain For interactive content, please access module 3: Care of the newborn exposed to substances during pregnancy (lesson 3) via https://ubccpd.ca/course/perinatal-substance-use
# Signs and Symptoms
NAS consists of neurologic, gastrointestinal, and musculoskeletal disturbances associated with withdrawal once the source of the substance(s) is interrupted at birth. However, these disturbances are highly variable and there is currently no reliable way to predict presence or severity of withdrawal symptoms.
# SYSTEM SIGNS AND SYMPTOMS Central Nervous System
Irritability, high pitched cry, tremors, hypertonic, sleep disturbances
# Gastrointestinal System
Loose stools, vomiting, dysrhythmic sucking and swallowing, poor intake with weight loss
# Respiratory System
Excessive secretions, nasal stuffiness, tachypnea
# Autonomic Nervous System
Sweating, sneezing, yawning, hyperthermia
# Variation in Expression and Severity of Withdrawal Symptoms
The incidence, timing of onset, presentation, and severity of NAS varies significantly among the population of newborns exposed to substances. 10,23,33,34 Variation can be attributed to a variety of factors such as:
⦁ ⦁
type of maternal opioid replacement therapy 35,37 ⦁ ⦁ maternal polysubstance use and patterns of substance use 38,39 ⦁ ⦁ period of substance exposure and total accumulation of substance/s
# Comorbidities (HIV, HepB)
Not all newborns exposed to substances are at risk of HIV and Hepatitis B transmission. Review the maternal history to determine risk and need for prophylaxis.
Mother to child transmission of HIV can occur during pregnancy, at the time of delivery, or via breastmilk. [44][45][46] For more information on screening for risk factors and management of the newborn visit the BC Women's Hospital and Health Centre HIV/AIDS Resource webpage at http://www.bcwomens.ca/health-professionals/professional-resources/hiv-aids-resources.
Mother to child transmission of Hepatitis B can occur during pregnancy. 47 Consult the BC Centre for Disease Control website at for most current information on screening the newborn at risk for Hepatitis B, prophylaxis indications and interventions.
# Diagnostic Testing for Prenatal Drug Exposure
Although neonatal drug testing is often performed to inform treatment planning, the decision to screen a newborn can be stigmatizing. 48 Routine testing for suspected prenatal substance use is not advisable, 49 as it can adversely affect the therapeutic relationship between the mother and health providers and can affect child welfare services. 50 A positive screen does not necessarily indicate the need for child protection nor influence the type of support required. Informed consent must be obtained prior to testing. However, tests may still be ordered by the primary care provider in the absence of maternal consent if deemed medically necessary.
# Issues with diagnostic testing for substance exposure ⦁ ⦁
Pharmacokinetics of drugs through the maternal-placental-fetal unit and in the newborn are not well understood. 48
# ⦁ ⦁
Variation in specimen collection methods, storage, and transport of the specimen to the laboratory can influence test accuracy. 51,52
# ⦁ ⦁
Poor sensitivity and specificity may generate false positive or negative results. 53,54 ⦁ ⦁ Local laboratories may lack the ability to further analyze positive screens required to inform clinical management, or the resources to process them in a timely manner. 55,56 Newborn Drug Testing Information
# SPECIMEN EASE OF COLLECTION WINDOW OF DETECTION
# SENSITIVITY AND SPECIFICTY
# ASSESSMENT OF WITHDRAWAL SYMPTOMS Tools for Assessment
Several neonatal withdrawal assessment tools have been developed over the years. 67 The Finnegan Neonatal Abstinence Scoring Tool (FNAST) is the most commonly used tool to assess the severity of withdrawal and inform clinical management. [68][69][70][71][72] However, with the increased understanding of neonatal substance withdrawal the usefulness of the FNSAT is being questioned.
Limitations of the FNSAT:
⦁ ⦁
Modified and unvalidated versions are often used due to its intimidating length and complexity 67,73,74 ⦁ ⦁
To minimize subjectivity and maximize inter-rater reliability, extensive and continuous training is required [74][75][76][77] ⦁ ⦁
Assessment of some criteria (e.g., Moro reflex) requires the newborn to be disturbed, which may artificially inflate scores
⦁ ⦁
Validated for use in full term newborns only 72
# ⦁ ⦁
Likely to prompt earlier initiation and greater intensity of pharmacological management 48
# The Eat, Sleep and Console (ESC) Care Tool
In 2008, a quality improvement initiative was launched at Yale New Haven Children's Hospital, Connecticut, USA to improve inpatient outcomes for Neonatal Abstinence Syndrome. 78 The objective was to decrease the average length of hospital stay by 50% for newborns exposed to substances in utero. One of the key interventions of the Yale New Haven quality improvement project was the development and implementation of a novel assessment tool; the Eat, Sleep and Console (ESC) Care Tool. [78][79][80] This work was influenced by the innovative work done by Dr Ron Abrahams, Dr Paul Thiessen and Sarah Payne on Fir Square, BC Women's Hospital where mothers and babies were kept together, and functional assessments and weight gain were used to assess withdrawal in the newborn. [81][82][83] The ESC Care Tool, developed in 2017, is a function-based assessment tool that assesses how the newborn eats, sleeps, and consoles. [84][85][86] The ESC Care Tool was adapted by BC with permission from the developers of the original ESC Care Tool and:
⦁ ⦁
Is best practice evidence-based care. 86
# ⦁ ⦁
Aligns with trauma informed, culturally safe care and newborn responsive care
⦁ ⦁
# Promotes mother and baby togetherness ⦁ ⦁
Promotes the use of non-pharmacological strategies to support the newborn during the acute phase of substance withdrawal
⦁ ⦁
Allows for easy adoption and implementation across all care settings in BC.
# ⦁ ⦁
Is an objective assessment tool with high inter-rater reliability. 84
# ⦁ ⦁
Promotes standardized documentation and care.
# ⦁ ⦁
Is low cost, simple and achievable. 85
# Principles of the ESC Approach
# ⦁ ⦁
Aims to support the newborn exposed to substances to achieve developmentally normal eating, sleeping, consoling, and weight gain milestones.
# ⦁ ⦁
Mother/caregiver is the primary provider of responsive, newborn-centered care and integral to managing NAS.
# ⦁ ⦁
Encourage the mother and health care professional to consider reasons other than withdrawal that may affect how the baby is eating, sleeping, consoling, and/or gaining weight.
# Recommendations
ESC Care Tool is developed to track the newborns ESC behaviours and interventions over a 24-hour period:
⦁ ⦁
Initiate ESC assessments and non-pharmacological strategies within 4 -6 hours of birth.
# ⦁ ⦁
Perform ESC assessment every 2 -4 hours after feeding in collaboration with parent/ caregiver. 84
# ⦁ ⦁
Continue for at minimum of 4 -7 days for the newborn exposed to long-acting opioids such as methadone, and a minimum of 48 hours for shorter acting opioids (e.g., oxycodone, codeine). 84,87,88 ⦁ ⦁
For newborns that required pharmacological management, ESC assessments should continue for at least 24 hours after administration of the last dose of morphine. 89,90 ⦁ ⦁
Gestational age at birth and actual postnatal age needs to be considered when assessing ESC behaviours. Some of these behaviours may be normal age appropriate behaviour such as cluster feeding and natural fluctuations in sleep-wake patterns.
# ⦁ ⦁
Assessments include all ESC behaviours that occurred since the newborn's last assessment as well as all non-pharmacological care interventions implemented. Incorporate input from all caregivers who interacted with the newborn during this period. Monitor excessive weight loss and slow weight gain due to higher energy requirements, poor feeding, loose stools, and vomiting.
# ⦁ ⦁
Weight loss more than 10% requires a full care team huddle regardless of ESC assessment.
# ESC Assessment Eating
Assess eating behaviour.
Poor eating is defined as follows:
⦁ ⦁ Newborn is unable to coordinate feeding within 10 minutes of showing hunger cues AND/OR ⦁ ⦁ Newborn is unable to sustain feeding for age appropriate duration at breast OR
⦁ ⦁
Newborn is unable to take in age and weight appropriate volume by alternative feeding method
If the newborn is eating well answer NO and move to section that assess sleeping.
If the newborn is eating poorly answer YES and answer the next question to determine if poor eating is due to substance withdrawal or not.
# ⦁ ⦁
Substance withdrawal symptoms such as fussiness, tremors, uncoordinated suck, and excessive rooting can affect the newborn's ability to eat and gain weight effectively. If poor eating is due to symptoms of substance withdrawal answer YES.
# ⦁ ⦁
If poor eating is clearly due to reasons other than symptoms of withdrawal such as prematurity, transitional sleepiness, excess mucus in the first 24 hours, and inability to latch due to infant / maternal anatomical factors, answer NO. Implement appropriate management strategies (e.g., NG feeds for preterm infants), optimize nonpharmacological interventions, and monitor closely.
# ⦁ ⦁
If it is unclear whether substance withdrawal symptoms are responsible for poor eating, answer YES and continue to monitor closely as this may be an indication of escalating withdrawal symptoms.
Review optimal feeding recommendations with the parent/caregiver and continue to optimize nonpharmacological strategies.
If the newborn is eating poorly a Parent/caregiver-RN huddle is recommended to review optimal feeding recommendations with parent/caregiver. If eating has not improved on subsequent assessment, despite interventions, a full care team huddle is indicated.
# Sleeping
Assess sleeping behaviour.
If the newborn sleeps for more than one hour after feeding answer NO and move to the section that assess consoling.
If the newborn is unable to sleep for at least one hour after feeding answer YES for poor sleeping and answer the next question to determine if poor sleeping is due to substance withdrawal or not.
# ⦁ ⦁
Substance withdrawal symptoms such as fussiness, restlessness, increased startle, and tremors can affect sleeping behaviour. If the newborn is unable to sleep for at least one hour after feeding due to substance withdrawal symptoms answer YES.
# ⦁ ⦁
If the baby sleep less than 1 hour due to reasons other than substance withdrawal such as physiologic cluster feeding in first few days of life, interruptions in sleep due to external noise and ambient light, and interruption of sleep due to clinical care answer NO.
# ⦁ ⦁
If it is unclear whether substance withdrawal symptoms are responsible for poor sleeping or not answer YES and continue to monitor.
A Parent/caregiver-RN huddle is recommended to review nonpharmacological strategies to promote sleeping. If, on subsequent assessment, baby is still sleeping less than one hour after feeding due to symptoms of withdrawal, despite interventions, a full care team huddle is indicated.
# Console
Assess consoling behaviour.
If the newborn consoles easily within 10 minutes and remains consoled for longer than 10 minutes answer NO to indicated that the newborn does not experience any difficulty in consoling and move to the section that assess parental/caregiver presence.
If the newborn is unable to console within 10 minutes or remain consoled for longer than 10 minutes answer YES for difficulty in consoling and answer the next question to determine if difficulty in consoling is due to substance withdrawal or not.
# ⦁ ⦁
Altered neurotransmitter release due to substance withdrawal increase agitation and difficulty in consoling. If the newborn is unable to console easily within 10 minutes and remains consoled for longer than 10 minutes due to substance withdrawal symptoms answer YES.
# ⦁ ⦁
Answer NO if the newborn's inconsolability is clearly due to other factors such as caregiver non-responsiveness to infant hunger cues.
# ⦁ ⦁
If it is unclear whether substance withdrawal symptoms are responsible for inconsolability or not answer YES and continue to monitor.
If newborn has difficulty in consoling regardless of reason a Parent/caregiver-RN Huddle is recommended to review appropriate care interventions and Consoling Support Interventions.
Monitor the newborn closely and continue to optimize non-pharmacological strategies. If newborn is still unable to console at subsequent assessment, despite effective implementation of all levels of consoling support, a full care team huddle is indicated.
Document consoling support needed using the numerical codes 1, 2 or 3:
1. Newborn is able to self-console 2. Newborn can console (and stay consoled) with caregiver support within 10 min 3. Newborn is unable to console with caregiver support within, or cannot stay consoled for 10 minutes Please note the numbers are NOT intended as a "score" but to indicate an escalation of withdrawal symptoms and identify a need for increased intervention.
# Parent/Caregiver Section
Parent/Caregiver Presence and Involvement in Care of the Newborn ⦁ ⦁ Document the time, since last assessment, that the parent/s, or another caregiver, spent with the infant.
# ⦁ ⦁
Caregiver can be a parent, other family member, designated visitor, cuddler, or healthcare worker that can deliver responsive care in a timely manner.
# ⦁ ⦁
Document the caregiver who provided the most care.
Numbers above are NOT intended as a "score" but used for ease of documentation and to identify parental/caregiver involvement in the care of the baby. A Parent/caregiver-RN huddle is recommended if parent/caregiver is not spending enough time at the bedside, and/or not delivering newborn care in a responsive and timely manner. During the huddle the parent/ bedside RN will review options to assist the parent/caregiver to provide responsive and timely care.
# Plan of Care
Parent/Caregiver and Bedside RN huddle
⦁ ⦁
Parent/caregiver and Bedside RN should meet if infant receives a YES for any ESC item, to determine if non-pharmacological care interventions can be optimized further.
# ⦁ ⦁
During the huddle, the parent/caregiver and RN review and discuss how to optimize non-pharmacological care interventions to improve feeding, sleeping and consoling behaviour.
# Full Care Team Huddle
Bedside meeting of entire team (parents/caregiver, bedside RN, nurse leadership if applicable, and provider) is indicated if the newborn:
⦁ ⦁
Has more than 10% weight loss
⦁ ⦁
Continued YES for any ESC items despite optimal non-pharmacological care
⦁ ⦁
Is unable to console despite effective implementation of all levels of consoling support
⦁ ⦁
Has any other significant concerns
The full care team will:
⦁ ⦁
Review non-pharmacological strategies and parental presence
⦁ ⦁
If non-pharmacological care interventions are maximized to the fullest and the newborn continues to have poor eating, sleeping, or consoling behaviour (or other significant concerns are present) and symptoms are felt to be due to substance withdrawal, pharmacological management may be indicated.
# ⦁ ⦁
# Continue to follow the infant closely, optimizing all non-pharmacological interventions regardless of management decision
# Non-Pharmacological Care Interventions
The ESC Care Tool promotes the use of non-pharmacological strategies to support the newborn during the acute phase of substance withdrawal. Use this section to indicate the use of these strategies using the following codes:
# NON-PHARMACOLOGICAL MANAGEMENT
Withdrawal from substances after birth results in physiological and physical dysregulation. This may impact sensory stimulation integration, state regulation, motor and tone control, and the autonomic nervous system. 91 The objective of non-pharmacological care interventions are to provide the infant with an environment that supports their ability to self-regulate. Although these strategies are commonly used to comfort and support infants, high quality research to determine their effectiveness is lacking. Despite the current shortcomings in research methodology, data suggests that non-pharmacological interventions may decrease the severity of withdrawal, the need for medical intervention, and duration of hospitalization. 34,92
# Sensory Stimulation Integration
The following strategies may be helpful to support the infant and prevent sensory overload during the active period of withdrawal: approach the bedside using a gentle voice prior to touching the infant 96 ⦁ ⦁ slow, gentle handling 91,96 ⦁ ⦁ hold infant closely when transferring infant from one space to another to prevent startling 91 ⦁ ⦁ swaddling contains and prevents erratic movements and startling 91,95 ⦁ ⦁ tactile stimulation should be gentle and firm; avoid stroking 80 ⦁ ⦁ apply gentle pressure over the infant's head or body 91,94 ⦁ ⦁ bringing arms/hands midline and positioning infants in a fetal position 91,96,97
# Swaddling
In the newborn exposed to substances swaddling has been shown to:
⦁ ⦁
reduce crying, startles, and physiological stress 98,99 ⦁ ⦁ improve sleep, motor organization and self-regulation 98,99
# Safety
Combination of swaddling with prone position increases the risk of sudden infant death syndrome. Discontinue use of swaddling prior to discharge, as soon as withdrawal symptoms have resolved. See https://www.caringforkids.cps.ca/handouts/swaddling.
# State Regulation
Sleep-wake regulation is an indication of how effectively the infant can regulate his/her internal processes and the influence of external stimulations. Full-term infants will transition between quiet sleep, active sleep, drowsy, quiet awake, and crying.
The infant exposed to substances may:
# Skin-to-Skin
Encourage skin-to-skin contact as much as possible to help calm the baby, promote neurobehavioural organization, bonding and attachment, and increase breastmilk supply (if breastfeeding). Skin-to-skin care is associated with improved sleep patterns, 102 a reduction in excessive crying and motor agitation associated with NAS, and a decreased need for pharmacological management. 103 Parent/caregiver should sit in a comfortable chair and be fully awake and focused on the infant.
Distractions such as cell phones should be avoided. Infant should be naked except for diaper and placed directly on mother's/parent/caregiver's chest with a blanket placed over both for warmth.
A wrap can also be used to secure infant.
# Ensure infant's:
⦁ ⦁
head is turned to one side
⦁ ⦁
head is in the sniffing position and neck straight to maintain airway
⦁ ⦁ face is visible ⦁ ⦁
nose and mouth are not covered by the blanket or wrap
⦁ ⦁
legs are flexed and is lying chest to chest with mother/parent
# Vertical Rocking
Vertical rocking has been shown to decrease neurological hyperactivity and promote selfregulation. 191,104,105 The Hold 106
# ⦁ ⦁
See https://youtu.be/j2C8MkY7Co8.
# ⦁ ⦁
Infant can be swaddled. If not, fold infant's arms snugly across his/her chest.
# ⦁ ⦁
Pick up infant and hold in a vertical, flexed position.
# ⦁ ⦁
Gently but securely hold infant's bottom with the dominant hand.
# ⦁ ⦁
Maintain airway by supporting infant's chin with the other hand.
# ⦁ ⦁
Bring infant's head a bit forward to position infant at a 45-degree angle, as it will be easier to control the infant.
# ⦁ ⦁
Slowly and rhythmically rock infant up and down.
# Rhythmic movement using swings, chairs or beds ⦁ ⦁
Swings or vibrating bouncy seats can also be used to provide rhythmical rocking.
# ⦁ ⦁
Adhere to manufacturer's safety recommendations and site-specific protocols when using. 107
# Motor and Tone Control
The newborn exposed to substances may display: dysmature pattern of swallow-breath interaction 111 These feeding difficulties and the hypermetabolic state due to withdrawal may result in difficulties with weight gain.
# Feeding
Mothers are encouraged to breastfeed unless there is concern related to continued substance use or other medical contraindication is present such as HIV.
# ⦁ ⦁
Despite the documented benefits of human milk, breastfeeding rates are low in women with substance use disorder. [112][113][114] ⦁ ⦁
The risk-benefits of breastfeeding should be carefully considered, and attempts should be made to minimize barriers and promote breastfeeding.
# ⦁ ⦁
In the infant exposed to substances, breastfeeding is associated with:
⦁ ⦁ delayed onset of withdrawal symptoms 96,115 ⦁ ⦁ decreased severity of withdrawal symptoms 82,112,115,116 ⦁ ⦁ decreased need for pharmacological management 115,11,12 ⦁ ⦁ decreased length of pharmacological management 96,112 ⦁ ⦁ shorter length of hospital stay 7,13,14 The Following General Strategies May Be Helpful to Support Optimal Feeding ⦁ ⦁ optimal feeding at early hunger cues without any limits placed in duration or volume of feeding If newborn is breastfeeding, ensure the newborn is latching deeply, with a comfortable latch for mother, and with sustained active suckling with only brief pauses noted. If necessary, assist the mother to achieve more optimal latch/position. To organize suck prior to latching, use expressed breastmilk and have the infant suck on an adult finger. Withhold pacifier use if possible.
# ⦁ ⦁
To organize suck prior to latching, use expressed breastmilk and have the infant suck on an adult finger. Withhold pacifier use if possible.
# ⦁ ⦁
Consider fortifying breastmilk or supplementation with a high-calorie breast milk substitute for poor weight gain. 15,16,17 Bottle Feeding
If newborn is bottle feeding:
⦁ ⦁
Reduce GI discomfort by using mother's expressed breast milk, donor breast milk or breastmilk substitute with a low osmolality. 117
# ⦁ ⦁
Mimic breastfeeding by letting baby pause and rest periodically.
# Skin Care
Newborns are at risk for skin injuries as adaptation to the extrauterine environment is still ongoing. The functionally immature epidermal barrier and acid-mantle increases the risk of chemical, microbial, or friction skin injuries. 119,120 Due to irritability, uncontrolled movements, and diarrhea related to withdrawal, the newborn exposed to substances is at risk for excoriations and diaper dermatitis. 121
# Types of skin injuries Excoriation/abrasions
Redness of the skin or broken/bleeding skin often found on chin, ankles and face.
Cause: Rubbing of an extremity or face on a linen covered surface/blankets due to excessive and uncontrolled movements of the extremities and/or head.
# PHARMACOLOGICAL MANAGEMENT Current Status
The current evidence as to when to initiate medication, treatment regimens, dosing, weaning protocols and use of adjunctive management is limited. 124,125,126 Evidence does show that a standardized pharmacological management protocol with clear weaning guidelines decreases the length of pharmacological intervention and hospital stay. 116,124,127,128 While suboxone and methadone can be used to manage substance withdrawal symptoms in the newborn, morphine is the most commonly used drug to manage newborn opioid withdrawal. 10,23,129 Morphine is a full mu-opioid receptor agonist with well-established pharmacokinetic features and a short half-life.
# General Principles ⦁ ⦁
Rooming-in and implementing non-pharmacological is paramount. Pharmacological intervention should be employed as an adjunct.
# ⦁ ⦁
Use ESC Care Tool to guide management.
# ⦁ ⦁
Minimize opiate replacement exposure in the newborn.
# ⦁ ⦁
The need for pharmacological management alone is not an indication for admission to the NICU. Transfer to the NICU only if there is a medical indication.
Treatment Algorithm for the Newborn Exposed to Substance(s) in Pregnancy
# APPENDIX: CONSOLING SUPPORT INTERVENTIONS CONSOLING SUPPORT INTERVENTIONS THAT CAN BE USED WHEN BABY IS DIFFICULT TO CONSOLE
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To briefly review the clinical presentation and diagnosis of Post Thrombotic Syndrome (PTS) - To help identify deep vein thrombosis (DVT) patients who are at risk of developing PTS - To review strategies to prevent and treat PTS- PTS is a chronic condition that develops in 20% to 50% of patients after DVT. - PTS is a burdensome condition in terms of effect on quality of life and costly in terms of lost productivity and dollars spent.DVT-related residual venous obstruction and valvular reflux lead to increased venous pressure (venous hypertension), which results in leg swelling, reduced calf muscle and skin perfusion, increased vascular permeability, and the associated clinical manifestations of PTS.#
- PTS is primarily diagnosed on clinical grounds.
- There is no gold standard laboratory testing, imaging or functional test that establishes the diagnosis. - The Villalta PTS scale (Table 2) has been adopted by the International Society on Thrombosis and Haemostasis (ISTH) as a standard to diagnose and grade the severity of PTS in clinical studies. - In some patients, it may take a few months for the initial pain and swelling associated with acute DVT to resolve, hence a diagnosis of PTS should be deferred until after the acute phase (i.e. 3-6 months) has passed. This scale is not specific to PTS and a significant proportion of PTS (up to 40%) may be at least in part attributable to preexisting primary venous insufficiency. Assessment of contralateral leg can constitute a simple way of documenting preexisting venous insufficiency. - Symptoms of PTS usually begin within 3-6 months after DVT, but can occur up to 2 years after DVT. Approximately 60% of patients with DVT will recover without any residual symptoms, 30% will have some degree of PTS, and 5-10% will develop severe PTS. Of note, up to 15% of patients with upper extremity DVT also develop PTS. It is not possible to reliably predict which patients with DVT will develop PTS.
# Specific risk factors for PTS:
- Recurrent ipsilateral DVT: Increases risk of PTS by 6-fold (by damaging already compromised venous valves or aggravating venous outflow obstruction). - Extent of initial DVT: Risk of PTS is 2-4 fold higher after proximal (especially iliofemoral) versus distal (calf) DVT. - Higher body mass index: Increases risk of PTS.
- Quality of oral anticoagulation: PTS risk increases if the initial anticoagulation is inadequate (e.g. subtherapeutic INR >50% time during first three months of treatment) but risk is not affected by the intensity or duration of long-term anticoagulation. - Residual thrombosis on ultrasound: Modest (odds ratio of 2) increased risk of PTS.
- Persistent elevation of D-dimer: Elevated levels of D-dimer in the weeks to months after DVT may be a modest risk factor for PTS. - DVT in pregnancy: Increases the risk of PTS.
Age, sex, inherited thrombophilia and whether the DVT was unprovoked or secondary (due to surgery, trauma or cancer) do not appear to influence the likelihood of PTS. Furthermore, as compared with vitamin K antagonist treatment, treatment with low molecular weight heparin and direct oral anticoagulants was shown to be associated with a lower risk of PTS but these results need to be confirmed.
A clinical prediction model, the SOX-PTS score, was recently developed to identify patients at increased risk of developing PTS. High-risk predictors were index DVT affecting the iliac vein, body mass index ≥35 kg/m 2 , and moderate-severe Villalta score severity category at the time of DVT diagnosis. Compared with patients with a score of 0, those with a score of ≥4 had an odds ratio of 5.9 for developing PTS. External validation of the score will be required before it can be put into clinical use.
# PREVENTION OF PTS (TABLE 3): Primary and secondary prevention of DVT
The best way to prevent PTS is to prevent DVT. As ipsilateral DVT recurrence is a strong risk factor for PTS, preventing recurrent DVT by providing therapeutic and adequate duration of anticoagulation for the initial DVT is important.
# Thrombolysis
- Although anticoagulant therapy is the mainstay of treatment for DVT , thrombolysis may be considered for those at high risk of developing PTS. Currently, selection of patients for these thrombolytic techniques is done on a case-by-case basis, and is typically reserved for select patients with extensive (e.g. iliofemoral) thrombosis, onset of symptoms less than 14 days, low risk of bleeding, and long life expectancy. - Thrombolytic therapy in conjunction with heparin to treat acute DVT leads to higher rates of vein patency and better preservation of valve function than the use of heparin alone. - Catheter-directed thrombolysis, which involves infusion of thrombolytic therapy through a catheter inserted directly into the affected vein, is considered to have a lower bleeding risk than systemic thrombolysis; however, this intervention is still associated with an increased risk of major bleeding compared to anticoagulant therapy. - Pharmacomechanical catheter-directed thrombolysis (PCDT) involves infusion of thrombolytic therapy through a catheter inserted directly into the affected vein, along with catheter-based devices that can break up clots. - Three contemporary randomized trials of PCDT did not demonstrate a reduction in the overall frequency of PTS in otherwise unselected patients with proximal DVT or in those with iliofemoral DVT compared to anticoagulant therapy. In one study, PTS severity was reduced and, hence, venous disease quality of life appeared better in patients with iliofemoral DVT who received lytic therapy compared to those randomized to standard care. However, in the second randomized trial, lytic therapy did not significantly affect quality of life; both the generic as well as disease-specific patient-reported health-related quality of life scores showed a similar improvement in both groups during follow-up. However, long term-follow-up data showed that benefit of thrombolytic therapy became more apparent and significant with time. Longer follow-up (>2 years) is needed to appropriately assess efficacy of thrombolysis.
# Elastic Compression Stockings (ECS)
- There are conflicting RCT data on the long-term effectiveness of ECS.
- Two previous small open label trials reported that ECS were effective in preventing PTS, but a more recent large, multicenter, placebo-controlled trial showed no evidence of benefit of active compression stocking used for two years to prevent PTS. Thus, routine use of ECS for two years to prevent PTS in DVT patients is no longer recommended. - A recent multicenter trial showed that if one decides to prescribe ECS to prevent PTS, individualized duration of therapy based on post-thrombotic symptoms/signs is non-inferior to standard duration of therapy of 24 months. - In patients with significant DVT-related swelling, ECS should be tried to relieve symptoms and used for as long as the patient finds them to be effective. - If stockings are used, knee-length and thigh-length ECS have similar physiologic effects; kneelength are easier to apply, more comfortable and less costly.
# TREATMENT OF PTS:
There are few treatment options for symptomatic PTS (Table 3).
- Regular daily use of good-quality ECS as well as exercise may reduce leg swelling and discomfort. - Exercise training program was reported to improve patients' QOL and PTS symptoms.
- Intermittent pneumatic compression sleeve units can help severe, intractable PTS symptoms or severe edema; however they are cumbersome and expensive. - The portable, battery-powered Venowave® intermittent compression device benefits some patients with moderate to severe PTS. - There is no evidence that diuretics or "venoactive" drugs are effective for PTS-related edema or other manifestations. - Post-thrombotic venous ulcers are treated with compression therapy, leg elevation and topical dressings but can be refractory to therapy and tend to recur. Consultation with a dermatologist or wound clinic is often helpful. - Surgical or endovascular treatments for PTS such as venous valve repair, venous bypass and venous stents have only been evaluated in small patient series at single, specialized centers and appear to be of limited value. The ongoing NIH/NHLBI-funded Chronic Venous Thrombosis: Relief With Adjunctive Catheter-Directed Therapy (C-TRACT Trial) will determine if the use of image-guided, endovascular therapy is effective to reduce PTS disease severity and improve quality of life in patients with disabling iliac-obstructive PTS (NCT03250247).
# SPECIAL CONSIDERATIONS:
# Pediatrics
- The incidence of PTS is reported to be as high as 15% in children with DVT.
- There are no pediatric studies evaluating safety and efficacy of therapy for PTS.
- Symptomatic management of PTS in children may follow adult guidelines.
- Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with DVT. When this is not possible, a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of Version: 03August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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To briefly review the clinical presentation and diagnosis of Post Thrombotic Syndrome (PTS) • To help identify deep vein thrombosis (DVT) patients who are at risk of developing PTS • To review strategies to prevent and treat PTS• PTS is a chronic condition that develops in 20% to 50% of patients after DVT. • PTS is a burdensome condition in terms of effect on quality of life and costly in terms of lost productivity and dollars spent.DVT-related residual venous obstruction and valvular reflux lead to increased venous pressure (venous hypertension), which results in leg swelling, reduced calf muscle and skin perfusion, increased vascular permeability, and the associated clinical manifestations of PTS.#
• PTS is primarily diagnosed on clinical grounds.
• There is no gold standard laboratory testing, imaging or functional test that establishes the diagnosis. • The Villalta PTS scale (Table 2) has been adopted by the International Society on Thrombosis and Haemostasis (ISTH) as a standard to diagnose and grade the severity of PTS in clinical studies. • In some patients, it may take a few months for the initial pain and swelling associated with acute DVT to resolve, hence a diagnosis of PTS should be deferred until after the acute phase (i.e. 3-6 months) has passed. This scale is not specific to PTS and a significant proportion of PTS (up to 40%) may be at least in part attributable to preexisting primary venous insufficiency. Assessment of contralateral leg can constitute a simple way of documenting preexisting venous insufficiency. • Symptoms of PTS usually begin within 3-6 months after DVT, but can occur up to 2 years after DVT. Approximately 60% of patients with DVT will recover without any residual symptoms, 30% will have some degree of PTS, and 5-10% will develop severe PTS. Of note, up to 15% of patients with upper extremity DVT also develop PTS. It is not possible to reliably predict which patients with DVT will develop PTS.
# Specific risk factors for PTS:
• Recurrent ipsilateral DVT: Increases risk of PTS by 6-fold (by damaging already compromised venous valves or aggravating venous outflow obstruction). • Extent of initial DVT: Risk of PTS is 2-4 fold higher after proximal (especially iliofemoral) versus distal (calf) DVT. • Higher body mass index: Increases risk of PTS.
• Quality of oral anticoagulation: PTS risk increases if the initial anticoagulation is inadequate (e.g. subtherapeutic INR >50% time during first three months of treatment) but risk is not affected by the intensity or duration of long-term anticoagulation. • Residual thrombosis on ultrasound: Modest (odds ratio of 2) increased risk of PTS.
• Persistent elevation of D-dimer: Elevated levels of D-dimer in the weeks to months after DVT may be a modest risk factor for PTS. • DVT in pregnancy: Increases the risk of PTS.
Age, sex, inherited thrombophilia and whether the DVT was unprovoked or secondary (due to surgery, trauma or cancer) do not appear to influence the likelihood of PTS. Furthermore, as compared with vitamin K antagonist treatment, treatment with low molecular weight heparin and direct oral anticoagulants was shown to be associated with a lower risk of PTS but these results need to be confirmed.
A clinical prediction model, the SOX-PTS score, was recently developed to identify patients at increased risk of developing PTS. High-risk predictors were index DVT affecting the iliac vein, body mass index ≥35 kg/m 2 , and moderate-severe Villalta score severity category at the time of DVT diagnosis. Compared with patients with a score of 0, those with a score of ≥4 had an odds ratio of 5.9 for developing PTS. External validation of the score will be required before it can be put into clinical use.
# PREVENTION OF PTS (TABLE 3): Primary and secondary prevention of DVT
The best way to prevent PTS is to prevent DVT. As ipsilateral DVT recurrence is a strong risk factor for PTS, preventing recurrent DVT by providing therapeutic and adequate duration of anticoagulation for the initial DVT is important.
# Thrombolysis
• Although anticoagulant therapy is the mainstay of treatment for DVT [See the Clinical Guide Deep Vein Thrombosis (DVT): Treatment], thrombolysis may be considered for those at high risk of developing PTS. Currently, selection of patients for these thrombolytic techniques is done on a case-by-case basis, and is typically reserved for select patients with extensive (e.g. iliofemoral) thrombosis, onset of symptoms less than 14 days, low risk of bleeding, and long life expectancy. • Thrombolytic therapy in conjunction with heparin to treat acute DVT leads to higher rates of vein patency and better preservation of valve function than the use of heparin alone. • Catheter-directed thrombolysis, which involves infusion of thrombolytic therapy through a catheter inserted directly into the affected vein, is considered to have a lower bleeding risk than systemic thrombolysis; however, this intervention is still associated with an increased risk of major bleeding compared to anticoagulant therapy. • Pharmacomechanical catheter-directed thrombolysis (PCDT) involves infusion of thrombolytic therapy through a catheter inserted directly into the affected vein, along with catheter-based devices that can break up clots. • Three contemporary randomized trials of PCDT did not demonstrate a reduction in the overall frequency of PTS in otherwise unselected patients with proximal DVT or in those with iliofemoral DVT compared to anticoagulant therapy. In one study, PTS severity was reduced and, hence, venous disease quality of life appeared better in patients with iliofemoral DVT who received lytic therapy compared to those randomized to standard care. However, in the second randomized trial, lytic therapy did not significantly affect quality of life; both the generic as well as disease-specific patient-reported health-related quality of life scores showed a similar improvement in both groups during follow-up. However, long term-follow-up data showed that benefit of thrombolytic therapy became more apparent and significant with time. Longer follow-up (>2 years) is needed to appropriately assess efficacy of thrombolysis.
# Elastic Compression Stockings (ECS)
• There are conflicting RCT data on the long-term effectiveness of ECS.
• Two previous small open label trials reported that ECS were effective in preventing PTS, but a more recent large, multicenter, placebo-controlled trial showed no evidence of benefit of active compression stocking used for two years to prevent PTS. Thus, routine use of ECS for two years to prevent PTS in DVT patients is no longer recommended. • A recent multicenter trial showed that if one decides to prescribe ECS to prevent PTS, individualized duration of therapy based on post-thrombotic symptoms/signs is non-inferior to standard duration of therapy of 24 months. • In patients with significant DVT-related swelling, ECS should be tried to relieve symptoms and used for as long as the patient finds them to be effective. • If stockings are used, knee-length and thigh-length ECS have similar physiologic effects; kneelength are easier to apply, more comfortable and less costly.
# TREATMENT OF PTS:
There are few treatment options for symptomatic PTS (Table 3).
• Regular daily use of good-quality ECS as well as exercise may reduce leg swelling and discomfort. • Exercise training program was reported to improve patients' QOL and PTS symptoms.
• Intermittent pneumatic compression sleeve units can help severe, intractable PTS symptoms or severe edema; however they are cumbersome and expensive. • The portable, battery-powered Venowave® intermittent compression device benefits some patients with moderate to severe PTS. • There is no evidence that diuretics or "venoactive" drugs are effective for PTS-related edema or other manifestations. • Post-thrombotic venous ulcers are treated with compression therapy, leg elevation and topical dressings but can be refractory to therapy and tend to recur. Consultation with a dermatologist or wound clinic is often helpful. • Surgical or endovascular treatments for PTS such as venous valve repair, venous bypass and venous stents have only been evaluated in small patient series at single, specialized centers and appear to be of limited value. The ongoing NIH/NHLBI-funded Chronic Venous Thrombosis: Relief With Adjunctive Catheter-Directed Therapy (C-TRACT Trial) will determine if the use of image-guided, endovascular therapy is effective to reduce PTS disease severity and improve quality of life in patients with disabling iliac-obstructive PTS (NCT03250247).
# SPECIAL CONSIDERATIONS:
# Pediatrics
• The incidence of PTS is reported to be as high as 15% in children with DVT.
• There are no pediatric studies evaluating safety and efficacy of therapy for PTS.
• Symptomatic management of PTS in children may follow adult guidelines.
• Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with DVT. When this is not possible, a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist is recommended.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
•
# Date of Version: 03August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.
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Supporting families through loss and grief is an integral part of Family-Centred Maternity and Newborn Care. Perinatal loss includes infertility during the preconception period, fetal death during pregnancy (miscarriage, ectopic pregnancy, induced abortion and stillbirth) and infant death in the first year of life (neonatal or post-neonatal death). Principles for the care of families that experience a loss 1. Individualized care is provided to meet bereaved parents' personal, cultural and religious needs. 2. Compassionate communication with parents is important both before and after their loss. 3. Parents are given the information and support they need to make informed decisions about their own and their baby's care. 4. Accept and validate parents' feelings and make no assumptions about the intensity and duration of their grief. 5. Parents are cared for in an environment they feel is appropriate and private. 6. Ideally, the same health care providers (HCPs) are responsible for providing care during and following the loss. 7. The support meets the needs of partners or support people and families. 8. Parents have opportunities to create memories of their baby. 9. Parents are helped in performing rituals they consider important. 10. The remains of babies and fetuses are always treated with respect. Options around sensitive care and disposition of the baby after death are discussed. 11. Effective interdisciplinary communication is essential to ensure that all health care team members have accurate and current information. 12. Ongoing support is an essential part of care and is available to everyone, including during a subsequent pregnancy and after the birth of another baby. 13. HCPs involved in the care of bereaved parents have opportunities to develop and update their knowledge and skills, and have access to emotional support for themselves.#
Grief is the normal response to losing a loved one. The experience of loss is unique to each person and to the circumstances. 1 Grief reactions are not based on gestational age, age of the infant, socioeconomic or educational status, number of losses experienced or number of living children. Nor is there a right or wrong way to grieve after a loss. 2 High quality bereavement care includes compassionate and open communication, with informed choice and individualized care. 3 Compassionate communication, the most important element of bereavement care, is required in all aspects of care throughout and following the loss. It includes listening and providing clear information in a sensitive manner.
Effective communication between individual HCPs and care teams and services is also essential to ensure consistent care and accurate information about all available options. Parents and families need the necessary information and time to make the decisions that are right for them, their baby and their family.
Care and support should always be tailored to meet individual needs, preferences and, to the extent possible, cultural practices. It is important not to make assumptions about peoples' wishes and decisions. Institutional practices, protocols and practitioners' belief systems can be unhelpful and even harmful when what is required is empathy, compassion and providing the family with a sense of control.
# > ADDITIONAL RESOURCES ON LOSS AND GRIEF: SEE APPENDIX A
Supporting families through loss and grief is an integral part of Family-Centred Maternity and Newborn Care. The emotional impact of perinatal loss is felt by parents, family members, friends and the health care providers (HCPs) caring for the bereaved family. For some parents and families, this is their first major bereavement and they are unfamiliar with the process and effects of grieving. The role of health care services and community organizations is critical in supporting families experiencing loss any time during the perinatal care trajectory.
# PERINATAL LOSS
A significant portion of Canadian families experience a perinatal loss each year. Perinatal loss includes infertility during the preconception period, fetal death during pregnancy (miscarriage, ectopic pregnancy, induced abortion and stillbirth) and infant death in the first year of life (neonatal or post-neonatal death). The type of loss does not predict or dictate a family's experience of the loss.
TYPES OF PERINATAL LOSS Prior to pregnancy
# Infertility
The inability to conceive after 1 year of regular unprotected sexual intercourse.
# During pregnancy
Fetal mortality An intrauterine death of a fetus at any gestational age.
# Early pregnancy losses (<20 weeks of gestation)
Ectopic pregnancy: A pregnancy that occurs outside of the uterus; usually diagnosed in the first trimester.
# Miscarriage (spontaneous abortion):
The death of a fetus in the womb during the first 20 weeks of pregnancy.
Induced abortion: A procedure to terminate a pregnancy for personal reasons, a prenatal diagnosis of a fetus with a life-limiting anomaly or a significant maternal medical concern.
# Late pregnancy losses (≥ 20 weeks of gestation)
Stillbirth: The death of a fetus at ≥20 weeks' gestation or ≥500 g birth weight that occurs prior to its complete expulsion of or extraction from the mother. i
# After birth
# Infant mortality
The death of an infant during the first year of life.
# Infant deaths (0-364 days)
Neonatal death: The death of a baby who dies within 27 days of being born.
Post-neonatal death: The death of a baby between 28 and 364 days of life.
i In Quebec, only deaths of fetuses weighing ≥500 g (i.e., stillbirths), regardless of the gestation period, must be reported.
In Canada, fetal mortality rate is defined as the number of fetal deaths per 1,000 total births (live births and stillbirths). All provinces and territories (excluding Quebec) require that all stillbirths with a birth weight of 500 g or greater or a gestational age at delivery of 20 weeks or greater be registered (including those following pregnancy termination). Quebec requires the registration of stillbirths with a birth weight of 500 g or greater and does not register pregnancy terminations. 5 Infant mortality rate is defined as the number of deaths of live born babies in the first year after birth per 1,000 live births.
Comparison of the rates of pregnancy and infant loss is affected by the different definitions used provincially, nationally and internationally. Data from some Canadian provinces (e.g., Ontario, Quebec) are excluded because the provinces do not contribute to the Canadian Institute for Health Information-Discharge Abstract Database (CIHI-DAD) or because of data quality concerns.
In addition, some rates are reported per total births (including stillbirths) or only per total live births.
# LOSS PRIOR TO PREGNANCY
Infertility is the inability for a couple to conceive after 1 year of regular unprotected sexual intercourse for couples where the woman is aged less than 35 years and 6 months of regular unprotected sexual intercourse where the women is aged over 35 years. 4 In Canada, the overall number of people facing fertility problems or impaired fecundity increased by 10.3% between 1984 and 2009-2010. The percentage of couples with fertility problems was estimated at 5.4% in 1984, 8.5% in 1992 and 15.7% in 2009-2010, representing almost 1 in 6 couples. 9,10 Although the rate of infertility increases with women's age, the trend in rising infertility rates is not exclusive to older women. The infertility rate was 4.9% in 1984 among couples with a female partner aged 18-29 years and between about 7% and 13.7% in 2009-2010. 9,10 Among couples with a female partner aged 40-44 years, the infertility rate was estimated to be between 14.3% and 20.7% in 2009-2010. 10 In 1984, the rate was only 4.6%. 9 Factors that adversely affect fertility include obesity, smoking, alcohol use and sexually transmitted infections. The most common causes of female infertility include problems with ovulation, damage to the fallopian tubes or uterus or issues with the cervix. 14 The increase in the incidence of infertility is due, in part, to a delay in childbearing. Possible explanations for the postponement of pregnancy include couples starting to live together or getting married at older ages, readily available and effective birth control options and more women in the workforce.
# LOSS DURING PREGNANCY
Fetal mortality is the intrauterine death of a fetus at any gestational age. Fetal death can be due to ectopic pregnancy, miscarriage, induced abortion or stillbirth. Between 2005 and 2014, the overall rate of fetal mortality fluctuated between 7.5 and 8.1 per 1,000 total births. The fetal mortality rate is significantly higher among multiple births (13.5 per 1,000 total births in 2014) than among singletons (4.8 per 1,000 total births). 15 A fetal death may be a complete surprise, with no warning signs, that is diagnosed during a routine ultrasound scan; in other cases, women may notice decreased fetal movements or otherwise suspect that something is wrong. 16 An ectopic pregnancy is a pregnancy that develops outside of the uterus, usually in the fallopian tubes. An ectopic pregnancy occurs in approximately 1-2% of diagnosed pregnancies. 17 Parents may be frightened or distressed if they are waiting for the confirmation of a suspected ectopic pregnancy or receiving treatment for an ectopic pregnancy. Some parents may not have known they were pregnant. Sometimes, HCPs become so focused on the medical/surgical and potential life-threatening nature of ectopic pregnancy, they forget to address the fear and distress as well as the feeling of loss.
Spontaneous losses occur most frequently in the first trimester, with genetic defects the most common cause. Approximately 15% to 25% of pregnancies end in a miscarriage, and the rate increases with maternal age. 18 The miscarriage rate may in fact be higher because many women do not know they were pregnant, but think they had a heavy menstrual period. In addition, some women choose not to disclose their miscarriage to their HCP.
Parents may feel many emotions during or following a miscarriage-grief, distress, shock, confusion, regret, anger, guilt, stress or mixed emotions. For some, these emotions may be intense or overwhelming. 21 Others may feel relieved if the pregnancy was unwanted. Not all women or partners believe that a miscarriage represents the death of a baby. Regardless of what meaning they ascribe to the loss, all parents deserve the same degree of attention and support from HCPs. 22 An induced abortion is a procedure performed to terminate a pregnancy. The reasons may be personal (e.g., the pregnancy is unwanted, financial situation or relationship issues) or medical (e.g., a prenatal diagnosis of a lifelimiting anomaly such as fatal syndromes, congenital anomalies; a significant maternal medical concern such that continuing the pregnancy would be hazardous to the mother's physical or mental health). The rate of termination of pregnancy with a birth weight of at least 500 g or 20 weeks gestational age has remained steady, ranging between 0.5 and 0.6 per 1,000 total births in 2005 and 2014, respectively. 15 In all the provinces except Quebec, stillbirth is defined as fetal death at a birth weight of at least 500 g or a gestational age at delivery of at least 20 weeks and no signs of life (i.e., no heartbeat or breathing). In Quebec, stillbirth is defined as fetal death at a weight greater than 500 g irrespective of gestational age. 5 National stillbirth rates have fluctuated at between 7.9 and 8.3 per 1,000 total births between 2013 and 2017. 23 Parents of multiples face a unique situation when 1 or more of their babies die. One of a set of multiples may die in utero or in the Neonatal Intensive Care Unit (NICU) after a premature birth. 24 In such situations, parents often feel torn between grief at the loss of the baby and joy at the survival of the other baby or babies. They may also feel afraid, guilty and helpless. When the death occurs in utero, some parents are unable to start grieving for the baby or babies who died until after the birth, possibly because they feel they cannot say goodbye or have a funeral. 25 Some parents worry that their fear or grief may affect the surviving baby or babies. 25 It is important for HCPs to acknowledge that parents' feelings are normal and to provide opportunities for parents to voice their concerns.
# LOSS AFTER BIRTH
Infant mortality is defined as the death of an infant in the first year of life. Between 2002 and 2011, the infant mortality rate in Canada fluctuated between 4.9 and 5.4 per 1,000 live births. During that time, neonatal mortality rates fluctuated between 3.5 and 3.9 per 1,000 live births, while post-neonatal mortality rates fluctuated between 1.2 and 1.6 per 1,000 neonatal survivors. Neonatal mortality accounted for 73% of infant deaths in 2011. 15
# CONGENITAL ANOMALIES
Learning that a baby has a congenital anomaly (also known as a birth defect, a congenital disorder or a congenital malformation) can be devastating to families. Congenital anomalies are usually structural or functional. 26 They occur during intrauterine life and can be identified prenatally, at birth or later in infancy (e.g., hearing loss).
Although approximately 50% of all congenital anomalies cannot be linked to a specific cause, some have known genetic, environmental or other causes or risk factors (e.g., maternal age, infections, maternal nutritional status). 26 Between 2005 and 2014, the prevalence of congenital anomalies in Canada fluctuated between 377.5 and 430.5 per 10,000 live births. 15 Congenital anomalies are the second leading cause of infant mortality in Canada. Congenital anomalies detected prenatally may affect decisions about continuing the pregnancy. What parents decide to do when they learn about their baby's anomaly depends on factors such as the knowledge, attitude and communication style of the provider, the information they receive about the condition, their personal beliefs, culture and education level as well as available services and support. 27 After a baby is diagnosed with a congenital anomaly, parents often go through stages of grief similar to those they would have experienced if they had lost the baby. They mourn the loss of the "normal" healthy baby they were expecting. 27 Congenital anomalies can lead to long-term disability, significantly impacting individuals, families and health care systems. 26 Challenges families face include barriers due to bias, quality of life issues, finding resources and support, and helping their child transition to appropriate specialized adult care. It is important that information be provided to parents in clear, timely and sensitive ways that enhance collaborative decision making. 28 During All preterm infants are at greater risk than term infants for lifelong health problems. Medical problems associated with preterm birth include respiratory distress syndrome, chronic lung disease, cardiovascular disorder, asthma, and hearing and vision loss. 30,31 Early births also take a financial toll on families. Emotional tolls can be exacerbated by the lost weeks of pregnancy that would have been spent preparing for parenthood, the inability to take the baby home immediately after birth due to the need for specialized care, financial burdens and the potential or real possibility of the infant dying. 1 In NICUs, infant death commonly occurs after a decision is reached to limit or withdraw lifesustaining treatments when it becomes evident that continuing treatment may prolong the baby's suffering without improving his or her quality of life. 32 These types of decisions can be ethically challenging and morally distressing for parents and HCPs. 33 Helping parents with these decisions through an interdisciplinary, family-centred approach can reduce the provision of ineffective and unnecessary interventions and reduce the suffering of both babies and parents. 33,34 HCPs can also help prepare parents by initiating discussions of how their baby will be cared for, including pain management, when limits to or withdrawal of life-sustaining treatments are being considered. It is important to advise parents that it is difficult to predict how soon a baby will die following withdrawal of life support. 35 When duration of survival is uncertain, it is necessary to prepare them for the possibility that their baby may survive for longer than they may expect.
A perinatal psychologist or clinical ethicist can play a significant role is assisting the family and the attending HCPs. 36 7-7
# PRINCIPLES OF CARE FOR
# FAMILIES EXPERIENCING A LOSS
The support and care that parents receive around the time of a perinatal loss is crucial as it may affect their long-term wellbeing. 15,37 In order to provide holistic care that is sensitive to individual needs, it is important to take a family-centred integrated approach.
A family-centred approach requires that HCPs consider parents' personal, cultural, spiritual and religious needs and be aware of how these may affect their decisions on care for themselves and the baby who has died or is expected to die. Parents' opinions and beliefs may affect the decisions they make regarding antenatal screening and diagnostic testing, miscarriage, termination of pregnancy, continuing a pregnancy after a fetal anomaly is diagnosed, postmortem examinations or funeral practices. 3 These factors may also influence how parents express emotions and grief or how they view themselves as parents.
The role of integrated care-ensuring good coordination, cooperation and communication between and within services provided by health care services, social care systems and local and national support organizations-is also crucial when providing holistic care. 38 PRINCIPLES FOR THE CARE OF FAMILIES THAT EXPERIENCE A LOSS 3, P.11,15,18,39,40 1. Individualized care is provided to meet bereaved parents' personal, cultural and religious needs.
- Compassionate communication with parents is important both before and after their loss. This means information is communicated sensitively and clearly and is tailored to meet the individual needs of parents, using the language they use when discussing their baby or fetus. HCPs are careful to avoid using terms that may be misinterpreted or considered inappropriate.
- Parents are given the information and support they need to make informed decisions about their own and their baby's care. The HCP ensures parents' concerns are heard and addressed.
- HCPs accept and validate parents' feelings and make no assumptions about the intensity and duration of their grief. Responses are personal and not determined by the gestational age or infant's age.
- Parents are cared for in an environment they feel is appropriate, ideally in a single room or dedicated bereavement room for the sake of privacy.
- If possible, the same HCPs are responsible for providing care during and following the loss. Parents can benefit from the support of a continuous team of HCPs who are trained in providing bereavement care and are comfortable offering anticipatory guidance.
- The support meets the needs of partners or support people and families.
- Parents have opportunities to create memories of their baby.
- Parents are helped in performing rituals they consider important.
- The remains of babies and fetuses are always treated with respect. Options around sensitive care and disposition of the baby after death are discussed.
- Effective interdisciplinary communication is essential to ensure that all health care team members have accurate and current information. This means that all involved in caring for the family know their preferences and decisions, and parents do not need to repeatedly explain their situation.
A seamless and informed handover of care from the hospital to the community is equally important.
- Ongoing support is an essential part of care and is available to everyone. Support is available to all women and their partners during a subsequent pregnancy and after the birth of another baby.
- HCPs involved in the care of bereaved parents have opportunities to develop and update their knowledge and skills and have access to emotional support for themselves.
# 7-9 3 GRIEF AND MOURNING
A loss during pregnancy or infancy is a complex and unique tragedy that profoundly affects parents as individuals, as couples and as families. 41,42 The death of an unborn baby or newborn can represent the loss of a significant person and a family member and the loss of hopes, dreams and expectations for the future. The loss may extend to some aspect of self, the loss of self-esteem, the loss of a stage of life or a failure in parenting. This may be the first time parents have felt bereaved and the first time they experience emotional turmoil and devastation
# THEORIES OF GRIEF
Several theories and frameworks help HCPs understand why perinatal loss is unique and how it can affect bereaved families, as well as the HCPs who care for them. The focus of models of loss and bereavement has gone from theories of attachment and loss, to concepts of acute grief, to tasks of mourning, to stages, to psychological processes and phases.
THEORIES OF GRIEF Theory Description
# Attachment Theory
- Emphasizes the interrelationships between attachment, affectional bonds, separation and loss in human relationships.
- Provides a framework for understanding the grief and bereavement that people feel and how these relate to pre-existing relational bond.
# Psychodynamic Theory
- Provides an introspective view of the process of coping with any loss in an adaptive manner.
- Conceptualizes that the duration and intensity of the grieving process force a psychological restructuring of self.
# Interpersonal Theory
- Offers a lens through which to understand the impact prolonged depression (or events that contribute to similar symptoms) can have on interpersonal relationships as well as social relations.
- Focuses on addressing the experience of symptoms as well as social adjustment and interpersonal relations.
# Cognitive Stress Theory
- Stipulates that any stress-inducing situation requires cognitive processing and restructuring.
- "Cognitive schemas" that guide thoughts, beliefs and assumptions about the origin and outlook of events are used to help make sense of the world.
THEORIES OF GRIEF Theory Description
Five Stages of Grief 52 - The stages of grief typically experienced are denial, anger, bargaining, depression and acceptance.
- Individuals do not necessarily go through all these stages in an orderly manner; the experience of grief is varied and unpredictable.
# Dual Process Model of Coping
- Bereaved people alternate between 2 coping modes: loss orientation (focused on adjusting to a loss) and restoration orientation (focused on how to move on in light of the loss).
- Oscillation is a dynamic process where grief work and confrontation overlap. Both are necessary in adaptive grief work, that is, adjusting to life without the loved one.
# Tasks of Mourning
Individuals accomplish 4 tasks in order to complete the process of mourning and for equilibrium to be restored:
- Accepting the reality of the loss;
- Processing the pain of grief;
- Adjusting to the world without the deceased; and
- Finding an enduring connection with the deceased while moving forward with life.
# Theory of Caring
- Caring: "nurturing way of relating to a valued other toward whom one feels a personal sense of commitment and responsibility." 55,p. 165 - Involves 5 caring processes: knowing, being with, doing for, enabling and maintaining belief.
# EXPRESSIONS OF GRIEF
Grief is a multifaceted response to loss that affects the entire person. It includes physical, emotional, intellectual, spiritual, social and occupational elements. 57 While grief can affect a person's emotional and mental wellbeing, it is a normal response to bereavement.
The experience, expression and intensity of grief following a perinatal loss are unique to each individual. 3,58 Grieving style is formed by a person's culture, personality and gender. Individuals need to be allowed to express grief in their own way. Some parents and family members have mental health problems following a loss during pregnancy or in infancy. Some of the more common mental health problems that affect bereaved parents include prolonged grief, clinical depression, anxiety disorders and post-traumatic stress disorder. It is incumbent upon HCPs to assess bereaved parents and offer treatment. 3 Ideally, parents are referred to mental health professionals (e.g., counsellors, psychologists, mental health support workers, psychiatrists) with perinatal bereavement training who understand the unique experiences and challenges the family may be facing. 3
# GRIEF EXPERIENCES OF PARENTS
Parental grief has been recognized as the most intense and overwhelming type of grief. 59 Because individuals grieve in different ways, parents' reactions may be incongruent even though both have had the same loss. 60 The depth and length of each parent's grief depends to some extent on their personality, life experiences and previous experiences of loss, attachment to the baby or to pregnancy, the significance and circumstances of the loss and the support network available to them. 54 It is often assumed that partners bond less deeply than mothers with an unborn child and that they are less severely affected by a loss, especially one that occurs early in pregnancy. 61 In fact, many partners grieve deeply and intensely in response to the death of their baby. 62 Partners may believe they must put their grief on hold in order to support the mother and focus on other practical tasks. 58, Gender expectations may also affect men's ability to acknowledge their own needs. Men may feel they have to be the supporter or strong when faced with a pregnancy loss. Continued research is needed on how men experience pregnancy and infant loss, including the experiences of gay and transgendered men. 66 As a protective mechanism from the pain of loss and grief, parents may withdraw emotionally and physically from the experience or from the family. 63 A perinatal loss may create an added strain on the couple's relationship or it may strengthen it. 63, Some parents have difficulties in their relationship if both do not have the same experiences of grief and are unable to accept each other's different ways of grieving or do not feel they have support from their partner. The parents may also experience sexual difficulties after a loss that affects their relationship. 71 Although the intensity of grief can ease with time, it can also fluctuate depending on circumstances. 58,64 Significant dates such as the baby's due date, the date the baby died, the baby's birth date, Mothers' day, Fathers' day, family celebrations and important life events may trigger parents' feelings of grief.
# GRIEF EXPERIENCES OF OTHER FAMILY MEMBERS AND OF FRIENDS Siblings
Children are usually profoundly affected when their parents are grieving. Just like adults, children's grief response can range from a minor reaction to feeling their world has shattered. Siblings in bereaved families suffer 2 losses: the sibling they were expecting and their parents as they knew them before their sibling's death. 72 Children's response to loss is determined by their personality, age, developmental stage and how the family is coping. Children often cope with grief and loss through play. Support from adults is important as they learn how to grieve from the adults that surround them. While many people want to protect children from the reality of death, as with adults, it is important to provide children with clear, developmentally appropriate explanations for the loss and involve them in memory making and legacy building. How much children are involved in rituals after a loss depends to some extent on age, personal preferences and cultural norms.
" Children's response to loss is determined by their personality, age, developmental stage and how the family is coping.
# Grandparents
Many grandparents are deeply affected by a perinatal loss. For some, the loss evokes painful memories of their own losses for which they did not receive adequate support. Grandparents often grieve for their much anticipated grandchild and for their child whose baby has died. 44,58 They may feel distress in their inability to lessen their child's pain and grief. Grandparents may want to see and hold the baby and participate in the funeral, memorials and other rituals.
# Extended family members and friends
For some families or cultures, there is no division between immediate and extended family, and grandparents, aunts, uncles, siblings and cousins are all regarded as close family, with a new baby considered an addition to the whole family.
For some people, the definition of family may also include close friends. This means that a larger number of people than anticipated may be grieving over the death and want to be directly involved.
# ASSESSMENT OF THE BEREAVED FAMILIES' CARE AND SUPPORT NEEDS
A detailed assessment of the family's grief reactions helps HCPs understand the meaning that each family member has ascribed to the perinatal loss. Such an assessment includes physical, emotional, intellectual, spiritual and social components. A continuous assessment ensures that the care and support provided in the hospital and the community is appropriate and meets family members' needs.
# ELEMENTS OF GRIEF AND LOSS NEEDS ASSESSMENT
Social assessment:
- The person's past experiences and customary way of dealing with death or other crisis situations
- The cultural or religious practices that the person may wish to observe or that may constrain them - The person's past perinatal and other losses, which may influence the grieving process
- The relationships between partners, children and grandparents (and the involvement the parents wish others to have in the grieving process
- The family support system
- The ages of other children and how the parents plan to explain the death to them Psychological assessment:
- Where the parents and the family are in their grieving process
- Help families and supporters accept their feelings, understand the importance of expressing these feelings, and gain hope that the pain will diminish Physical assessment:
- The physical effects of pregnancy, labour and birth and the state of the mother's health during the early postpartum period. This might include excessive bleeding or cramping following a D & C, exhaustion following a long and difficult labour, pain following a caesarean birth and breastmilk production
- The medications taken that might dull her perception of events and limit her ability to recall the details of her loss
- Recognition of any health problems that might affect the mother's ability to conceive and bear children in the future
# Spiritual assessment:
- May be easily overlooked, especially if the person does not profess affiliation with a recognized group - A person's spiritual nature is broader than organized religions; all individuals have a spiritual self with needs that are likely to be heightened at the time of perinatal loss 15,37,73 In order to create a climate of trust, the behaviours, language and timing as well as how much and the way information is provided are important factors affecting parents' experiences of care.
Allowing enough time to process the information also promotes feelings of being cared for. 15 Parents appreciate when HCPs talk with them in a sensitive but clear and honest manner. 31 It is important that HCPs consider the possible impact of the words, terms and phrases they use. 36,37 A sentence that seems inoffensive and practical when speaking to a colleague may be disturbing for bereaved parents. For example, although the terms the products of conception, the embryo or the fetus are clinically correct, they may be distressing for the family. If the baby has been named, parents may consider it important that they and HCPs use his or her name, spell the name correctly and refer to the baby by the appropriate gender pronoun. 31 Other parents may feel more comfortable using the clinical expressions (e.g., "the fetus"), while other parents may prefer to think of their loss as the end of a pregnancy rather than the death of a baby.
Posture, gestures, facial expression and tone of voice are the non-verbal communication cues that can affect how bereaved parents perceive and understand the information HCPs are conveying. 37,74 Parents may discount information if body language does not conform to what is being said. HCPs need to be conscious of the cues and behaviours they display, as individuals may interpret components of non-verbal communication in different ways (i.e., cultural differences in the meanings of touch, some gestures, facial expressions and eye contact).
COMMUNICATING WITH FAMILIES EXPERIENCING A PERINATAL LOSS What to Say What Not to Say
- "I'm sorry" or "I'm sorry for your loss"
- "I wish things had turned out differently"
- "I feel sad" or "I am sad for you"
- "How are you doing with all of this?"
- "Can you tell me about what you are feeling?"
- "Can you tell me what happened today?"
- "What is going on right now?"
- "What is the hardest part for you right now?"
- "What can I do for you?" or "How can I help?"
- "I'm here and ready to listen"
- "Do you have any questions?"
- "Can I call someone for you?"
- "What do you need right now?"
- "We can talk again later"
- "Take all the time you need"
- "We are here to help"
- "Call us if you need us"
- "Tell me about your supports at home"
- "It's ok to cry"
- "This happened for the best" or "Everything happens for a reason"
- "This is nature's way"
- "This is God's will" or "God knows best" or "God needed an angel"
- "It could be worse"
- "At least it all came out"
- "At least you didn't know the baby"
- "You're young, you can try again" or "You can have more children"
- "Time will heal"
- "You have an angel in heaven"
- "It's good your baby died before you got to know him / her well"
- "It was not meant to be"
- "Over time you will forget your baby"
- "It's just your body's way of ending an unhealthy pregnancy"
- "This happens all the time"
- "Be grateful for the children you have"
- "You need to move on"
# BREAKING BAD NEWS
Bad news may be defined as "any information which adversely and seriously affects an individual's view of his or her future". 79 Breaking bad news is a complex communication task. HCPs will want to ensure that they have the privacy and time to convey bad news; respond to parents' emotional reactions; include them in decision making; help them deal with the stress created by their expectations; and allow for the involvement of multiple family members. Also important is the dilemma of how to provide hope when the situation appears bleak. 80 Although breaking bad news is frequently necessary, this responsibility poses a major challenge and can create difficult, painful situations. One of the hardest aspects of breaking bad news is not knowing how parents will react (i.e., will they be silent, tearful, angry, disbelieving or distressed and will they feel guilty or blame themselves or other people).
Communication is a process that requires time and effort. It is best to offer information about the baby's condition in small increments, rather than a "single or isolated act" given all at once, taking care to avoid medical jargon but using terms the parents can understand. Allow time for parents to process the information and grieve, and give them opportunities to express their feelings, share their concerns and determine a strategy for the care of their baby. It is important that HCPs be trained and prepared to face these difficult situations with the skills to sensitively inform parents when something is wrong. Regardless of the circumstances and the parents' reactions to the news, remaining calm and supportive is key. The "Setting, Perception, Invitation, Knowledge, Empathy, Summary and Strategies" approach attempts to lessen the confusion parents feel and provide authentic empathy to alleviate some of the family's grief.
" Allow time for parents to process the information and grieve, and give them opportunities to express their feelings, share their concerns and determine a strategy for the care of their baby.
# PROVIDING INFORMATION AND FACILITATING INFORMED CHOICE
HCPs will want to communicate information about test results, diagnoses and available procedures or care options with consistency, sensitivity, honesty and clarity. 3 Recognize that different sets of parents will have varying information requirements-all communication should be tailored to meet these specific needs and wishes. 3 Verbal explanations are key to high quality bereavement care. Information in hardcopy (e.g., pamphlets, brochures) and other formats (e.g., websites, mobile applications, DVDs) may be useful resources for some people, especially those with sensory or learning disabilities. Despite the potential benefits of such resources, they should be considered a complement to, and not a substitute for, regular face-to-face discussions. 3 HCPs can help parents make informed choices by: 3
- Ensuring that parents are provided timely, accurate and unbiased information about the situation including all available care options or procedures and the potential benefits and risks related to these;
- Being sensitive when providing information;
- Using clear, explicit language;
- Verifying with each parent if additional support is required to help in their decision making;
- Being careful not to overload parents with information;
- Repeating information to parents as necessary; and
- Providing access to specialists as required.
# COMMUNICATION BETWEEN MEMBERS OF THE INTERDISCIPLINARY TEAM
Providing high quality bereavement care requires that all members of the interdisciplinary team involved in caring for the family be well informed, work collaboratively and communicate effectively with each other. Poor communication may add to bereaved parents' distress and cause them to be traumatized through exposure to unnecessary enquiries or insensitive comments. 3 All members of the interdisciplinary team have a responsibility to share relevant information with other team members and document, in medical records, discussions with parents and decisions taken. Regular reviews of the mother's or baby's medical records ensure that they are up to date and include what parents have been told and what decisions have been made.
When there is a transfer of care from one team, unit or service to another, it is essential to also immediately transfer all medical records, including any specific decisions or requests the parents have made and details of any investigations, test results and treatments. The woman's primary care provider (e.g., family physician or nurse practitioner who can provide ongoing follow-up care and support in the community) also needs to be notified.
Ideally, all units and healthcare services have in place policies and procedures to ensure the prompt and efficient transfer of information. When a referral is made or parents are being discharged from the health care facility, immediately inform (with the mother's informed consent) all relevant HCPs by telephone, followed as soon as possible by a written discharge letter. The letter would include a full history of the woman's or baby's care and postmortem examination/test results (if applicable), and information about the condition, follow-up plan, health care services offered, and recommended support services including contact coordinates. 3
# HELPING FAMILIES PLAN FOR LOSS
In instances where a perinatal death is anticipated (i.e., prenatal diagnosis of a fetus with a life-limiting anomaly or a genetic disorder, extremely preterm infants), HCPs can help families prepare for the impending loss by providing sensitive, respectful and well-coordinated care and support. 84,85 Waiting for follow-up tests (e.g., repeat ultrasound) to confirm a possible diagnosis of a fetal anomaly is emotionally difficult. The best outcomes will be achieved when the care provided is individualized to address the parents' needs and their specific situation with, wherever possible, their particular requests accommodated. 3
WHEN HELPING FAMILIES PLAN FOR A PERINATAL LOSS, CONSIDER: 1
- The family's cultural and spiritual beliefs
- The family's level of acceptance of their baby's condition
- The support the members of the family get from one another and from others
- The family's acceptance that the goal is their baby's comfort and care, rather than a cure
# BIRTH PLANS
An individualized birth plan sets down parents' wishes and desires for the upcoming birth. A death that occurs during pregnancy necessitates establishing a birth plan with a different outcome. The family's participation in creating a plan may give them some sense of control. Following the plan allows HCPs to honour the family's choices for their baby without repeatedly asking them for direction. Appendix B provides a sample birth plan for pregnancy loss.
# PERINATAL AND NEONATAL PALLIATIVE CARE
Perinatal palliative care, often referred to as perinatal hospice care, requires the provision of family-centred care for those who choose to continue a pregnancy after their baby is diagnosed with a life-limiting condition. It includes anticipating, preventing and relieving suffering (physical, psychological and spiritual), preserving dignity and promoting quality of life for the baby and family, while respecting the parents' choices and wishes. 86 Perinatal palliative care emphasizes creating a relationship with parents and guiding them in making decisions. Depending on the setting and community, the perinatal palliative care team may include nurses; midwives; physicians (maternal-fetal medicine, OB/GYN, neonatology, pediatrics, family medicine); genetic counsellors; social workers; chaplains; spiritual leaders; child life specialists; doulas; psychologists and other psychotherapists; funeral directors; and volunteers. 86 Bereavement support begins at the time of suspected or actual diagnosis and continues through follow-up care after the baby dies. 86 As with perinatal palliative care, neonatal palliative care can be offered when a baby is quite ill and likely to die. The goals of palliative care are quality of life, comfort or relief from symptoms, and support with tasks and bereavement. 87 Although the development of a palliative or end-of-life care pathway or plan may help parents and HCPs, these are not meant to be used as 'checklists' where all the items or interventions must be completed. Instead, such guides serve as prompts for ensuring babies and their families receive the best care.
Some NICUs include perinatal psychologists as full-time members of their staff to help both parents and HCPs cope with the care of babies who are ill and dying. 36 Collaboration across disciplines and agreement on the plan of care is critical to providing quality neonatal palliative and end-of-life care. It is essential that NICUs have in place policies to ensure good communication between members of the health care team involved in decision making about a baby's care. 90 Including parents in decision making shifts the focus from HCPs to the family and can help defuse professional disagreements.
If possible, parents should have the option of taking their baby home or to a hospice. 91,92 NICUs need policies to ensure that HCPs know of, and can refer parents to a hospice that support parents before and after their baby's death. Parents should be attended in a dedicated and private bereavement care room that is adequately soundproofed so that they cannot hear babies or other parents. 15 It is also important to consider the practical needs of partners or birth partners who may be spending many hours with the bereaved parents (e.g., comfortable chairs, toilet facilities nearby, access to meals). 3 The quality of the care that parents receive immediately after a miscarriage, termination, stillbirth or neonatal death is crucial. This support may have long-term effects on parents' emotional and mental health. 15,37 It is critical that parents have the necessary time to make informed decisions at their own pace. 3 HCPs can support parents by suggesting options and guidance in the hours after the death. 94 That said, parents benefit from the continuous support of a limited number of effective HCPs to minimize the number of interactions. 84
# PROVISION OF EMOTIONAL SUPPORT
HCPs can offer emotional support in many ways to parents who have lost a baby: 3
- Listen and be prepared to listen again and again;
- Accept what parents and family say without judgment, but correct factual misconceptions and misunderstandings;
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Supporting families through loss and grief is an integral part of Family-Centred Maternity and Newborn Care. Perinatal loss includes infertility during the preconception period, fetal death during pregnancy (miscarriage, ectopic pregnancy, induced abortion and stillbirth) and infant death in the first year of life (neonatal or post-neonatal death). Principles for the care of families that experience a loss 1. Individualized care is provided to meet bereaved parents' personal, cultural and religious needs. 2. Compassionate communication with parents is important both before and after their loss. 3. Parents are given the information and support they need to make informed decisions about their own and their baby's care. 4. Accept and validate parents' feelings and make no assumptions about the intensity and duration of their grief. 5. Parents are cared for in an environment they feel is appropriate and private. 6. Ideally, the same health care providers (HCPs) are responsible for providing care during and following the loss. 7. The support meets the needs of partners or support people and families. 8. Parents have opportunities to create memories of their baby. 9. Parents are helped in performing rituals they consider important. 10. The remains of babies and fetuses are always treated with respect. Options around sensitive care and disposition of the baby after death are discussed. 11. Effective interdisciplinary communication is essential to ensure that all health care team members have accurate and current information. 12. Ongoing support is an essential part of care and is available to everyone, including during a subsequent pregnancy and after the birth of another baby. 13. HCPs involved in the care of bereaved parents have opportunities to develop and update their knowledge and skills, and have access to emotional support for themselves.#
Grief is the normal response to losing a loved one. The experience of loss is unique to each person and to the circumstances. 1 Grief reactions are not based on gestational age, age of the infant, socioeconomic or educational status, number of losses experienced or number of living children. Nor is there a right or wrong way to grieve after a loss. 2 High quality bereavement care includes compassionate and open communication, with informed choice and individualized care. 3 Compassionate communication, the most important element of bereavement care, is required in all aspects of care throughout and following the loss. It includes listening and providing clear information in a sensitive manner.
Effective communication between individual HCPs and care teams and services is also essential to ensure consistent care and accurate information about all available options. Parents and families need the necessary information and time to make the decisions that are right for them, their baby and their family.
Care and support should always be tailored to meet individual needs, preferences and, to the extent possible, cultural practices. It is important not to make assumptions about peoples' wishes and decisions. Institutional practices, protocols and practitioners' belief systems can be unhelpful and even harmful when what is required is empathy, compassion and providing the family with a sense of control.
# > ADDITIONAL RESOURCES ON LOSS AND GRIEF: SEE APPENDIX A
Supporting families through loss and grief is an integral part of Family-Centred Maternity and Newborn Care. The emotional impact of perinatal loss is felt by parents, family members, friends and the health care providers (HCPs) caring for the bereaved family. For some parents and families, this is their first major bereavement and they are unfamiliar with the process and effects of grieving. The role of health care services and community organizations is critical in supporting families experiencing loss any time during the perinatal care trajectory.
# PERINATAL LOSS
A significant portion of Canadian families experience a perinatal loss each year. Perinatal loss includes infertility during the preconception period, fetal death during pregnancy (miscarriage, ectopic pregnancy, induced abortion and stillbirth) and infant death in the first year of life (neonatal or post-neonatal death). The type of loss does not predict or dictate a family's experience of the loss.
TYPES OF PERINATAL LOSS [4][5][6][7][8] Prior to pregnancy
# Infertility
The inability to conceive after 1 year of regular unprotected sexual intercourse.
# During pregnancy
Fetal mortality An intrauterine death of a fetus at any gestational age.
# Early pregnancy losses (<20 weeks of gestation)
Ectopic pregnancy: A pregnancy that occurs outside of the uterus; usually diagnosed in the first trimester.
# Miscarriage (spontaneous abortion):
The death of a fetus in the womb during the first 20 weeks of pregnancy.
Induced abortion: A procedure to terminate a pregnancy for personal reasons, a prenatal diagnosis of a fetus with a life-limiting anomaly or a significant maternal medical concern.
# Late pregnancy losses (≥ 20 weeks of gestation)
Stillbirth: The death of a fetus at ≥20 weeks' gestation or ≥500 g birth weight that occurs prior to its complete expulsion of or extraction from the mother. i
# After birth
# Infant mortality
The death of an infant during the first year of life.
# Infant deaths (0-364 days)
Neonatal death: The death of a baby who dies within 27 days of being born.
Post-neonatal death: The death of a baby between 28 and 364 days of life.
i In Quebec, only deaths of fetuses weighing ≥500 g (i.e., stillbirths), regardless of the gestation period, must be reported.
In Canada, fetal mortality rate is defined as the number of fetal deaths per 1,000 total births (live births and stillbirths). All provinces and territories (excluding Quebec) require that all stillbirths with a birth weight of 500 g or greater or a gestational age at delivery of 20 weeks or greater be registered (including those following pregnancy termination). Quebec requires the registration of stillbirths with a birth weight of 500 g or greater and does not register pregnancy terminations. 5 Infant mortality rate is defined as the number of deaths of live born babies in the first year after birth per 1,000 live births.
Comparison of the rates of pregnancy and infant loss is affected by the different definitions used provincially, nationally and internationally. Data from some Canadian provinces (e.g., Ontario, Quebec) are excluded because the provinces do not contribute to the Canadian Institute for Health Information-Discharge Abstract Database (CIHI-DAD) or because of data quality concerns.
In addition, some rates are reported per total births (including stillbirths) or only per total live births.
# LOSS PRIOR TO PREGNANCY
Infertility is the inability for a couple to conceive after 1 year of regular unprotected sexual intercourse for couples where the woman is aged less than 35 years and 6 months of regular unprotected sexual intercourse where the women is aged over 35 years. 4 In Canada, the overall number of people facing fertility problems or impaired fecundity increased by 10.3% between 1984 and 2009-2010. The percentage of couples with fertility problems was estimated at 5.4% in 1984, 8.5% in 1992 and 15.7% in 2009-2010, representing almost 1 in 6 couples. 9,10 Although the rate of infertility increases with women's age, the trend in rising infertility rates is not exclusive to older women. The infertility rate was 4.9% in 1984 among couples with a female partner aged 18-29 years and between about 7% and 13.7% in 2009-2010. 9,10 Among couples with a female partner aged 40-44 years, the infertility rate was estimated to be between 14.3% and 20.7% in 2009-2010. 10 In 1984, the rate was only 4.6%. 9 Factors that adversely affect fertility include obesity, smoking, alcohol use and sexually transmitted infections. [11][12][13] The most common causes of female infertility include problems with ovulation, damage to the fallopian tubes or uterus or issues with the cervix. 14 The increase in the incidence of infertility is due, in part, to a delay in childbearing. Possible explanations for the postponement of pregnancy include couples starting to live together or getting married at older ages, readily available and effective birth control options and more women in the workforce.
# LOSS DURING PREGNANCY
Fetal mortality is the intrauterine death of a fetus at any gestational age. Fetal death can be due to ectopic pregnancy, miscarriage, induced abortion or stillbirth. Between 2005 and 2014, the overall rate of fetal mortality fluctuated between 7.5 and 8.1 per 1,000 total births. The fetal mortality rate is significantly higher among multiple births (13.5 per 1,000 total births in 2014) than among singletons (4.8 per 1,000 total births). 15 A fetal death may be a complete surprise, with no warning signs, that is diagnosed during a routine ultrasound scan; in other cases, women may notice decreased fetal movements or otherwise suspect that something is wrong. 16 An ectopic pregnancy is a pregnancy that develops outside of the uterus, usually in the fallopian tubes. An ectopic pregnancy occurs in approximately 1-2% of diagnosed pregnancies. 17 Parents may be frightened or distressed if they are waiting for the confirmation of a suspected ectopic pregnancy or receiving treatment for an ectopic pregnancy. Some parents may not have known they were pregnant. Sometimes, HCPs become so focused on the medical/surgical and potential life-threatening nature of ectopic pregnancy, they forget to address the fear and distress as well as the feeling of loss.
Spontaneous losses occur most frequently in the first trimester, with genetic defects the most common cause. Approximately 15% to 25% of pregnancies end in a miscarriage, and the rate increases with maternal age. 18 The miscarriage rate may in fact be higher because many women do not know they were pregnant, but think they had a heavy menstrual period. In addition, some women choose not to disclose their miscarriage to their HCP.
Parents may feel many emotions during or following a miscarriage-grief, distress, shock, confusion, regret, anger, guilt, stress or mixed emotions. [19][20][21] For some, these emotions may be intense or overwhelming. 21 Others may feel relieved if the pregnancy was unwanted. Not all women or partners believe that a miscarriage represents the death of a baby. Regardless of what meaning they ascribe to the loss, all parents deserve the same degree of attention and support from HCPs. 22 An induced abortion is a procedure performed to terminate a pregnancy. The reasons may be personal (e.g., the pregnancy is unwanted, financial situation or relationship issues) or medical (e.g., a prenatal diagnosis of a lifelimiting anomaly such as fatal syndromes, congenital anomalies; a significant maternal medical concern such that continuing the pregnancy would be hazardous to the mother's physical or mental health). The rate of termination of pregnancy with a birth weight of at least 500 g or 20 weeks gestational age has remained steady, ranging between 0.5 and 0.6 per 1,000 total births in 2005 and 2014, respectively. 15 In all the provinces except Quebec, stillbirth is defined as fetal death at a birth weight of at least 500 g or a gestational age at delivery of at least 20 weeks and no signs of life (i.e., no heartbeat or breathing). In Quebec, stillbirth is defined as fetal death at a weight greater than 500 g irrespective of gestational age. 5 National stillbirth rates have fluctuated at between 7.9 and 8.3 per 1,000 total births between 2013 and 2017. 23 Parents of multiples face a unique situation when 1 or more of their babies die. One of a set of multiples may die in utero or in the Neonatal Intensive Care Unit (NICU) after a premature birth. 24 In such situations, parents often feel torn between grief at the loss of the baby and joy at the survival of the other baby or babies. They may also feel afraid, guilty and helpless. When the death occurs in utero, some parents are unable to start grieving for the baby or babies who died until after the birth, possibly because they feel they cannot say goodbye or have a funeral. 25 Some parents worry that their fear or grief may affect the surviving baby or babies. 25 It is important for HCPs to acknowledge that parents' feelings are normal and to provide opportunities for parents to voice their concerns.
# LOSS AFTER BIRTH
Infant mortality is defined as the death of an infant in the first year of life. Between 2002 and 2011, the infant mortality rate in Canada fluctuated between 4.9 and 5.4 per 1,000 live births. During that time, neonatal mortality rates fluctuated between 3.5 and 3.9 per 1,000 live births, while post-neonatal mortality rates fluctuated between 1.2 and 1.6 per 1,000 neonatal survivors. Neonatal mortality accounted for 73% of infant deaths in 2011. 15
# CONGENITAL ANOMALIES
Learning that a baby has a congenital anomaly (also known as a birth defect, a congenital disorder or a congenital malformation) can be devastating to families. Congenital anomalies are usually structural or functional. 26 They occur during intrauterine life and can be identified prenatally, at birth or later in infancy (e.g., hearing loss).
Although approximately 50% of all congenital anomalies cannot be linked to a specific cause, some have known genetic, environmental or other causes or risk factors (e.g., maternal age, infections, maternal nutritional status). 26 Between 2005 and 2014, the prevalence of congenital anomalies in Canada fluctuated between 377.5 and 430.5 per 10,000 live births. 15 Congenital anomalies are the second leading cause of infant mortality in Canada. Congenital anomalies detected prenatally may affect decisions about continuing the pregnancy. What parents decide to do when they learn about their baby's anomaly depends on factors such as the knowledge, attitude and communication style of the provider, the information they receive about the condition, their personal beliefs, culture and education level as well as available services and support. 27 After a baby is diagnosed with a congenital anomaly, parents often go through stages of grief similar to those they would have experienced if they had lost the baby. They mourn the loss of the "normal" healthy baby they were expecting. 27 Congenital anomalies can lead to long-term disability, significantly impacting individuals, families and health care systems. 26 Challenges families face include barriers due to bias, quality of life issues, finding resources and support, and helping their child transition to appropriate specialized adult care. It is important that information be provided to parents in clear, timely and sensitive ways that enhance collaborative decision making. 28 During All preterm infants are at greater risk than term infants for lifelong health problems. Medical problems associated with preterm birth include respiratory distress syndrome, chronic lung disease, cardiovascular disorder, asthma, and hearing and vision loss. 30,31 Early births also take a financial toll on families. Emotional tolls can be exacerbated by the lost weeks of pregnancy that would have been spent preparing for parenthood, the inability to take the baby home immediately after birth due to the need for specialized care, financial burdens and the potential or real possibility of the infant dying. 1 In NICUs, infant death commonly occurs after a decision is reached to limit or withdraw lifesustaining treatments when it becomes evident that continuing treatment may prolong the baby's suffering without improving his or her quality of life. 32 These types of decisions can be ethically challenging and morally distressing for parents and HCPs. 33 Helping parents with these decisions through an interdisciplinary, family-centred approach can reduce the provision of ineffective and unnecessary interventions and reduce the suffering of both babies and parents. 33,34 HCPs can also help prepare parents by initiating discussions of how their baby will be cared for, including pain management, when limits to or withdrawal of life-sustaining treatments are being considered. It is important to advise parents that it is difficult to predict how soon a baby will die following withdrawal of life support. 35 When duration of survival is uncertain, it is necessary to prepare them for the possibility that their baby may survive for longer than they may expect.
A perinatal psychologist or clinical ethicist can play a significant role is assisting the family and the attending HCPs. 36 7-7
# PRINCIPLES OF CARE FOR
# FAMILIES EXPERIENCING A LOSS
The support and care that parents receive around the time of a perinatal loss is crucial as it may affect their long-term wellbeing. 15,37 In order to provide holistic care that is sensitive to individual needs, it is important to take a family-centred integrated approach.
A family-centred approach requires that HCPs consider parents' personal, cultural, spiritual and religious needs and be aware of how these may affect their decisions on care for themselves and the baby who has died or is expected to die. Parents' opinions and beliefs may affect the decisions they make regarding antenatal screening and diagnostic testing, miscarriage, termination of pregnancy, continuing a pregnancy after a fetal anomaly is diagnosed, postmortem examinations or funeral practices. 3 These factors may also influence how parents express emotions and grief or how they view themselves as parents.
The role of integrated care-ensuring good coordination, cooperation and communication between and within services provided by health care services, social care systems and local and national support organizations-is also crucial when providing holistic care. 38 PRINCIPLES FOR THE CARE OF FAMILIES THAT EXPERIENCE A LOSS 3, P.11,15,18,39,40 1. Individualized care is provided to meet bereaved parents' personal, cultural and religious needs.
2. Compassionate communication with parents is important both before and after their loss. This means information is communicated sensitively and clearly and is tailored to meet the individual needs of parents, using the language they use when discussing their baby or fetus. HCPs are careful to avoid using terms that may be misinterpreted or considered inappropriate.
3. Parents are given the information and support they need to make informed decisions about their own and their baby's care. The HCP ensures parents' concerns are heard and addressed.
4. HCPs accept and validate parents' feelings and make no assumptions about the intensity and duration of their grief. Responses are personal and not determined by the gestational age or infant's age.
5. Parents are cared for in an environment they feel is appropriate, ideally in a single room or dedicated bereavement room for the sake of privacy.
6. If possible, the same HCPs are responsible for providing care during and following the loss. Parents can benefit from the support of a continuous team of HCPs who are trained in providing bereavement care and are comfortable offering anticipatory guidance.
7. The support meets the needs of partners or support people and families.
8. Parents have opportunities to create memories of their baby.
9. Parents are helped in performing rituals they consider important.
10. The remains of babies and fetuses are always treated with respect. Options around sensitive care and disposition of the baby after death are discussed.
11. Effective interdisciplinary communication is essential to ensure that all health care team members have accurate and current information. This means that all involved in caring for the family know their preferences and decisions, and parents do not need to repeatedly explain their situation.
A seamless and informed handover of care from the hospital to the community is equally important.
12. Ongoing support is an essential part of care and is available to everyone. Support is available to all women and their partners during a subsequent pregnancy and after the birth of another baby.
13. HCPs involved in the care of bereaved parents have opportunities to develop and update their knowledge and skills and have access to emotional support for themselves.
# 7-9 3 GRIEF AND MOURNING
A loss during pregnancy or infancy is a complex and unique tragedy that profoundly affects parents as individuals, as couples and as families. 41,42 The death of an unborn baby or newborn can represent the loss of a significant person and a family member and the loss of hopes, dreams and expectations for the future. The loss may extend to some aspect of self, the loss of self-esteem, the loss of a stage of life or a failure in parenting. [43][44][45][46] This may be the first time parents have felt bereaved and the first time they experience emotional turmoil and devastation
# THEORIES OF GRIEF
Several theories and frameworks help HCPs understand why perinatal loss is unique and how it can affect bereaved families, as well as the HCPs who care for them. The focus of models of loss and bereavement has gone from theories of attachment and loss, to concepts of acute grief, to tasks of mourning, to stages, to psychological processes and phases.
THEORIES OF GRIEF [47][48][49][50][51][52][53][54][55][56] Theory Description
# Attachment Theory
• Emphasizes the interrelationships between attachment, affectional bonds, separation and loss in human relationships.
• Provides a framework for understanding the grief and bereavement that people feel and how these relate to pre-existing relational bond.
# Psychodynamic Theory
• Provides an introspective view of the process of coping with any loss in an adaptive manner.
• Conceptualizes that the duration and intensity of the grieving process force a psychological restructuring of self.
# Interpersonal Theory
• Offers a lens through which to understand the impact prolonged depression (or events that contribute to similar symptoms) can have on interpersonal relationships as well as social relations.
• Focuses on addressing the experience of symptoms as well as social adjustment and interpersonal relations.
# Cognitive Stress Theory
• Stipulates that any stress-inducing situation requires cognitive processing and restructuring.
• "Cognitive schemas" that guide thoughts, beliefs and assumptions about the origin and outlook of events are used to help make sense of the world.
THEORIES OF GRIEF [47][48][49][50][51][52][53][54][55][56] Theory Description
Five Stages of Grief 52 • The stages of grief typically experienced are denial, anger, bargaining, depression and acceptance.
• Individuals do not necessarily go through all these stages in an orderly manner; the experience of grief is varied and unpredictable.
# Dual Process Model of Coping
• Bereaved people alternate between 2 coping modes: loss orientation (focused on adjusting to a loss) and restoration orientation (focused on how to move on in light of the loss).
• Oscillation is a dynamic process where grief work and confrontation overlap. Both are necessary in adaptive grief work, that is, adjusting to life without the loved one.
# Tasks of Mourning
Individuals accomplish 4 tasks in order to complete the process of mourning and for equilibrium to be restored:
• Accepting the reality of the loss;
• Processing the pain of grief;
• Adjusting to the world without the deceased; and
• Finding an enduring connection with the deceased while moving forward with life.
# Theory of Caring
• Caring: "nurturing way of relating to a valued other toward whom one feels a personal sense of commitment and responsibility." 55,p. 165 • Involves 5 caring processes: knowing, being with, doing for, enabling and maintaining belief.
# EXPRESSIONS OF GRIEF
Grief is a multifaceted response to loss that affects the entire person. It includes physical, emotional, intellectual, spiritual, social and occupational elements. 57 While grief can affect a person's emotional and mental wellbeing, it is a normal response to bereavement.
The experience, expression and intensity of grief following a perinatal loss are unique to each individual. 3,58 Grieving style is formed by a person's culture, personality and gender. Individuals need to be allowed to express grief in their own way. Some parents and family members have mental health problems following a loss during pregnancy or in infancy. Some of the more common mental health problems that affect bereaved parents include prolonged grief, clinical depression, anxiety disorders and post-traumatic stress disorder. It is incumbent upon HCPs to assess bereaved parents and offer treatment. 3 Ideally, parents are referred to mental health professionals (e.g., counsellors, psychologists, mental health support workers, psychiatrists) with perinatal bereavement training who understand the unique experiences and challenges the family may be facing. 3
# GRIEF EXPERIENCES OF PARENTS
Parental grief has been recognized as the most intense and overwhelming type of grief. 59 Because individuals grieve in different ways, parents' reactions may be incongruent even though both have had the same loss. 60 The depth and length of each parent's grief depends to some extent on their personality, life experiences and previous experiences of loss, attachment to the baby or to pregnancy, the significance and circumstances of the loss and the support network available to them. 54 It is often assumed that partners bond less deeply than mothers with an unborn child and that they are less severely affected by a loss, especially one that occurs early in pregnancy. 61 In fact, many partners grieve deeply and intensely in response to the death of their baby. 62 Partners may believe they must put their grief on hold in order to support the mother and focus on other practical tasks. 58,[63][64][65] Gender expectations may also affect men's ability to acknowledge their own needs. Men may feel they have to be the supporter or strong when faced with a pregnancy loss. Continued research is needed on how men experience pregnancy and infant loss, including the experiences of gay and transgendered men. 66 As a protective mechanism from the pain of loss and grief, parents may withdraw emotionally and physically from the experience or from the family. 63 A perinatal loss may create an added strain on the couple's relationship or it may strengthen it. 63,[67][68][69][70] Some parents have difficulties in their relationship if both do not have the same experiences of grief and are unable to accept each other's different ways of grieving or do not feel they have support from their partner. The parents may also experience sexual difficulties after a loss that affects their relationship. 71 Although the intensity of grief can ease with time, it can also fluctuate depending on circumstances. 58,64 Significant dates such as the baby's due date, the date the baby died, the baby's birth date, Mothers' day, Fathers' day, family celebrations and important life events may trigger parents' feelings of grief.
# GRIEF EXPERIENCES OF OTHER FAMILY MEMBERS AND OF FRIENDS Siblings
Children are usually profoundly affected when their parents are grieving. Just like adults, children's grief response can range from a minor reaction to feeling their world has shattered. Siblings in bereaved families suffer 2 losses: the sibling they were expecting and their parents as they knew them before their sibling's death. 72 Children's response to loss is determined by their personality, age, developmental stage and how the family is coping. Children often cope with grief and loss through play. Support from adults is important as they learn how to grieve from the adults that surround them. While many people want to protect children from the reality of death, as with adults, it is important to provide children with clear, developmentally appropriate explanations for the loss and involve them in memory making and legacy building. How much children are involved in rituals after a loss depends to some extent on age, personal preferences and cultural norms.
" Children's response to loss is determined by their personality, age, developmental stage and how the family is coping.
# Grandparents
Many grandparents are deeply affected by a perinatal loss. For some, the loss evokes painful memories of their own losses for which they did not receive adequate support. Grandparents often grieve for their much anticipated grandchild and for their child whose baby has died. 44,58 They may feel distress in their inability to lessen their child's pain and grief. Grandparents may want to see and hold the baby and participate in the funeral, memorials and other rituals.
# Extended family members and friends
For some families or cultures, there is no division between immediate and extended family, and grandparents, aunts, uncles, siblings and cousins are all regarded as close family, with a new baby considered an addition to the whole family.
For some people, the definition of family may also include close friends. This means that a larger number of people than anticipated may be grieving over the death and want to be directly involved.
# ASSESSMENT OF THE BEREAVED FAMILIES' CARE AND SUPPORT NEEDS
A detailed assessment of the family's grief reactions helps HCPs understand the meaning that each family member has ascribed to the perinatal loss. Such an assessment includes physical, emotional, intellectual, spiritual and social components. A continuous assessment ensures that the care and support provided in the hospital and the community is appropriate and meets family members' needs.
7-13
# ELEMENTS OF GRIEF AND LOSS NEEDS ASSESSMENT
Social assessment:
• The person's past experiences and customary way of dealing with death or other crisis situations
• The cultural or religious practices that the person may wish to observe or that may constrain them • The person's past perinatal and other losses, which may influence the grieving process
• The relationships between partners, children and grandparents (and the involvement the parents wish others to have in the grieving process
• The family support system
• The ages of other children and how the parents plan to explain the death to them Psychological assessment:
• Where the parents and the family are in their grieving process
• Help families and supporters accept their feelings, understand the importance of expressing these feelings, and gain hope that the pain will diminish Physical assessment:
• The physical effects of pregnancy, labour and birth and the state of the mother's health during the early postpartum period. This might include excessive bleeding or cramping following a D & C, exhaustion following a long and difficult labour, pain following a caesarean birth and breastmilk production
• The medications taken that might dull her perception of events and limit her ability to recall the details of her loss
• Recognition of any health problems that might affect the mother's ability to conceive and bear children in the future
# Spiritual assessment:
• May be easily overlooked, especially if the person does not profess affiliation with a recognized group • A person's spiritual nature is broader than organized religions; all individuals have a spiritual self with needs that are likely to be heightened at the time of perinatal loss 15,37,73 In order to create a climate of trust, the behaviours, language and timing as well as how much and the way information is provided are important factors affecting parents' experiences of care.
Allowing enough time to process the information also promotes feelings of being cared for. 15 Parents appreciate when HCPs talk with them in a sensitive but clear and honest manner. 31 It is important that HCPs consider the possible impact of the words, terms and phrases they use. 36,37 A sentence that seems inoffensive and practical when speaking to a colleague may be disturbing for bereaved parents. For example, although the terms the products of conception, the embryo or the fetus are clinically correct, they may be distressing for the family. If the baby has been named, parents may consider it important that they and HCPs use his or her name, spell the name correctly and refer to the baby by the appropriate gender pronoun. 31 Other parents may feel more comfortable using the clinical expressions (e.g., "the fetus"), while other parents may prefer to think of their loss as the end of a pregnancy rather than the death of a baby.
Posture, gestures, facial expression and tone of voice are the non-verbal communication cues that can affect how bereaved parents perceive and understand the information HCPs are conveying. 37,74 Parents may discount information if body language does not conform to what is being said. HCPs need to be conscious of the cues and behaviours they display, as individuals may interpret components of non-verbal communication in different ways (i.e., cultural differences in the meanings of touch, some gestures, facial expressions and eye contact).
# 7-15
COMMUNICATING WITH FAMILIES EXPERIENCING A PERINATAL LOSS [75][76][77] What to Say What Not to Say
• "I'm sorry" or "I'm sorry for your loss"
• "I wish things had turned out differently"
• "I feel sad" or "I am sad for you"
• "How are you doing with all of this?"
• "Can you tell me about what you are feeling?"
• "Can you tell me what happened today?"
• "What is going on right now?"
• "What is the hardest part for you right now?"
• "What can I do for you?" or "How can I help?"
• "I'm here and ready to listen"
• "Do you have any questions?"
• "Can I call someone for you?"
• "What do you need right now?"
• "We can talk again later"
• "Take all the time you need"
• "We are here to help"
• "Call us if you need us"
• "Tell me about your supports at home"
• "It's ok to cry"
• "This happened for the best" or "Everything happens for a reason"
• "This is nature's way"
• "This is God's will" or "God knows best" or "God needed an angel"
• "It could be worse"
• "At least it all came out"
• "At least you didn't know the baby"
• "You're young, you can try again" or "You can have more children"
• "Time will heal"
• "You have an angel in heaven"
• "It's good your baby died before you got to know him / her well"
• "It was not meant to be"
• "Over time you will forget your baby"
• "It's just your body's way of ending an unhealthy pregnancy"
• "This happens all the time"
• "Be grateful for the children you have"
• "You need to move on"
# BREAKING BAD NEWS
Bad news may be defined as "any information which adversely and seriously affects an individual's view of his or her future". 79 Breaking bad news is a complex communication task. HCPs will want to ensure that they have the privacy and time to convey bad news; respond to parents' emotional reactions; include them in decision making; help them deal with the stress created by their expectations; and allow for the involvement of multiple family members. Also important is the dilemma of how to provide hope when the situation appears bleak. 80 Although breaking bad news is frequently necessary, this responsibility poses a major challenge and can create difficult, painful situations. One of the hardest aspects of breaking bad news is not knowing how parents will react (i.e., will they be silent, tearful, angry, disbelieving or distressed and will they feel guilty or blame themselves or other people).
Communication is a process that requires time and effort. It is best to offer information about the baby's condition in small increments, rather than a "single or isolated act" given all at once, taking care to avoid medical jargon but using terms the parents can understand. Allow time for parents to process the information and grieve, and give them opportunities to express their feelings, share their concerns and determine a strategy for the care of their baby. [81][82][83] It is important that HCPs be trained and prepared to face these difficult situations with the skills to sensitively inform parents when something is wrong. Regardless of the circumstances and the parents' reactions to the news, remaining calm and supportive is key. The "Setting, Perception, Invitation, Knowledge, Empathy, Summary and Strategies" approach attempts to lessen the confusion parents feel and provide authentic empathy to alleviate some of the family's grief.
" Allow time for parents to process the information and grieve, and give them opportunities to express their feelings, share their concerns and determine a strategy for the care of their baby.
# PROVIDING INFORMATION AND FACILITATING INFORMED CHOICE
HCPs will want to communicate information about test results, diagnoses and available procedures or care options with consistency, sensitivity, honesty and clarity. 3 Recognize that different sets of parents will have varying information requirements-all communication should be tailored to meet these specific needs and wishes. 3 Verbal explanations are key to high quality bereavement care. Information in hardcopy (e.g., pamphlets, brochures) and other formats (e.g., websites, mobile applications, DVDs) may be useful resources for some people, especially those with sensory or learning disabilities. Despite the potential benefits of such resources, they should be considered a complement to, and not a substitute for, regular face-to-face discussions. 3 HCPs can help parents make informed choices by: 3
• Ensuring that parents are provided timely, accurate and unbiased information about the situation including all available care options or procedures and the potential benefits and risks related to these;
• Being sensitive when providing information;
• Using clear, explicit language;
• Verifying with each parent if additional support is required to help in their decision making;
• Being careful not to overload parents with information;
• Repeating information to parents as necessary; and
• Providing access to specialists as required.
# COMMUNICATION BETWEEN MEMBERS OF THE INTERDISCIPLINARY TEAM
Providing high quality bereavement care requires that all members of the interdisciplinary team involved in caring for the family be well informed, work collaboratively and communicate effectively with each other. Poor communication may add to bereaved parents' distress and cause them to be traumatized through exposure to unnecessary enquiries or insensitive comments. 3 All members of the interdisciplinary team have a responsibility to share relevant information with other team members and document, in medical records, discussions with parents and decisions taken. Regular reviews of the mother's or baby's medical records ensure that they are up to date and include what parents have been told and what decisions have been made.
When there is a transfer of care from one team, unit or service to another, it is essential to also immediately transfer all medical records, including any specific decisions or requests the parents have made and details of any investigations, test results and treatments. The woman's primary care provider (e.g., family physician or nurse practitioner who can provide ongoing follow-up care and support in the community) also needs to be notified.
Ideally, all units and healthcare services have in place policies and procedures to ensure the prompt and efficient transfer of information. When a referral is made or parents are being discharged from the health care facility, immediately inform (with the mother's informed consent) all relevant HCPs by telephone, followed as soon as possible by a written discharge letter. The letter would include a full history of the woman's or baby's care and postmortem examination/test results (if applicable), and information about the condition, follow-up plan, health care services offered, and recommended support services including contact coordinates. 3
# HELPING FAMILIES PLAN FOR LOSS
In instances where a perinatal death is anticipated (i.e., prenatal diagnosis of a fetus with a life-limiting anomaly or a genetic disorder, extremely preterm infants), HCPs can help families prepare for the impending loss by providing sensitive, respectful and well-coordinated care and support. 84,85 Waiting for follow-up tests (e.g., repeat ultrasound) to confirm a possible diagnosis of a fetal anomaly is emotionally difficult. The best outcomes will be achieved when the care provided is individualized to address the parents' needs and their specific situation with, wherever possible, their particular requests accommodated. 3
# 7-19
WHEN HELPING FAMILIES PLAN FOR A PERINATAL LOSS, CONSIDER: 1
• The family's cultural and spiritual beliefs
• The family's level of acceptance of their baby's condition
• The support the members of the family get from one another and from others
• The family's acceptance that the goal is their baby's comfort and care, rather than a cure
# BIRTH PLANS
An individualized birth plan sets down parents' wishes and desires for the upcoming birth. A death that occurs during pregnancy necessitates establishing a birth plan with a different outcome. The family's participation in creating a plan may give them some sense of control. Following the plan allows HCPs to honour the family's choices for their baby without repeatedly asking them for direction. Appendix B provides a sample birth plan for pregnancy loss.
# PERINATAL AND NEONATAL PALLIATIVE CARE
Perinatal palliative care, often referred to as perinatal hospice care, requires the provision of family-centred care for those who choose to continue a pregnancy after their baby is diagnosed with a life-limiting condition. It includes anticipating, preventing and relieving suffering (physical, psychological and spiritual), preserving dignity and promoting quality of life for the baby and family, while respecting the parents' choices and wishes. 86 Perinatal palliative care emphasizes creating a relationship with parents and guiding them in making decisions. Depending on the setting and community, the perinatal palliative care team may include nurses; midwives; physicians (maternal-fetal medicine, OB/GYN, neonatology, pediatrics, family medicine); genetic counsellors; social workers; chaplains; spiritual leaders; child life specialists; doulas; psychologists and other psychotherapists; funeral directors; and volunteers. 86 Bereavement support begins at the time of suspected or actual diagnosis and continues through follow-up care after the baby dies. 86 As with perinatal palliative care, neonatal palliative care can be offered when a baby is quite ill and likely to die. The goals of palliative care are quality of life, comfort or relief from symptoms, and support with tasks and bereavement. 87 Although the development of a palliative or end-of-life care pathway or plan may help parents and HCPs, these are not meant to be used as 'checklists' where all the items or interventions must be completed. [88][89][90] Instead, such guides serve as prompts for ensuring babies and their families receive the best care.
Some NICUs include perinatal psychologists as full-time members of their staff to help both parents and HCPs cope with the care of babies who are ill and dying. 36 Collaboration across disciplines and agreement on the plan of care is critical to providing quality neonatal palliative and end-of-life care. It is essential that NICUs have in place policies to ensure good communication between members of the health care team involved in decision making about a baby's care. 90 Including parents in decision making shifts the focus from HCPs to the family and can help defuse professional disagreements.
If possible, parents should have the option of taking their baby home or to a hospice. 91,92 NICUs need policies to ensure that HCPs know of, and can refer parents to a hospice that support parents before and after their baby's death. Parents should be attended in a dedicated and private bereavement care room that is adequately soundproofed so that they cannot hear babies or other parents. 15 It is also important to consider the practical needs of partners or birth partners who may be spending many hours with the bereaved parents (e.g., comfortable chairs, toilet facilities nearby, access to meals). 3 The quality of the care that parents receive immediately after a miscarriage, termination, stillbirth or neonatal death is crucial. This support may have long-term effects on parents' emotional and mental health. 15,37 It is critical that parents have the necessary time to make informed decisions at their own pace. 3 HCPs can support parents by suggesting options and guidance in the hours after the death. 94 That said, parents benefit from the continuous support of a limited number of effective HCPs to minimize the number of interactions. 84
# PROVISION OF EMOTIONAL SUPPORT
HCPs can offer emotional support in many ways to parents who have lost a baby: 3
• Listen and be prepared to listen again and again;
• Accept what parents and family say without judgment, but correct factual misconceptions and misunderstandings;
• Acknowledge the parents' feelings and respond with empathy, expressing sympathy and sorrow;
• Avoid assumptions, clichés and empty reassurances;
• Remain calm when parents express strong feelings;
• Be genuine and willing to help and show compassion and kindness;
• Support parents in making informed choices; and
• Resist the temptation to give advice unless specifically asked.
The support offered should be based on the needs of parents so that they can maintain a measure of control over their own care.
When offering and providing emotional support to parents, it is important that HCPS remember that grief can be expressed in different ways and to avoid assumptions based on parents' outward expressions of grief. Some parents may be open about their feelings, while others may not show any outward signs of emotion while hurting deeply inside.
# SEEING AND HOLDING THE BABY
Ask bereaved parents whether they wish to see or hold their baby. Offering this opportunity needs to occur within the context of relationship-based care, supportive conversations with parents, respect for their autonomy and support for them throughout the process. 3,77,95,96 Cultural and religious variances should be taken into account to the full extent possible. In some cultures, close contact with a dead body is prohibited, while in others, it is considered the highest form of respect to remain with a body until burial.
If parents decide to see and hold their baby, contact should not be restricted. Parents deserve to hold their baby for as long or as short a time as they wish. 77 A growing number of hospitals are now providing parents with specialized cooling cots to allow them to spend more time making memories with their baby. 97 The Pregnancy Loss and Infant Death Alliance has released a position statement on supporting parents in spending time with their baby. 98
# CREATING MEMORIES
Many bereaved parents want to cherish their baby and preserve his or her memory and importance in their lives. [99][100][101][102] Parents appreciate having photos and often express regret if these were not provided by the hospital. 99 Many find creating and sharing mementoes of their deceased baby helpful in their grieving process. 103,104 Mementoes can include bathing and dressing the baby; talking to the baby and using the baby's name; engaging in religious or naming ceremonies; introducing the baby to extended family; and capturing interactions in photographs and videos. 69 Parents often decide to choose a meaningful name for their baby. This and other checklists can be used to make suggestions to parents. 105 They are not meant to be adhered to as directives, rules or tasks that must be completed-at the end of the day, parental choice is paramount. 3 For example, while many parents will choose to retain mementoes of their baby, others may decline on personal, cultural or religious grounds. 106
# FAMILY INVOLVEMENT
After losing a pregnancy or baby, some parents want to be alone while others find comfort and support in having extended family and friends around them. HCPs will want to determine the parents' needs and then support them in doing what they feel is right for them. HCPs can help family and friends understand the types of support the bereaved parents usually require (e.g., suggest avoiding statements that minimize the parents' experience, explain the benefits of small gestures of kindness). 107
# RITUAL AND SERVICES
Most bereaved parents who participate in rituals find support, meaning and facilitation of their grief. 59,64,108,109 Participating in such rituals acknowledges the reality of the baby's death, provides social support, encourages the expression of emotions and helps convert the relationship with the baby from presence to memory. 110 HCPs need to be aware of services available at their institution and discuss all available options with parents. By helping parents arrange services and participate in their chosen rituals, HCPs have the unique opportunity to support grieving parents. 111
# INDIGENOUS CULTURAL CONSIDERATIONS
Many Indigenous teachings explain that the creation of life is sacred. For First Nations people, it represents the beginning of a new journey.
A baby is a gift of the Spirit to parents and the community. When a baby dies, it is a tragedy for the whole community.
Some Indigenous peoples believe that when an individual dies, that person's spirit stays around for 4 days. During this time, the funeral and related traditional ceremonies need to take place to help remember and honour the person and the person's spirit.
Each First Nations, Inuit and Métis community has its own cultural and religious beliefs, rituals and ceremonies. Traditional rituals include smudging, sweat lodges, feasts, condolence ceremonies, "wiping the tears" ceremonies, journey ceremonies, songs and prayer. Medicines, sage, sweet grass, cedar, herbs and grief tea are also used to help with the grief. 112,113 It is important that HCPs familiarize themselves with the customs and traditions of Indigenous families they care for and provide culturally sensitive care.
Funerals and memorials are the customary rituals to ease the transition when a death occurs. 1 These events can occur shortly after the death or they may be postponed. It is important to consult and involve the hospital chaplain or local religious advisers for guidance and to help provide culturally sensitive care for different faith traditions. Some parents may wish to organize a funeral or ceremony for their baby, regardless of the length of gestation or nature of their loss. Other parents will decide not to have a service for their baby.
Bereaved parents may choose to commemorate and remember their baby in some of the following ways: 3
• Framing or hanging a photograph, drawing or painting of the baby
• Making a memory book or memory box about the pregnancy or birth or the baby's life and death
• Pressing flowers from the baby's funeral to keep or to display in a frame
• Making an embroidery or piece of patchwork
• Writing or framing a poem or letter to the baby
• Making, buying or commissioning a picture, sculpture, engraving or piece of jewellery
• Lighting a candle on anniversaries or other special days
• Putting flowers on the baby's grave, in the crematorium grounds or in a special vase on anniversaries and other significant dates
• Visiting a special place or sending flowers or a gift to a hospital or hospice on anniversaries
• Planting a tree or shrub
• Putting up a bench with a memorial plaque in a well-loved place, in the cemetery where the baby is buried or in the crematorium grounds
• Raising money or donating to a charity in memory of the baby
• Keeping the baby's ashes Some hospitals and not-for-profit organizations hold an annual act of remembrance (e.g., awareness walk/run; butterfly release; family picnic; candlelighting ceremony) or memorial service to which all bereaved parents are invited. It is important that these events remain open and suited to the needs of bereaved parents from different backgrounds who have experienced any type of loss.
# ORGAN AND TISSUE DONATION
Deceased term or near-term babies can be considered for organ and tissue donation, and donation can be discussed with parents if their baby meets the relevant criteria. Parents often consider organ and tissue donation to be a positive event following their baby's death. [114][115][116] That being said, the subject of organ and tissue donation must be broached with the utmost sensitivity, compassion and respect. When discussing this option, HCPs will want to carefully adhere to ethical principles to avoid conflicts of interest and ensure that families are free to make a fully informed decision that is consistent with their values and beliefs.
It is important that HCPs familiarize themselves with the details of the donation after circulatory determination of death (DCDD) in order to be able to effectively keep parents informed. [114][115][116] Discussions in the period leading up to the planned organ recovery procedure should focus on end-of-life care and how DCDD will affect the process (e.g., whether the parents can hold the baby before determination of death, the inclusion of music, personal mementoes, parents' desire to spend time with their child after the procedure).
Families wishing to participate in the DCDD process need to be aware that the setting will be more clinical and less personal as their child will require continuous invasive monitoring after the withdrawal of interventions. The immediacy of the organ recovery process will limit the amount of time the family will have with their dying child. It is imperative that the medical and transport teams ensure that the child and parents remain their priority throughout this process. 114
# POSTMORTEM INVESTIGATIONS
Fetal and perinatal postmortem investigations, or autopsies, are an essential part of caring for families that experience the loss of a fetus or newborn. 117 HCPs are responsible for knowing about and explaining the provincial or territorial laws regarding postmortem investigations to the parents. In some provinces and territories, a postmortem investigation is required by law; in others, it is the parent's choice. All parents should be offered the option of a full postmortem examination, even if the cause of the baby's death appears obvious, because additional information may be important for genetic counselling and the parents' decisions about future pregnancies. 40,92,117 Regardless of the gestational age of the baby, consent is required for any postmortem examinations, tests or investigations. 3 When approaching parents for consent, discuss the options for a full, limited or step-wise postmortem examination, as well as the issue of retained fetal tissues, the value of autopsy, and the possibility that the information gained may not only benefit the family but also others. This information needs to be provided with sensitivity, while respecting the personal, cultural and religious values of the family. 118 Parents may not choose a postmortem examination of their baby for many reasons. If they do not wish a full autopsy, alternative investigative options (e.g., radiological examination only) can be suggested and their limitations disclosed. 117 Some parents may consent to an external examination only; partial examination confined to a specific region of the body; blood or urine test; skin biopsy, needle biopsy and aspiration of body fluids; postmortem imaging; or placental examination. 3 A postmortem examination begins with the HCP inspecting the placenta and physically assessing the baby. This informs the health care team and family of the clinical presentation for the remaining postmortem investigation.
Postmortem investigations may provide a cause of death or reasons for the pregnancy loss.
# REASONS WHY PARENTS MAY NOT WANT
A POSTMORTEM INVESTIGATION 15,118,120 • They feel that the baby has suffered enough
• They believe that a postmortem examination is not necessary
• They do not want the baby to be cut open or harmed in any way
• The information a postmortem examination provides may not be of benefit to them
• They are concerned that a postmortem examination may delay the funeral
• They know a postmortem examination will shorten the time they can spend with the baby
• The postmortem examination involves transferring the baby to another hospital or facility
• Postmortem examinations are uncommon in their culture or go against their religious beliefs
• They may have to wait to receive results
For more information about maternal, fetal and placental investigations to determine the cause of a fetal death, refer to the Society of Obstetricians and Gynaecologists of Canada (SOGC) clinical practice guideline Stillbirth and Bereavement: Guidelines for Stillbirth Investigation. 119 For more information on the approach to perinatal autopsy, refer to the SOGC technical update Fetal and Perinatal Autopsy in Prenatally Diagnosed Fetal Abnormalities with Normal Karyotype. 117 Giving parents a realistic idea of when the results might be available is important. 120 Parents should be offered a follow-up appointment with the primary HCP to discuss test or postmortem investigation results, obtain consent for additional testing and offer genetic counselling when appropriate. Such an appointment could also provide an opportunity to plan the management of future pregnancies.
# CREMATION, BURIAL AND FUNERAL AND TISSUE DISPOSAL
Regulations with respect to cremation, burial and tissue disposal differ across provinces and territories. Hospitals must ensure that all remains are handled and treated with respect, regardless of gestation length or circumstances of death. 3 HCPs will want to know their institution's policies regarding cremation, burial and tissue disposal, as well as relevant provincial/territorial regulations, in order to have informed conversations with parents.
Before making a decision, parents need to be provided with information about all available burial and cremation options that can be arranged by the hospital or privately. It is important to encourage parents to become involved in the burial plans and arrangements by, for example, referring families to local funeral homes and advising them of any available financial help with funeral costs.
If parents have not decided on cremation, burial or tissue disposal before leaving the hospital or birth centre, they need to be told how long the baby's remains will be stored and what arrangements will be made if they do not make a decision within this timeframe. 3
# GETTING READY TO GO HOME
Leaving the hospital or birth centre and going home to baby items and reminders of pregnancy is difficult for grieving families. HCPs can suggest ways that bereaved parents can prepare for these reminders and deal with telling others about what happened and the possible responses.
Prior to the parents leaving the health care facility, inform them of the community and hospital resources they can access, as well as the birth and death registration processes, and provide them with any appointments for follow-up care.
Some families may not be ready to discuss certain issues at discharge. These subjects can be introduced for discussion by their family physician, midwife or community resources in the weeks/months following discharge. 58 Discharge routines should be flexible and adapted to meet the family's current physical and emotional state.
If the mother has given informed consent, contact her primary care provider on the day of discharge, followed as soon as possible by a detailed discharge letter with a full history of the woman's or baby's care and postmortem examination/test results (if applicable), and information about the condition, follow-up plan, health care services offered, and recommended support services including contact coordinates.
# FACILITATING AND SUPPORTING GRIEVING IN THE COMMUNITY
A family that experiences a perinatal loss needs access to support and referrals in the community. Because a perinatal loss usually occurs in a health care facility, the parents may return home without the necessary support. It is up to hospital and community HCPs to ensure that families receive follow-up and appropriate support services-all with their informed consent. Both immediate and long-term follow-up care should be made available to all parents who experience a pregnancy or infant loss. 3 Depending on the size and nature of the community, support resources may include parents or grandparents, close friends, peer support groups and professionals.
Community support varies by geography and urban versus rural setting. Collaboration between hospitals and community agencies is needed to determine what resources are available in the community and how to make appropriate referrals. Community support is best provided by a team. Team members may include family members, friends, HCPs (e.g., nurses, social workers, physicians, midwives), doulas, clergy, funeral directors, bereavement counsellors and other parents who have experienced a perinatal loss. The family physician or midwife and community health nurses are particularly significant members of this follow-up team.
Families are to be provided with written information about appropriate sources of continuing support, both professional and voluntary. Bereaved parents who are having trouble coping with their normal day-to-day activities or are experiencing marital problems require a referral to the appropriate consultants.
# FOLLOW-UP CARE
Parents will need follow-up care and support in the community as they go through their grieving process, and an offer of ongoing care (beyond the initial follow-up appointment) should be made to all bereaved parents. 3 The care could include listening to their experience and understanding their grief; physical and emotional support; validating the cause of death when postmortem investigations become available; making referrals to specialist services (e.g., genetic counselling), appropriate support organizations/groups or counselling services; and exploring lingering doubts and questions. Family needs will dictate the frequency and schedule of the follow-up care.
Isolated communities often present special challenges for follow-up care. HCPs in larger urban centres may not be aware of the resources and networks available to the family once they return home. Coordination with the woman's primary care provider, local public health agency and local community resources is essential. 121
# RESOURCES FOR PARENTS WHO HAVE LOST A BABY
In recent years, there has been a tremendous growth of media and print resources geared to the needs of bereaved parents. These materials are especially helpful when families have little or no opportunity or inclination to interact directly with other bereaved individuals. For some, reading about grief puts words to feelings. Many find stories about other families who have experienced loss to be the most useful. The personal voice of these stories helps normalize peoples' grief and helps them to give shape and language to their own feelings.
Media and print resources can be made available for loan or reference via the hospital, home, support group or public library. Some organizations, for example, the Pregnancy and Infant Loss (PAIL) Network and Parents Orphelins, provide a resource library for bereaved parents that include recommended readings, suggested perinatal loss support groups and online resources (provincial, national and international) as well as support forums about pregnancy and infant loss.
# BEREAVEMENT SUPPORT GROUPS
Bereavement support groups, which can be facilitated by HCPs or by trained peers, provide support, education and resources in a safe and supportive environment. 122,123 Different themes are discussed during sessions. Bereavement support programs are delivered in various formats (e.g., open meetings, closed support groups, one-to-one support) and provide a safe space where the bereaved can be heard, accepted and supported through their grief. Regardless of the type of support program offered, confidentiality is critical to enhancing a trusting relationship among group members.
Despite growing evidence on the positive effects of perinatal loss support groups, some communities still lack such services. 124 However, the Internet has opened a new world of bereavement support that is widely accessible and economical to use. Many individuals feel less isolated in their grief through online resources such as blogs, online chat groups (closed or open), message boards and scheduled online support group meetings. Some people feel freer to talk when they are not visibly emotional and do not have to deal with people's reaction face to face. 125
# TOPICS IN BEREAVEMENT MATERIALS
• Common responses to grief and loss • Potential differences in expressions of grief (e.g., mother and father)
• Bereavement of family members (e.g., parents, grandparents, siblings, extended family and friends)
• Mother's physical care needs (e.g., vaginal bleeding, breast care, sleep and rest, signs of infection, pain relief instructions, expected recovery trajectory)
• Symptoms and concerns that warrant contacting an HCP (e.g., depression, anxiety or an inability to sleep and eat that last for several weeks)
• Sexuality and communication after a perinatal death
• Paid parental leave and alternatives for fathers (e.g., sick leave)
• Coping strategies
• Community and online resources
• Funeral arrangements and other rituals
• The autopsy, tests and related timing and anticipated results
# • Planning a subsequent pregnancy
Most Internet support group users prefer having a group moderator or facilitator with psychological or medical knowledge of pregnancy loss. 125 The moderator plays a key role in confirming the validity of information shared within the group. 126 The flexibility, convenience, anonymity and privacy of Internet communication in general and online bereavement support in particular are aspects that bereaved parents appreciate. 125 Some disadvantages of online support groups include trolling (messages intended to sow discord or controversy), exclusion, watching the suffering of others, difficulty in developing close personal friendships and adoption of a new identity as a griever. 127 It is important to note that peer support groups do not respond to the needs of all bereaved families. In addition, the timing and access to groups can differ widely. Professional grief counselling may be necessary, and interventions could include individual counselling or facilitated therapy groups staffed by professionals with expertise in bereavement work.
# ANNUAL MEMORIAL SERVICES AND EVENTS
Some health care facilities provide annual memorial services or a burial area to allow group commemoration of pregnancy losses and infant deaths. Bereaved families and HCPs can participate in services or events, which may be held at the health care facility, a local cemetery or elsewhere. Some of the organizations that provide bereavement support services also hold annual acts of remembrance (e.g., awareness walk/run; butterfly release; family picnic; garden vigil; candle-lighting vigil; benefit concert; lighting up a building such as a tower, bridge or tourist attraction).
A supportive community for perinatal grieving can be created by increasing public awareness of the experience of perinatal loss and addressing the stigma that families face.
# AFTER LOSS
Most women who become pregnant after a perinatal loss do so with an awareness that their current pregnancy may not end with a live birth. Worries and concerns about the current pregnancy and its potential outcomes are the hallmark of pregnancy after loss. 129 One of the most important things that HCPs can offer parents is sensitive support to help them deal with their feelings and worries. 130 It is imperative that all HCPs know about parents' history so that they can respond sensitively to any anxieties or concerns those parents express and be aware of the potential difficulties and challenges they face, this includes: 1,131 • Learning the stories of past pregnancies
• Noting past significant milestones or dates that might trigger anxiety during the current pregnancy
• Recognizing that certain procedures such as ultrasounds and fetal heartbeat auscultation may be stressful for the parents
Bereaved parents are at higher risk of having complex pregnancies after a perinatal loss, and require care for anxiety, depression, fear of attachment or post-traumatic stress disorder (PTSD). 1,132,133 Some parents may need more intensive support and treatment. 132 For some parents, attending a subsequent pregnancy support group may be helpful for processing their new identify. The group helps parents reconstruct meaning in their continued bond and attachment to a deceased baby while creating and sharing a narrative of their fears about attaching to a new unborn baby. 134 It is important for HCPs to be aware of the range of emotional reactions that parents may have during a subsequent labour and birth. Parents are likely to need additional support and encouragement. Families may have many questions throughout labour and birth that need to be answered thoroughly and as they are asked. Interprofessional certification for the numerous disciplines providing perinatal and pediatric bereavement care is available through the Hospice and Palliative Credentialing Center (HPCC). 139 The Certified in Perinatal Loss Care (CPLC) credential and the Certified Hospice and Palliative Pediatric Nurse (CHPNN) credential provide opportunities for recognition of expertise in bereavement support and end-of-life care for families.
# SUPPORT FOR CAREGIVERS
HCPs who support bereaved parents often require support themselves. The type and amount of support that HCPs require can vary depending on the individual and the situation, and it is important to have different support options available. These may include: 3,31,36,39,[140][141][142][143][144][145][146][147] • Promotion of self-care and self-awareness strategies
• Instrumental support and breaks and co-creation of rituals for caregivers
•
# ACKNOWLEDGEMENTS LEAD AUTHOR
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Biologics target specific inflammatory pathways in the body that cause asthma and can help to improve asthma control and substantially reduce exacerbations (asthma attacks). - Guidance to 'hold' a therapy is made based on the assumption that the patient has well-enough controlled disease to allow for a temporary interruption; if not, decision-making should be determined on a case-by-case basis, considering the circumstances involved. These recommendations do not cover non-asthma biologics, such as used in rheumatology, etc.#
- Different biologics target different cells and inflammatory pathways in the lungs, depending on the type of asthma you have -allergic and/or eosinophilic.
Approved biologic therapies for asthma in Canada:
- Cinquair (reslizumab injection -anti-IL5 -eosinophilic asthma)
- Dupixent (dupilumab injection -anti-IL4/13 -eosinophilic/type 2 asthma)
- Fasenra (benralizumab injection -anti-IL5Rα -eosinophilic asthma)
- Nucala (mepolizumab injection -anti-IL5 -eosinophilic asthma)
- Xolair (omalizumab injection -anti-IgE -allergic asthma)
Which patients with asthma might be treated with a biologic?
- Those with physician-diagnosed severe asthma - Whose symptoms remain uncontrolled despite being adherent to their regular inhaler medications - Or who require multiple bursts or maintenance treatment with oral prednisone - Or have had any Emergency Room visits or hospitalizations because of their asthma within the last year - Those patients with asthma where the biologic is prescribed for another reason (bad eczema, nasal polyps, etc.)
Which patients with asthma should not receive a biologic?
- Those who have not yet been assessed by a lung specialist or allergy specialist
- Those who do not take their prescribed inhaler medications on a daily basis
- Those who are allergic to the biologic medication Following COVID-19 vaccination, patients should continue to observe public health guidelines and other preventive measures to decrease risk of virus transmission by:
- washing hands regularly or using alcohol-based hand sanitizers,
- wearing face masks in indoor public places
- practicing physical distancing
- monitoring for symptoms of COVID-19 and getting tested if symptoms present Household members and other frequent, close contacts of patients with asthma should undergo COVID-19 vaccination when available to them to facilitate a 'bubble effect' that may help protect them.
# CTS and CSACI recommend that:
- The COVID-19 vaccine should not be administered on the same day as a biologic for asthma where possible.
- Patients with asthma should ideally receive a COVID vaccine 72 hours apart from their regular biologic, to make it easier to tell what injection may have caused a problem if the patient has a reaction.
- Individuals with a history of reaction to injectable medications, or a previous COVID-19 vaccine must advise the staff at the vaccination site.
There is no evidence of safety or efficacy concerns for patients with asthma on biologic therapy.
There is no biological rationale as to why anti-IgE, anti-IL5, anti-IL5Ra, or anti-IL4/13 therapies should place patients at higher risk of adverse events.
Many patients with severe asthma also have a history of severe allergies and anaphylaxis.
Health care professionals should engage their patients in a shared decision-making process to discuss risks and benefits of receiving a COVID-19 vaccine.
NACI preferentially recommends that a complete two-dose vaccine series with an mRNA COVID-19 vaccine (Pfizer-BioNTech, Moderna) should be offered to individuals in the authorized age group, including those who are immunosuppressed, have an autoimmune condition, are pregnant or are breastfeeding. If they are not able to receive an mRNA vaccine, for example because of an allergy, another authorized COVID-19 vaccine should be offered.
Individuals with a history of severe allergic reaction to a component of the COVID-19 vaccine should not receive the COVID-19 vaccine.
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Biologics target specific inflammatory pathways in the body that cause asthma and can help to improve asthma control and substantially reduce exacerbations (asthma attacks). * Guidance to 'hold' a therapy is made based on the assumption that the patient has well-enough controlled disease to allow for a temporary interruption; if not, decision-making should be determined on a case-by-case basis, considering the circumstances involved. These recommendations do not cover non-asthma biologics, such as used in rheumatology, etc.#
• Different biologics target different cells and inflammatory pathways in the lungs, depending on the type of asthma you have -allergic and/or eosinophilic.
Approved biologic therapies for asthma in Canada:
• Cinquair (reslizumab injection -anti-IL5 -eosinophilic asthma)
• Dupixent (dupilumab injection -anti-IL4/13 -eosinophilic/type 2 asthma)
• Fasenra (benralizumab injection -anti-IL5Rα -eosinophilic asthma)
• Nucala (mepolizumab injection -anti-IL5 -eosinophilic asthma)
• Xolair (omalizumab injection -anti-IgE -allergic asthma)
Which patients with asthma might be treated with a biologic?
• Those with physician-diagnosed severe asthma • Whose symptoms remain uncontrolled despite being adherent to their regular inhaler medications • Or who require multiple bursts or maintenance treatment with oral prednisone • Or have had any Emergency Room visits or hospitalizations because of their asthma within the last year • Those patients with asthma where the biologic is prescribed for another reason (bad eczema, nasal polyps, etc.)
Which patients with asthma should not receive a biologic?
• Those who have not yet been assessed by a lung specialist or allergy specialist
• Those who do not take their prescribed inhaler medications on a daily basis
• Those who are allergic to the biologic medication Following COVID-19 vaccination, patients should continue to observe public health guidelines and other preventive measures to decrease risk of virus transmission by:
• washing hands regularly or using alcohol-based hand sanitizers,
• wearing face masks in indoor public places
• practicing physical distancing
• monitoring for symptoms of COVID-19 and getting tested if symptoms present Household members and other frequent, close contacts of patients with asthma should undergo COVID-19 vaccination when available to them to facilitate a 'bubble effect' that may help protect them.
# CTS and CSACI recommend that:
• The COVID-19 vaccine should not be administered on the same day as a biologic for asthma where possible.
• Patients with asthma should ideally receive a COVID vaccine 72 hours apart from their regular biologic, to make it easier to tell what injection may have caused a problem if the patient has a reaction.
• Individuals with a history of reaction to injectable medications, or a previous COVID-19 vaccine must advise the staff at the vaccination site.
There is no evidence of safety or efficacy concerns for patients with asthma on biologic therapy.
There is no biological rationale as to why anti-IgE, anti-IL5, anti-IL5Ra, or anti-IL4/13 therapies should place patients at higher risk of adverse events.
Many patients with severe asthma also have a history of severe allergies and anaphylaxis.
Health care professionals should engage their patients in a shared decision-making process to discuss risks and benefits of receiving a COVID-19 vaccine.
NACI preferentially recommends that a complete two-dose vaccine series with an mRNA COVID-19 vaccine (Pfizer-BioNTech, Moderna) should be offered to individuals in the authorized age group, including those who are immunosuppressed, have an autoimmune condition, are pregnant or are breastfeeding. If they are not able to receive an mRNA vaccine, for example because of an allergy, another authorized COVID-19 vaccine should be offered.
Individuals with a history of severe allergic reaction to a component of the COVID-19 vaccine should not receive the COVID-19 vaccine.
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c6d840d573554c71f94292b19c1df2eb4ad024f6
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cma
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At CancerCare Manitoba (CCMB) the Clinical Practice Guidelines Initiative (CPGI) seeks to improve patient outcomes through the development, dissemination, implementation and evaluation of guidelines for the management of common clinical scenarios encountered by cancer patients throughout the province. This clinical practice guideline was created through the efforts of a large interdisciplinary group from CCMB in collaboration with community partners. Members of the CCMB Gastro-Intestinal Disease Site Group (DSG) and Departments of Gastroenterology, Medical Oncology, Radiation Therapy, Thoracic Surgery, and General Surgery have participated in its development.# I. Introduction
Gastric cancer is a low incidence cancer with high mortality rates in Canada. 5 Surgery for gastric cancer is complex and of variable quality, at least in low incident non-Asian countries, with potential for morbidity and mortality. 6 Similarly, the fairly recent advent of adjuvant and neoadjuvant therapies for gastric cancer has made the landscape of treatment of this serious illness complex and at times confusing. Provision of substandard care decreases the survival rates of gastric cancer, and mechanisms to provide clarity, standardization and competence of treatment will be of significant benefit to the Manitoban population.
Thus, the purpose of this guideline is to outline the appropriate work-up and treatment of potential curable gastric carcinoma in Manitoba.
The guideline does not cover the following treatment scenarios:
- Carcinoma of the gastro-esophageal junction (GEJ), gastric GIST, gastric neuroendocrine tumours, and gastric lymphoma - Unresectable and/or metastatic gastric carcinoma - Gastric metastases from other primary tumours
The guideline is intended to outline the appropriate investigations of a known or suspected gastric carcinoma, as well as an overview of the appropriate use of chemotherapy, radiotherapy and surgery in treating this disease. The reliance on multidisciplinary care is also emphasized.
# III. Guideline Methodology
Using standard search strategies, the clinical practice guideline office performed a review of published literature to identify all existing published guidelines. Committee members reviewed each document and assessed for quality and appropriateness. The committee met in person on March 2, 2018 to review this evidence and for in-depth discussion.
The plan of review was as follows:
- Adopt a guideline(s) if deemed appropriate - Adopt portions of guidelines if no single document was of sufficient quality - Create a new guideline de novo if guidelines were of poor quality or not appropriate to our patient population or health system
The review meeting consisted of evaluating each guideline on the following criteria:
- Does it cover our stated purpose and scope?
- Is it evidence-based?
- Is it missing any significant areas or evidence with respect to work up and treatment?
- Are there general concerns regarding content or format?
Published Guideline Review
Ten guideline documents were identified in the literature search. On further review, two were found to be frankly out of scope of our goal and discarded. An in-depth discussion of the remaining eight occurred. Two guidelines were essentially a part A and B from the same organization (Cancer Care Ontario) and were considered a single comprehensive document for the purposes of our review. One further guideline (a 2018 guideline from the BC Cancer Agency) was reviewed after the in-person meeting, but was deemed to reflect similar information to the other documents. The ten articles reviewed are listed in Table 1.
# Internal and External Review
Internal and external peer reviews were pursued, the results of which are appended to this guideline. The internal review consists of revision by the working group. An external review was undertaken by one radiation oncologist who completed a full review of the guideline document and submitted practitioner feedback comments. Feedback was reviewed and discussed.
Table 1. List of published guidelines reviewed.
# Conclusions
The group unanimously agreed to the adoption of the Cancer Care Ontario guidelines for the curable treatment of gastric cancer. 1,2 These guidelines were felt to be comprehensive and evidence-based.
Their guideline documents were also found to be easily readable for physicians and surgeons, with an appropriate amount of detail and explanation.
Of mention, the ESMO guideline was deemed to be of equivalent quality and scope. We favoured the Ontario guideline for its depth of explanation, including methodology, and readability, as well as its Canadian origin (and thus applicable to our health system). The BC guideline was similarly of good quality but only covered the surgical aspects of care, so not as comprehensive as required for our purposes. It should be noted that all three guidelines deliver essentially the same message.
The CCO guideline relating to staging and surgery dates from 2017 and is contemporaneous in all aspects. No alterations, or qualifying statements, were recommended by the committee. In regards to the non-surgical aspects of treatment, however, this aspect of the guideline is dated, with no other published guidelines in our search to replace it. Thus the committee felt it appropriate to adopt the 2011 guideline as a base for our recommendation and then add further data to it, as an informal mechanism of updating. The qualifying statements agreed to are listed below: 1. Clinical Trials. We wish to encourage enrollment of gastric cancer patients into clinical trials when feasible, and locally available. The landscape of gastric cancer treatment has seen significant improvements over the last two decades, since the publication of the first major randomized control trial showing benefit of adjuvant therapy in gastric cancer 3 ; yet there is significant work still needed to improve our survival statistics and quality of life. Clinical trial enrolment is felt to be beneficial in that it ensures current high quality care and allows for the development of new treatment paradigms. It does require uncoerced and informed consent of the patient, with their acceptance of the inherent unknowns in experimental regimens, and often has strict enrolment criteria as well as limitations to where care can be delivered; as such, trial enrolment is not for everyone.
# Guideline Title Guideline Group Year
- FLOT perioperative chemotherapy. The choice of perioperative chemo in stage 1B to 3 cancers should include the option of the FLOT (docetaxel, oxaliplatin, and fluorouracil/leucovorin) regimen. 7 The German AIO group published their results on this regimen in abstract form at ASCO 2017. These results show a dramatic improvement over the previous standard of ECF (epirubicin, cisplatin, and fluorouracil). 4 As the abstract results are extraordinarily compelling, the Canadian gastric cancer medical oncology community has widely adopted this protocol and we concur with that approach. FLOT should be considered for all advanced stage gastric cancer patients who are healthy enough for aggressive chemotherapy. As this data is still preliminary, review of patients through P and T or case conference mechanisms is prudent. Upon publication of final results, strong consideration to placing this regimen on formulary is recommended, assuming the final publication is congruent with the published abstract.
- Additional trials. Several non-practice changing trials were discussed at our committee meeting.
The CRITICS trial was one such trial. 8 This trial randomized patients to post-operative chemoradiotherapy versus chemotherapy alone in patients receiving preoperative chemotherapy and surgery for gastric cancer. The study found that a postoperative chemoradiotherapy regimen did not improve overall survival compared to chemotherapy therapy alone. It did note poor compliance to both postoperative regimens and sits as a reminder that all studies show patients to be less apt to tolerate therapy in the postoperative period. The ARTIST trial was also briefly discussed. 9 This trial compared postoperative chemotherapy to postoperative chemoradiotherapy in patients who had recovered from a D2 lymphadenectomy. This trial did not find an advantage to chemoradiotherapy in the intention-to-treat analysis, but post hoc analysis did reveal a potential advantage to that strategy in node positive patients, as well as those with intestinal-type histology. The relevance of this trial to our local population is also uncertain, as a majority of patients do not receive extended lymphadenectomy currently; as such, it does not supplant the information gained for the SWOG trial 3 , but does provide for some reflection in the utility of radiation in the minority of patients with extended lymphadenectomies. Finally, there must be some note that many of our gastric cancer studies come from Asian populations, and in general, they report survival rates well in excess of what is seen in Western populations, regardless of what treatment protocol is used. The differences in patient population, screening, centralization of care, and treatment strategies make applicability of many Asian trials to be challenging to our provincial context. Thus, we must exercise caution in interpreting such data.
# GUIDELINE OBJECTIVES
To develop recommendations on the optimal surgical management of gastric cancer in Ontario.
# TARGET POPULATION
These recommendations apply to adult men and women with Stage I to IV gastric cancer (specifically gastric adenocarcinoma) who are being considered for surgery. Gastroesophageal junction (GEJ) tumours and early gastric cancers are excluded because they require additional considerations.
# INTENDED USERS
Intended users of this guidance document are surgeons, gastroenterologists, medical oncologists, radiation oncologists, and the multidisciplinary team who treat gastric cancer.
# RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE Recommendation 1
Endorsed from Lerut et al. 2012 :
- All patients diagnosed with gastric cancer should be discussed at a multidisciplinary team meeting. In patients with newly diagnosed gastric cancer, CT scan of the chest and abdomen should always be performed. Endoscopic ultrasound (EUS) can be considered in patients planned for curative treatment on the basis of clinical presentation and/or CT. Fine -needle aspiration cytology of suspicious lymph nodes or metastases can be considered if tech nically feasible. The following examinations can be considered for specific indications: PET scan, magnetic resonance imaging, laparoscopy.
# Qualifying Statements for Recommendation 1
- As the accuracy for CT scans in detecting M1 disease is 81% , diagnostic laparoscopy may allow patients to avoid a laparotomy in up to 44% of cases of advanced stage cancer . Both Scottish Intercollegiate Guidelines Network (SIGN) and Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guidelines suggest diagnostic laparoscopy in patients with clinically suspected T3 and T4 cancers, or those at higher risk for M1 disease, such as poorly differentiated cancers and those with a higher nodal burden. Diagnostic laparoscopy should be performed p rior to starting chemotherapy for patients in whom a neoadjuvant approach is considered. Washing may increase the accuracy of diagnostic laparoscopy. PET and MRI may be useful for further characterization of liver lesions, in clinical scenarios in which treatment plans would be changed by the finding of metastatic disease, but should not be routinely performed. EUS should only be performed if results may change management plans (i.e., to assess for local invasion, nodal status or metastatic spread).
# Key Evidence for Recommendation 1
- Key evidence derived from one clinical practice guideline conducted by Lerut at al. of the Belgian Health Care Knowledge Centre.
# Interpretation of Evidence for Recommendation 1
- There was agreement among the Working Group members that the overall certainty of the evidence was moderate. The Working Group considered accurate staging of each patient to be of paramount importance in order for patients to be provided appropriate treatment. Therefore, the Working Group was unanimous in their opinion that patients would also value the importance of accurate staging, although patient input was not sought. The desirable effect (i.e., accurate staging) is large as patients who are improperly staged will not be provided with appropriate treatment. At the same time, the undesirable effects (morbidity of the staging investigations) are manageable in this population. The Working Group believed the desirable effect (accurate staging) is large relative to the undesirable effects (potential increased morbidity) in this population of patients because inaccurate staging will result in patient being treated inappropriately, either by under-treating or over-treating them.
- The evidence is generalizable to the entire population of gastric cancer patients. The Working Group believed that all interpretations of the evidence for staging of gastric cancer patients would be similar. showed fewer gastric cancer-related deaths in patients undergoing a D2 LND for all Tstages (gastric cancer related deaths were 48% in D1 vs. 37% in D2, p=0.01, per protocol analysis) .
# Interpretation of Evidence for Recommendation 2
- See Section after Recommendation 4.
# Recommendation 3
- At least 16 lymph nodes should be assessed for adequate staging of curative -resected gastric cancer.
# Qualifying Statements for Recommendation 3
- American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) guidelines state that 16 lymph nodes are necessary for adequate staging. Studies suggest that removal and examination of more than 16 nodes may improve survival and increases accuracy of staging by decreasing under staging which leads to stage migration.
# Key Evidence for Recommendation 3
- One systematic review reported significantly improved disease -free survival (DFS) as the number of lymph nodes harvested increased, especially when more than 15 nodes were retrieved, and concluded that 16 lymph nodes should be harvested as a minimum. More current studies of moderate quality also report that harvesting more than 15 nodes significantly improved survival.
# Interpretation of Evidence for Recommendation 3
- See Section after Recommendation 4.
# Recommendation 4
- Surgery for gastric cancer should aim at achieving an R0 margin. guidelines suggest 4 cm margins in order to assure negative margins, while the Japanese Gastric Cancer Treatment Guidelines suggest that margins of 3 cm for T1/T2 cancer and 5 cm for T3/T4 cancers be obtained. Intra-operative frozen section analysis should be considered in cases where there is concern about a high risk of positive margin. Cancers with higher T and N stage, and higher grade tumours, such as diffuse -type histology including signet ring carcinoma, are more likely to have microscopic margins involved, and intra-operative planning or neoadjuvant therapy should take these factors into consideration. For patients with poor biology (>5 lymph nodes positive, diffuse -type histology including signet ring carcinoma), an extended resection of the adjacent organs or intra-thoracic esophagus may not result in improved long-term survival, as multivariable analyses in many studies have shown that tumour biology may be a stronger determinant of outcomes than a positive margin. Extended resection should be undertaken selectively and with multidis ciplinary discussion.
# Key Evidence for Recommendation 4
- Data from one study suggest that margins of 5 cm for T3/T4 cancer and 3 cm for T1/T2 cancers are sufficient to obtain resection margins negative for microscopic cancer . Median overall survival (OS) and median recurrence-free survival (RFS) for patients was significantly better in those with proximal margins of 3.1 to 5.0 cm compared with margins ≤3.0 cm (48.1 vs. 29.3 months, p=0.01; and 38.9 vs. 21.1 months, p=0.02, respectively). Median OS and median RFS for patients with margins >5.0 cm were not significantly different than those with proximal margins of 3.1 to 5.0 cm. However, the OS and RFS advantage of a proximal margin ≥3.1 cm was only associated with Stage I disease only and was not associated with Stage II or III disease .
# Interpretation of Evidence for Recommendation 4
- See Section after Recommendation 4.
# Interpretation of Evidence for Recommendations 2, 3 and 4.
- There was agreement among the Working Group members that the overall certainty of the evidence was moderate based on the entire body of the evidence. Although the Working Group looked at survival, mortality, reoperation rates, and RFS, OS was considered to be the most important outcome, followed by RFS. The Working Group was unanimous in their opinion that patients would also value the increased survival benefit associated with each of the surgical parameters evaluated (extent of lymphadenectomy, number of lymph nodes retrieved, and minimal gross margins) although patient input was not sought. The Working Group valued survival when drafting the recommendations as they believed that the morbidities associated with each of these surgical parameters were manageable. The desirable effect is increased survival. The undesirable effects (morbidity) are manageable in this population. The Working Group believed the desirable effect (longer survival) is large relative to the undesirable effects (extra morbidity) in the selected group of Stage III patients especially since inadequate LND, positive margins, and retrieval of an inadequate number of lymph nodes are all asso ciated with disease recurrence. The evidence is generalizable to the entire gastric cancer population as defined in this guidance document.1 The Working Group believed that there might be an alternate interpretation of the evidence for D2 versus D1 LND if the focus remains on several negative trials available and not on the compelling subgroup analysis of these trials and the emerging long-term survival benefits in ongoing trials.
# Recommendation 5
- In the metastatic setting, nonsurgical management options are preferred in patients without symptoms. In the metastatic setting, surgery should only be considered for palliation of symptoms that cannot be addressed through less-invasive means (i.e., radiation, chemotherapy, stenting).
# Qualifying Statements for Recommendation 5
- As the rate of complications appears to be highest in more extensive resections, a palliative total gastrectomy should be performed only in exceptional circumstances, and with multidisciplinary discussion. Key Evidence for Recommendation 5 In one systematic review of 59 studies, procedure-related morbidity occurred in all types of surgical interventions and irrespective of the intent of the surgery. Morbidity ranged from 3.8% to 49% for gastrectomy and 14% to 21% for non-resectional surgeries . In the literature update, procedure-related morbidity in moderate-quality noncurative studies ranged from 15.1% to 88.8% for gastrectomy and 11.5% to 21% for non-resectional surgeries. In the systematic review by Mahar et al. , procedure-related mortality was lower in palliative resections (0% to 7%) compared with either non -curative (0% to 21%) or not otherwise specified surgeries (0% to 20.4%). The mortality rate for gastrectomy performed for any intent was 0% to 21% whereas the mortality rate for non -resectional surgeries was 0% to 39% . In the literature update, which included all moderate quality studies, procedure-related mortality for gastrectomy performed in noncurative studies was 1.1% to 9.1% , whereas the mortality rate for nonresectional surgeries in non-curative studies was 4.8% to 10% . The REGATTA trial showed no survival benefit of gastrectomy + chemotherapy over chemotherapy alone (25.1% vs. 31.7%) in patients with non -curable gastric cancer (hazard ratio , 1.09; 95% CI, 0.78 to 1.52; p=0.70), and more complications for patients in the gastrectomy + chemotherapy arm.
# Interpretation of Evidence for Recommendation 5
- There was agreement among the Working Group members that the overall certainty of the evidence was moderate. Although the Working Group looked at survival, morbidity, mortality, and quality of life (QOL), morbidity and QOL (where available) were considered to be the most important outcomes. The Working Group was unanimous in their opinion that patients would also likely value these outcomes, although patient input was not sought. The Working Group valued OS over toxicity when drafting the recommendations as they felt that the toxicities were manageable. The desirable effect (i.e., better QOL, less morbidity) is probably not large, especially for Stage IV patients in whom the goal of surgery is not palliation of symptoms. At the same time, the undesirable effects are moderate. The mortality rates for surgery in Stage IV gastric cancer can be high especially when the surgery is not performed for CCMB, Disease Management: Guideline for the Curative Treatment of Gastric Cancer p.17
Date Updated: December 2018 palliation of symptoms. The Working Group believed the desirable e ffect (better QOL) was not large relative to the undesirable effects (mortality) and should, therefore, only be performed for palliation of symptoms. If the surgery is not likely to improve QOL, it should not be done. The evidence is not generalizable to the entire Stage IV gastric cancer population as defined in this guidance document. The Working Group believed that the REGATTA trial may be interpreted differently by others. REGATTA was stopped early for futility and possible harm in the surgery arm. It is conceivable that these data may be interpreted as meaning that survival was equivalent in the surgery and the surgery + chemotherapy arms, but most are not making this interpretation.
# Recommendation 6
- Given evidence that higher-volume centres are associated with lower rates of procedure-related mortality, patients should be referred to higher-volume centres for surgical resection. Gastric cancer surgery should be performed in centres with sufficient support to prevent or manage complications (e.g., interventional radiology, anesthesia, level 1 intensive care unit).
# Qualifying Statements for Recommendation 6
- In most studies, higher-volume centres are associated with improved outcomes. There is no common definition of a high-volume centre within the studies; however, it should be noted that five or fewer annual cases are considered low or very low volume in all studies. An expected 30-day or in-hospital peri-operative mortality should be less than 5%. This is based on published mortality rates from high-volume centres, as well as the "Hepatic, Pancreatic and Biliary (HPB) Tract Surgical Oncology Standards" (EBS#17-2) , which recommends a 30-day or in-hospital mortality rate of less than 5% for major pancreatic resection and 3% for anatomical liver resection. As these procedures are more complicated than gastric cancer surgery, it is reasonable to expect a similar or lower mortality rate. Hospitals performing gastric cancer surgery should know their mortality rates, and recognize that lower volumes create larger confidence intervals for mortality estimates.
# Key Evidence for Recommendation 6
- In one systematic review containing 22 studies looking at institutional volumes, procedure-related morbidity was not significantly different in high-volume compared with low-volume hospitals (19% to 46.5% in high-volume hospitals vs. 19% to 43% in low-volume hospitals). However, meta-analysis of procedure-related mortality favoured high-volume hospitals (OR, 0.73; 95% CI, 0.65 to 0.81; p<0.00001). Improved five-year survival was significantly associated with higher institutional volumes in three of seven studies that evaluated this outcome . In the updated literature search, procedure-related mortality was not significantly different in high-versus low-volume hospitals in four of the five studies evaluating this outcome . However, in 2013, Dikken et al. reported that procedurerelated mortality significantly favours high-volume hospitals (OR, 0.64; 95% CI, 0.41 to 0.99; p=0.025). The updated literature search only yielded moderate quality non-RCTs.
# Interpretation of Evidence for Recommendation 6
CCMB, Disease Management: Guideline for the Curative Treatment of Gastric Cancer p.18
Date Updated: December 2018 There was agreement among the Working Group members that the overall certainty of the evidence was low to moderate. Although the Working Group looked at mortality (especially 30-day and in-hospital mortality) and morbidity, the Working Group was unanimous in their opinion that patients would value mortality as an assessment of surgeon and/or institutional volumes, although patient input was not sought. The desirable effect (i.e., lower short-term mortality) is large. At the same time, the undesirable effects (i.e., death) are not small. The Working Group believed the desirable effect (living) was larger relative to the undesirable effects (death). The evidence is generalizable to gastric cancer surgery in all institutions. The Working Group believed that others may have slightly different interpretations of the volume data by setting definite numerical volume standards, whereas in the present guidance document the focus was on mortality rate instead.
# Recommendation 7
- Quality metrics for lymph nodes, margins, peri-operative mortality, and oncologic outcomes should be met regardless of surgical technique (e.g., open or minimally invasive).
# Qualifying Statements for Recommendation 7
- While laparoscopic resection has been shown to be equal or superior to open surgery for short-term outcomes, there is no evidence regarding long-term cancer outcomes. Several ongoing randomized trials will report on oncologic survival.
# Key Evidence for Recommendation 7
- Short-term outcomes (e.g., blood loss, time to first flatus, length of hospital stay, and post-operative complications) favour laparoscopic compared with open gastrectomy . This is based on one systematic review and several more recent primary studies. Long-term cancer-related survival results are currently being examined in several RCTs.
# Interpretation of Evidence for Recommendation 7
- There was agreement among the Working Group members that the overall certainty of the evidence was moderate. Although the Working Group looked at short-term outcomes (blood loss, time to first flatus, length of hospital stay, post-operative complications, hospital mortality rates, and surgical time) and long-term outcomes (survival), no long-term outcomes have been reported from RCTs to date. The Working Group was unanimous in their opinion that patients would also value both long-and short-term outcomes, although patient input was not sought. Once these longer-term outcome data become more available, the emphasis on short-term outcomes may change. The desirable effects (i.e., better short-term outcomes such as blood loss, time to first flatus, length of hospital stay, post-operative complications, hospital mortality rates) are large. At the same time, the undesirable effects (longer surgical times) are manageable in this population with adequate surgeon training in laparoscopic procedures. The Working Group believed the desirable effect (better short -term surgical outcomes) is large relative to the undesirable effects (longer surgical times). Once these longer-term outcome data become more available, the emphasis on shortterm outcomes may change. The evidence is generalizable to the entire gastric cancer population as defined in this guidance document.
# IMPLEMENTATION CONSIDERATIONS
The Working Group considered the recommendations provided above to be the ideal standard of care and would be feasible to implement. Furthermore, they may improve current health inequities by ensuring the same standards of care for all patients no matter where they are treated in Ontario. Thus, there is the potential for better outcomes for gastric cancer patients across the province. To support in this endeavour it would be useful if hospital mortality rates for gastric cancer surgery were available to hospitals as they are for other types of surgeries such as pancreas, lung, and esophagus. These recommendations may change current practice as many patients are currently only receiving a D1 LND even when a D2 is more appropriate. Moreover, laparoscopic surgeries may occur more often as time goes on and more surgeons are adequately trained in these procedures. These recommendations may come with no additional costs. In fact, overall costs may decrease owing to fewer recurrences, possibly fewer unnecessary surgeries, and reduced length of hospital stays as the number of laparoscopic surgeries performed increases. The Working Group believed the outcomes valued in this guideline would align well with patient values and patients would view these recommendations as acceptable. Disclaimer Care has been taken in the preparation of the information contained in this report. Nevertheless, any person seeking to consult the report or apply its recommendations is expected to use independent medical judgment in the context of individual clinical circumstances or to seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representations or guarantees of any kind whatsoever regarding the report content or its use or application and disclaims any responsibility for its application or use in any way.
# RELATED GUIDELINES
# VI. Implementation and Dissemination
The value of guidelines truly lies in their implementation and use. For that purpose, consideration was given to implementation during the drafting of this guideline document.
# CancerCare Resources
It was recognized that resources would be needed to distribute these guidelines to the community. For that purpose, the guideline will be accessible online through the CancerCare Manitoba website. Online availability will be preceded by an e-blast notification with the website embedded. Announcement of the guideline and updates will be through established provincial communication channels: Community Oncology Program to CCPN rural sites, UPCON clinics and WRHA Community Oncology Program sites. Use of the guideline in clinic will be through the online version.
# Educational Events
The guideline's recommendations were presented at Disease Site Group Meetings and the Cancer Surgery Update (2019).
# Concordance Measurement and Performance Audit
A plan is being developed regarding the guideline concordance measurement and will be presented to the CCMB standards committee for approval. Briefly, a panel will review each gastric cancer case at CCMB and provide a confidential feedback form covering the key recommendations to the treating physicians/surgeons. Suggestions will be presented in an encouraging format. The audit and feedback process will be done under the auspices of the CCMB standards committee, and include the protections therein. This plan will be finalized and implemented after the settling of the Covid-19 pandemic.
# VIII. Conflicts of Interest
In accordance with the CCMB policy no. 01.001, "Conflict of Interest", the authors of this guideline disclosed no conflicts of interest and declares that no commercial support was received during the development of this guideline.
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At CancerCare Manitoba (CCMB) the Clinical Practice Guidelines Initiative (CPGI) seeks to improve patient outcomes through the development, dissemination, implementation and evaluation of guidelines for the management of common clinical scenarios encountered by cancer patients throughout the province. This clinical practice guideline was created through the efforts of a large interdisciplinary group from CCMB in collaboration with community partners. Members of the CCMB Gastro-Intestinal Disease Site Group (DSG) and Departments of Gastroenterology, Medical Oncology, Radiation Therapy, Thoracic Surgery, and General Surgery have participated in its development.# I. Introduction
Gastric cancer is a low incidence cancer with high mortality rates in Canada. 5 Surgery for gastric cancer is complex and of variable quality, at least in low incident non-Asian countries, with potential for morbidity and mortality. 6 Similarly, the fairly recent advent of adjuvant and neoadjuvant therapies for gastric cancer has made the landscape of treatment of this serious illness complex and at times confusing. Provision of substandard care decreases the survival rates of gastric cancer, and mechanisms to provide clarity, standardization and competence of treatment will be of significant benefit to the Manitoban population.
Thus, the purpose of this guideline is to outline the appropriate work-up and treatment of potential curable gastric carcinoma in Manitoba.
The guideline does not cover the following treatment scenarios:
• Carcinoma of the gastro-esophageal junction (GEJ), gastric GIST, gastric neuroendocrine tumours, and gastric lymphoma • Unresectable and/or metastatic gastric carcinoma • Gastric metastases from other primary tumours
The guideline is intended to outline the appropriate investigations of a known or suspected gastric carcinoma, as well as an overview of the appropriate use of chemotherapy, radiotherapy and surgery in treating this disease. The reliance on multidisciplinary care is also emphasized.
# III. Guideline Methodology
Using standard search strategies, the clinical practice guideline office performed a review of published literature to identify all existing published guidelines. Committee members reviewed each document and assessed for quality and appropriateness. The committee met in person on March 2, 2018 to review this evidence and for in-depth discussion.
The plan of review was as follows:
• Adopt a guideline(s) if deemed appropriate • Adopt portions of guidelines if no single document was of sufficient quality • Create a new guideline de novo if guidelines were of poor quality or not appropriate to our patient population or health system
The review meeting consisted of evaluating each guideline on the following criteria:
• Does it cover our stated purpose and scope?
• Is it evidence-based?
• Is it missing any significant areas or evidence with respect to work up and treatment?
• Are there general concerns regarding content or format?
Published Guideline Review
Ten guideline documents were identified in the literature search. On further review, two were found to be frankly out of scope of our goal and discarded. An in-depth discussion of the remaining eight occurred. Two guidelines were essentially a part A and B from the same organization (Cancer Care Ontario) and were considered a single comprehensive document for the purposes of our review. One further guideline (a 2018 guideline from the BC Cancer Agency) was reviewed after the in-person meeting, but was deemed to reflect similar information to the other documents. The ten articles reviewed are listed in Table 1.
# Internal and External Review
Internal and external peer reviews were pursued, the results of which are appended to this guideline. The internal review consists of revision by the working group. An external review was undertaken by one radiation oncologist who completed a full review of the guideline document and submitted practitioner feedback comments. Feedback was reviewed and discussed.
Table 1. List of published guidelines reviewed.
# Conclusions
The group unanimously agreed to the adoption of the Cancer Care Ontario guidelines for the curable treatment of gastric cancer. 1,2 These guidelines were felt to be comprehensive and evidence-based.
Their guideline documents were also found to be easily readable for physicians and surgeons, with an appropriate amount of detail and explanation.
Of mention, the ESMO guideline was deemed to be of equivalent quality and scope. We favoured the Ontario guideline for its depth of explanation, including methodology, and readability, as well as its Canadian origin (and thus applicable to our health system). The BC guideline was similarly of good quality but only covered the surgical aspects of care, so not as comprehensive as required for our purposes. It should be noted that all three guidelines deliver essentially the same message.
The CCO guideline relating to staging and surgery dates from 2017 and is contemporaneous in all aspects. No alterations, or qualifying statements, were recommended by the committee. In regards to the non-surgical aspects of treatment, however, this aspect of the guideline is dated, with no other published guidelines in our search to replace it. Thus the committee felt it appropriate to adopt the 2011 guideline as a base for our recommendation and then add further data to it, as an informal mechanism of updating. The qualifying statements agreed to are listed below: 1. Clinical Trials. We wish to encourage enrollment of gastric cancer patients into clinical trials when feasible, and locally available. The landscape of gastric cancer treatment has seen significant improvements over the last two decades, since the publication of the first major randomized control trial showing benefit of adjuvant therapy in gastric cancer 3 ; yet there is significant work still needed to improve our survival statistics and quality of life. Clinical trial enrolment is felt to be beneficial in that it ensures current high quality care and allows for the development of new treatment paradigms. It does require uncoerced and informed consent of the patient, with their acceptance of the inherent unknowns in experimental regimens, and often has strict enrolment criteria as well as limitations to where care can be delivered; as such, trial enrolment is not for everyone.
# Guideline Title Guideline Group Year
2. FLOT perioperative chemotherapy. The choice of perioperative chemo in stage 1B to 3 cancers should include the option of the FLOT (docetaxel, oxaliplatin, and fluorouracil/leucovorin) regimen. 7 The German AIO group published their results on this regimen in abstract form at ASCO 2017. These results show a dramatic improvement over the previous standard of ECF (epirubicin, cisplatin, and fluorouracil). 4 As the abstract results are extraordinarily compelling, the Canadian gastric cancer medical oncology community has widely adopted this protocol and we concur with that approach. FLOT should be considered for all advanced stage gastric cancer patients who are healthy enough for aggressive chemotherapy. As this data is still preliminary, review of patients through P and T or case conference mechanisms is prudent. Upon publication of final results, strong consideration to placing this regimen on formulary is recommended, assuming the final publication is congruent with the published abstract.
3. Additional trials. Several non-practice changing trials were discussed at our committee meeting.
The CRITICS trial was one such trial. 8 This trial randomized patients to post-operative chemoradiotherapy versus chemotherapy alone in patients receiving preoperative chemotherapy and surgery for gastric cancer. The study found that a postoperative chemoradiotherapy regimen did not improve overall survival compared to chemotherapy therapy alone. It did note poor compliance to both postoperative regimens and sits as a reminder that all studies show patients to be less apt to tolerate therapy in the postoperative period. The ARTIST trial was also briefly discussed. 9 This trial compared postoperative chemotherapy to postoperative chemoradiotherapy in patients who had recovered from a D2 lymphadenectomy. This trial did not find an advantage to chemoradiotherapy in the intention-to-treat analysis, but post hoc analysis did reveal a potential advantage to that strategy in node positive patients, as well as those with intestinal-type histology. The relevance of this trial to our local population is also uncertain, as a majority of patients do not receive extended lymphadenectomy currently; as such, it does not supplant the information gained for the SWOG trial 3 , but does provide for some reflection in the utility of radiation in the minority of patients with extended lymphadenectomies. Finally, there must be some note that many of our gastric cancer studies come from Asian populations, and in general, they report survival rates well in excess of what is seen in Western populations, regardless of what treatment protocol is used. The differences in patient population, screening, centralization of care, and treatment strategies make applicability of many Asian trials to be challenging to our provincial context. Thus, we must exercise caution in interpreting such data.
# GUIDELINE OBJECTIVES
To develop recommendations on the optimal surgical management of gastric cancer in Ontario.
# TARGET POPULATION
These recommendations apply to adult men and women with Stage I to IV gastric cancer (specifically gastric adenocarcinoma) who are being considered for surgery. Gastroesophageal junction (GEJ) tumours and early gastric cancers are excluded because they require additional considerations.
# INTENDED USERS
Intended users of this guidance document are surgeons, gastroenterologists, medical oncologists, radiation oncologists, and the multidisciplinary team who treat gastric cancer.
# RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE Recommendation 1
Endorsed from Lerut et al. 2012 [1]:
All patients diagnosed with gastric cancer should be discussed at a multidisciplinary team meeting. In patients with newly diagnosed gastric cancer, CT scan of the chest and abdomen should always be performed. Endoscopic ultrasound (EUS) can be considered in patients planned for curative treatment on the basis of clinical presentation and/or CT. Fine -needle aspiration cytology of suspicious lymph nodes or metastases can be considered if tech nically feasible. The following examinations can be considered for specific indications: PET scan, magnetic resonance imaging, laparoscopy.
# Qualifying Statements for Recommendation 1
As the accuracy for CT scans in detecting M1 disease is 81% [2], diagnostic laparoscopy may allow patients to avoid a laparotomy in up to 44% of cases of advanced stage cancer [3]. Both Scottish Intercollegiate Guidelines Network (SIGN) [4] and Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) [5] guidelines suggest diagnostic laparoscopy in patients with clinically suspected T3 and T4 cancers, or those at higher risk for M1 disease, such as poorly differentiated cancers and those with a higher nodal burden. Diagnostic laparoscopy should be performed p rior to starting chemotherapy for patients in whom a neoadjuvant approach is considered. Washing may increase the accuracy of diagnostic laparoscopy. PET and MRI may be useful for further characterization of liver lesions, in clinical scenarios in which treatment plans would be changed by the finding of metastatic disease, but should not be routinely performed. EUS should only be performed if results may change management plans (i.e., to assess for local invasion, nodal status or metastatic spread).
# Key Evidence for Recommendation 1
Key evidence derived from one clinical practice guideline conducted by Lerut at al. [1] of the Belgian Health Care Knowledge Centre.
# Interpretation of Evidence for Recommendation 1
There was agreement among the Working Group members that the overall certainty of the evidence was moderate. The Working Group considered accurate staging of each patient to be of paramount importance in order for patients to be provided appropriate treatment. Therefore, the Working Group was unanimous in their opinion that patients would also value the importance of accurate staging, although patient input was not sought. The desirable effect (i.e., accurate staging) is large as patients who are improperly staged will not be provided with appropriate treatment. At the same time, the undesirable effects (morbidity of the staging investigations) are manageable in this population. The Working Group believed the desirable effect (accurate staging) is large relative to the undesirable effects (potential increased morbidity) in this population of patients because inaccurate staging will result in patient being treated inappropriately, either by under-treating or over-treating them.
The evidence is generalizable to the entire population of gastric cancer patients. The Working Group believed that all interpretations of the evidence for staging of gastric cancer patients would be similar. showed fewer gastric cancer-related deaths in patients undergoing a D2 LND for all Tstages (gastric cancer related deaths were 48% in D1 vs. 37% in D2, p=0.01, per protocol analysis) [13].
# Interpretation of Evidence for Recommendation 2
See Section after Recommendation 4.
# Recommendation 3
At least 16 lymph nodes should be assessed for adequate staging of curative -resected gastric cancer.
# Qualifying Statements for Recommendation 3
American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) guidelines [6] state that 16 lymph nodes are necessary for adequate staging. Studies [7,8] suggest that removal and examination of more than 16 nodes may improve survival and increases accuracy of staging by decreasing under staging which leads to stage migration.
# Key Evidence for Recommendation 3
One systematic review [14] reported significantly improved disease -free survival (DFS) as the number of lymph nodes harvested increased, especially when more than 15 nodes were retrieved, and concluded that 16 lymph nodes should be harvested as a minimum. More current studies of moderate quality [15,16] also report that harvesting more than 15 nodes significantly improved survival.
# Interpretation of Evidence for Recommendation 3
See Section after Recommendation 4.
# Recommendation 4
Surgery for gastric cancer should aim at achieving an R0 margin. [9] guidelines suggest 4 cm margins in order to assure negative margins, while the Japanese Gastric Cancer Treatment Guidelines [10] suggest that margins of 3 cm for T1/T2 cancer and 5 cm for T3/T4 cancers be obtained. Intra-operative frozen section analysis should be considered in cases where there is concern about a high risk of positive margin. Cancers with higher T and N stage, and higher grade tumours, such as diffuse -type histology including signet ring carcinoma, are more likely to have microscopic margins involved, and intra-operative planning or neoadjuvant therapy should take these factors into consideration. For patients with poor biology (>5 lymph nodes positive, diffuse -type histology including signet ring carcinoma), an extended resection of the adjacent organs or intra-thoracic esophagus may not result in improved long-term survival, as multivariable analyses in many studies have shown that tumour biology may be a stronger determinant of outcomes than a positive margin. Extended resection should be undertaken selectively and with multidis ciplinary discussion.
# Key Evidence for Recommendation 4
Data from one study suggest that margins of 5 cm for T3/T4 cancer and 3 cm for T1/T2 cancers are sufficient to obtain resection margins negative for microscopic cancer [17]. Median overall survival (OS) and median recurrence-free survival (RFS) for patients was significantly better in those with proximal margins of 3.1 to 5.0 cm compared with margins ≤3.0 cm (48.1 vs. 29.3 months, p=0.01; and 38.9 vs. 21.1 months, p=0.02, respectively). Median OS and median RFS for patients with margins >5.0 cm were not significantly different than those with proximal margins of 3.1 to 5.0 cm. However, the OS and RFS advantage of a proximal margin ≥3.1 cm was only associated with Stage I disease only and was not associated with Stage II or III disease [17].
# Interpretation of Evidence for Recommendation 4
See Section after Recommendation 4.
# Interpretation of Evidence for Recommendations 2, 3 and 4.
There was agreement among the Working Group members that the overall certainty of the evidence was moderate based on the entire body of the evidence. Although the Working Group looked at survival, mortality, reoperation rates, and RFS, OS was considered to be the most important outcome, followed by RFS. The Working Group was unanimous in their opinion that patients would also value the increased survival benefit associated with each of the surgical parameters evaluated (extent of lymphadenectomy, number of lymph nodes retrieved, and minimal gross margins) although patient input was not sought. The Working Group valued survival when drafting the recommendations as they believed that the morbidities associated with each of these surgical parameters were manageable. The desirable effect is increased survival. The undesirable effects (morbidity) are manageable in this population. The Working Group believed the desirable effect (longer survival) is large relative to the undesirable effects (extra morbidity) in the selected group of Stage III patients especially since inadequate LND, positive margins, and retrieval of an inadequate number of lymph nodes are all asso ciated with disease recurrence. The evidence is generalizable to the entire gastric cancer population as defined in this guidance document.1 The Working Group believed that there might be an alternate interpretation of the evidence for D2 versus D1 LND if the focus remains on several negative trials available and not on the compelling subgroup analysis of these trials and the emerging long-term survival benefits in ongoing trials.
# Recommendation 5
In the metastatic setting, nonsurgical management options are preferred in patients without symptoms. In the metastatic setting, surgery should only be considered for palliation of symptoms that cannot be addressed through less-invasive means (i.e., radiation, chemotherapy, stenting).
# Qualifying Statements for Recommendation 5
As the rate of complications appears to be highest in more extensive resections, a palliative total gastrectomy should be performed only in exceptional circumstances, and with multidisciplinary discussion. Key Evidence for Recommendation 5 In one systematic review of 59 studies, procedure-related morbidity occurred in all types of surgical interventions and irrespective of the intent of the surgery. Morbidity ranged from 3.8% to 49% for gastrectomy and 14% to 21% for non-resectional surgeries [18]. In the literature update, procedure-related morbidity in moderate-quality noncurative studies ranged from 15.1% [19] to 88.8% [20]for gastrectomy and 11.5% [21] to 21% [22]for non-resectional surgeries. In the systematic review by Mahar et al. [18], procedure-related mortality was lower in palliative resections (0% to 7%) compared with either non -curative (0% to 21%) or not otherwise specified surgeries (0% to 20.4%). The mortality rate for gastrectomy performed for any intent was 0% to 21% whereas the mortality rate for non -resectional surgeries was 0% to 39% [18]. In the literature update, which included all moderate quality studies, procedure-related mortality for gastrectomy performed in noncurative studies was 1.1% [19] to 9.1% [23], whereas the mortality rate for nonresectional surgeries in non-curative studies was 4.8% [21] to 10% [22]. The REGATTA trial [24] showed no survival benefit of gastrectomy + chemotherapy over chemotherapy alone (25.1% vs. 31.7%) in patients with non -curable gastric cancer (hazard ratio [HR], 1.09; 95% CI, 0.78 to 1.52; p=0.70), and more complications for patients in the gastrectomy + chemotherapy arm.
# Interpretation of Evidence for Recommendation 5
There was agreement among the Working Group members that the overall certainty of the evidence was moderate. Although the Working Group looked at survival, morbidity, mortality, and quality of life (QOL), morbidity and QOL (where available) were considered to be the most important outcomes. The Working Group was unanimous in their opinion that patients would also likely value these outcomes, although patient input was not sought. The Working Group valued OS over toxicity when drafting the recommendations as they felt that the toxicities were manageable. The desirable effect (i.e., better QOL, less morbidity) is probably not large, especially for Stage IV patients in whom the goal of surgery is not palliation of symptoms. At the same time, the undesirable effects are moderate. The mortality rates for surgery in Stage IV gastric cancer can be high especially when the surgery is not performed for CCMB, Disease Management: Guideline for the Curative Treatment of Gastric Cancer p.17
Date Updated: December 2018 palliation of symptoms. The Working Group believed the desirable e ffect (better QOL) was not large relative to the undesirable effects (mortality) and should, therefore, only be performed for palliation of symptoms. If the surgery is not likely to improve QOL, it should not be done. The evidence is not generalizable to the entire Stage IV gastric cancer population as defined in this guidance document. The Working Group believed that the REGATTA trial [24] may be interpreted differently by others. REGATTA was stopped early for futility and possible harm in the surgery arm. It is conceivable that these data may be interpreted as meaning that survival was equivalent in the surgery and the surgery + chemotherapy arms, but most are not making this interpretation.
# Recommendation 6
Given evidence that higher-volume centres are associated with lower rates of procedure-related mortality, patients should be referred to higher-volume centres for surgical resection. Gastric cancer surgery should be performed in centres with sufficient support to prevent or manage complications (e.g., interventional radiology, anesthesia, level 1 intensive care unit).
# Qualifying Statements for Recommendation 6
In most studies, higher-volume centres are associated with improved outcomes. There is no common definition of a high-volume centre within the studies; however, it should be noted that five or fewer annual cases are considered low or very low volume in all studies. An expected 30-day or in-hospital peri-operative mortality should be less than 5%. This is based on published mortality rates from high-volume centres, as well as the "Hepatic, Pancreatic and Biliary (HPB) Tract Surgical Oncology Standards" (EBS#17-2) [11], which recommends a 30-day or in-hospital mortality rate of less than 5% for major pancreatic resection and 3% for anatomical liver resection. As these procedures are more complicated than gastric cancer surgery, it is reasonable to expect a similar or lower mortality rate. Hospitals performing gastric cancer surgery should know their mortality rates, and recognize that lower volumes create larger confidence intervals for mortality estimates.
# Key Evidence for Recommendation 6
In one systematic review containing 22 studies looking at institutional volumes, procedure-related morbidity was not significantly different in high-volume compared with low-volume hospitals (19% to 46.5% in high-volume hospitals vs. 19% to 43% in low-volume hospitals). However, meta-analysis of procedure-related mortality favoured high-volume hospitals (OR, 0.73; 95% CI, 0.65 to 0.81; p<0.00001). Improved five-year survival was significantly associated with higher institutional volumes in three of seven studies that evaluated this outcome [25]. In the updated literature search, procedure-related mortality was not significantly different in high-versus low-volume hospitals in four of the five studies evaluating this outcome [26][27][28][29]. However, in 2013, Dikken et al. [30] reported that procedurerelated mortality significantly favours high-volume hospitals (OR, 0.64; 95% CI, 0.41 to 0.99; p=0.025). The updated literature search only yielded moderate quality non-RCTs.
# Interpretation of Evidence for Recommendation 6
CCMB, Disease Management: Guideline for the Curative Treatment of Gastric Cancer p.18
Date Updated: December 2018 There was agreement among the Working Group members that the overall certainty of the evidence was low to moderate. Although the Working Group looked at mortality (especially 30-day and in-hospital mortality) and morbidity, the Working Group was unanimous in their opinion that patients would value mortality as an assessment of surgeon and/or institutional volumes, although patient input was not sought. The desirable effect (i.e., lower short-term mortality) is large. At the same time, the undesirable effects (i.e., death) are not small. The Working Group believed the desirable effect (living) was larger relative to the undesirable effects (death). The evidence is generalizable to gastric cancer surgery in all institutions. The Working Group believed that others may have slightly different interpretations of the volume data by setting definite numerical volume standards, whereas in the present guidance document the focus was on mortality rate instead.
# Recommendation 7
Quality metrics for lymph nodes, margins, peri-operative mortality, and oncologic outcomes should be met regardless of surgical technique (e.g., open or minimally invasive).
# Qualifying Statements for Recommendation 7
While laparoscopic resection has been shown to be equal or superior to open surgery for short-term outcomes, there is no evidence regarding long-term cancer outcomes. Several ongoing randomized trials will report on oncologic survival.
# Key Evidence for Recommendation 7
Short-term outcomes (e.g., blood loss, time to first flatus, length of hospital stay, and post-operative complications) favour laparoscopic compared with open gastrectomy [31][32][33][34][35][36][37][38]. This is based on one systematic review and several more recent primary studies. Long-term cancer-related survival results are currently being examined in several RCTs.
# Interpretation of Evidence for Recommendation 7
There was agreement among the Working Group members that the overall certainty of the evidence was moderate. Although the Working Group looked at short-term outcomes (blood loss, time to first flatus, length of hospital stay, post-operative complications, hospital mortality rates, and surgical time) and long-term outcomes (survival), no long-term outcomes have been reported from RCTs to date. The Working Group was unanimous in their opinion that patients would also value both long-and short-term outcomes, although patient input was not sought. Once these longer-term outcome data become more available, the emphasis on short-term outcomes may change. The desirable effects (i.e., better short-term outcomes such as blood loss, time to first flatus, length of hospital stay, post-operative complications, hospital mortality rates) are large. At the same time, the undesirable effects (longer surgical times) are manageable in this population with adequate surgeon training in laparoscopic procedures. The Working Group believed the desirable effect (better short -term surgical outcomes) is large relative to the undesirable effects (longer surgical times). Once these longer-term outcome data become more available, the emphasis on shortterm outcomes may change. The evidence is generalizable to the entire gastric cancer population as defined in this guidance document.
# IMPLEMENTATION CONSIDERATIONS
The Working Group considered the recommendations provided above to be the ideal standard of care and would be feasible to implement. Furthermore, they may improve current health inequities by ensuring the same standards of care for all patients no matter where they are treated in Ontario. Thus, there is the potential for better outcomes for gastric cancer patients across the province. To support in this endeavour it would be useful if hospital mortality rates for gastric cancer surgery were available to hospitals as they are for other types of surgeries such as pancreas, lung, and esophagus. These recommendations may change current practice as many patients are currently only receiving a D1 LND even when a D2 is more appropriate. Moreover, laparoscopic surgeries may occur more often as time goes on and more surgeons are adequately trained in these procedures. These recommendations may come with no additional costs. In fact, overall costs may decrease owing to fewer recurrences, possibly fewer unnecessary surgeries, and reduced length of hospital stays as the number of laparoscopic surgeries performed increases. The Working Group believed the outcomes valued in this guideline would align well with patient values and patients would view these recommendations as acceptable. Disclaimer Care has been taken in the preparation of the information contained in this report. Nevertheless, any person seeking to consult the report or apply its recommendations is expected to use independent medical judgment in the context of individual clinical circumstances or to seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representations or guarantees of any kind whatsoever regarding the report content or its use or application and disclaims any responsibility for its application or use in any way.
# RELATED GUIDELINES
# VI. Implementation and Dissemination
The value of guidelines truly lies in their implementation and use. For that purpose, consideration was given to implementation during the drafting of this guideline document.
# CancerCare Resources
It was recognized that resources would be needed to distribute these guidelines to the community. For that purpose, the guideline will be accessible online through the CancerCare Manitoba website. Online availability will be preceded by an e-blast notification with the website embedded. Announcement of the guideline and updates will be through established provincial communication channels: Community Oncology Program to CCPN rural sites, UPCON clinics and WRHA Community Oncology Program sites. Use of the guideline in clinic will be through the online version.
# Educational Events
The guideline's recommendations were presented at Disease Site Group Meetings and the Cancer Surgery Update (2019).
# Concordance Measurement and Performance Audit
A plan is being developed regarding the guideline concordance measurement and will be presented to the CCMB standards committee for approval. Briefly, a panel will review each gastric cancer case at CCMB and provide a confidential feedback form covering the key recommendations to the treating physicians/surgeons. Suggestions will be presented in an encouraging format. The audit and feedback process will be done under the auspices of the CCMB standards committee, and include the protections therein. This plan will be finalized and implemented after the settling of the Covid-19 pandemic.
# VIII. Conflicts of Interest
In accordance with the CCMB policy no. 01.001, "Conflict of Interest", the authors of this guideline disclosed no conflicts of interest and declares that no commercial support was received during the development of this guideline.
# Acknowledgements
We gratefully acknowledge the support of CancerCare Manitoba, the CancerCare Manitoba Foundation, the Provincial Oncology Clinical Practice Guidelines Initiative, and external reviewer: Dr. Rebecca Wong, Radiation Oncologist, Princess Margaret Hospital (Toronto, Ontario, Canada).
CCO Gastric Guideline used with permission December 2018.
# QUESTION
Should patients with resectable gastric cancer (Stage 1B [invasion of the muscularis propria] and above) receive neoadjuvant or adjuvant therapy in addition to surgery? Outcomes of interest are overall survival (OS), disease-free survival (DFS), and adverse events.
# TARGET POPULATION
These recommendations apply to adult patients with potentially curable, surgically resectable (Stage 1B [invasion of the muscularis propria] and above) gastric cancer.
# INTENDED USERS
These guidelines are intended for use by clinicians and healthcare providers involved in the management and referral of patients with resectable gastric cancer.
RECOMMENDATIONS results of S-1 trials in Asia as well as the improved safety profile of S-1 in the First-Line Advanced Gastric Cancer Study (FLAGS) trial in advanced gastric cancer (8), a trial of S-1 in the neoadjuvant and adjuvant setting in North America may be warranted. Finally, a trial of neoadjuvant chemoradiation would be helpful. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.
# RELATED GUIDELINES
# Disclaimer
Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way.
# Contact Information
# IX. Appendix Appendix 1
External Review:
Dr. Rebecca Wong, a Radiation Oncologist from the Princess Margaret Center in Toronto, Ontario, who was an author on the adopted CCO guidelines, was contacted to act as an external reviewer. Her completed checklist, comments, and our responses are included herein.
# External Guideline Review Results
# Dr. Rebecca Wong Radiation Oncologist Princess Margaret Center
Toronto, Ontario, Canada
# 1.
Scope of the guideline The stated purpose of the guideline is to outline the appropriate work up and treatment of potentially curable gastric carcinoma in Manitoba. On page 6, it is stated that the group agrees to adapt the CCO guideline (1,2). However, in the document provided, only guideline 2-14 was included. I do not see information for guideline 2-19 represented in this document. If it is only guideline 2-14 that is being included, then the recommendations will not be addressing the appropriate workup part of the objective.
# 2.
Recommendations There is no section where I am able to review the actual recommendations from the panel to the practitioner. Is it the intention for the reader to refer to page 11-12 and use the statements provided here as the recommendation for Manitoba? The format used by the ITP guideline is more explicit -i.e. Having a section that states "Summary of recommendations".
# 3.
Guideline Methodology (for adaptation) The main concern I would raise for the guideline as presented is the lack of a literature search for primary evidence when the guideline 2-14 in its current form is archived. "An assessment conducted in December 2018 ARCHIVED Evidence based Series (EBS) 2-14 Version 3. This means that the recommendations will no longer be maintained but may still be useful for academic or other information purposes". I agree providing a discussion on key evidence as on page 7 is a reasonable way of addressing any practice changing trials that should be considered, as an evidence based guided document, it seems inadequate (especially when the source document is listed as archived). If the guidelines panel is happy to limit the literature Disease Management| 32 CCMB, Disease Management: Guidelines for the Curative Treatment of Gastric Cancer p.32 Date Updated: December 2018 review to existing guidelines as use that as the reference point as stated, including the literature search strategy employed would enhance the methods employed. A statement to the effect that the references of existing guideline, expert panel was used to identify potential practice changing trials that may be missed may be worth including in the methods section. A "matrix" aligning the questions and recommendations from the published guideline review may serve to provide support that the recommendations are consistent with other existing guidelines that you have reviewed.
# Response to External Review:
Dr. Pamela Hebbard I kindly thank Dr. Wong for her time and insightful feedback on our guideline process. Her comments are all well taken and used to strengthen the guideline document and process.
# Modifications/Actions
1
The Manitoba guideline references CCO guidelines 2-19 and 2-14. We will ensure that this is more clearly noted in our document.
# 2
A recommendation section will be added to the MB document so that clinicians do not have to flip between the CCO guidelines and our own.
3
The guideline committee was given instructions to review existing guidelines first and adopt or adapt one if possible. As all committee members are practicing in gastric cancer treatment, we did have a good working knowledge of missing studies due to the age of the guidelines reviewed and included this in our discussion portion. The guideline literature search was performed by staff no longer under the employment of CancerCare Manitoba and given the length of time since we did the exercise, I do not have a memory of the search strategy. Unfortunately, this item will remain unreconciled, but I do take the comment under advisement to employ during any future update of the guideline.
4
The reference updates will be noted and have been made.
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# Introduction
Metastatic prostate cancer remains an incurable disease. In Canada, approximately 8% of men with prostate cancer are diagnosed de novo with metastatic disease and, in 2018, roughly 1200 men were diagnosed with de novo metastatic prostate cancer (PCa). 1 The mainstay of treatment for de novo metastatic PCa is androgen deprivation therapy (ADT), either surgical or medical castration, which is initially effective in almost all patients; however, progression is inevitable, heralded by a rise in prostate-specific antigen (PSA), increasing disease burden, and/or worsening symptoms -a disease state called metastatic castrationresistant prostate cancer (mCRPC).
Men with metastatic PCa have a poor prognosis, with an estimated median overall survival (OS) of approximately 3-4 years. 2 Compared to PCa that develops metastases after diagnosis of localized disease, de novo metastatic PCa has been shown to have a worse overall prognosis. 3,4 Over the past decade, practice-changing trials have demonstrated improved survival in men with metastatic castration-naive/ castration-sensitive prostate cancer (mCNPC/mCSPC) using ADT intensification strategies that include both systemic therapy and treatment of the primary cancer.
The Canadian Uro-Oncology Group (CUOG), in collaboration with the Canadian Urological Association (CUA), sought to provide management guidelines to optimize the treatment of patients with mCNPC/mCSPC.
# Methods
EmBASE and Medline databases were accessed to identify all relevant articles focused on mCNPC or mCSPC published between January 2000 and April 2022 with the following keywords strategy: "prostate cancer," "hormone sensitive," "castration naive," "castration sensitive," "androgen deprivation," "chemotherapy," "androgen receptor-axis targeted therapy," and "metastatic." An expert panel comprised of urologists, medical oncologists, and radiation oncologists with significant experience managing mCNPC/mCSPC developed the recommendations. Guidelines were developed by consensus among the panel. Levels of evidence and grades of recommendation employ the WHO modified Oxford Center for Evidence-Based Medicine grading system. 5 Based on a modified GRADE methodology, the strength of each recommendation is represented by the words strong or weak. 5 Wherever level 1 evidence is lacking, the guideline attempts to provide expert opinion to aid in the management of patients.
# Indications for staging in prostate cancer
For patients with newly diagnosed PCa, staging with computed tomogragphy (CT) scans of the chest, abdomen, and pelvis, and bone scan ( 99 mTc-MDP) should be performed for men with any high-risk features: PSA >20 ng/mL, Gleason score >7, clinical stage T3 or greater (Level of evidence 3, Strong recommendation).
Conventional imaging to stage PCa includes bone scintigraphy using technetium-99 mmethylene diphosphonate ( 99 mTc-MDP) to assess for bone metastases and abdominopelvic CT imaging to assess for lymphadenopathy and visceral metastases. In patients with high-risk disease, CT imaging of the chest may also be considered, as lung metastases are the most common site of visceral metastases. 6 Novel diagnostic imaging to stage PCa, particularly prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET)/CT, improves the sensitivity and specificity of conventional imaging; however, these tests are not universally available Canada, and they are still considered investigational by Health Canada. Most importantly, all the phase 3 trials in mCNPC/mCSPC used conventional imaging for staging and risk determination, and conclusions were based on these.
# Assessment of prognosis
# Patients diagnosed with mPCa should be classified as highvolume/high-risk or low-volume/low-risk based on conventional imaging and prostate cancer biopsy for prognostication (Level of evidence 2, Weak recommendation).
Recent clinical trials of patients with mCNPC/mCSPC have used pragmatic prognostic factors to stratify prognosis. The CHAARTED trial classified PCa based on volume of disease. High-volume was defined by the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis; and low-volume was defined as all other mCNPC/mCSPC. 7 The LATITUDE trial classified high-risk patients based on three different criteria: visceral metastases, ≥3 bony metastases, or Gleason score ≥8; high risk was defined as having two or more of these criteria, whereas low risk was defined having less than two. 8 Interestingly, a comparative study of the classification of each of these trials showed an overall discordance of 18.2% between the CHAARTED and LATITUDE criterion; however, it appears that disease burden (defined radiologically or by PSA) and high-grade tumors portend a worse prognosis. 9
# Androgen deprivation therapy
# ADT should be started on patients with newly diagnosed with mPCa (Level of evidence 1, Strong recommendation).
Continuous ADT is the standard of care for patients with mPCa, while intermittent may be considered in select patients.
Androgen receptor signaling plays a key role in the progression of PCa, and thus, de novo mCNPC remains highly driven by testosterone. Hence, the primary step in the management of mCNPC, which remains the backbone of treatment for all men with mPCa until death, is ADT. ADT can be achieved by surgical castration (orchiectomy) or pharmacologically with agents that inhibit Leydig cell production of testosterone (gonadotropin-releasing hormone agonists or antagonists). The optimal timing of androgen deprivation has been the subject of many trials, with two systematic reviews suggesting early treatment is associated with improved OS and cancer-specific survival and decreases the rate of skeletal events compared to deferred treatment. 10,11 More importantly, the early treatment of mCNPC with ADT is required if other systemic treatment, such as docetaxel or androgen receptor axis inhibitors, are used.
ADT is associated with side effects and may increase the risk of cardiovascular events, but evidence has been contradictory. Intermittent androgen suppression (IAS) that cycles ADT based on PSA values has been shown to improve quality of life; however, continuous ADT should be used in mCNPC and IAS only used as an exception in select patients with close followup. 12,13 As well, the benefit of combined treatment of mCNPC with additional systemic therapy was demonstrated in the context of continuous ADT.
# Local therapy: treatment of the primary cancer in mCNPC
# Patients with low-volume metastatic disease burden of PCa should be considered for external beam radiation to the prostate (Level of evidence 2, Strong recommendation).
In the context of low-volume mCNPC, treatment of the primary disease in the prostate has theoretical benefits, including reducing local side effects that may occur due to local disease progression, as well as removing the cancer that could be the source of cytokines and growth factors that may induce disease progression. 14 Two recent randomized trials assessed the impact of external beam radiation therapy (EBRT) in mCNPC. The HORRAD trial randomized 432 men with mCNPC and PSA >20 ng/mL to receive EBRT of the prostate with ADT or ADT alone. The initial prescribed dose was 70 Gy in 35 fractions of 2 Gy, during an overall treatment time of seven weeks. During the study period, an optional schedule considered biologically Guideline: mCNPC & mCSPC equivalent was added and consisted of a dose schedule of 57.7 Gy in 19 fractions of 3.04 Gy three times a week for six weeks. At baseline, the median PSA was 142 ng/ml and 67% of patients had more than five bone metastases. No significant difference was found in OS (hazard ratio 0.90, 95% confidence interval 0.70-1.14, p = 0.4), but there was a benefit to median time to PSA progression in the radiotherapy group (15 months vs. 12 months, crude HR 0.78, 95% CI 0.63-0.97, p=0.02). Subgroup analysis showed that mCNPC with <5 metastases (HR 0.90, 95% CI 0.70-1.14, p=NS) and no bony pain (HR 0.83, 95% CI 0.69-1.14, p=NS) appeared to have the most benefit of EBRT.
The STAMPEDE trial, also known as MRC PR08, is a multiarm, multistage (MAMS) randomized trial recruiting in the United Kingdom and Switzerland. It aimed to evaluate multiple therapeutic strategies in the management of high-risk locally advanced and mCNPC compared to standard of care (SOC) (ADT only). In the EBRT component of the study, the trial randomized 2061 men with mCNPC to either EBRT and ADT or ADT alone. 15 The median PSA was 97 ng/mL, 819 (40%) men had low metastatic burden based on CHAARTED criteria, and 1664 (81%) had no pain. 7,15 EBRT was given as one of two schedules: either 36 Gy in six consecutive weekly fractions of 6 Gy, or 55 Gy in 20 daily fractions of 2.75 Gy over four weeks. Subgroup analyses were prespecified for baseline metastatic burden (low vs. high).
Similar to the HORRAD trial, EBRT improved failure-free survival (FFS) (HR 0.76, 95% CI 0.68-0.84, p<0.0001) but not OS (HR 0.92, 95% CI 0.80-1.06, p=0.266). Subgroup analysis by metastatic burden showed FFS was improved in both low and high metastatic burden (low metastatic burden: HR 0.59, 95% CI 0.49-0.72, p<0.0001 and metastatic burden interaction p=0.002; HR 0.88, 95% CI 0.77-1.01, p=0.059). Overall survival was improved in patients with low metastatic burden at baseline who were allocated EBRT (HR 0.68, 95% CI 0.52-0.90, p=0.007), whereas in patients with a high metastatic burden, there was no impact on OS (HR 1.07, 95% CI 0.90-1.28, p=0.420).
Although both trials showed a lack of benefit of EBRT in unselected men in mCNPC, both HORRAD and STAMPEDE reveal the benefits of local therapy in those with low-burden disease. A recent STOPCAP meta-analysis combining data from the trials confirm the benefits of EBRT in men with fewer than five bone metastases. 16 This meta-analysis showed that there was 7% improvement in three-year survival in men with fewer than four bone metastases.
# Radical prostatectomy in mCNPC should only be performed in a clinical trial setting (Expert opinion, Strong recommendation).
Currently, there is limited evidence showing the benefit of radical prostatectomy in mCNPC; however, the results from HORRAD and STAMPEDE imply that there may also be certain men with mCNPC that may benefit from surgical extirpation. There are many clinical trials currently assessing this question, including TRoMBONE (Testing Radical prOstatectomy in Men with PCa and oligometastases to the BONE: A randomized controlled feasibility trial), 17 SWOG1802 (Standard systemic therapy with or without definitive treatment in treating participants with mPCa ), G-RAMPP/AUO-AP-75/13 (Impact of radical prostatectomy as primary treatment in patients with PCa with limited bone metastases), 18 and IP2-ATLANTA (Additional Treatments to the Local tumor for metastatic prostate cancer -Assessment of Novel Treatment Algorithms: Protocol for a multicenter, phase 2, randomized controlled trial). 19 Until the results of these trials clarify the impact of radical prostatectomy in mCNPC, and more importantly, which patients would benefit most, surgery of the primary is not recommended in patients with mPCa.
Systemic therapies: chemotherapy, abiraterone acetate, enzalutamide, and apalutamide Docetaxel (75 mg/m 2 every three weeks for six cycles) plus ADT is an option for patients with mCNPC/mCSPC, good performance status, and high-volume metastatic disease defined as: presence of visceral metastases or four or more bone lesions with at least one beyond the vertebral bodies and pelvis (Level of evidence 1, Strong recommendation).
# Docetaxel plus ADT may also be an option for patients with mCNPC/mCSPC and good performance status with low-volume disease (Level of evidence 2, Weak recommendation).
Consideration of patients with high-risk mCNPC/mCSPC (defined as at least two of: Gleason score of 8-10, visceral metastases, and three or more bone metastases) and good performance status can also be considered for docetaxel chemotherapy (Level of evidence 1, Strong recommendation). Docetaxel, a taxane derivative that binds to tubulin and inhibits mitosis and tumor proliferation, was the initial chemotherapeutic agent that improved survival in men mCRPC. 20 Three large, randomized trials assessed the impact of introducing docetaxel in mCNPC/mCSPC: CHAARTED, STAMPEDE, and GETUG-AFU 15. 7,21,22 The CHAARTED trial randomized 790 with mCNPC/mCSPC patients to ADT plus docetaxel (75 mg/m 2 every three weeks for six cycles) or ADT alone. 7 Within this trial, 35% (n=277) had low-volume metastases and 65% (n=513) had high-volume metastases (high volume of metastases was defined by the presence of visceral metastases or four or more bone lesions with at least one beyond the vertebral bodies and pelvis). Overall, the median OS was 13.6 months longer with ADT plus docetaxel than with ADT alone (57.6 months vs. 44.0 months; HR 0.61, 95% CI 0.47-0.80, p<0.001). Subgroup analysis showed that OS benefits of combination there were maintained in the high-volume mCNPC/mCSPC (n=513, HR 0.63, 95% CI 0.50-0.79, p<0.001), whereas survival benefits were lost in low-volume disease (n=277, HR 1.04, 95% CI 0.70-1.55, p=0.86). 23 The GETUG-AFU15 trial randomized 385 patients with mCNPC/mCSPC to receive ADT plus docetaxel or ADT alone. 22 Although the dosage of docetaxel was the same as in CHAARTED, patients were allowed to receive up to nine cycles compared to the six cycles in CHAARTED. There was no survival difference between the groups (58.9 months in the combined group vs. 54.2 months in the ADT alone group, HR 1.01, 95% CI 0.75-1.36). The differences in the outcomes of the two studies is likely due to the differences in the burden of disease in the two studies. Although 65% of patients in CHAARTED had high-volume metastases, only 48% in the docetaxel arm of GETUG-AFU15 had high-volume disease. An unplanned post-hoc analysis of the high-volume cohort of GETUG-AFU 15 showed a nonsignificant trend toward improved OS in this cohort (39.8 months vs. 35.1 months, HR 0.78, 95% CI 0.56-1.09). 24 A recent pooled analysis of both studies confirms the benefit of combined docetaxel and ADT in high-volume disease and lack of benefit on low-volume metastatic burden. 25 The third trial to assess the impact of docetaxel in mCNPC/ mCSPC was the docetaxel component of the STAMPEDE trial. 21 Unlike the CHAARTED and GETUG-AFU15 trials, patients with high-risk non-metastatic PCa were included. Eligible patients included: newly diagnosed metastatic, node-positive, or high-risk locally advanced (with high-risk features defined as at least two of: T3/4, Gleason score of 8-10, and PSA ≥40 ng/mL) prostate cancer; or previously treated with radical surgery and/or radiotherapy with highrisk features. Of the 2962 patients randomized, 1817 (61%) patients had bony metastases and 592 patients received only ADT and six cycles of docetaxel (75 mg/m 2 every three weeks for six cycles). The combination of ADT and docetaxel had a survival advantage compared to ADT alone (HR 0.78, 95% CI 0.66-0.93, p=0.006). Although patients were not classified having high-or low-volume metastases, only patients with metastatic disease had evidence of benefit with ADT and docetaxel (HR 0.76, 95% CI 0.62-0.92, p=0.005).
A post-hoc, non-prespecified analysis of STAMPEDE was published. 26 Metastatic burden was assessable in only 76% of patients for the analysis (830 of 1086 patients) and 362 (44%) had low and 468 (56%) high metastatic burden. Although OS was neither statistically significant in low-burden nor in high-burden disease (HR 0.76, 95% CI 0.54-1.07, p=0.107 vs. HR 0.81, 95% CI 0.64-1.02, p=0.064), the authors found no evidence of heterogeneity of docetaxel effect between metastatic burden subgroups (interaction p=0.827). The authors concluded that upfront docetaxel should be considered for patients with mCNPC/mCSPC regardless of metastatic burden. This retrospective analysis contradicts the results of CHAARTED, but the authors point out that this may be due to the larger number of patients with de novo mCNPC/mCSPC (n=362) in the low-burden group compared to the low-burden group in the CHAARTED trial (n<160).
A recent meta-analysis of CHAARTED, GETUG-AFU15, and STAMPEDE confirms the benefit of the addition of docetaxel to ADT for patients with mCNPC/mCSPC (HR 0.77, 95% CI 0.68-0.87, p<0.0001). The authors of the metaanalysis show that this translates to an absolute improvement in four-year survival of 9%.
Abiraterone acetate (1000 mg daily) with prednisone (5 mg daily) plus ADT is an option for patients with mCNPC with at least two of the three: (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis) (Level of evidence 1, Strong recommendation).
# Abiraterone acetate (1000 mg daily) with prednisone (5 mg daily) plus ADT may be considered for patients with low-volume mCNPC (Level of evidence 3, Weak recommendation).
Abiraterone acetate is a prodrug of abiraterone, which is a CYP17A1 inhibitor; CYP17A1 is expressed in and is required for androgen biosynthesis. Abiraterone acetate, when combined with prednisone, was initially shown to improve survival in mCRPC, both prior to and after docetaxel treatment. 27,28 Two trials, LATITUDE and STAMPEDE, assessed the impact of abiraterone in mCNPC/mCSPC. 8,29,30 In the LATITUDE trial, 1199 patients were randomly assigned to either the abiraterone acetate (1000 mg) plus prednisone (5 mg) once daily orally and ADT vs. ADT alone. Eligible patients included patients with mCNPC with at least two of three high-risk features (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis). Updated OS data with median followup of 51.8 months showed that OS was significantly longer in the abiraterone acetate plus prednisone group (median 53.3 months ) than in the placebo group (median 36.5 months ), with a HR of 0.66 (95% CI 0.56−0.78, p<00001). A post-hoc exploratory analysis of the impact of disease burden showed that OS was improved only in patients with high-volume disease (n=487 in the abiraterone acetate plus prednisone and ADT and 468 in the ADT only group ); however, only few patients had low-volume disease in this study (n=110 in the abiraterone acetate plus prednisone and ADT and n=133 in the ADT only group (HR 0.72, 95% CI 0.47−1.10, p=0.1242).
# Guideline: mCNPC & mCSPC
In the abiraterone component of the STAMPEDE trial, the efficacy of abiraterone acetate and prednisolone was assessed in men with mCNPC. 29 In this study, 1917 patients with mCNPC were enrolled with: newly diagnosed and metastatic, node-positive, or high-risk locally advanced prostate cancer (with at least two of following: cT3 or cT4, a Gleason score of 8−10, or PSA level ≥40 ng/mL) or disease that was previously treated with radical surgery or radiotherapy and was now relapsing with high-risk features (PSA >4 ng/mL with a doubling time of 20 ng/mL, nodal or metastatic relapse). Men were randomized to receive abiraterone acetate (1000 mg daily) plus prednisolone (5 mg) plus ADT or ADT alone. Just over half of the patients (52%) had metastatic disease, 20% had node-positive or node-indeterminate non-metastatic disease, and 28% had node-negative, non-metastatic disease; 95% had newly diagnosed disease. In a subgroup analysis, the OS benefit was seen in PCa patients with metastatic disease (HR 0.61, 95% CI 0.49-0.75) but not patients with non-metastatic high-risk PCa (HR 0.75, 95% CI 0.48-1.18). 29 The impact of volume tumor burden was not reported.
A recent, unplanned, post-hoc analysis of 759 evaluable patients with bone metastases in the STAMPEDE trial were reclassified using CHAARTED "high-or low-volume" criterion or LATITUDE "high-or low-risk" criterion. 31 Men with mCNPC had OS benefit with the addition of abiraterone acetate and prednisone to ADT irrespective of stratification for "risk" or "volume." Using CHAARTED criteria, low-volume HR was 0.66 (95% CI 0.44-0.98) and high-volume HR was 0.54 (95% CI 0.41-0.70); using the LATITUDE criteria, low-risk HR was 0.64 (95% CI 0.42-0.97) and high-risk HR was 0.60 (95% CI 0.46-0.78). Although these results are intriguing, the retrospective nature of the reclassification of risk and tumor volume is a significant limitation and thus the results can only be considered hypothesis-generating.
# Enzalutamide (160 mg/day) is a treatment option for patients with mCNPC/mCSPC regardless of volume of disease (Level of evidence 1, Strong recommendation).
# Enzalutamide should not be used in combination (concurrent use) with docetaxel to treat patients mCNPC/mCSPC (Level of evidence 2, Strong recommendation).
# Enzalutamide may be considered in patients with mCSPC previously treated with docetaxel chemotherapy (sequential use) (Level of evidence 1, Weak recommendation).
Enzalutamide binds to the androgen receptor (AR) and inhibits the AR nuclear translocation and interaction with DNA. Suppression of the AR with enzalutamide was initially shown to improve survival in docetaxel-naive or -treated mCRPC. 32,33 Two recent studies assessed the role of enzalutamide for patients with mCNPC: ARCHES and ENZAMET. 34,35 The ARCHES trial randomized 1150 patients with mCNPC/ mCSPC to either enzalutamide (160 mg/day) plus ADT or placebo plus ADT. The primary endpoint was radiologic progression-free survival (rPFS), defined as the time from randomization to the first objective evidence of radiographic disease progression or death. The combination of enzalutamide plus ADT improved rPFS compared to placebo-ADT (HR 0.39, 95% CI 0.30-0.50, p=0.001; median not reached vs. 19.0 months). A recent final analysis showed improved OS in the enzalutamide treatment arm (HR 0.66, 95% CI 0.53-0.81, p<0.0001). 36 Prior docetaxel of up to six cycles was allowed, and 18% (205) patients received at least one dose of docetaxel prior to randomization; subgroup analysis showed that rPFS benefit was seen in both patients who were chemotherapy-treated and chemotherapy-naive. Benefit with enzalutamide in rPFS and OS was seen regardless of disease burden and timing of metastases (de novo vs. metachronous).
ENZAMET was an open-label clinical trial that randomized 1125 patients with mCNPC/mCSPC to receive ADT and enzalutamide daily (160 mg) or a non-steroidal antiandrogen (NSAA; bicalutamide, nilutamide, or flutamide) with a primary endpoint of OS. There was an OS benefit in the enzalutamide plus ADT arm compared to NSAA (HR 0.67, 95% CI 0.52-0.86, p=0.002). Kaplan-Meier estimates of OS at three years were 80% in the enzalutamide group and 72% in the NSAA arm. Unlike ARCHES, concurrent use of docetaxel was allowed and decision to treat with chemotherapy was at the discretion of the investigator. Use of chemotherapy was well-balanced between the two arms (45% of those receiving enzalutamide and 44% of those receiving a NSAA planned for early docetaxel use). In a subgroup analysis, the benefits of enzalutamide on OS appeared only in the group without planned early docetaxel use (concurrent docetaxel: HR 0.9, 95% CI 0.62-1.31; no concurrent docetaxel: HR 0.8, 95% CI 0.59-1.07). Although the authors state that the study is underpowered and data is too immature to specifically answer whether combination docetaxel and enzalutamide is beneficial in mCNPC/mCSPC, these results show that this combination should not be used until further evidence is shown for its benefits.
# Apalutamide (240 mg) is a treatment option for patients with mCNPC/mCSPC regardless of volume of disease (Level of evidence 1, Strong recommendation).
Apalutamide inhibits the AR by preventing its nuclear translocation and DNA binding. The first large, randomized clinical trial assessing apalutamide in mCNPC/mCSPC was the TITAN trial, which randomized 1052 patients with mCNPC/mCSPC (any) to receive apalutamide (240 mg once daily) plus ADT or ADT alone. As well, 10.7% received previous docetaxel therapy and 37.3% had low-volume disease. With a median of 40.0 months of followup, rPFS at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (HR 0.48, 95% CI 0.39-0.60, p<0.001). Benefit with apalutamide in rPFS was seen regardless of prior chemotherapy use or disease burden. Final analysis of OS showed apalutamide improved OS, reducing the risk of death by 35% (median OS for apalutamide not reached vs. 52.2 months in the placebo group; HR 0.65, 95% CI 0.53-0.79, p<0.0001). 37,38 Benefit with apalutamide in rPFS and OS was seen regardless of disease burden and timing of metastases (de novo vs. metachronous).
# Triplet therapy
In patients who can safely tolerate docetaxel and in whom docetaxel is felt to be appropriate, triplet regimen should be considered as a treatment option.
# Abiraterone acetate plus prednisone in combination with ADT and docetaxel is a treatment option for patients with mCNPC/mCSPC in high-volume disease (Level of evidence 1, Strong recommendation).
# Abiraterone acetate plus prednisone in combination with docetaxel may be considered for patients with mCNPC/ mCSPC with low-volume disease (Level of evidence 3, Weak recommendation).
Recent data from the PEACE-1 trial showed the benefits of the combination of ADT plus prednisone plus docetaxel and abiraterone acetate compared to docetaxel and ADT. 39 In a 2×2 factorial design, patients with de novo mCSPC (n=1173) were randomly assigned to receive SOC (n=296), SOC plus abiraterone and prednisone (n=29), SOC plus radiotherapy (n=293), or SOC plus abiraterone plus radiotherapy (n=291). SOC treatments included ADT with or without docetaxel, and overall, 60% of participants received a median of six cycles of docetaxel.
Compared with SOC (ADT plus docetaxel without abiraterone), the addition of abiraterone improved the median OS and reduced the relative risk of death from any cause by 25% (adjusted HR for OS 0.75, 95.1% CI 0.59-0.95, p=0.017). Using CHAARTED study criteria, high-volume patients treated with abiraterone and prednisone with SOC (including docetaxel) compared to SOC alone reduced the relative risk of radiographic progression or death (adjusted HR 0.47, 99.9% CI 0.30-0.72, p<00001); OS was improved from 3.47 years with SOC without abiraterone to 5.14 years when abiraterone was added, corresponding to a 28% reduction in relative risk of death (adjusted HR 0.72, 95.1% CI 0.55-0.95, p=0.019). In low-volume patients, the addition of abiraterone to SOC reduced the relative risk of radio-graphic progression or death (adjusted HR 0.58, 99.9% CI 0.29-1.15, p=0.0061); OS benefits were not found due to lack of maturity of the data (median OS not reached in either group). Importantly, although the addition of abiraterone to SOC increased the risk of hypertension (22% vs. 13%), the combination did not significantly increase grade 3 adverse events or other severe adverse events, such as neutropenia or fatigue.
# Darolutamide in combination with ADT and docetaxel is a treatment option for patients with mCNPC/mCSPC regardless of volume of disease (Level of evidence 1, Strong recommendation).
The ARASENS trial randomized 1306 patients with mCSPC to receive docetaxel and ADT with (n=651) or without (n=655) darolutamide. 40 A significant improvement in OS was observed in those receiving darolutamide; the risk of death was 32.5% lower in the darolutamide group than in the placebo group (HR 0.68, 95% CI 0.57-0.80, p<0.001) and OS at four years was 62.7% (95% CI 58.7-66.7) in the darolutamide group and 50.4% (95% CI 46.3-54.6) in the placebo group. Although efficacy based on volume of disease was not defined, benefits of the addition of darolutamide with docetaxel was seen regardless of metastatic stage at initial diagnosis (M1: HR 0.71, 95% CI 0.59-0.85; M0: HR 0.61, 95% CI 0.35-1.05). The addition of darolutamide to docetaxel did not increase adverse events, such as neutropenia or fatigue; the addition darolutamide slightly increased the rate of rash (16.6% vs. 13.5%) and hypertension (13.7% vs. 9.2%).
The ARASENS and PEACE-1 trials both show the benefits of adding an androgen receptor pathway inhibitor (ARPi) to docetaxel in CSPC. The studies show the benefits of triplet therapy (ADT, ARPi, and docetaxel) compared to ADT and docetaxel, but did not directly compare efficacy of triplet therapy to the combination therapy of ADT and ARPi. As such, these guidelines do not identify an "optimal" treatment option, and various triplet or doublet treatments are recommended.
Both studies show, in subgroup analyses, that there are limited patient characteristics that may influence the use of triplet vs. doublet therapy, as benefits in OS and rPFS were seen in a majority of prespecified patient factors. One patient characteristic, tumor volume based on CHARRTED study criteria, 7 was shown to be important in the PEACE-1 trial; in patients with low-volume disease, the addition of abiraterone to SOC reduced the relative risk of radiographic progression or death (adjusted HR 0.58, 99.9% CI 0.29-1.15, p=0.0061) but OS benefits seen in patients with high-volume disease were not found, likely due to lack of maturity of the data (median OS not reached in either group). The influence of tumor volume was not reported in the ARASENS trials, but survival benefit Guideline: mCNPC & mCSPC was regardless of stage of diagnosis. 40 In summary, although volume of disease appears to differentiate survival advantage in the PEACE-1 trial, recommendations of triplet therapy regardless of volume of disease are made.
# Prevention of osteoporosis
All patients with mCNPC/mCSPC treated with ADT should be assessed for fracture risk. All patients treated with ADT require vitamin D supplementation (800-1200 IU daily) and calcium supplementation (800-1000 mg total intake daily). Those at high risk of fractures should be treated (zoledronic acid 5 mg once a year, alendronate 70 mg weekly, denosumab 60 mg every six months) (Level of evidence 1, Strong recommendation).
Due to the evolution of combined therapy with ADT to treat mCNPC, the survival of patients with de novo PCa is increasing and length of time bone is exposed to the effects of ADT is also increasing. As such, these patients are at risk of significant bone loss, osteoporosis, and fragility fractures. Bone loss occurs quickly while on ADT, and within one year, patients can lose up to 10% of their bone mineral density (BMD). Patients with mCNPC initiating ADT should have baseline BMD measured with dual-energy x-ray absorptiometry (DXA), and fracture risk calculators, such as FRAX, should be used. 44 DXA should be performed at least every two years and more often in untreated patients at high risk or if there is a history of osteoporosis/osteopenia.
Patients with mCNPC/mCSPC treated with ADT should be encouraged to take vitamin D (1000 IU daily) and have a total calcium intake of 800-1000 mg daily. Specific lifestyle changes, including smoking cessation, reduction in alcohol and caffeine intake, and increase weight-bearing exercises, should also be encouraged. If DXA scanning shows any evidence of osteopenia (T-score of -2.5) or osteoporosis (T-score of <-2.5), men should be started on a bone-targeted therapy to improve BMD and reduce the risk of fragility fractures (zoledronic acid 5 mg once a year, alendronate 70 mg weekly, denosumab 60 mg every six months). 42,43,45 These doses are much lower than those needed to prevent skeletal-related events (SREs) in patients with mCRPC and, therefore, are associated with significantly reduced side effects; incidences of clinically significant hypocalcemia and osteonecrosis of the jaw are rare using denosumab or zoledronic acid at these lower doses. 46,47
# Treatment of oligo-metastatic disease
There is evolving evidence of the role of radiation in asymptomatic distant metastases, especially in low-burden "oligometastatic" disease. Currently, there is limited data with which to provide general recommendations; however, a mul-tidisciplinary approach would provide the best opportunity to determine optimal management on a case-by-case basis and to consider patient enrollment in ongoing clinical trials.
# Multidisciplinary consultation
Patients with mCNPC/mCSPC should be assessed in a multidisciplinary manner whenever possible (Level of evidence 3, Strong recommendation).
Timing of treatment initiation and selecting the optimal systemic therapy from a multitude of options requires careful consideration of several different clinical factors, such as eligibility of chemotherapy, side effect profile of medications, disease burden, symptoms, and presence of visceral metastases. Since treatment may require a multifaceted approach, including upfront docetaxel-based regimes, early assessment of eligibility of chemotherapy is essential. As well, combined opinions from urology, medical oncology, and radiation oncology may be required to provide optimal care of patients with mCNPC/mCSPC. Additionally, as mCNPC/mCSPC continues to be an incurable disease, strong consideration should be given to inclusion of patients in clinical trials.
# Conclusions
The last few years have seen a significant growth of lifeextending therapies for PCa patients that has changed the landscape of treatment for mCNPC/mCSPC. All patients with mCNPC/mCSPC, regardless of disease volume and whether metastases were de novo or metachronous, should be offered treatment-intensifying systemic therapy in addition to ADT. For those with low-risk/low-volume disease, radiation therapy to the prostate should be strongly considered in addition to systemic therapy.
A summary on the recommended treatment for mCNPC/ mCSPC is shown in Figure 1.
# Low-risk/volume disease
High-risk/volume disease ADT (SOC)
Competing interests: Dr. So has been an advisory board member for AbbVie, Astellas, Bayer, Janssen, Merck, and TerSera. Dr. Chi has received honoraria from Astellas, AstraZeneca, Daiichi Sanyko, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche, and Sanofi; and has participated in clinical trials supported by Astellas, AstraZeneca, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche, and Sanofi. Dr. Danielson has been an advisory board member for and/or has received honoraria from AAA Amgen, Astellas, Bayer, EMD Serono, Ferring, Janssen, Novartis, and Tolmar. Dr. Fleshner has received honoraria, advisory consulting, and speaker bureau fees from AbbVie, Astellas, Janssen, Merck, and Sanofi; has received research funding (received by the institution) from Astellas, Bayer, and Janssen; holds stock in Verity; has participated in clinical trials supported by Astellas, Bayer, and Janssen; and is a medical officer for Point Biopharma. Dr. Kinnaird has received honoraria from Advanced Accelerator Applications and Boston Scientific and has participated in a clinical trial supported by Exact Imaging. Dr. Kapoor has been an advisory board member for Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, TerSera, Tolmar, and Sanofi; has received grants/honoraria from Amgen, Novartis, and Pfizer; and has participated in clinical trials supported by Amgen, BMS, CCTG, Merck, Novartis, and Pfizer. Dr. Niazi has been an advisory So et al board member for GURC and Janssen; has received grants and/or honoraria from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Jansen, Knight, Sanofi, and TerSera; holds investments in Knight; and has participated in clinical trials supported by Astellas, AstraZeneca, Bayer, Janssen, Sanofi, and TerSera. Dr. Pouliot has been an advisory board member for and received payment or grants from Amgen, Astellas, Astra Zeneca, Bayer, Janssen, Merck, Novartis, TerSera, and Tolmar; holds investments in Allogene Therapeutics; and has participated in clinical trials supported by CUOG and Kidney Cancer Canada. Dr. Rendon has been an advisory board and speakers' bureau member for and has received honoraria from AbbVie, Amgen, Astellas, Astra Zeneca, Bayer, Ferring, Jansen, Pfizer, Roche, Sanofi, and Tolmar; has received honoraria/grants from AbbVie, Astellas, Bayer, Ferring, Janssen, Sanofi, TerSera, and Tolmar; holds investments in Myovant; and has participated in clinical trials supported by AbbVie, Astellas, Bavarian Nordic, Bayer, Ferring, Janssen, Myovant, and Sanofi. Dr. Shayegan has been an advisory board member for AbbVie, Astellas, Bayer, Ferring, Janssen, Knight, Merck, Pfizer, and TerSera; and has participated in clinical trials supported by Ipsen, Janssen, Merck, Myovant, and Pfizer. Dr. Sridhar has been an advisory board member for Astellas, AstraZeneca, Bayer, BMS, Immunomedex, Janssen, Merck, Pfizer, Roche, and Seagen. Dr. Vigneault has been an advisory board member for Abbvie, Bayer, Ferring, and Sanofi. Dr. Saad has been an advisory board member for and has received payment/honoraria from Amgen, Astellas, AstraZeneca, Bayer, Janssen, Knight, Myovant, Novartis, Pfizer, Sanofi, and Tolmar; and has participated in clinical trials supported by Amgen, Astellas, AstraZeneca, Bayer, Janssen, Novartis, Pfizer, and Sanofi.
Prior to original publication, this guideline underwent review by the CUA Guidelines Committee, CUA members at large, and the CUA Executive Board. Updates were approved by the CUA Guidelines Committee and CUA Executive Board.
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# Introduction
Metastatic prostate cancer remains an incurable disease. In Canada, approximately 8% of men with prostate cancer are diagnosed de novo with metastatic disease and, in 2018, roughly 1200 men were diagnosed with de novo metastatic prostate cancer (PCa). 1 The mainstay of treatment for de novo metastatic PCa is androgen deprivation therapy (ADT), either surgical or medical castration, which is initially effective in almost all patients; however, progression is inevitable, heralded by a rise in prostate-specific antigen (PSA), increasing disease burden, and/or worsening symptoms -a disease state called metastatic castrationresistant prostate cancer (mCRPC).
Men with metastatic PCa have a poor prognosis, with an estimated median overall survival (OS) of approximately 3-4 years. 2 Compared to PCa that develops metastases after diagnosis of localized disease, de novo metastatic PCa has been shown to have a worse overall prognosis. 3,4 Over the past decade, practice-changing trials have demonstrated improved survival in men with metastatic castration-naive/ castration-sensitive prostate cancer (mCNPC/mCSPC) using ADT intensification strategies that include both systemic therapy and treatment of the primary cancer.
The Canadian Uro-Oncology Group (CUOG), in collaboration with the Canadian Urological Association (CUA), sought to provide management guidelines to optimize the treatment of patients with mCNPC/mCSPC.
# Methods
EmBASE and Medline databases were accessed to identify all relevant articles focused on mCNPC or mCSPC published between January 2000 and April 2022 with the following keywords strategy: "prostate cancer," "hormone sensitive," "castration naive," "castration sensitive," "androgen deprivation," "chemotherapy," "androgen receptor-axis targeted therapy," and "metastatic." An expert panel comprised of urologists, medical oncologists, and radiation oncologists with significant experience managing mCNPC/mCSPC developed the recommendations. Guidelines were developed by consensus among the panel. Levels of evidence and grades of recommendation employ the WHO modified Oxford Center for Evidence-Based Medicine grading system. 5 Based on a modified GRADE methodology, the strength of each recommendation is represented by the words strong or weak. 5 Wherever level 1 evidence is lacking, the guideline attempts to provide expert opinion to aid in the management of patients.
# Indications for staging in prostate cancer
For patients with newly diagnosed PCa, staging with computed tomogragphy (CT) scans of the chest, abdomen, and pelvis, and bone scan ( 99 mTc-MDP) should be performed for men with any high-risk features: PSA >20 ng/mL, Gleason score >7, clinical stage T3 or greater (Level of evidence 3, Strong recommendation).
Conventional imaging to stage PCa includes bone scintigraphy using technetium-99 mmethylene diphosphonate ( 99 mTc-MDP) to assess for bone metastases and abdominopelvic CT imaging to assess for lymphadenopathy and visceral metastases. In patients with high-risk disease, CT imaging of the chest may also be considered, as lung metastases are the most common site of visceral metastases. 6 Novel diagnostic imaging to stage PCa, particularly prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET)/CT, improves the sensitivity and specificity of conventional imaging; however, these tests are not universally available Canada, and they are still considered investigational by Health Canada. Most importantly, all the phase 3 trials in mCNPC/mCSPC used conventional imaging for staging and risk determination, and conclusions were based on these.
# Assessment of prognosis
# Patients diagnosed with mPCa should be classified as highvolume/high-risk or low-volume/low-risk based on conventional imaging and prostate cancer biopsy for prognostication (Level of evidence 2, Weak recommendation).
Recent clinical trials of patients with mCNPC/mCSPC have used pragmatic prognostic factors to stratify prognosis. The CHAARTED trial classified PCa based on volume of disease. High-volume was defined by the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis; and low-volume was defined as all other mCNPC/mCSPC. 7 The LATITUDE trial classified high-risk patients based on three different criteria: visceral metastases, ≥3 bony metastases, or Gleason score ≥8; high risk was defined as having two or more of these criteria, whereas low risk was defined having less than two. 8 Interestingly, a comparative study of the classification of each of these trials showed an overall discordance of 18.2% between the CHAARTED and LATITUDE criterion; however, it appears that disease burden (defined radiologically or by PSA) and high-grade tumors portend a worse prognosis. 9
# Androgen deprivation therapy
# ADT should be started on patients with newly diagnosed with mPCa (Level of evidence 1, Strong recommendation).
Continuous ADT is the standard of care for patients with mPCa, while intermittent may be considered in select patients.
Androgen receptor signaling plays a key role in the progression of PCa, and thus, de novo mCNPC remains highly driven by testosterone. Hence, the primary step in the management of mCNPC, which remains the backbone of treatment for all men with mPCa until death, is ADT. ADT can be achieved by surgical castration (orchiectomy) or pharmacologically with agents that inhibit Leydig cell production of testosterone (gonadotropin-releasing hormone [GnRH] agonists or antagonists). The optimal timing of androgen deprivation has been the subject of many trials, with two systematic reviews suggesting early treatment is associated with improved OS and cancer-specific survival and decreases the rate of skeletal events compared to deferred treatment. 10,11 More importantly, the early treatment of mCNPC with ADT is required if other systemic treatment, such as docetaxel or androgen receptor axis inhibitors, are used.
ADT is associated with side effects and may increase the risk of cardiovascular events, but evidence has been contradictory. Intermittent androgen suppression (IAS) that cycles ADT based on PSA values has been shown to improve quality of life; however, continuous ADT should be used in mCNPC and IAS only used as an exception in select patients with close followup. 12,13 As well, the benefit of combined treatment of mCNPC with additional systemic therapy was demonstrated in the context of continuous ADT.
# Local therapy: treatment of the primary cancer in mCNPC
# Patients with low-volume metastatic disease burden of PCa should be considered for external beam radiation to the prostate (Level of evidence 2, Strong recommendation).
In the context of low-volume mCNPC, treatment of the primary disease in the prostate has theoretical benefits, including reducing local side effects that may occur due to local disease progression, as well as removing the cancer that could be the source of cytokines and growth factors that may induce disease progression. 14 Two recent randomized trials assessed the impact of external beam radiation therapy (EBRT) in mCNPC. The HORRAD trial randomized 432 men with mCNPC and PSA >20 ng/mL to receive EBRT of the prostate with ADT or ADT alone. The initial prescribed dose was 70 Gy in 35 fractions of 2 Gy, during an overall treatment time of seven weeks. During the study period, an optional schedule considered biologically Guideline: mCNPC & mCSPC equivalent was added and consisted of a dose schedule of 57.7 Gy in 19 fractions of 3.04 Gy three times a week for six weeks. At baseline, the median PSA was 142 ng/ml and 67% of patients had more than five bone metastases. No significant difference was found in OS (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.70-1.14, p = 0.4), but there was a benefit to median time to PSA progression in the radiotherapy group (15 months vs. 12 months, crude HR 0.78, 95% CI 0.63-0.97, p=0.02). Subgroup analysis showed that mCNPC with <5 metastases (HR 0.90, 95% CI 0.70-1.14, p=NS) and no bony pain (HR 0.83, 95% CI 0.69-1.14, p=NS) appeared to have the most benefit of EBRT.
The STAMPEDE trial, also known as MRC PR08, is a multiarm, multistage (MAMS) randomized trial recruiting in the United Kingdom and Switzerland. It aimed to evaluate multiple therapeutic strategies in the management of high-risk locally advanced and mCNPC compared to standard of care (SOC) (ADT only). In the EBRT component of the study, the trial randomized 2061 men with mCNPC to either EBRT and ADT or ADT alone. 15 The median PSA was 97 ng/mL, 819 (40%) men had low metastatic burden based on CHAARTED criteria, and 1664 (81%) had no pain. 7,15 EBRT was given as one of two schedules: either 36 Gy in six consecutive weekly fractions of 6 Gy, or 55 Gy in 20 daily fractions of 2.75 Gy over four weeks. Subgroup analyses were prespecified for baseline metastatic burden (low vs. high).
Similar to the HORRAD trial, EBRT improved failure-free survival (FFS) (HR 0.76, 95% CI 0.68-0.84, p<0.0001) but not OS (HR 0.92, 95% CI 0.80-1.06, p=0.266). Subgroup analysis by metastatic burden showed FFS was improved in both low and high metastatic burden (low metastatic burden: HR 0.59, 95% CI 0.49-0.72, p<0.0001 and metastatic burden interaction p=0.002; HR 0.88, 95% CI 0.77-1.01, p=0.059). Overall survival was improved in patients with low metastatic burden at baseline who were allocated EBRT (HR 0.68, 95% CI 0.52-0.90, p=0.007), whereas in patients with a high metastatic burden, there was no impact on OS (HR 1.07, 95% CI 0.90-1.28, p=0.420).
Although both trials showed a lack of benefit of EBRT in unselected men in mCNPC, both HORRAD and STAMPEDE reveal the benefits of local therapy in those with low-burden disease. A recent STOPCAP meta-analysis combining data from the trials confirm the benefits of EBRT in men with fewer than five bone metastases. 16 This meta-analysis showed that there was 7% improvement in three-year survival in men with fewer than four bone metastases.
# Radical prostatectomy in mCNPC should only be performed in a clinical trial setting (Expert opinion, Strong recommendation).
Currently, there is limited evidence showing the benefit of radical prostatectomy in mCNPC; however, the results from HORRAD and STAMPEDE imply that there may also be certain men with mCNPC that may benefit from surgical extirpation. There are many clinical trials currently assessing this question, including TRoMBONE (Testing Radical prOstatectomy in Men with PCa and oligometastases to the BONE: A randomized controlled feasibility trial), 17 SWOG1802 (Standard systemic therapy with or without definitive treatment in treating participants with mPCa [https://www. swog.org/clinical-trials/s1802]), G-RAMPP/AUO-AP-75/13 (Impact of radical prostatectomy as primary treatment in patients with PCa with limited bone metastases), 18 and IP2-ATLANTA (Additional Treatments to the Local tumor for metastatic prostate cancer -Assessment of Novel Treatment Algorithms: Protocol for a multicenter, phase 2, randomized controlled trial). 19 Until the results of these trials clarify the impact of radical prostatectomy in mCNPC, and more importantly, which patients would benefit most, surgery of the primary is not recommended in patients with mPCa.
Systemic therapies: chemotherapy, abiraterone acetate, enzalutamide, and apalutamide Docetaxel (75 mg/m 2 every three weeks for six cycles) plus ADT is an option for patients with mCNPC/mCSPC, good performance status, and high-volume metastatic disease defined as: presence of visceral metastases or four or more bone lesions with at least one beyond the vertebral bodies and pelvis (Level of evidence 1, Strong recommendation).
# Docetaxel plus ADT may also be an option for patients with mCNPC/mCSPC and good performance status with low-volume disease (Level of evidence 2, Weak recommendation).
Consideration of patients with high-risk mCNPC/mCSPC (defined as at least two of: Gleason score of 8-10, visceral metastases, and three or more bone metastases) and good performance status can also be considered for docetaxel chemotherapy (Level of evidence 1, Strong recommendation). Docetaxel, a taxane derivative that binds to tubulin and inhibits mitosis and tumor proliferation, was the initial chemotherapeutic agent that improved survival in men mCRPC. 20 Three large, randomized trials assessed the impact of introducing docetaxel in mCNPC/mCSPC: CHAARTED, STAMPEDE, and GETUG-AFU 15. 7,21,22 The CHAARTED trial randomized 790 with mCNPC/mCSPC patients to ADT plus docetaxel (75 mg/m 2 every three weeks for six cycles) or ADT alone. 7 Within this trial, 35% (n=277) had low-volume metastases and 65% (n=513) had high-volume metastases (high volume of metastases was defined by the presence of visceral metastases or four or more bone lesions with at least one beyond the vertebral bodies and pelvis). Overall, the median OS was 13.6 months longer with ADT plus docetaxel than with ADT alone (57.6 months vs. 44.0 months; HR 0.61, 95% CI 0.47-0.80, p<0.001). Subgroup analysis showed that OS benefits of combination there were maintained in the high-volume mCNPC/mCSPC (n=513, HR 0.63, 95% CI 0.50-0.79, p<0.001), whereas survival benefits were lost in low-volume disease (n=277, HR 1.04, 95% CI 0.70-1.55, p=0.86). 23 The GETUG-AFU15 trial randomized 385 patients with mCNPC/mCSPC to receive ADT plus docetaxel or ADT alone. 22 Although the dosage of docetaxel was the same as in CHAARTED, patients were allowed to receive up to nine cycles compared to the six cycles in CHAARTED. There was no survival difference between the groups (58.9 months in the combined group vs. 54.2 months in the ADT alone group, HR 1.01, 95% CI 0.75-1.36). The differences in the outcomes of the two studies is likely due to the differences in the burden of disease in the two studies. Although 65% of patients in CHAARTED had high-volume metastases, only 48% in the docetaxel arm of GETUG-AFU15 had high-volume disease. An unplanned post-hoc analysis of the high-volume cohort of GETUG-AFU 15 showed a nonsignificant trend toward improved OS in this cohort (39.8 months vs. 35.1 months, HR 0.78, 95% CI 0.56-1.09). 24 A recent pooled analysis of both studies confirms the benefit of combined docetaxel and ADT in high-volume disease and lack of benefit on low-volume metastatic burden. 25 The third trial to assess the impact of docetaxel in mCNPC/ mCSPC was the docetaxel component of the STAMPEDE trial. 21 Unlike the CHAARTED and GETUG-AFU15 trials, patients with high-risk non-metastatic PCa were included. Eligible patients included: newly diagnosed metastatic, node-positive, or high-risk locally advanced (with high-risk features defined as at least two of: T3/4, Gleason score of 8-10, and PSA ≥40 ng/mL) prostate cancer; or previously treated with radical surgery and/or radiotherapy with highrisk features. Of the 2962 patients randomized, 1817 (61%) patients had bony metastases and 592 patients received only ADT and six cycles of docetaxel (75 mg/m 2 every three weeks for six cycles). The combination of ADT and docetaxel had a survival advantage compared to ADT alone (HR 0.78, 95% CI 0.66-0.93, p=0.006). Although patients were not classified having high-or low-volume metastases, only patients with metastatic disease had evidence of benefit with ADT and docetaxel (HR 0.76, 95% CI 0.62-0.92, p=0.005).
A post-hoc, non-prespecified analysis of STAMPEDE was published. 26 Metastatic burden was assessable in only 76% of patients for the analysis (830 of 1086 patients) and 362 (44%) had low and 468 (56%) high metastatic burden. Although OS was neither statistically significant in low-burden nor in high-burden disease (HR 0.76, 95% CI 0.54-1.07, p=0.107 vs. HR 0.81, 95% CI 0.64-1.02, p=0.064), the authors found no evidence of heterogeneity of docetaxel effect between metastatic burden subgroups (interaction p=0.827). The authors concluded that upfront docetaxel should be considered for patients with mCNPC/mCSPC regardless of metastatic burden. This retrospective analysis contradicts the results of CHAARTED, but the authors point out that this may be due to the larger number of patients with de novo mCNPC/mCSPC (n=362) in the low-burden group compared to the low-burden group in the CHAARTED trial (n<160).
A recent meta-analysis of CHAARTED, GETUG-AFU15, and STAMPEDE confirms the benefit of the addition of docetaxel to ADT for patients with mCNPC/mCSPC (HR 0.77, 95% CI 0.68-0.87, p<0.0001). The authors of the metaanalysis show that this translates to an absolute improvement in four-year survival of 9%.
Abiraterone acetate (1000 mg daily) with prednisone (5 mg daily) plus ADT is an option for patients with mCNPC with at least two of the three: (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis) (Level of evidence 1, Strong recommendation).
# Abiraterone acetate (1000 mg daily) with prednisone (5 mg daily) plus ADT may be considered for patients with low-volume mCNPC (Level of evidence 3, Weak recommendation).
Abiraterone acetate is a prodrug of abiraterone, which is a CYP17A1 inhibitor; CYP17A1 is expressed in and is required for androgen biosynthesis. Abiraterone acetate, when combined with prednisone, was initially shown to improve survival in mCRPC, both prior to and after docetaxel treatment. 27,28 Two trials, LATITUDE and STAMPEDE, assessed the impact of abiraterone in mCNPC/mCSPC. 8,29,30 In the LATITUDE trial, 1199 patients were randomly assigned to either the abiraterone acetate (1000 mg) plus prednisone (5 mg) once daily orally and ADT vs. ADT alone. Eligible patients included patients with mCNPC with at least two of three high-risk features (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis). Updated OS data with median followup of 51.8 months showed that OS was significantly longer in the abiraterone acetate plus prednisone group (median 53.3 months [95% CI 48.2-not reached]) than in the placebo group (median 36.5 months [95% CI 33.5-40.0]), with a HR of 0.66 (95% CI 0.56−0.78, p<0•0001). A post-hoc exploratory analysis of the impact of disease burden showed that OS was improved only in patients with high-volume disease (n=487 in the abiraterone acetate plus prednisone and ADT and 468 in the ADT only group [HR 0.62, 95% CI 0.52−0.74, p<0.0001]); however, only few patients had low-volume disease in this study (n=110 in the abiraterone acetate plus prednisone and ADT and n=133 in the ADT only group (HR 0.72, 95% CI 0.47−1.10, p=0.1242).
# Guideline: mCNPC & mCSPC
In the abiraterone component of the STAMPEDE trial, the efficacy of abiraterone acetate and prednisolone was assessed in men with mCNPC. 29 In this study, 1917 patients with mCNPC were enrolled with: newly diagnosed and metastatic, node-positive, or high-risk locally advanced prostate cancer (with at least two of following: cT3 or cT4, a Gleason score of 8−10, or PSA level ≥40 ng/mL) or disease that was previously treated with radical surgery or radiotherapy and was now relapsing with high-risk features (PSA >4 ng/mL with a doubling time of <6 months, a PSA level >20 ng/mL, nodal or metastatic relapse). Men were randomized to receive abiraterone acetate (1000 mg daily) plus prednisolone (5 mg) plus ADT or ADT alone. Just over half of the patients (52%) had metastatic disease, 20% had node-positive or node-indeterminate non-metastatic disease, and 28% had node-negative, non-metastatic disease; 95% had newly diagnosed disease. In a subgroup analysis, the OS benefit was seen in PCa patients with metastatic disease (HR 0.61, 95% CI 0.49-0.75) but not patients with non-metastatic high-risk PCa (HR 0.75, 95% CI 0.48-1.18). 29 The impact of volume tumor burden was not reported.
A recent, unplanned, post-hoc analysis of 759 evaluable patients with bone metastases in the STAMPEDE trial were reclassified using CHAARTED "high-or low-volume" criterion or LATITUDE "high-or low-risk" criterion. 31 Men with mCNPC had OS benefit with the addition of abiraterone acetate and prednisone to ADT irrespective of stratification for "risk" or "volume." Using CHAARTED criteria, low-volume HR was 0.66 (95% CI 0.44-0.98) and high-volume HR was 0.54 (95% CI 0.41-0.70); using the LATITUDE criteria, low-risk HR was 0.64 (95% CI 0.42-0.97) and high-risk HR was 0.60 (95% CI 0.46-0.78). Although these results are intriguing, the retrospective nature of the reclassification of risk and tumor volume is a significant limitation and thus the results can only be considered hypothesis-generating.
# Enzalutamide (160 mg/day) is a treatment option for patients with mCNPC/mCSPC regardless of volume of disease (Level of evidence 1, Strong recommendation).
# Enzalutamide should not be used in combination (concurrent use) with docetaxel to treat patients mCNPC/mCSPC (Level of evidence 2, Strong recommendation).
# Enzalutamide may be considered in patients with mCSPC previously treated with docetaxel chemotherapy (sequential use) (Level of evidence 1, Weak recommendation).
Enzalutamide binds to the androgen receptor (AR) and inhibits the AR nuclear translocation and interaction with DNA. Suppression of the AR with enzalutamide was initially shown to improve survival in docetaxel-naive or -treated mCRPC. 32,33 Two recent studies assessed the role of enzalutamide for patients with mCNPC: ARCHES and ENZAMET. 34,35 The ARCHES trial randomized 1150 patients with mCNPC/ mCSPC to either enzalutamide (160 mg/day) plus ADT or placebo plus ADT. The primary endpoint was radiologic progression-free survival (rPFS), defined as the time from randomization to the first objective evidence of radiographic disease progression or death. The combination of enzalutamide plus ADT improved rPFS compared to placebo-ADT (HR 0.39, 95% CI 0.30-0.50, p=0.001; median not reached vs. 19.0 months). A recent final analysis showed improved OS in the enzalutamide treatment arm (HR 0.66, 95% CI 0.53-0.81, p<0.0001). 36 Prior docetaxel of up to six cycles was allowed, and 18% (205) patients received at least one dose of docetaxel prior to randomization; subgroup analysis showed that rPFS benefit was seen in both patients who were chemotherapy-treated and chemotherapy-naive. Benefit with enzalutamide in rPFS and OS was seen regardless of disease burden and timing of metastases (de novo vs. metachronous).
ENZAMET was an open-label clinical trial that randomized 1125 patients with mCNPC/mCSPC to receive ADT and enzalutamide daily (160 mg) or a non-steroidal antiandrogen (NSAA; bicalutamide, nilutamide, or flutamide) with a primary endpoint of OS. There was an OS benefit in the enzalutamide plus ADT arm compared to NSAA (HR 0.67, 95% CI 0.52-0.86, p=0.002). Kaplan-Meier estimates of OS at three years were 80% in the enzalutamide group and 72% in the NSAA arm. Unlike ARCHES, concurrent use of docetaxel was allowed and decision to treat with chemotherapy was at the discretion of the investigator. Use of chemotherapy was well-balanced between the two arms (45% of those receiving enzalutamide and 44% of those receiving a NSAA planned for early docetaxel use). In a subgroup analysis, the benefits of enzalutamide on OS appeared only in the group without planned early docetaxel use (concurrent docetaxel: HR 0.9, 95% CI 0.62-1.31; no concurrent docetaxel: HR 0.8, 95% CI 0.59-1.07). Although the authors state that the study is underpowered and data is too immature to specifically answer whether combination docetaxel and enzalutamide is beneficial in mCNPC/mCSPC, these results show that this combination should not be used until further evidence is shown for its benefits.
# Apalutamide (240 mg) is a treatment option for patients with mCNPC/mCSPC regardless of volume of disease (Level of evidence 1, Strong recommendation).
Apalutamide inhibits the AR by preventing its nuclear translocation and DNA binding. The first large, randomized clinical trial assessing apalutamide in mCNPC/mCSPC was the TITAN trial, which randomized 1052 patients with mCNPC/mCSPC (any) to receive apalutamide (240 mg once daily) plus ADT or ADT alone. As well, 10.7% received previous docetaxel therapy and 37.3% had low-volume disease. With a median of 40.0 months of followup, rPFS at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (HR 0.48, 95% CI 0.39-0.60, p<0.001). Benefit with apalutamide in rPFS was seen regardless of prior chemotherapy use or disease burden. Final analysis of OS showed apalutamide improved OS, reducing the risk of death by 35% (median OS for apalutamide not reached vs. 52.2 months in the placebo group; HR 0.65, 95% CI 0.53-0.79, p<0.0001). 37,38 Benefit with apalutamide in rPFS and OS was seen regardless of disease burden and timing of metastases (de novo vs. metachronous).
# Triplet therapy
In patients who can safely tolerate docetaxel and in whom docetaxel is felt to be appropriate, triplet regimen should be considered as a treatment option.
# Abiraterone acetate plus prednisone in combination with ADT and docetaxel is a treatment option for patients with mCNPC/mCSPC in high-volume disease (Level of evidence 1, Strong recommendation).
# Abiraterone acetate plus prednisone in combination with docetaxel may be considered for patients with mCNPC/ mCSPC with low-volume disease (Level of evidence 3, Weak recommendation).
Recent data from the PEACE-1 trial showed the benefits of the combination of ADT plus prednisone plus docetaxel and abiraterone acetate compared to docetaxel and ADT. 39 In a 2×2 factorial design, patients with de novo mCSPC (n=1173) were randomly assigned to receive SOC (n=296), SOC plus abiraterone and prednisone (n=29), SOC plus radiotherapy (n=293), or SOC plus abiraterone plus radiotherapy (n=291). SOC treatments included ADT with or without docetaxel, and overall, 60% of participants received a median of six cycles of docetaxel.
Compared with SOC (ADT plus docetaxel without abiraterone), the addition of abiraterone improved the median OS and reduced the relative risk of death from any cause by 25% (adjusted HR for OS 0.75, 95.1% CI 0.59-0.95, p=0.017). Using CHAARTED study criteria, high-volume patients treated with abiraterone and prednisone with SOC (including docetaxel) compared to SOC alone reduced the relative risk of radiographic progression or death (adjusted HR 0.47, 99.9% CI 0.30-0.72, p<0•0001); OS was improved from 3.47 years with SOC without abiraterone to 5.14 years when abiraterone was added, corresponding to a 28% reduction in relative risk of death (adjusted HR 0.72, 95.1% CI 0.55-0.95, p=0.019). In low-volume patients, the addition of abiraterone to SOC reduced the relative risk of radio-graphic progression or death (adjusted HR 0.58, 99.9% CI 0.29-1.15, p=0.0061); OS benefits were not found due to lack of maturity of the data (median OS not reached in either group). Importantly, although the addition of abiraterone to SOC increased the risk of hypertension (22% vs. 13%), the combination did not significantly increase grade 3 adverse events or other severe adverse events, such as neutropenia or fatigue.
# Darolutamide in combination with ADT and docetaxel is a treatment option for patients with mCNPC/mCSPC regardless of volume of disease (Level of evidence 1, Strong recommendation).
The ARASENS trial randomized 1306 patients with mCSPC to receive docetaxel and ADT with (n=651) or without (n=655) darolutamide. 40 A significant improvement in OS was observed in those receiving darolutamide; the risk of death was 32.5% lower in the darolutamide group than in the placebo group (HR 0.68, 95% CI 0.57-0.80, p<0.001) and OS at four years was 62.7% (95% CI 58.7-66.7) in the darolutamide group and 50.4% (95% CI 46.3-54.6) in the placebo group. Although efficacy based on volume of disease was not defined, benefits of the addition of darolutamide with docetaxel was seen regardless of metastatic stage at initial diagnosis (M1: HR 0.71, 95% CI 0.59-0.85; M0: HR 0.61, 95% CI 0.35-1.05). The addition of darolutamide to docetaxel did not increase adverse events, such as neutropenia or fatigue; the addition darolutamide slightly increased the rate of rash (16.6% vs. 13.5%) and hypertension (13.7% vs. 9.2%).
The ARASENS and PEACE-1 trials both show the benefits of adding an androgen receptor pathway inhibitor (ARPi) to docetaxel in CSPC. The studies show the benefits of triplet therapy (ADT, ARPi, and docetaxel) compared to ADT and docetaxel, but did not directly compare efficacy of triplet therapy to the combination therapy of ADT and ARPi. As such, these guidelines do not identify an "optimal" treatment option, and various triplet or doublet treatments are recommended.
Both studies show, in subgroup analyses, that there are limited patient characteristics that may influence the use of triplet vs. doublet therapy, as benefits in OS and rPFS were seen in a majority of prespecified patient factors. One patient characteristic, tumor volume based on CHARRTED study criteria, 7 was shown to be important in the PEACE-1 trial; in patients with low-volume disease, the addition of abiraterone to SOC reduced the relative risk of radiographic progression or death (adjusted HR 0.58, 99.9% CI 0.29-1.15, p=0.0061) but OS benefits seen in patients with high-volume disease were not found, likely due to lack of maturity of the data (median OS not reached in either group). The influence of tumor volume was not reported in the ARASENS trials, but survival benefit Guideline: mCNPC & mCSPC was regardless of stage of diagnosis. 40 In summary, although volume of disease appears to differentiate survival advantage in the PEACE-1 trial, recommendations of triplet therapy regardless of volume of disease are made.
# Prevention of osteoporosis
All patients with mCNPC/mCSPC treated with ADT should be assessed for fracture risk. All patients treated with ADT require vitamin D supplementation (800-1200 IU daily) and calcium supplementation (800-1000 mg total intake daily). Those at high risk of fractures should be treated (zoledronic acid 5 mg once a year, alendronate 70 mg weekly, denosumab 60 mg every six months) (Level of evidence 1, Strong recommendation).
Due to the evolution of combined therapy with ADT to treat mCNPC, the survival of patients with de novo PCa is increasing and length of time bone is exposed to the effects of ADT is also increasing. As such, these patients are at risk of significant bone loss, osteoporosis, and fragility fractures. Bone loss occurs quickly while on ADT, and within one year, patients can lose up to 10% of their bone mineral density (BMD). [41][42][43] Patients with mCNPC initiating ADT should have baseline BMD measured with dual-energy x-ray absorptiometry (DXA), and fracture risk calculators, such as FRAX, should be used. 44 DXA should be performed at least every two years and more often in untreated patients at high risk or if there is a history of osteoporosis/osteopenia.
Patients with mCNPC/mCSPC treated with ADT should be encouraged to take vitamin D (1000 IU daily) and have a total calcium intake of 800-1000 mg daily. Specific lifestyle changes, including smoking cessation, reduction in alcohol and caffeine intake, and increase weight-bearing exercises, should also be encouraged. If DXA scanning shows any evidence of osteopenia (T-score of <-1 and >-2.5) or osteoporosis (T-score of <-2.5), men should be started on a bone-targeted therapy to improve BMD and reduce the risk of fragility fractures (zoledronic acid 5 mg once a year, alendronate 70 mg weekly, denosumab 60 mg every six months). 42,43,45 These doses are much lower than those needed to prevent skeletal-related events (SREs) in patients with mCRPC and, therefore, are associated with significantly reduced side effects; incidences of clinically significant hypocalcemia and osteonecrosis of the jaw are rare using denosumab or zoledronic acid at these lower doses. 46,47
# Treatment of oligo-metastatic disease
There is evolving evidence of the role of radiation in asymptomatic distant metastases, especially in low-burden "oligometastatic" disease. Currently, there is limited data with which to provide general recommendations; however, a mul-tidisciplinary approach would provide the best opportunity to determine optimal management on a case-by-case basis and to consider patient enrollment in ongoing clinical trials.
# Multidisciplinary consultation
Patients with mCNPC/mCSPC should be assessed in a multidisciplinary manner whenever possible (Level of evidence 3, Strong recommendation).
Timing of treatment initiation and selecting the optimal systemic therapy from a multitude of options requires careful consideration of several different clinical factors, such as eligibility of chemotherapy, side effect profile of medications, disease burden, symptoms, and presence of visceral metastases. Since treatment may require a multifaceted approach, including upfront docetaxel-based regimes, early assessment of eligibility of chemotherapy is essential. As well, combined opinions from urology, medical oncology, and radiation oncology may be required to provide optimal care of patients with mCNPC/mCSPC. Additionally, as mCNPC/mCSPC continues to be an incurable disease, strong consideration should be given to inclusion of patients in clinical trials.
# Conclusions
The last few years have seen a significant growth of lifeextending therapies for PCa patients that has changed the landscape of treatment for mCNPC/mCSPC. All patients with mCNPC/mCSPC, regardless of disease volume and whether metastases were de novo or metachronous, should be offered treatment-intensifying systemic therapy in addition to ADT. For those with low-risk/low-volume disease, radiation therapy to the prostate should be strongly considered in addition to systemic therapy.
A summary on the recommended treatment for mCNPC/ mCSPC is shown in Figure 1.
# Low-risk/volume disease
High-risk/volume disease ADT (SOC)
+
#
Competing interests: Dr. So has been an advisory board member for AbbVie, Astellas, Bayer, Janssen, Merck, and TerSera. Dr. Chi has received honoraria from Astellas, AstraZeneca, Daiichi Sanyko, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche, and Sanofi; and has participated in clinical trials supported by Astellas, AstraZeneca, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche, and Sanofi. Dr. Danielson has been an advisory board member for and/or has received honoraria from AAA Amgen, Astellas, Bayer, EMD Serono, Ferring, Janssen, Novartis, and Tolmar. Dr. Fleshner has received honoraria, advisory consulting, and speaker bureau fees from AbbVie, Astellas, Janssen, Merck, and Sanofi; has received research funding (received by the institution) from Astellas, Bayer, and Janssen; holds stock in Verity; has participated in clinical trials supported by Astellas, Bayer, and Janssen; and is a medical officer for Point Biopharma. Dr. Kinnaird has received honoraria from Advanced Accelerator Applications and Boston Scientific and has participated in a clinical trial supported by Exact Imaging. Dr. Kapoor has been an advisory board member for Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, TerSera, Tolmar, and Sanofi; has received grants/honoraria from Amgen, Novartis, and Pfizer; and has participated in clinical trials supported by Amgen, BMS, CCTG, Merck, Novartis, and Pfizer. Dr. Niazi has been an advisory So et al board member for GURC and Janssen; has received grants and/or honoraria from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Jansen, Knight, Sanofi, and TerSera; holds investments in Knight; and has participated in clinical trials supported by Astellas, AstraZeneca, Bayer, Janssen, Sanofi, and TerSera. Dr. Pouliot has been an advisory board member for and received payment or grants from Amgen, Astellas, Astra Zeneca, Bayer, Janssen, Merck, Novartis, TerSera, and Tolmar; holds investments in Allogene Therapeutics; and has participated in clinical trials supported by CUOG and Kidney Cancer Canada. Dr. Rendon has been an advisory board and speakers' bureau member for and has received honoraria from AbbVie, Amgen, Astellas, Astra Zeneca, Bayer, Ferring, Jansen, Pfizer, Roche, Sanofi, and Tolmar; has received honoraria/grants from AbbVie, Astellas, Bayer, Ferring, Janssen, Sanofi, TerSera, and Tolmar; holds investments in Myovant; and has participated in clinical trials supported by AbbVie, Astellas, Bavarian Nordic, Bayer, Ferring, Janssen, Myovant, and Sanofi. Dr. Shayegan has been an advisory board member for AbbVie, Astellas, Bayer, Ferring, Janssen, Knight, Merck, Pfizer, and TerSera; and has participated in clinical trials supported by Ipsen, Janssen, Merck, Myovant, and Pfizer. Dr. Sridhar has been an advisory board member for Astellas, AstraZeneca, Bayer, BMS, Immunomedex, Janssen, Merck, Pfizer, Roche, and Seagen. Dr. Vigneault has been an advisory board member for Abbvie, Bayer, Ferring, and Sanofi. Dr. Saad has been an advisory board member for and has received payment/honoraria from Amgen, Astellas, AstraZeneca, Bayer, Janssen, Knight, Myovant, Novartis, Pfizer, Sanofi, and Tolmar; and has participated in clinical trials supported by Amgen, Astellas, AstraZeneca, Bayer, Janssen, Novartis, Pfizer, and Sanofi.
Prior to original publication, this guideline underwent review by the CUA Guidelines Committee, CUA members at large, and the CUA Executive Board. Updates were approved by the CUA Guidelines Committee and CUA Executive Board.
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Thalassemia is an inherited blood cell disorder. Patients with both transfusion-dependent thalassemia (TDT) and nontransfusion dependent thalassemia (NTDT) may have risk factors associated severe SARS-CoV-2 infection including iron overload, endocrinopathies like diabetes, asplenia due to previous splenectomy, and coagulopathy. 1 Some people with thalassemia are at a higher risk for severe COVID-19 infections than others. The Thalassemia International Federation has categorized "highest risk" and "high risk" thalassemia on the basis of age, disease, and comorbidity related factors. 2 #
Persons with a diagnosis of thalassemia and any two of the following can be considered as high to highest risk:
- People over 50 years of age - Transfusion dependent - Non-transfused with hemoglobin values chronically below 70 g/L for the past two to three years - People receiving iron chelation therapy - Splenectomized persons or persons with asplenia - Those with comorbidities including diabetes, pulmonary hypertension, endocrine, cardiac, or respiratory disease Is COVID-19 immunization recommended for people with thalassemia?
COVID-19 vaccines should be encouraged for adults and youth with thalassemia and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
- A multicentre, retrospective, cross-sectional study from Iran including adult TDT and NTDT patients described a death rate of 26.6% in patients with confirmed COVID infection by PCR and 25% in those with suspected COVID infection. 3 - A systematic review identified seven publications with a total of 34 adult beta thalassemia patients (76.5% had TDT) with a death rate of 26.5%. 4 While data specific to the safety and efficacy of COVID-19 vaccines in people with thalassemia is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 5 The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization.
COVID-19 Vaccines for People with Thalassemia Updated: April 18, 2023
Are COVID-19 vaccines efficacious and safe for people with thalassemia?
As thalassemia is considered to be a severe underlying medical condition, both adults and children with thalassemia were excluded from the COVID-19 vaccine clinical trials. Therefore, it is unknown if COVID-19 vaccines are as efficacious for patients with thalassemia as they were found to be for the clinical trial participants.
Many people with thalassemia have been splenectomised, which compromises immune function. 6 Chronic transfusion and iron overload are also thought to impair a person with thalassemia's immune response. As with most vaccines, there is a potential for blunted immune response in individuals who are immunocompromised due to their disease or treatment. 7,8 In one study, people with TDT produced protective antibodies comparable to healthy population following COVID-19 vaccination. 9 Therefore, it is possible that people with thalassemia may not respond as well to the vaccine as the general population, and should continue to follow local public health guidelines and adhere to precautionary procedures following vaccination for as long as SARS-CoV-2 continues to circulate at high rates in the community.
Currently, there are no serious warnings or precautions associated with the mRNA (COMIRNATY or SPIKEVAX ) vaccines in persons with thalassemia beyond those of the general population. If vaccination with the Janssen COVID-19 Vaccine (Janssen) vaccine is considered, clinicians should be aware of the rare potential for development of venous or arterial thrombosis accompanied by thrombocytopenia 4 to 30 days after vaccination.
Are there any specific contraindications or exceptions for people with thalassemia?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 10 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
COVID-19 Vaccines for People with Thalassemia Updated: April 18, 2023
Thalassemia patients who have received gene therapy should be immunized in accordance with guidelines for patients who have received high-dose chemotherapy and autologous hematopoietic stem cell transplant.
Otherwise, there are no contraindications or exceptions to immunization for individuals within the thalassemia population beyond those for the general population.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. Are there specific recommendations or considerations for safe and/or most effective administration?
There are no specific timing considerations for the administration of the COVID-19 vaccine relative to treatment other than for patients who are receiving gene therapy. These patients should be immunized according to guidelines for autologous stem cell transplant recipients (e.g., two doses at least two weeks pre-treatment and more than three months post-treatment).
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Thalassemia is an inherited blood cell disorder. Patients with both transfusion-dependent thalassemia (TDT) and nontransfusion dependent thalassemia (NTDT) may have risk factors associated severe SARS-CoV-2 infection including iron overload, endocrinopathies like diabetes, asplenia due to previous splenectomy, and coagulopathy. 1 Some people with thalassemia are at a higher risk for severe COVID-19 infections than others. The Thalassemia International Federation has categorized "highest risk" and "high risk" thalassemia on the basis of age, disease, and comorbidity related factors. 2 #
Persons with a diagnosis of thalassemia and any two of the following can be considered as high to highest risk:
• People over 50 years of age • Transfusion dependent • Non-transfused with hemoglobin values chronically below 70 g/L for the past two to three years • People receiving iron chelation therapy • Splenectomized persons or persons with asplenia • Those with comorbidities including diabetes, pulmonary hypertension, endocrine, cardiac, or respiratory disease Is COVID-19 immunization recommended for people with thalassemia?
COVID-19 vaccines should be encouraged for adults and youth with thalassemia and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
• A multicentre, retrospective, cross-sectional study from Iran including adult TDT and NTDT patients described a death rate of 26.6% in patients with confirmed COVID infection by PCR and 25% in those with suspected COVID infection. 3 • A systematic review identified seven publications with a total of 34 adult beta thalassemia patients (76.5% had TDT) with a death rate of 26.5%. 4 While data specific to the safety and efficacy of COVID-19 vaccines in people with thalassemia is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 5 The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization.
COVID-19 Vaccines for People with Thalassemia Updated: April 18, 2023
2
Are COVID-19 vaccines efficacious and safe for people with thalassemia?
As thalassemia is considered to be a severe underlying medical condition, both adults and children with thalassemia were excluded from the COVID-19 vaccine clinical trials. Therefore, it is unknown if COVID-19 vaccines are as efficacious for patients with thalassemia as they were found to be for the clinical trial participants.
Many people with thalassemia have been splenectomised, which compromises immune function. 6 Chronic transfusion and iron overload are also thought to impair a person with thalassemia's immune response. As with most vaccines, there is a potential for blunted immune response in individuals who are immunocompromised due to their disease or treatment. 7,8 In one study, people with TDT produced protective antibodies comparable to healthy population following COVID-19 vaccination. 9 Therefore, it is possible that people with thalassemia may not respond as well to the vaccine as the general population, and should continue to follow local public health guidelines and adhere to precautionary procedures following vaccination for as long as SARS-CoV-2 continues to circulate at high rates in the community.
Currently, there are no serious warnings or precautions associated with the mRNA (COMIRNATY [Pfizer-BioNTech] or SPIKEVAX [Moderna]) vaccines in persons with thalassemia beyond those of the general population. If vaccination with the Janssen COVID-19 Vaccine (Janssen) vaccine is considered, clinicians should be aware of the rare potential for development of venous or arterial thrombosis accompanied by thrombocytopenia 4 to 30 days after vaccination.
Are there any specific contraindications or exceptions for people with thalassemia?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 10 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
COVID-19 Vaccines for People with Thalassemia Updated: April 18, 2023
3
Thalassemia patients who have received gene therapy should be immunized in accordance with guidelines for patients who have received high-dose chemotherapy and autologous hematopoietic stem cell transplant.
Otherwise, there are no contraindications or exceptions to immunization for individuals within the thalassemia population beyond those for the general population.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. [11][12][13][14] Are there specific recommendations or considerations for safe and/or most effective administration?
There are no specific timing considerations for the administration of the COVID-19 vaccine relative to treatment other than for patients who are receiving gene therapy. These patients should be immunized according to guidelines for autologous stem cell transplant recipients (e.g., two doses at least two weeks pre-treatment and more than three months post-treatment).
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